Derivatives of aza adamantane and uses thereof

专利摘要:
The present invention relates to certain amide derivatives that have the ability to inhibit 11-β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) and which are therefore useful in the treatment of certain disorders that can be prevented or treated by inhibition of this enzyme. In addition the invention relates to the compounds, methods for their preparation, pharmaceutical compositions containing the compounds and the uses of these compounds in the treatment of certain disorders. It is expected that the compounds of the invention will find application in the treatment of conditions such as non-insulin dependent type 2 diabetes mellitus (NIDDM), insulin resistance, obesity, impaired fasting glucose, impaired glucose tolerance, lipid disorders such as dyslipidemia, hypertension and as well as other diseases and conditions.
公开号:AU2012367780A1
申请号:U2012367780
申请日:2012-12-21
公开日:2014-07-24
发明作者:Sivanageswara Rao DOPPALAPUDI；George FERNAND；Jenson George；S. Jagannath；V. S. Naga Rajesh KADAMBARI；Bommegowda Yadaganahalli KENCHEGOWDA；B. Siva Senthil Kumar；T. Senthil Kumar；G. R. Madhavan；Rayi MALLIKARJUNA；R. Manivannan；Gorle Paidapu NAIDU；Jagannath Madanahalli Ranganath RAO；Uppala VENKATESHAM
申请人:Connexios Life Sciences Pvt Ltd；
IPC主号:C07D471-08

专利说明:
WO 2013/111150 PCT/IN2012/000842 DERIVATIVES OF AZA ADAMANTANES AND USES THEREOF FIELD OF THE INVENTION The present invention relates to aza adamantane derivatives that have the ability to inhibit 11-p-hydroxysteroid dehydrogenase type 1 (11p-HSD-1) and which are therefore 5 useful in the treatment of certain disorders that can be prevented or treated by inhibition of this enzyme. In addition the invention relates to the compounds, methods for their preparation, pharmaceutical compositions containing the compounds and the uses of these compounds in the treatment of certain disorders. It is expected that the compounds of the invention will find application in the treatment of conditions such as non-insulin dependent 10 type 2 diabetes mellitus (NIDDM), insulin resistance, obesity, impaired fasting glucose, impaired glucose tolerance, lipid disorders such as dyslipidemia, hypertension and as well as other diseases and conditions. BACKGROUND OF THE INVENTION 15 Glucocorticoids are stress hormones with regulatory effects on carbohydrate, protein and lipid metabolism. Cortisol (or hydrocortisone in rodent) is the most important human glucocorticoid. 11-beta hydroxyl steroid dehydrogenase or 11 beta-HSD1 (11 p-HSD-1) is a member of the short chain dehydrogenase super-family of enzymes which converts functionally inert cortisone to active cortisol locally, in a pre-receptor manner. Given that the 20 enzyme is abundantly expressed in metabolically important tissues, such as adipose, muscle, and liver, that become resistant to insulin action in Type 2 Diabetes, inhibition of 11 p-HSD-1 offers the potential to restore the glucose lowering action of insulin in these tissues without impacting the central HPA. Another important 11-beta hydroxyl steroid dehydrogenase, namely Type 2 11-beta-HSD (11P-HSD-2), which converts cortisol into cortisone, is a 25 unidirectional dehydrogenase mainly located in kidney and protects minerallocorticoid receptors from illicit activation by glucocorticoids. Multiple lines of evidence indicate that 11 p-HSD-1-mediated intracellular cortisol production may have a pathogenic role in Obesity, Type 2 Diabetes and its co-morbidities. 30 In humans, treatment with non-specific inhibitor carbenoxolone improves insulin sensitivity in lean healthy volunteers and people with type2 diabetes (Walker B R et al (1995)). Likewise, 11p-HSD-1 activity was decreased in liver and increased in the adipose tissue of obese individuals. Similarly 11 P-HSD-1 mRNA was found to be increased in both 35 visceral and subcutaneous adipose tissue of obese patients (Desbriere R et al (2006)) and was positively related to BMI and central obesity in Pima Indians, Caucasians and Chinese youth (Lindsay RS et al (2003), Lee ZS et al (1999)). Adipose tissue 11p-HSD-1 and 1 WO 2013/111150 PCT/IN2012/000842 Hexose-6-Phosphate Dehydrogenase gene expressions have also been shown to increase in patients with type 2 diabetes mellitus (Ugkaya G et al (2008)). In human skeletal muscle 11p HSD-1 expression was found to be positively associated with insulin resistance (Whorwood CB et al (2002)). Increased 110-HSD-1 expression was also seen in diabetic myotubes 5 (Abdallah BM et al (2005)). Various studies have been conducted in rodent models to substantiate the role of 11p HSD-1 in diabetes and obesity. For example, over-expression of 110-HSD-1 specifically in adipose tissue causes development of metabolic syndrome (glucose intolerance, obesity, 10 dyslipidemia and hypertension) in mice (Masuzaki H et al (2001)). Conversely, when 11 p HSD-1 gene was knocked out, the resulting mice showed resistance to diet induced obesity and improvement of the accompanying dysregulation of glucose and lipid metabolism (Kotelevtsev Y et al (1997), Morton NM et al (2001), Morton NM et al (2004)). In addition, treatment of diabetic mouse models with specific inhibitors of 11 P-HSD-1 caused a decrease 15 in glucose output from the liver and overall increase in insulin sensitivity (Alberts P et al (2003)). The results of the preclinical and early clinical studies suggest that the treatment with a selective and potent inhibitor of 11P-HSD-1 will be an efficacious therapy for type 2 20 diabetes, obesity and metabolic syndrome. The role of 11 p-HSD-1 as an important regulator of liver glucocorticoid level and thus of hepatic glucose production is well substantiated. Hepatic insulin sensitivity was improved in healthy human volunteers treated with the non-specific 11 p-HSD-1 inhibitor carbenoxolone 25 (Walker BR (1995)). Many in vitro and in vivo (animal model) studies showed that the mRNA levels and activities of two key enzymes (PEPCK and G6PC) in gluconeogenesis and glycogenolysis were reduced by reducing 11 p-HSD-1 activity. Data from these models also confirm that inhibition of 11 p-HSD-1 will not cause hypoglycemia, as predicted since the basal levels of PEPCK and G6Pase are regulated independently of glucocorticoids (Kotelevtsev Y 30 (1997)). In the pancreas cortisol is shown to inhibit glucose induced insulin secretion as well as increase stress induced beta cell apoptosis. Inhibition of 11P-HSD-1 by carbenoxolone in isolated murine pancreatic beta-cells improves glucose-stimulated insulin secretion (Davani B 35 et al (2000)). Recently, it was shown that 11 P-HSD-1 within alpha cells regulates glucagon secretion and in addition may act in a paracrine manner to limit insulin secretion from beta cells (Swali A et al (2008)). Levels of 11 p-HSD-1 in islets from ob/ob mice were shown to be 2 WO 2013/111150 PCT/IN2012/000842 positively regulated by glucocorticoids and were lowered by a selective 11 P-HSD-1 inhibitor and a glucocorticoid receptor antagonist. Increased levels of 11 p-HSD-1 were associated with impaired GSIS (Ortsater H et al (2005)). In Zuker diabetic rats, troglitazone treatment improved metabolic abnormalities with a 40% decline in expression of 11 p-HSD-1 in the islets 5 (Duplomb L et al (2004)). Cortisol inhibition may lead to an increase in the insulin gene transcription and a normalization of first phase insulin secretion (Shinozuka Y et al (2001)). In human skeletal muscle 11p-HSD-1 expression is positively associated insulin resistance and increased expression of 11P-HSD-1 was also reported in type 2 diabetic 10 myotubes (Abdallah BM et al (2005)). Recently the contribution of cortisol in muscle pathology is being considered for modulating its action. Very recently it has been demonstrated that targeted reduction or pharmacological inhibition of 11 p-HSD-1 in primary human skeletal muscle prevents the effect of cortisone on glucose metabolism and palmitate oxidation (Salehzadeh F et al (2009)). Over activity of cortisol in muscle leads to muscle 15 atrophy, fibre type switch and poor utilization of glucose due to insulin resistance. Cortisol might have a direct role in reducing muscle glucose uptake. Obesity is an important factor in Metabolic syndrome as well as in the majority (>80%) of type 2 diabetics, and omental (visceral) fat appears to be of central importance. 11 P 20 HSD-1 activity is increased in the both visceral and subcutaneous adipose tissue of obese individual (Lindsay R S et al (2003)). Cortisol activity in adipose is known to increase the adipogenic program. Inhibition of 11 6-HSD-1 activity in pre-adipocytes has been shown to decrease the rate of differentiation into adipocytes (Bader T et al (2002)). This is predicted to result in diminished expansion (possibly reduction) of the omental fat depot, i.e., reduced 25 central obesity (Bujalska IJ et al (1997) and (2006)). Intra-adipose cortisol levels have been associated with adipose hypertrophy, independent of obesity (Michailidou Z et al (2006)). Cortisol in coordination with adrenergic signalling is also known to increase lipolysis which leads to increase in plasma free fatty acid concentrations which, in turn, is the primary 30 cause of many deleterious effects of obesity (TomLinson JW et al (2007)). Adrenalectomy attenuates the effect of fasting to increase both food intake and hypothalamic neuropeptide Y expression. This supports the role of glucocorticoids in promoting food intake and suggests that inhibition of 11 p-HSD-1 in the brain might increase 35 satiety and therefore reduce food intake (Woods SC (1998)). Inhibition of 110-HSD-1 by a small molecule inhibitor also decreased food intake and weight gain in diet induced obese mice (Wang SJY et al (2006)). 3 WO 2013/111150 PCT/IN2012/000842 The effects discussed above therefore suggest that an effective 11 P-HSD-1 inhibitor would have activity as an anti-obesity agent. 5 Cortisol in excess can also trigger triglyceride formation and VLDL secretion in liver, which can contribute to hyperlipidemia and associated dyslipidemia. It has been shown that 11 p-HSD-1-/- transgenic mice have markedly lower plasma triglyceride levels and increased HDL cholesterol levels indicating a potential atheroprotective phenotype (Morton NM et al (2001)). In a diet-induced obese mouse model, a non-selective inhibitor of 110-HSD-1 10 reduced plasma free fatty acid as well as triacylglycerol (Wang SJ et al (2006)). Over expression of 11 p-HSD-1 in liver increased liver triglyceride and serum free fatty acids with the up regulation of hepatic lipogenic genes (Paterson JM et al (2004). It has been illustrated that inhibition of 116-HSD-1 improves triglyceridemia by reducing hepatic VLDL-TG secretion, with a shift in the pattern of TG-derived fatty acid uptake toward oxidative tissues, in which 15 lipid accumulation is prevented by increased lipid oxidation (Berthiaume M et al (2007)). Atherosclerotic mouse model (APOE -/-) which are susceptible to atheroma when fed high fat diet, are protected against development of atherosclerosis when treated with 116 HSD-1 inhibitors (Hermanowski-Vostaka A et al, (2005)). 20 Inhibition of 11 6-HSD-1 in mature adipocytes is expected to attenuate secretion of the plasminogen activator inhibitor 1 (PAI-1)--an independent cardiovascular risk factor (Halleux CM et al (1999)). Furthermore, there is a clear correlation between glucocorticoid activity and cardiovascular risk factor suggesting that a reduction of the glucocorticoid effects would be 25 beneficial (Walker BR et al (1998), Fraser R et al (1999)). The association between hypertension and insulin resistance might be explained by increased activity of cortisol. Recent data show that the intensity of dermal vasoconstriction after topical application of glucocorticoids is increased in patients with essential hypertension 30 (Walker BR et al (1998)). Glucocorticoid was shown to increase the expression of angiotensin receptor in vascular cell and thus potentiating the renin-angiotensin pathway (Ullian ME et al (1996)), (Sato A et al (1994)). Role of cortisol in NO signalling and hence vasoconstriction has been proved recently (Liu Y et al (2009)). These findings render 11 p HSD-1 a potential target for controlling hypertension and improving blood-flow in target 35 tissues. 4 WO 2013/111150 PCT/IN2012/000842 In the past decade, concern on glucocorticoid-induced osteoporosis has increased with the widespread use of exogenous glucocorticoids (GC). GC-induced osteoporosis is the most common and serious side-effect for patients receiving GC. Loss of bone mineral density (BMD) is greatest in the first few months of GC use. Mature bone-forming cells (osteoblasts) 5 are considered to be the principal site of action of GC in the skeleton. The whole differentiation of mesenchymal stem cell toward the osteoblast lineage has been proven to be sensitive to GC as well as collagen synthesis (Kim CH et al (1999)). The effects of GC on this process are different according to the stage of differentiation of bone cell precursors. The presence of intact GC signalling is crucial for normal bone development and physiology, as 10 opposed to the detrimental effect of high dose exposure (Pierotti S et al (2008), Cooper MS et al (2000)). Other data suggest a role of 11@-HSD-1 in providing sufficiently high levels of active glucocorticoid in osteoclasts, and thus in augmenting bone resorption (Cooper M S et al (2000)). The negative effect on bone nodule formation could be blocked by the non specific inhibitor carbenoxolone suggesting an important role of 11p-HSD-1 in the 15 glucocorticoid effect (Bellows C G et al (1998)). Stress and glucocorticoids influence cognitive function (de Quervain DJ et al (1998)). The enzyme 11@-HSD-1controls the level of glucocorticoid action in the brain also known to contributes to neurotoxicity (Rajan V et al (1996)). It has been also suggested that inhibiting 20 11 P-HSD-1 in the brain may result in reduced anxiety (Tronche F et al (1999)). Thus, taken together, the hypothesis is that inhibition of 11@-HSD-lin the human brain would prevent reactivation of cortisone into cortisol and protect against deleterious glucocorticoid-mediated effects on neuronal survival and other aspects of neuronal function, including cognitive impairment, depression, and increased appetite. 25 Recent data suggest that the levels of the glucocorticoid target receptors and the 11@ HSD-1 enzymes determine the susceptibility to glaucoma (Stokes, J. et al. (2000)). Ingestion of carbenoxolone, a non-specific inhibitor of 11 @-HSD-1, was shown to reduce the intraocular pressure by 20% in normal subjects. There are evidences that 11@0-HSD-1 isozyme may 30 modulate steroid-regulated sodium transport across the NPE, thereby influencing intra ocular pressure (IOP). 11@P-HSD-1 is suggested to have a role in aqueous production, rather than drainage, but it is presently unknown if this is by interfering with activation of the glucocorticoid or the mineralocorticoid receptor, or both (Rauz S et al (2001; 2003)). 35 The multitude of glucocorticoid action is exemplified in patients with prolonged increase in plasma glucocorticoids, so called "Cushing's syndrome". These patients have prolonged increase in plasma glucocorticoids and exhibit impaired glucose tolerance, type 2 5 WO 2013/111150 PCT/IN2012/000842 diabetes, central obesity, and osteoporosis. These patients also have impaired wound healing and brittle skin. Administration of glucocorticoid receptor agonist (RU38486) in Cushing's syndrome patients reverses the features of metabolic syndrome (Neiman LK et al (1985)). 5 Glucocorticoids have been shown to increase risk of infection and delay healing of open wounds. Patients treated with glucocorticoids have 2-5-fold increased risk of complications when undergoing surgery. Glucocorticoids influence wound healing by interfering with production or action of cytokines and growth factors like IGF, TGF-beta, EGF, 10 KGF and PDGF (Beer HD et al (2000)). TGF-beta reverses the glucocorticoid-induced wound-healing deficit in rats by PDGF regulation in macrophages (Pierce GF et al (1989)). It has also been shown that glucocorticoids decrease collagen synthesis in rat and mouse skin in vivo and in rat and human fibroblasts (Oishi Y et al, 2002). 15 Glucocorticoids have also been implicated in conditions as diverse aspolycystic Ovaries Syndrome, infertility, memory dydsfunction, sleep disorders, myopathy (Endocrinology. 2011 Jan; 152(1):93-102. Epub 2010 Nov 24.PMID: 21106871) and muscular dystrophy. As such the ability to target enzymes that have an impact on glucocorticoid levels is expected to provide promise for the treatment of these conditions. 20 Based on patent literature and company press releases, there are many compound tested for 1 1D-HSD-1 inhibition in the different stages of drug discovery pipeline. Incyte Corporation's INCB13739 has proceeded furthest to phase lib stage of clinical 25 trial. The results of phase Ila trial for type 2 diabetes (28-days, placebo-controlled, two-step hyperinsulinemic clamp studies) showed that it was safe and well tolerated without any serious side effects and hypoglycemia. Though this molecule significantly improved hepatic insulin sensitivity there was no 30 appreciable improvement in plasma glucose levels. The molecule appeared to be having positive effects on risk factors for cardiovascular disease including reduction of LDL, total cholesterol and triglycerides as well as more modest increases in HDL. INCB13739 is currently being studied in a dose ranging phase lIb trials in T2D patients whose glucose levels are not controlled by metformin monotherapy. 35 In the pre-clinical stage, Incyte's lead inhibitor INCB13739 was tested in rhesus monkey and was shown to inhibit adipose 11 P-HSD-1 (INCBO13739, a selective inhibitor of 6 WO 2013/111150 PCT/IN2012/000842 11P-Hydroxysteroid Dehydrogenase Type 1 (11pHSD1) improves insulin sensitivity and lowers plasma cholesterol over 28 days in patients with type 2 diabetes mellitus. The evidence therefore strongly suggests that compounds that are inhibitors of 11 P 5 Hydroxysteroid Dehydrogenase would be useful in the treatment of a number of clinical conditions associated with the expression of this enzyme. In addition it would be desirable if the inhibitors were selective inhibitors so as not to interfere with the functioning of closely related enzymes such as 11 P-HSD-2 which is known to provide a protective effect in the body. 10 OBJECTS OF INVENTION The principal object of the invention is to provide compounds that are inhibitors of 11 p Hydroxysteroid Dehydrogenase. These compounds would be expected to be useful in the treatment of 11 P-Hydroxysteroid Dehydrogenase related conditions as discussed above. 15 A further object is to provide a pharmaceutical composition containing a compound that is an inhibitor of 11 6-Hydroxysteroid Dehydrogenase and a pharmaceutically acceptable excipient, diluent or carrier. 20 A further object is to provide a method of prevention or treatment of a condition associated with 11 P-Hydroxysteroid Dehydrogenase activity in a mammal. STATEMENT OF INVENTION The present invention provides compounds of Formula (1): 25 O Rla A (R 2 )a Ar"A B N R la R1 R4 Formula (1) wherein: each R 1 , Rl" and R 2 is independently selected from the group consisting of H, halogen, OH, 30 NO 2 , CN, SH, NH 2 , CF 3 , OCF 3 , OCH 3 , CH 2
OH,CH
2
CO
2 H, CH 2
CH
2
CO
2 H, CH 2
NH
2 , optionally substituted C 1
-C
1 2 alkyl, optionally substituted C 1
-O
12 haloalkyl optionally substituted C2 7 WO 2013/111150 PCT/IN2012/000842
C
12 alkenyl, optionally substituted C 2 -Cl 2 alkynyl, optionally substituted C 2 -Cl 2 heteroalkyl, optionally substituted C 3
-C
12 cycloalkyl, optionally substituted C 3
-C
12 cycloalkenyl, optionally substituted C 2 -Cl 2 heterocycloalkyl, optionally substituted C 2
-C
2 heterocycloalkenyl, optionally substituted C 6
-C
18 aryl, optionally substituted C-C 18 heteroaryl, optionally substituted C 5 C 12 alkyloxy, optionally substituted C 2 -Cl 2 alkenyloxy; optionally substituted C 2 -Cl 2 alkynyloxy, optionally substituted C 2
-C
1 oheteroalkyloxy, optionally substituted C 3
-C
12 cycloalkyloxy, optionally substituted C 3 -Cl 2 cycloalkenyloxy, optionally substituted C 2 -Cl 2 heterocycloalkyloxy, optionally substituted C 2
-C
12 heterocycloalkenyloxy, optionally substituted C 6
-C
18 aryloxy, optionally substituted C-C 1 8 heteroaryloxy, optionally substituted C-C 12 alkylamino, SR 3 , 10 SO 3 H, SO 2
NR
3
R
4 , S0 2
R
3 , SONR 3
R
4 , SOR', COR 3 , COOH, COOR 3 , CONR 3
R
4 , NR 3
COR
4 ,
NR
3
COOR
4 , NR'SO 2
R
4 , NR3CONR 3
R
4 , and NR 3
R
4 ; Ar is an optionally substituted C-C 18 heteroaryl group or an optionally substituted C2r
C
12 heterocycloalkyl group; 15 A is selected from the group consisting of S, SO, SO 2 , 0, and -CRaRb_ B is a group of the formula -(CRcRd),_ 20 wherein each R", Rb, Rc and Rd is independently selected from the group consisting of H, halogen, OH, NO 2 , CN, SH, NH 2 , CF 3 , OCF 3 , optionally substituted 0 1
-C
2 alkyl, optionally substituted C 2
-C
1 oheteroalkyl, optionally substituted 0 1
-C
2 haloalkyl, optionally substituted C3 C1 2 cycloalkyl, optionally substituted C 6
-C
18 aryl, optionally substituted C-C 18 heteroaryl, SR 3 ,
SO
3 H, SO 2
NR
3
R
4 , SO 2
R
3 , SONR 3
R
4 , SOR 3 , COR 3 , COOH, COOR, CONR 3
R
4 , NR 3 COR4 3 , 25 NR 3
COOR
4 , NR'SO 2
R
4 , NR3CONR 3
R
4 , NR 3
R
4 ; or any two Ra, Rb, Rc and Rd on the same carbon atom when taken together may form a substituent of the formula:
R
5 30 wherein each R 3 and R 4 is independently selected from the group consisting of H, optionally substituted C 1
-C
12 alkyl, optionally substituted C 2
-C
1 oheteroalkyl, optionally substituted 0 1
-C
2 haloalkyl, optionally substituted C 3
-C
12 cycloalkyl, optionally substituted C6 35 C 1 8 aryl, and optionally substituted C-C 18 heteroaryl; 8 WO 2013/111150 PCT/IN2012/000842 R' is selected from the group consisting of 0, S, and NR 6 ;
R
6 is selected from the group consisting of H, OR 7 , optionally substituted C-C 1 2 alkyl, optionally substituted C-C 12 haloalkyl optionally substituted C 2
-C
12 alkenyl, optionally 5 substituted C 2
-C
12 alkynyl, optionally substituted C-C 1 2 alkyloxy, optionally substituted C
C
12 haloalkyloxy, optionally substituted C 2
-C
1 oheteroalkyl, optionally substituted C3
C
12 cycloalkyl, optionally substituted C 3
-C
12 cycloalkenyl, optionally substituted C2
C
12 heterocycloalkyl, optionally substituted C2-C12 heterocycloalkenyl, optionally substituted
C
6
-C
15 aryl, and optionally substituted C-C 18 heteroaryl; 10
R
7 is selected from the group consisting of H, optionally substituted C-C 1 2 alkyl, optionally substituted C 2
-C
1 oheteroalkyl, optionally substituted C 3
-C
1 2 cycloalkyl, optionally substituted C 6
-C
15 aryl, and optionally substituted C-C 18 heteroaryl; 15 or any two or more R", Rb, Rc and Rd may join together to form a multiple bond between adjacent carbon atoms such as a double or triple bond, or a cyclic moiety connecting the carbon atoms to which they are attached; n is an integer selected from the group consisting of 0, 1, 2, 3, and 4; 20 a is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof. 25 As with any group of structurally related compounds which possess a particular utility, certain embodiments of variables of the compounds of the Formula (I), are particularly useful in their end use application. In some embodiments A is S. In some embodiments A is SO. In some embodiments 30 A is SO 2 . In some embodiments A is 0. In some embodiments A is CR"R . In some embodiments where A is CRaRb, Ra and Rb are each independently selected from the group consisting of H, CH 3 , CH 2
CH
3 , CH 2
CH
2
CH
3 , CH(CH 3
)
2 , (CH 2
)
3
CH
3 Cl, Br, F, I, OH, NO 2 , NH 2 , CN, SO 3 H, OCH 3 , OCH 2
CH
2
CH
3 , CF 3 , and OCF 3 . In some embodiments R' is 35 H. In some embodiments Rb is H. In some embodiments R" and Rb are different such that the carbon is a chiral carbon. In some embodiments one of Ra and Rb is H and the other is an optionally substituted alkyl. 9 WO 2013/111150 PCT/IN2012/000842 In some embodiments Rb is H and Ra is optionally substituted alkyl. In some embodiments Rb is H and R" is selected from the group consisting of methyl, ethyl, propyl, isopropyl and butyl. 5 B is a group of the formula -(CORcRd)n-. In some embodiments n is 0. In some embodiments n is 1. In some embodiments n is 2. In some embodiments Rc and Rd are each independently selected from the group 10 consisting of H, CH 3 , CH 2
CH
3 , CH 2
CH
2
CH
3 , CH(CH 3
)
2 , (CH 2
)
3
CH
3 Cl, Br, F, 1, OH, NO 2 , NH 2 , CN, SO 3 H, OCH 3 , OCH 2
CH
2
CH
3 , CF 3 , and OCF 3 . In some embodiments both Rc and Rd are H such that B is CH 2 . In some embodiments any two or more Ra, Rb, Rc and Rd mayjo together to form a 15 multiple bond between adjacent carbon atoms such as a double or triple bond, or a cyclic moiety connecting the carbon atoms to which they are attached. In some embodiments two of R", Rb, Rc and Rd on adjacent carbon atoms are joined to form a double bond. In some embodiments four of R", Rb, Rc and Rd on adjacent carbon 20 atoms are joined to form a triple bond. In some embodiments one of Ra and Rb and one or Rc and Rd when taken together with the carbon atoms to which they are attached form a cyclic moiety. Examples of cyclic moieties that may be formed include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 25 In some embodiments n = 2 and one of Ra and Rb and one or Rc and Rd on the carbon atom two carbons removed (on the beta carbon) when taken together with the carbon atoms to which they are attached and the alpha carbon atom form a cyclic moiety. Examples of cyclic moieties that may be formed include cyclobutyl, cyclopentyl and cyclohexyl. 30 In some embodiments A is CRaRb and B is CH 2 , this provides compounds of formula (Il): 10 WO 2013/111150 PCT/IN2012/000842
(R
2 )a Ar N RR Formula (II) wherein R 1 , R'", R", Rb, R 2 and Ar, are as defined above. 5 The group Ar may be any optionally substituted C1-C18 heteroaryl moiety. Suitable heteroaryl groups include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, 10 pyridazine, tetrazole, indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, pyridyl, quinolyl, isoquinolinyl, indolyl, and thienyl. In each instance where there is the possibility of multiple sites of substitution on the heteroaryl ring all possible attachment points 15 are contemplated. Merely by way of example if the heteroaryl is a pyridyl moiety it may be a 2-pyridyly, a 3- pyridyl or a 4-pyridyl. In some embodiments Ar is a group of the formula 3:
V
3 v3
V
2 1
U
1 20 (3) wherein each V 1 , V 2 , V 3 , V 4 , V 5 and V 6 is independently selected from the group consisting of N and CR 8 ; 25 U is selected from the group consisting of NR 9 , 0, S and CR 9 2 , 11 WO 2013/111150 PCT/IN2012/000842 wherein each R3 is independently selected from the group consisting of H, halogen, OH, NO 2 , CN, SH, NH 2 , CF 3 , OCF 3 , optionally substituted 0 1
-C
2 alkyl, optionally substituted 0 1
-C
2 haloalkyl, optionally substituted C 2
-CO
2 alkenyl, optionally substituted C 2
-CO
2 alkynyl, optionally substituted C 2
-C
2 heteroalkyl, optionally substituted 0 3
-C
2 cycloalkyl, optionally 5 substituted C 3
-C
12 cycloalkenyl, optionally substituted C2rCl 2 heterocycloalkyl, optionally substituted C 2
-C
2 heterocycloalkenyl, optionally substituted C 6
-C
18 aryl, optionally substituted
C
1 s-O 8 heteroaryl, optionally substituted 0 1
-C
2 alkyloxy, optionally substituted C 2 C 12 alkenyloxy, optionally substituted C 2
-CO
2 alkynyloxy, optionally substituted C2 C1 0 heteroalkyloxy, optionally substituted C 3
-C
12 cycloalkyloxy, optionally substituted C 10 CO 12 cycloalkenyloxy, optionally substituted C 2
-C
2 heterocycloalkyloxy, optionally substituted
C
2
-C
2 heterocycloalkenyloxy, optionally substituted C 6
-C
1 aryloxy, optionally substituted C
C
1 heteroaryloxy, optionally substituted Cr 1
CO
2 alkylamino, SR 0 , SO 3 H, S0 2 NR' R, S0 2 R' , OS0 2 R' , SONR 0 R", SOR' 0 , COR', COOH, COOR 10 , CONR' R, NR 1 4COR 11 , NR'COOR", NR'OS0 2 R", NR'CONR 'R", and NR'R"; 15 wherein R 9 is selected from the group consisting of H, optionally substituted Cr1
C
1 2 alkyl, optionally substituted C 2
-C
2 alkenyl, optionally substituted C 2
-C
2 alkynyl, optionally substituted 0 2
-C
2 heteroalkyl, optionally substituted 0 3
-C
12 cycloalkyl, optionally substituted 0 2
-C
2 heterocycloalkyl, optionally substituted C-C 18 aryl, optionally substituted C 20 C1 8 heteroaryl, SO 3 H, S0 2 NR' R", SO 2
R'
0 , SONR 0
R
11 , SOR 10 , COR 10 , COOH, COOR0, and CONRW'R"; wherein each R 1 0 and R" is independently selected from the group consisting of H, optionally substituted CrCO 2 alkyl, optionally substituted C 2
-C
1 oheteroalkyl, optionally 25 substituted Cr 1
CO
2 haloalkyl, optionally substituted C 3
-C
12 cycloalkyl, optionally substituted C C1 8 aryl, and optionally substituted C 1
-O
8 heteroaryl. In some embodiments Ar is selected from the group consisting of: 12 WO 2013/111150 PCT/IN2012/000842 (R8).
(R
8 )f
(R
8 ). R8 R8 N N N N N NN R9
R
9 R 9 (3a) (3b) (3c)
(R
8 ). (R 8 )e (R 8 ). N N N N S N Re (3d) (3e) (3f) (R11). a n d (N (3g) 5 wherein R 8 and R 9 is as defined above; e is an integer selected from the group consisting of 0, 1, 2, 3 and 4; 10 f is an integer selected the group consisting of 0, 1, 2, and 3. In some embodiments A is CRaR, B is CH 2 and Ar is a group of formula (3a), this provides compounds of formula (IVa): 13 WO 2013/111150 PCT/IN2012/000842 (R %Ra b Ol RD2 NR8 Rio R1 R1 R9 Formula (IVa) wherein R 1 , R 1 ", R", R , R 2 , R", R 9 and e, are as defined above. 5 In some embodiments A is CRaR b, B is CH 2 and Ar is a group of formula (3b), this provides compounds of formula (IVb): ( R 8)fR a b O R l a" 2 (RN(Ra NN R9 Formula (IVb) 10 wherein R 1 , Rla, R", R , R 2 , R , R 9 and f, are as defined above. In some embodiments A is CRaR , B is CH 2 and Ar is a group of formula (3c), this provides compounds of formula (IVc): (R ") Na R l (R2 )a N N R a R 1R 15 15 R9 Formula (IVc) 14 WO 2013/111150 PCT/IN2012/000842 wherein R 1 , R'", R", R , R 2 , R", R 9 and e, are as defined above. In some embodiments A is CRaR b, B is CH 2 and Ar is a group of formula (3d), this provides compounds of formula (IVd): Rb N N N 5 R 1 Formula (iVd) wherein R 1 , R"4, R", R , R 2 , R 8 and e, are as defined above. 10 In some embodiments A is CRaRb, B is CH 2 and Ar is a group of formula (3e), this provides compounds of formula (IVe): R a Rb O Ria R2 )a N N (W~e Rli" R R Formula (IVe) 15 wherein R 1 , R 1 a, R , R , R 2 , R 8 and e, are as defined above. In some embodiments A is CRaR, B is CH 2 and Ar is a group of formula (3f), this provides compounds of formula (IVf): 15 WO 2013/111150 PCT/IN2012/000842 Ra R b O Rla (R 2). N N (R8) eN R9 Rloa R1 R Formula (IVf) wherein R 1 , R'", Ra, R , R 2 , R", R 9 and e, are as defined above. 5 In some embodiments A is CR"R , B is CH 2 and Ar is a group of formula (3g), this provides compounds of formula (IVg): Ra R R Ra
(R
2 )a N N
(R
8 ) e -l 1 R Formula (IVg) 10 wherein R 1 , R 1 a, R", R , R 2 , R 8 , and e, are as defined above. In some embodiments e is 1. In some embodiments e is 2. In some embodiments e is 3. In some embodiments e is 4. In circumstances where e is 1 the R 8 group may be 15 located at either the 4, 5, 6, or 7 position on the six membered ring. In some embodiments where e is 1 the R 8 substituent is located at the 4 position on the ring. In some embodiments where e is 1 the R 8 substituent is located at the 5 position on the ring. In some embodiments where e is 1 the R 8 substituent is located at the 6 position on the ring. In some embodiments where e is 1 the R 8 substituent is located at the 7 position on the ring. 20 In some embodiments f is 1. In some embodiments f is 2. In some embodiments f is 3. In some embodiments where f is 1 the R 8 substituent is located at the 4 position on the ring. In some embodiments where f is 1 the R 8 substituent is located at the 5 position on the 16 WO 2013/111150 PCT/IN2012/000842 ring. In some embodiments where f is 1 the R 8 substituent is located at the 6 position on the ring. In some embodiments where f is 1 the R 8 substituent is located at the 7 position on the ring. 5 In some embodiments of the compounds described above each R 1 is independently selected from the group consisting of H, OH, F, Cl, Br, CH 3 , CH 2
CO
2 H, CH 2
CH
2
CO
2 H, C0 2 H,
CONH
2 , CH 2 OH, CH 2
NH
2 , CN, OCH 3 , Ocyclopropyl, and OCHF 2 . In some embodiments one
R
1 is H and the other R' is OH. In some embodiments both R 1 are H. 10 In some embodiments of the compounds described above each R'" is independently selected from the group consisting of H, OH, F, CI, Br, CO 2 H, CONH 2 , CH 2 OH, CN, OCH 3 , and OCHF 2 . In some embodiments one R 1 ' is H and the other Rl" is OH. In some embodiments both R'" are H. 15 In some embodiments each R 2 is independently selected from the group consisting of H, CH 3 , CH 2
CH
3 , CH 2
CH
2
CH
3 , CH(CH 3
)
2 , (CH 2
)
3
CH
3 . C, Br, F, I, OH, NO 2 , NH 2 , CN, SO 3 H,
OCH
3 , OCH 2
CH
2
CH
3 , CF 3 , and OCF 3 In some embodiments a is 0. In some embodiments a is 1. In some embodiments a 20 is 2. In some embodiments a is 3. In some embodiments a is 4. In some embodiments a is 5. In some embodiments a is 6. In some embodiments a is 7. In some embodiments a is 8. In some embodiments a is 9. In some embodiments a is 10. In some embodiments of the compounds of the invention containing an R 3 group, the 25 R 3 group is selected from H and C-C 12 alkyl. In some embodiments R 3 is H. in some embodiments R 3 is methyl. In some embodiments of the compounds of the invention containing an R 4 group, the R4 group is selected from H and C 1
-O
2 alkyl. In some embodiments R 4 is H. in some 30 embodiments R 4 is methyl. In some embodiments of the compounds of the invention containing an R 5 group, the R group is selected from 0 and S. In some embodiments R 5 is 0. in some embodiments R 5 is S. 35 17 WO 2013/111150 PCT/IN2012/000842 In some embodiments of the compounds of the invention containing an R 6 group, the
R
6 group is selected from H and CrC- 2 alkyl. In some embodiments R 6 is H. in some embodiments R 6 is methyl. 5 In some embodiments of the compounds of the invention containing an R 7 group, the
R
7 group is selected from H and C 1
-O
2 alkyl. In some embodiments R 7 is H. in some embodiments R 7 is methyl. R" may be selected from a wide range of possible substituents as discussed above. 10 In some embodiments each R8 is independently selected from the group consisting of H, halogen, OH, NO 2 , CN, C-CO 2 alkyl, C 1
-O
12 haloalkyl, Cr 1
CO
2 alkoxyl, and 0 1
-C
2 haloalkoxyl. Exemplary R 8 substituents include H, CH 3 , CH 2
CH
3 , CH 2
CH
2
CH
3 , CH(CH 3
)
2 , (CH 2
)
3
CH
3 , cyclopropyl, I, Br, F, I, OH, NO 2 , NH 2 , CN, SO 3 H, OCH 3 , OCH(CH 3
)
2 , OCH 2
CH
2
CH
3 ,
OSO
2
CF
3 , CF 3 , and OCF 3 . 15
R
9 may be selected from a wide range of possible substituents as discussed above. In some embodiments each R 9 is independently selected from the group consisting of H, halogen, OH, NO 2 , CN, 0 1
-C
2 alkyl, C-Cl 2 haloalkyl, C-Cl 2 alkoxyl, and C-Cl 2 haloalkoxyl. Exemplary R 9 substituents include CH 3 , CH 2
CH
3 , CH 2
CH
2
CH
3 , CH(CH 3
)
2 , (CH 2
)
3
CH
3 , I, Br, F, 20 1, OH, NO 2 , NH 2 , CN, SO 3 H, OCH 3 , OCH 2
CH
2
CH
3 , CF 3 , and OCF 3 . Many if not all of the variables discussed above may be optionally substituted. If the variable is optionally substituted then in some embodiments each optional substituent is independently selected from the group consisting of halogen, =0, =S, -CN, -NO 2 , -CF 3 , 25 -OCF 3 , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, 30 alkyloxycycloalkyl, alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, 35 arylsulfinyl, aminosulfinylaminoalkyl, -C(=O)OH, -C(=O)R", -C(=O)OR*, C(=O)NR*Rf, C(=NOH)Re, C(=NRe)NRR9, NReRf, NReC(=O)R', NReC(=O)OR', NR*C(=0)NR'Rg, NReC(=NR')NR9Rh, NReSO 2 R', -SR", SO 2 NReRf, -OR*. OC(=O)NR*R', OC(=O)Re and acyl, 18 WO 2013/111150 PCT/IN2012/000842 wherein R", Rf, R 9 and Rh are each independently selected from the group consisting of H, 0 1
-C
2 alkyl, 0 1
-C
2 haloalkyl, 0 2
-C
2 alkenyl, 0 2
-C
2 alkynyl, C-C 1 heteroalkyl, C3
C
12 cycloalkyl, C 3
-C
12 cycloalkenyl, C-Cl 2 heterocycloalkyl, C1C12 heterocycloalkenyl, C6 5 C 18 aryl, C-C 18 heteroaryl, and acyl, or any two or more of R', Rb, Rc and Rd, when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms. In some embodiments each optional substituent is independently selected from the 10 group consisting of: F, Cl, Br, =0, =S, -CN, -NO 2 , alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C(O)OR", COOH, SH, and acyl. 15 In some embodiments each optional substituent is independently selected from the group consisting of: F, Br, Cl, =0, =S, -CN methyl, trifluoro-methyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2 ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH 2 , -NO 2 , phenoxy, hydroxy, methoxy, trifluoro-methoxy, ethoxy, and methylenedioxy. 20 Alternatively, two optional substituents on the same moiety when taken together may be joined to form a fused cyclic substituent attached to the moiety that is optionally substituted. Accordingly the term optionally substituted includes a fused ring such as a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring or a heteroaryl ring. 25 In addition to compounds of formula I, the embodiments disclosed are also directed to pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites. 30 The invention also relates to pharmaceutical compositions including a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient. In a further aspect the present invention provides a method of prevention or treatment 35 of a condition in a mammal, the method comprising administering an effective amount of a compound of the invention. In one embodiment the condition is a condition that can be treated by inhibition of 11 p-HSD1. 19 WO 2013/111150 PCT/IN2012/000842 In yet an even further aspect the invention provides the use of a compound of the invention in the preparation of a medicament for the treatment of a condition in a mammal. In one embodiment the condition is a condition that can be treated by inhibition of 11 p-HSD1. 5 In yet an even further aspect the invention provides the use of a compound of the invention in the treatment of a condition in a mammal. In one embodiment the condition is a condition that can be treated by inhibition of 11 p-HSD1. 10 In some embodiments the condition is selected from the group consisting of is selected from the group consisting of diabetes, hyperglycemia, low glucose tolerance, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity, abdominal obesity, glaucoma, hypertension, atherosclerosis and its sequelae, retinopathy and other ocular disorders, nephropathy, neuropathy, myopathy, osteoporosis, 15 osteoarthritis, dementia, depression, neurodegenerative disease, psychiatric disorders, Polycystic ovaries syndrome, infertility, Cushing's Disease, Cushing's syndrome, viral diseases, and inflammatory diseases. In some embodiments the condition is diabetes. In some embodiments the condition 20 is type Il diabetes. In some embodiments the compound is administered in combination with an adjuvant. In some embodiments the adjuvant is selected from the group consisting of dipeptidyl peptidase-IV (DP-IV) inhibitors; (b) insulin sensitizing agents; (c) insulin and insulin mimetics; 25 (d) sulfonylureas and other insulin secretagogues; (e) alpha.-glucosidase inhibitors; (f) GLP-1, GLP-1 analogs, and GLP-1 receptor agonists; and combinations thereof. In one other embodiment the compound is administered as a substitute for monotherapy or combination therapy, in an event of failure of treatment by an agent selected 30 from the group consisting of dipeptidyl peptidase-IV (DP-IV) inhibitors; (b) insulin sensitizing agents; (c) insulin and insulin mimetics; (d) sulfonylureas and other insulin secretagogues; (e) alpha.-glucosidase inhibitors; (f) GLP-1, GLP-1 analogs, and GLP-1 receptor agonists; and combinations thereof. 35 In one embodiment the insulin sensitizing agent is selected from the group consisting of (i) PPAR-gamma-agonists, (ii) PPAR-alpha-agonists, - (iii) PPAR-alpha/gamma-dual agonists, (iv) biguanides, and combinations thereof. 20 WO 2013/111150 PCT/IN2012/000842 These and other teachings of the invention are set forth herein. DETAILED DESCRIPTION OF THE INVENTION 5 In this specification a number of terms are used which are well known to a skilled addressee. Nevertheless for the purposes of clarity a number of terms will be defined. As used herein, the term "unsubstituted" means that there is no substituent or that the only substituents are hydrogen. 10 The term "optionally substituted" as used throughout the specification denotes that the group may or may not be further substituted or fused (so as to form a condensed polycyclic system), with one or more non-hydrogen substituent groups. In certain embodiments the substituent groups are one or more groups independently selected from the group consisting 15 of halogen, =0, =S, -CN, -NO 2 , -CF 3 , -OCF 3 , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, 20 alkyloxy, alkyloxyalkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, 25 alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -C(=O)OH, -C(=O)R*, -C(=O)OR*, C(=O)NReRf, C(=NOH)Re, C(=NR*)NRfRg, NReRf, NReC(=O)R', NReC(=O)OR', NReC(=O)NRfR', NR*C(=NR')NRIRh, NR"SO 2 R', -SR*, SO 2 NReRf, -ORe OC(=O)NReRf, OC(=O)R* and acyl, 30 wherein R*, Rf, R9 and Rh are each independently selected from the group consisting of H, C-C 12 alkyl, C-C 12 haloalkyl, C 2
-C
12 alkenyl, C 2
-C
12 alkynyl, C 1
-C
1 oheteroalkyl, C3
C
12 cycloalkyl, C 3
-C
12 cycloalkenyl, Cl-C 12 heterocycloalkyl, C-C 12 heterocycloalkenyl, C6
C
1 8aryl, C-C 1 heteroaryl, and acyl, or any two or more of R*, Rb, Rc and Rd, when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 35 12 ring atoms. 21 WO 2013/111150 PCT/IN2012/000842 In some embodiments each optional substituent is independently selected from the group consisting of: halogen, =0, =S, -CN, -NO 2 , -CF 3 , -OCF 3 , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, 5 alkyloxyaryl, alkyloxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, -COOH, -SH, and acyl. 10 Examples of particularly suitable optional substituents include F, Cl, Br, I, CH 3 ,
CH
2
CH
3 , OH, OCH 3 , CF 3 , OCF 3 , NO 2 , NH 2 , and CN. In the definitions of a number of substituents below it is stated that "the group may be a terminal group or a bridging group". This is intended to signify that the use of the term is 15 intended to encompass the situation where the group is a linker between two other portions of the molecule as well as where it is a terminal moiety. Using the term alkyl as an example, some publications would use the term "alkylene" for a bridging group and hence in these other publications there is a distinction between the terms "alkyl" (terminal group) and "alkylene" (bridging group). In the present application no such distinction is made and most 20 groups may be either a bridging group or a terminal group. "Acyl" means an R-C(=O)- group in which the R group may be an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group as defined herein. Examples of acyl include acetyl and benzoyl. The group may be a terminal group or a bridging group. If the group is a 25 terminal group it is bonded to the remainder of the molecule through the carbonyl carbon. "Acylamino" means an R-C(=O)-NH- group in which the R group may be an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the 30 remainder of the molecule through the nitrogen atom. "Alkenyl" as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2-12 carbon atoms, more preferably 2-10 carbon atoms, most preferably 2 35 6 carbon atoms, in the normal chain. The group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z. The alkenyl group is preferably a 1-alkenyl group. Exemplary alkenyl groups include, but are not limited to, 22 WO 2013/111150 PCT/IN2012/000842 ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl. The group may be a terminal group or a bridging group. "Alkenyloxy" refers to an alkenyl-O- group in which alkenyl is as defined herein. 5 Preferred alkenyloxy groups are Cr1C6 alkenyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom. "Alkyl" as a group or part of a group refers to a straight or branched aliphatic 10 hydrocarbon group, preferably a C 1
-C
1 2 alkyl, more preferably a C-C 1 oalkyl, most preferably C01C6 unless otherwise noted. Examples of suitable straight and branched C-C 6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like. The group may be a terminal group or a bridging group. 15 "Alkylamino" includes both mono-alkylamino and dialkylamino, unless specified. "Mono-alkylamino" means an Alkyl-NH- group, in which alkyl is as defined herein. "Dialkylamino" means a (alkyl) 2 N- group, in which each alkyl may be the same or different and are each as defined herein for alkyl. The alkyl group is preferably a C-C 6 alkyl group. The group may be a terminal group or a bridging group. If the group is a terminal group it is 20 bonded to the remainder of the molecule through the nitrogen atom. "Alkylaminocarbonyl" refers to a group of the formula (Alkyl)x(H)yNC(=O)- in which alkyl is as defined herein, x is 1 or 2, and the sum of X+Y =2. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the 25 molecule through the carbonyl carbon. "Alkyloxy" refers to an alkyl-O- group in which alkyl is as defined herein. Preferably the alkyloxy is a 0 1
-C
6 alkyloxy. Examples include, but are not limited to, methoxy and ethoxy. The group may be a terminal group or a bridging group. 30 "Alkyloxyalkyl" refers to an alkyloxy-alkyl- group in which the alkyloxy and alkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group. 35 23 WO 2013/111150 PCT/IN2012/000842 "Alkyloxyaryl" refers to an alkyloxy-aryl- group in which the alkyloxy and aryl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the aryl group. 5 "Alkyloxycarbonyl" refers to an alkyl-O-C(=O)- group in which alkyl is as defined herein. The alkyl group is preferably a C1C6 alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon. 10. "Alkyloxycycloalkyl" refers to an alkyloxy-cycloalkyl- group in which the alkyloxy and cycloalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the cycloalkyl group. 15 "Alkyloxyheteroaryl" refers to an alkyloxy-heteroaryl- group in which the alkyloxy and heteroaryl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroaryl group. 20 "Alkyloxyheterocycloalkyl" refers to an alkyloxy-heterocycloalkyl- group in which the alkyloxy and heterocycloalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heterocycloalkyl group. 25 "Alkylsulfinyl" means an alkyl-S-(=O)- group in which alkyl is as defined herein. The alkyl group is preferably a Cr1C6 alkyl group. Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through 30 the sulfur atom. "Alkylsulfonyl" refers to an alkyl-S(=0) 2 - group in which alkyl is as defined above. The alkyl group is preferably a C-C 6 alkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl. The group may be a terminal group or a bridging group. If 35 the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom. 24 WO 2013/111150 PCT/IN2012/000842 "Alkynyl" as a group or part of a group means an aliphatic. hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-12 carbon atoms, more preferably 2-10 carbon atoms, more preferably 2-6 carbon atoms in the normal chain. Exemplary structures include, but are not limited to, 5 ethynyl and propynyl. The group may be a terminal group or a bridging group. "Alkynyloxy" refers to an alkynyl-O- group in which alkynyl is as defined herein. Preferred alkynyloxy groups are C 1
-C
6 alkynyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the 10 molecule through the oxygen atom. "Aminoalkyl" means an NH 2 -alkyl- group in which the alkyl group is as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group. 15 "Aminosulfonyl" means an NH 2 -S(=0) 2 - group. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom. 20 "Aryl" as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety-in which a phenyl and a C 5
-
7 cycloalkyl or C 5
-
7 cycloalkenyl group are fused 25 together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. The group may be a terminal group or a bridging group. Typically an aryl group is a C6-C18 aryl group. "Arylalkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as defined herein. Exemplary arylalkenyl groups include phenylallyl. The group may be a terminal 30 group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group. "Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as defined herein. Preferred arylalkyl groups contain a C1.
5 alkyl moiety. Exemplary arylalkyl 35 groups include benzyl, phenethyl, 1-naphthalenemethyl and 2-naphthalenemethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group. 25 WO 2013/111150 PCT/IN2012/000842 "Arylalkyloxy" refers to an aryl-alkyl-O- group in which the alkyl and aryl are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom. 5 "Arylamino" includes both mono-arylamino and di-arylamino unless specified. Mono-arylamino means a group of formula arylNH-, in which aryl is as defined herein. Di-arylamino means a group of formula (aryl) 2 N- where each aryl may be the same or different and are each as defined herein for aryl. The group may be a terminal group or a 10 bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom. "Arylheteroalkyl" means an aryl-heteroalkyl- group in which the aryl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If 15 the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group. "Aryloxy" refers to an aryl-O- group in which the aryl is as defined herein. Preferably the aryloxy is a C 6
-C
18 aryloxy, more preferably a C 6
-C
1 oaryloxy. The group may be a terminal 20 group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom. "Arylsulfonyl" means an aryl-S(=0) 2 - group in which the aryl group is as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal 25 group it is bonded to the remainder of the molecule through the sulfur atom. A "bond" is a linkage between atoms in a compound or molecule. The bond may be a single bond, a double bond, or a triple bond. 30 "Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be substituted by one or more substituent groups. A cycloalkenyl group typically is a C3-C12 alkenyl group. The group may be a 35 terminal group or a bridging group. 26 WO 2013/111150 PCT/IN2012/000842 "Cycloalkyl" refers to a saturated monocyclic or fused or spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic 5 systems such as adamantane. A cycloalkyl group typically is a C 3
-C
12 alkyl group. The group may be a terminal group or a bridging group. "Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as defined herein. Exemplary monocycloalkylalkyl groups include 10 cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group. "Cycloalkylalkenyl" means a cycloalkyl-alkenyl- group in which the cycloalkyl and 15 alkenyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group. "Cycloalkylheteroalkyl" means a cycloalkyl-heteroalkyl- group in which the cycloalkyl 20 and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group. "Cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined herein. 25 Preferably the cycloalkyloxy is a C-C 6 cycloalkyloxy. Examples include, but are not limited to, cyclopropanoxy and cyclobutanoxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom. 30 "Cycloalkenyloxy" refers to a cycloalkenyl-O- group in which the cycloalkenyl is as defined herein. Preferably the cycloalkenyloxy is a C-C 6 cycloalkenyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom. 35 Failure of treatment can be defined as condition in which a non-fasting blood glucose level of less than 200 mg/dl and a blood glucose level during fasting (deprived of food for at 27 WO 2013/111150 PCT/IN2012/000842 least 8 hr) of less than 126 mg/dl are retained after administration of the agent in its recommended dose. "Haloalkyl" refers to an alkyl group as defined herein in which one or more of the 5 hydrogen atoms has been replaced with a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine. A haloalkyl group typically has the formula CnH( 2 nsl. m)Xm wherein each X is independently selected from the group consisting of F, Cl, Br and I. In groups of this type n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3. m is typically 1 to 6, more preferably 1 to 3. Examples of haloalkyl include fluoromethyl, 10 difluoromethyl and trifluoromethyl. "Haloalkenyl" refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, Cl, Br and I. 15 "Haloalkynyl" refers to an alkynyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, Cl, Br and 1. 20 "Halogen" represents chlorine, fluorine, bromine or iodine. "Heteroalkyl" refers to a straight- or branched-chain alkyl group preferably having from 2 to 12 carbons, more preferably 2 to 6 carbons in the chain, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced by a 25 heteroatomic group selected from S, 0, P and NR' where R' is selected from the group consisting of H, optionally substituted C-C, 2 alkyl, optionally substituted C 3
-C
1 2 cycloalkyl, optionally substituted C 6
-C
18 aryl, and optionally substituted C-CBheteroaryl. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like. Examples of heteroalkyl also include hydroxyC-C 6 alkyl, C-CealkyloxyC 30 C 6 alkyl, aminoC-C 6 alkyl, C 1
-C
6 alkylaminoC 1
-C
6 alkyl, and di(C 1
-C
6 alkyl)aminoC-C 6 alky. The group may be a terminal group or a bridging group. "Heteroalkyloxy" refers to. a heteroalkyl-O- group in which heteroalkyl is as defined herein. Preferably the heteroalkyloxy is a C 2
-C
6 heteroalkyloxy. The group may be a terminal 35 group or a bridging group. 28 WO 2013/111150 PCT/IN2012/000842 "Heteroaryl" either alone or part of a group refers to groups containing an aromatic ring (preferably a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur. Examples of heteroaryl include 5 thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, 10 phenothiazine, oxazole, isooxazole, furazane, phenoxazine, 2-, 3- or 4- pyridyl, 2-, 3-, 4-, 5-, or 8- quinolyl, 1-, 3-, 4-, or 5- isoquinolinyl 1-, 2-, or 3- indolyl, and 2-, or 3-thienyl. A heteroaryl group is typically a C-C1 heteroaryl group. The group may be a terminal group or a bridging group. 15 "Heteroarylalkyl" means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as defined herein. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group. 20 "Heteroarylalkenyl" means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group. 25 "Heteroarylheteroalkyl" means a heteroaryl-heteroalkyl- group in which the heteroaryl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group. 30 "Heteroaryloxy" refers to a heteroaryl-O- group in which the heteroaryl is as defined herein. Preferably the heteroaryloxy is a C-C 1 8 heteroaryloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom. 35 "Heterocyclic" refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system containing at least one heteroatom selected 29 WO 2013/111150 PCT/IN2012/000842 from the group consisting of nitrogen, sulfur and oxygen as a ring atom. Examples of heterocyclic moieties include heterocycloalkyl, heterocycloalkenyl and heteroaryl. "Heterocycloalkenyl" refers to a heterocycloalkyl group as defined herein but 5 containing at least one double bond. A heterocycloalkenyl group typically is a C2r
C
12 heterocycloalkenyl group. The group may be a terminal group or a bridging group. "Heterocycloalkyl" refers to a saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 10 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and 1,4-oxathiapane. A heterocycloalkyl group typically is a 0 2
-C
2 heterocycloalkyl group. The group may be a 15 terminal group or a bridging group. "Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as defined herein. Exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl) methyl. The group may be 20 a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group. "Heterocycloalkylalkenyl" refers to a heterocycloalkyl-alkenyl- group in which the heterocycloalkyl and alkenyl moieties are as defined herein. The group may be a terminal 25 group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group. "Heterocycloalkylheteroalkyl" means a heterocycloalkyl-heteroalkyl- group in which the heterocycloalkyl and heteroalkyl moieties are as defined herein. The group may be a 30 terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group. "Heterocycloalkyloxy" refers to a heterocycloalkyl-O- group in which the heterocycloalkyl is as defined herein. Preferably the heterocycloalkyloxy is a C 35 C 6 heterocycloalkyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom. 30 WO 2013/111150 PCT/IN2012/000842 "Heterocycloalkenyloxy" refers to a heterocycloalkenyl-O- group in which heterocycloalkenyl is as defined herein. Preferably the Heterocycloalkenyloxy is a C
C
6 heterocycloalkenyloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen 5 atom. "Hydroxyalkyl" refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with an OH group. A hydroxyalkyl group typically has the formula CnH( 2 ,nllx)(OH)x. In groups of this type n is typically from 1 to 10, more preferably from 10 1 to 6, most preferably 1 to 3. x is typically 1 to 6, more preferably 1 to 3. "Sulfinyl" means an R-S(=O)- group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the 15 molecule through the sulfur atom. "Sulfinylamino" means an R-S(=O)-NH- group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the 20 remainder of the molecule through the nitrogen atom. "Sulfonyl" means an R-S(=0) 2 - group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the 25 remainder of the molecule through the sulfur atom. "Sulfonylamino" means an R-S(=0) 2 -NH- group. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom. 30 It is understood that included in the family of compounds of Formula (I) are isomeric forms including diastereoisomers, enantiomers, tautomers, and geometrical isomers in "E" or "Z" configurational isomer or a mixture of E and Z isomers. It is also understood that some isomeric forms such as diastereomers, enantiomers, and geometrical isomers can be 35 separated by physical and/or chemical methods and by those skilled in the art. For those compounds where there is the possibility of geometric isomerism the applicant has drawn the 31 WO 2013/111150 PCT/IN2012/000842 isomer that the compound is thought to be although it will be appreciated that the other isomer may be the correct structural assignment. Some of the compounds of the disclosed embodiments may exist as single 5 stereoisomers, racemates, and/or mixtures of enantiomers and lor diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to be within the scope of the subject matter described and claimed. Additionally, Formula (I) is intended to cover, where applicable, solvated as well as 10 unsolvated forms of the compounds. Thus, each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms. The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically 15 acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (1) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are 20 formic, acetic, propanoic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or 25 polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae. "Prodrug" means a compound that undergoes conversion to. a compound of formula (1) within a biological system, usually by metabolic means (e.g. by hydrolysis, reduction or 30 oxidation). For example an ester prodrug of a compound of formula (1) containing a hydroxyl group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of formula (1) containing a hydroxyl group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-p-hydroxynaphthoates, gestisates, isethionates, di-p-toluoyltartrates, 35 methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. As another example an ester prodrug of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the 32 WO 2013/111150 PCT/IN2012/000842 parent molecule. (Examples of ester prodrugs are those described by F.J. Leinweber, Drug Metab. Res., 18:379, 1987). Similarly, an acyl prodrug of a compound of formula (I) containing an amino group may be convertible by hydrolysis in vivo to the parent molecule (Many examples of prodrugs for these and other functional groups, including amines, are 5 described in Prodrugs: Challenges and Rewards (Parts I and 2); Ed V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag and J Tilley; Springer, 2007). The term "therapeutically effective amount" or "effective amount" is an amount sufficient to effect beneficial or desired clinical results. An effective amount can be 10 administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state. Specific compounds of the invention include the following: N N N N H H O N OH F N N H OH O N@ O N F N H O N'F O NF OH F FI N N H 33 WO 2013/111150 PCT/IN2012/000842 F O N O H O N / O H N H N N 0 N 0 N N N N N 0 OH F N N j F H N OH O Ne OH N 3 N N N N HH OHO N' N N H HO OH0 OH 'NN SN~ H N H 34 WO 2013/111150 PCT/1N2012/000842 o N F F N N H H 0 ~OH 0O F FXN N N H H Oa N' N N H H O N'a F F N N H H N N H H 0 ~OH0 cI1 N N N H H O 0~ 0 OH N J F N CIl F B r N N H H 35 WO 2013/111150 PCT/1N2012/000842 0 ~OH 0O ON N N H H OOH 0O oC Na O N N H H F O N' OH ci NH O0 N N N H 0 O OH 0 N r-NH, N CIl N N H H 0 N OH 0OH NN H N H OH O-Na* 0 0 N 0' Na \ NN H H 36 WO 2013/111150 PCT/1N2012/000842 OH NH, 0 Br N 0a24 NN N N H H OH OH NN H N H c 1 N' 0 Na OH &NN H H OH F 0O~ ' OH N HN H 0 0 ~OH OH NaJ 0 N N2 40H N H O0 ' CN 0N'a OH N H N H 37 WO 2013/111150 PCT/1N2012/000842 0 OH 0 OH N~ ~ N@ CiI N -~ N H H 0 OH 0 CON Na N ci N N H H CI O~ OHO / 0 /O NJJ N H N H F 0 OH 0 /')OH NN H IN H 0 OH HN-.N NNN F Cl N H N H aN- OH N NK N~r-'N N N H H 38 WO 2013/111150 PCT/1N2012/000842 O -/OH0 OH F N N H OH F OH 0 OHO 0 N@J F N AN N N HH N 0 N N OHH N N NH N~ N H H O N'-OH 0/O NN N N H H 0 / OH OH NN NT N N H N~ N N HH F O3 WO 2013/111150 PCT/1N2012/000842 F F j N N H H F 0 N OH 0 N -O N N N F N H H F 0 N OH 0 N -C F cI N N H HH 0 N OH N F NN N1 N NN H N N 0No s N (0 F N 0,z N N ~OHF O Na OH 0 N'a OH NN H N 40 WO 2013/111150 PCT/1N2012/000842 OH OH - 0 0 -- N F -~ NF N H H OH N 0 F N 0 F OH N H O0 '~ OH 0 ' OH NT N D~ H H ci N 0N 0 s N~-- N CN N N N ~OHN HO Cl0 N0 7/ON F CN H CI 0 O N 0 N CN N H 41 WO 2013/111150 PCT/IN2012/000842 F N OH - OH NHN F N NN H H O OH C N OH N CN N@C CN N N N H S O H FN O H F NN N OH NOH N N C, N H H O0 ' CN N CN c I N N N N H H O0 K OH 0 ' OH F ciN N CIH H 0 0 0*N rOH 0N@ OH -i N- N CIH H 42 WO 2013/111150 PCT/1N2012/000842 O N@ 'OH N@O CI I N H H 0 Oi 0X) H NO N N H OH H
HHH
HN F -~ N H -~ N H 0 N@'O 0 Ne- OH F Cil N -~ N H H N OH - 0 N ' OH - N -~ N H H 0N OH 0ON~jOH N N H H 0OS OH 0 OOH Br 0 aH - N -~ N H H 43 WO 2013/111150 PCT/1N2012/000842 0OH 0~l OH - N -~ N H H 0 ~OH N - O N OH NN HI N H H O '@-< OH0 H NNX N N H H 0 0 OH - N -~ N H H 0 A- OH0 N0 - N -~ N H H O N~ F0 OH 00 N N H -~N H N OH) OH CI a 0 O -~N N H H 44 WO 2013/111150 PCT/1N2012/000842 N, 0 N 0 Ni s- N i OH N N, 0 N 0 -~s N OH N N N 0 O NH, 0 N N H N N' O NN N N H N H N 0 N 0 / NH NH OH OH N r OH N' 0 N N N H 0 /D OH 0 ' OH N N 45 WO 2013/111150 PCT/1N2012/000842 0OH Na.
0 I l 0 N -~ N H H O A OH N N N~ N HH N.N H H OH F 00 N OH H H NaOH o0 OH -~N ~N H H 0OH 0oO N -~ N H H o,'-s46 WO 2013/111150 PCT/1N2012/000842 0 a OH 0 N NQJ -~ N -~ N H H 0/0 0 -~N OH NH HH 0 ' F 0 ' Br 0 O \ o
-
s
F
3 C \ I N 0 N H H 0 N') N N N HH 0 0 \ o 0 -SS
F
3 C \
H
3
C\
N 0 - N HH 0 N 0OH 0/ N N H H F OH ~ F 0 OH N N H H 47 WO 2013/111150 PCT/IN2012/000842 O N OH O N/ OH
CF
3 - N -~ N H H N OH O N NH 2 H H
NH
2 Na) N ON NNN H H O OOH 0 OH N @ F 3 C N 0 N N H
F
2 HC N' N' @ O C N 4N H H 0 0 ND N F CI - N N H H 0-N 0 N CI F 3 00 N N H H 48 WO 2013/111150 PCT/IN2012/000842 F-N N F N -N 0 N N~r F F F 00 F ON O H3H O N O N H H3C O H F 0 0
H
3 C N 0 O~ N N NN CH0 F CH 3 0 F oN O N O NN H H 0 0C3N N N F F
CF
3 0 CF 3 0 N . ~N H H 0 ~ N0 CI F
CF
3 0 CHFO - N . ~N H H 0 ~ N0
FCF
3 D F F
CH
3 0 CH 3 0 HN N N N F D F F
CH
3 0 CH 3 0 N N N N. H H 49 WO 2013/111150 PCT/IN2012/000842 -N -N N. F 0
CH
3 0 F\ o
H
3 C \ 0 N N N 0 0 N N H F
HCH
3 0
F
3 C5 \ 0 N N N N. H H. 0 0 N ND
CH
3 S0 2
CH
3 0 N: N N N H H F@
CH
3 0 N N N N H H 0 N SN' N H H -N o 0 N N H H 0 00 O N OH N OH 500 WO 2013/111150 PCT/IN2012/000842 0 ~ OH0 NJ -NS OH N N H H O OH N OH Oi NOHC Na N O/N N NN CI F O N -~ N' H H F N NH F0 N 'N O 0O N N NO N N H H 0 N N N N OHNO N N HI F 0 N F0 /NN - N * ~ N' H H 0-N 0Na- N O F N N F F C 1' /N N ~N "- N' H H O N o ~~-5O WO 2013/111150 PCT/1N2012/000842 % aOH 0N 0 -~0 F0N5- ~N FN0 N& OH 0 F 0 0~ N 0 Il F N"KaOH Il F Na = N N H H 0 00 F 0i N"KOH Il C Na O0kjK 0 N N H H F Na 7 OH I CI a I6j 0~ N N H H F 0N"aOH FCI N -= O 0 N N H H O~I 0 O-52 WO 2013/111150 PCT/1N2012/000842 al0 Na 1 7 ' H Il cia 0 02K N N H H o 0 N N H H o 0 N NI o HI N N H H 0 0 iN~ N N H H o=O0O~ 0 1F Na 7 0H c I Na N N H H F 0 7 -OH F CIN-= o 0 N N H H o 03 WO 2013/111150 PCT/IN2012/000842 H 0 O c NK OH / N N o 0 N N H H H 0 O N 7 OH F NN N H N N H H o 0 N Ni N"~0 I NI H H F 0 NayOH FCI a = N N N N H H o 0 F N ~ 0 NCN H H Os!O 0 =~ 0 IF Na OH I ~Cl N N NN N H H 0 0 N NN N H H 54 WO 2013/111150 PCT/IN2012/000842 / 0 Na O 0H /NC N 0 0 Z N N N N H H O/ 0 Na OH / Na -N 0 H N N N N H H I 0 Na OH I I N N 0 0 N H N N H H FN H O N N H H 0 A 0 F "'N (- HCI o 0 N N N N H H 00 _~ 0 o 0 N N N~ N H H IF Na KH F 0N"a - N N N N N H H WO 2013/111150 PCT/1N2012/000842 cl V NK2OH icl N/ =N N N N N H H ci ON Na~ ~OH F 0' N&j~-OH N N / I D ON N N N' N N N N 0 0 F 1 NeOH F N5 -N - N > *N N' N l 0 N5 - ~N 0ON&OH F0 N N N 0 pOH /F 0NQ 7 &OH ' N NN 56 WO 2013/111150 PCT/1N2012/000842 O 0 N5 -N N ' X N N N'N F 0 N5 -~ N c1 0 NOH N *N N N' F 0NJJOH cl0N5) ~ N N N N' 00 N N N N O 5 - 0 N N N O 5 - 0 N O N N N' N 57) WO 2013/111150 PCT/1N2012/000842 Fl 0X N&'~OH 0O N5 -N F F N . *N N'N cl 0 N = l 0N F 0 N *N N N' O 0 FN OH JCN IN
N
N N O 0 F N/ OH Cl Nj - N & N N' N' 0 0 N NNF N' N O 08 WO 2013/111150 PCT/1N2012/000842
NQ
2 -OH Ci N& ~-~OH N N' N Fl Nt 1 2 N F N NN - ,N . N N N' IN N NNF
N
1 N' N / . N N N' 0 N OH F 0~ OH O0 N ~N N F F' 0 0N Nl J O *N N O N N N' N' 59 WO 2013/111150 PCT/1N2012/000842 0N ~ N 0Nd -N cI K N N N N F 0Nd3 -N F0 d -O I-N, N *N N N' cI N1 0 lOH N N N N N ~N ci 0J3- Nd: OH F 0 "N N ~ N cl0NaOH F0Nd OH 0 0 ~N N' N OH ciJ O IN ~ NJ~O N ,N5..r N N' F ON OH 0 NN 60 WO 2013/111150 PCT/1N2012/000842 0l 0 N IN N NI N N I N Nt-OH CI N OH F F N N O 0 NJ NaOH Nd-=N 0 I NN N N* NN 0 - 0 s NL Oa0H H- OH c IH F 00 N 1 N N - N H OH 0 0 0N FS Na OH F FS N"aOH NF H N H 61 WO 2013/111150 PCT/1N2012/000842 F 0 F F1 7 S 0 NO N~~ N H" F F 0 0 F F N N H H F" /V7 F, 7 K F F 0 F , N 1 N N H H 0 F F F 0 Na OH 0N O N c NN H N F Fo F- F77 N~k 0OH 6F1O N~zt-OH F' O N N H H F 7 .F F 00 N 1 N N H H F 0 N0 F F 0 F N 1 N H N 62H WO 2013/111150 PCT/1N2012/000842 0 F 6 S 0FXK 0 -N OH IN N N N H H F F FX 0 0 N 7 4q0 0Na OH N N 1 N HH H N N H H O N 7 OH 4q0 0N OH F CI N N 0 H 0 *H Ni- F N N H H 0 0 N 0 CI s OH N H 00 N - 0 - N N 0 H HO N 0 H HO 63 WO 2013/111150 PCT/IN2012/000842 F CI O O O -0 N N N O N O H HO H HO F SO N - 0 - N N O H HO N O H HO Cl 0 0 N N N H HN IN N ~ 0N H HO F SO 0 0 N - O N N N ~ H HN, N N H HN i 0 "N H or pharmaceutically acceptable salt, isomer or prodrug thereof. 5 The compounds have the ability to inhibit 11 p-HSD1. The ability to inhibit 11 p-HSD1 may be a result of the compounds acting directly and solely on the 11p-HSD1 to modulate/potentiate biological activity. However, it is understood that the compounds may also act at least partially on other factors associated with 11 p-HSD1 activity. 64 WO 2013/111150 PCT/IN2012/000842 The inhibition of 11 p-HSD1 may be carried out in any of a number of ways known in the art. For example if inhibition of 11p -HSD1 in vitro is desired an appropriate amount of the compound may be added to a solution containing the 11 p-HSD1. In circumstances where it is desired to inhibit 11 p-HSD1 in a mammal, the inhibition of the 11 p-HSD1 typically involves 5 administering the compound to a mammal containing the 11 p-HSD1. Accordingly the compounds may find a multiple number of applications in which their ability to inhibit 11 p-HSD1 enzyme of the type mentioned above can be utilised. 10 Accordingly compounds of the invention would be expected to have useful therapeutic properties especially in relation to diabetes, hyperglycemia, low glucose tolerance, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity, abdominal obesity, glaucoma, hypertension, atherosclerosis and its sequelae, retinopathy, nephropathy, neuropathy, osteoporosis, osteoarthritis, dementia, depression, 15 neurodegenerative disease, psychiatric disorders, Cushing's Disease, Cushing's syndrome, virus diseases, and inflammatory diseases. Administration of compounds within Formula (I) to humans can be by any of the accepted modes for enteral administration such, as oral or rectal, or by parenteral 20 administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Injection can be bolus or via constant or intermittent infusion. The active compound is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to the patient a therapeutically effective dose. In various embodiments the activator compound may be selectively toxic or more toxic to rapidly proliferating cells, e.g. 25 cancerous tumours, than to normal cells. In using the compounds of the invention they can be administered in any form or mode which makes the compound bioavailable. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon 30 the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. We refer the reader to Remingtons Pharmaceutical Sciences, 19 th edition, Mack Publishing Co. (1995) for further information. 35 The compounds of the present invention can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, 65 WO 2013/111150 PCT/IN2012/000842 diluent or excipient. The compounds of the invention, while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts as these forms are typically more stable, more easily crystallised and have increased solubility. 5 The compounds are, however, typically used in the form of pharmaceutical compositions which are formulated depending on the desired mode of administration. As such in some embodiments the present invention provides a pharmaceutical composition including a compound of Formula (1) and a pharmaceutically acceptable carrier, diluent or excipient. The compositions are prepared in manners well known in the art. 10 The invention in other embodiments provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. In such a pack or kit can be found a container having a unit dosage of the agent(s). The kits can include a composition comprising an effective agent 15 either as concentrates (including lyophilized compositions), which can be diluted further prior to use or they can be provided at the concentration of use, where the vials may include one or more dosages. Conveniently, in the kits, single dosages can be provided in sterile vials so that the physician can employ the vials directly, where the vials will have the desired amount and concentration of agent(s). Associated with such container(s) can be various written 20 materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. 25 The compounds of the invention may be used or administered in combination with one or more additional drug(s) for the treatment of the disorder/diseases mentioned. The components can be administered in the same formulation or in separate formulations. If administered in separate formulations the compounds of the invention may be administered sequentially or simultaneously with the other drug(s). 30 In addition to being able to be administered in combination with one or more additional drugs, the compounds of the invention may be used in a combination therapy. When this is done the compounds are typically administered in combination with each other. Thus one or more of the compounds of the invention may be administered either simultaneously (as a 35 combined preparation) or sequentially in order to achieve a desired effect. This is especially desirable where the therapeutic profile of each compound is different such that the combined effect of the two drugs provides an improved therapeutic result. 66 WO 2013/111150 PCT/IN2012/000842 Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable 5 solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the 10 maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may 15 be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin. 20 If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres. 25 The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use. 30 Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, 35 gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) 67 WO 2013/111150 PCT/IN2012/000842 absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, 5 tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. 10 The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a 15 certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. 20 Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, 25 isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. 30 Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents as, 35 for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof. 68 WO 2013/111150 PCT/IN2012/000842 Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which 5 are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Dosage forms for topical administration of a compound of this invention include powders, patches, sprays, ointments and inhalants. The active compound is mixed under 10 sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required. The amount of compound administered will preferably treat and reduce or alleviate the condition. A therapeutically effective amount can be readily determined by an attending 15 diagnostician by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount a number of factors are to be considered including but not limited to, the species of animal, its size, age and general health, the specific condition involved, the severity of the condition, the response of the patient to treatment, the particular compound administered, the mode of administration, 20 the bioavailability of the preparation administered, the dose regime selected, the use of other medications and other relevant circumstances. A preferred dosage will be a range from about 0.01 to 300 mg per kilogram of body weight per day. A more preferred dosage will be in the range from 0.1 to 100 mg per 25 kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day. A suitable dose can be administered in multiple sub-doses per day. The compound of the invention may also be administered in combination with (or 30 simultaneously or sequentially with) an adjuvant to increase compound performance. Suitable adjuvants may include (a) dipeptidyl peptidase-IV (DP-IV) inhibitors; (b) insulin sensitizing agents; (iv) biguanides; (c) insulin and insulin mimetics; (d) sulfonylureas and other insulin secretagogues; (e) alpha-glucosidase inhibitors; and (f) GLP-1, GLP-1 analogs, and GLP-1 receptor agonists. The adjuvants may be part of the same composition, or the 35 adjuvants may be administered separately (either simultaneously or sequentially). The order of the administration of the composition and the adjuvant will generally known to the medical practitioner involved and may be varied. 69 WO 2013/111150 PCT/IN2012/000842 SYNTHESIS OF COMPOUNDS OF THE INVENTION The agents of the various embodiments may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art 5 using starting materials that are readily available. The preparation of particular compounds of the embodiments is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other agents of the various embodiments. For example, the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the 10 art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. A list of suitable protecting groups in organic synthesis can be found in T.W. Greene's Protective Groups in Organic Synthesis, 3 rd Edition, John Wiley & Sons, 1991. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing 15 other compounds of the various embodiments. Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art. 20 The symbols, abbreviations and conventions in the processes, schemes, and examples are consistent with those used in the contemporary scientific literature. Specifically but not meant as limiting, the following abbreviations may be used in the examples and throughout the specification. 25 e g (grams) * L (liters) a Hz (Hertz) * mol (moles) * RT (room temperature) 30 * min (minutes) 0 MeOH (methanol) * CHCl 3 (chloroform) * DCM (dichloromethane) * DMSO (dimethylsulfoxide) 35 0 EtOAc (ethyl acetate) * mg (milligrams) 70 WO 2013/111150 PCT/IN2012/000842 * mL ( milliliters) * psi ( pounds per square inch) * mM (millimolar) 0 MHz (megahertz) 5 e h (hours) 0 TLC (thin layer chromatography) 0 EtOH (ethanol) * CDCI a(deuterated chloroform) * HCI (hydrochloric acid) 10 0 DMF (N, N-dimethylformamide) 0 THF (tetrahydro furan) * K 2
CO
3 (potassium carbonate) * Na 2
SO
4 (sodium sulfate) * RM (Reaction Mixture) 15 Unless otherwise indicated, all temperatures are expressed in*C (degree centigrade). All reactions conducted at room temperature unless otherwise mentioned. All the solvents and reagents used are commercially available and purchased from 20 Sigma Aldrich, Fluka, Acros, Spectrochem, Alfa Aesar, Avra, Qualigens, Merck, Rankem and Leonid Chemicals. 1 H NMR spectra were recorded on a Bruker AV 300. Chemical shifts are expressed in parts per million (ppm, 6 units). Coupling constants are in units of hertz (Hz). Splitting 25 patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or br (broad). Mass spectra were obtained on single quadruple 6120 LCMS from Agilent technologies, using either atmospheric chemical ionization (APCI) or Electrospray ionization 30 (ESI) or in the combination of these two sources. All samples were run on SHIMADZU system with an LC-20 AD pump, SPD-M20A diode array detector, SIL-20A auto sampler. 35 71 WO 2013/111150 PCT/IN2012/000842 SYNTHETIC SCHEME 1 One scheme for making certain compounds of the invention is shown in scheme 1 below. Synthetic Scheme-1 MeSO3H K DPPA triflicacid .HCI O NaN 0sO HO TEA HN DCM di ane O "EOH OC 1 N Starting Material-1 Itr eit 1. Mtra- Intermediate- intermediate-2 Intermediate-3 Intermediate-4 Intermediate-5 OTFA HCOOH 0 HNO3 O N F oleum Boc20 N OHO --.. 2. Boc20 OH 0 Intermediate-6 Intermediate-7 Intermediate-8 Intermediate-9 / O Boc20 0 TFAA LiOH O N NaHCO3 O N " DCM O N & Intermediate-10 OH Intermediate-11 NH 2 Intermediate-13 N TFA, DCM TFA. DCM .TFA .TFA HN O HN ®
NH
2 Intermediate-12 Intermediate-14 0 0 TFA O N TH O N TFA HNZ Intermediate-9 / Intermediate-15 OH OH Intermediate-16 O N TFA KMel _ K FA C Intermediate-6 Intermediate-17 Intermediate-18 cyclopropy Methyl 0 _ _ ON F TFA, DCM .TFA 0 N lzkOH O 1 O_ 5 ermediate-6 I 'ntermeiate 1 Intermediate-20 Synthesis of 4-oxotricyclo [3.3.1.13,7 ] dec-2-yl methanesulfonate (Intermediate-1): A 1000mL RB flask fitted with magnetic stirrer was charged with methanesulfonic acid (416.0 g, 4328.8 mmol) and Starting Material-1 (50.0g, 333 mmol). To this sodium azide (23.0g, 351 10 mmol) was added portion wise for 2 hours. Then reaction mixture was stirred at 20-25*C for 3 days. Upon completion of the reaction (reaction monitored by TLC), reaction mixture was quenched with ice-water (3000 mL) and extracted with ethyl acetate (1000X3 mL). The organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated to give title Intermediate-1 (54.0g, yield = 66%). 72 WO 2013/111150 PCT/IN2012/000842 Synthesis of bicyclo[3.3.1]non-6-ene-3-carboxylic acid (Intermediate-2): A 2000 mL RB flask fitted with magnetic stirrer was charged with 1200 mL of ethanol and Intermediate-1 (54.0g, 221.3 mmol). Potassium hydroxide (84.0g, 150 mmol) was further 5 added to this reaction mixture followed by addition of 950 mL of water. The reaction mixture was stirred at 110*C for 12 hours. After completion of the reaction (reaction was monitored by TLC), reaction mixture was concentrated under vacuum. The resulted crude material was acidified with 1N HCI (pH = 2) and extracted with ethyl acetate (250 X 3 mL). The organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated 10 to give Intermediate-2 (32.0g, yield = 88%). Synthesis of methyl bicyclo[3.3.1]non-6-en-3-ylcarbamate (Intermediate-3) A 500mL RB flask fitted with magnetic stirrer under nitrogen atmosphere charged with toluene (100 mL), Intermediate-2 (16.0g, 96 mmol) and DPPA (28.8g, 105 mmol). Reaction mixture 15 was cooled to 0* C, and then triethylamine (15.4 g, 143.9 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Then reaction mixture was heated at 800C for 8h and 12h at room temperature. To this 100 mL of methanol was added and refluxed for 12 hours. After the reaction, it was concentrated under vacuum. Obtained Crude was extracted with ethyl acetate. The organic layer was washed with 1N HCl, Saturated 20 NaHCO 3 solution, brine solution and was then dried over anhydrous sodium sulfate and concentrated. Crude material was purified by silica gel column chromatography eluting with 6% of EtOAc in to give Intermediate-3 (8.0g, yield = 42%). Synthesis of methyl 2-azatricyclo [3.3.1.1 3
'
7 ]decane-2-carboxylate (Intermediate-4): 25 A 100 mL RB flask fitted with magnetic stirrer was charged with 50 mL of dichloromethane and Intermediate-3 (5.0 g, 25.6 mmol). To this reaction mixture, triflouromethane sulfonic acid (19.2g, 125.2 mmol) was added at 0*C. The reaction mixture was then stirred at room temperature for 12 hours. After completion of reaction, the reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with saturated 30 sodium bicarbonate solution, brine solution and the reaction mass was dried over anhydrous sodium sulfate and was concentrated to give Intermediate-4 (4.3 g, yield = 86%). Synthesis of 2-azatricyclo [3.3.1.1 3
,
7 ]decane (intermediate-5): A 5OmL pressurized seal tube fitted with magnetic stirrer was charged with Intermediate-4 35 (3.0g, 15mmol) in HCI containing 1,4-Dioxane (20 mL). Then the reaction mixture was stirred at 900C for 8 hours. After completion of the reaction (reaction was monitored by LCMS) it was 73 WO 2013/111150 PCT/IN2012/000842 concentrated followed by trituration with mixture of hexane : ether (1:1) to give Intermediate-5 (3.0g, yield = 100%). Synthesis of tert-butyl 5-hydroxy-2-azatricyclo [3.3.1.1 3
'
7 ]decane-2-carboxylate 5 (Intermediate-6): A 250mL RB fitted with magnetic stirrer was charged with Intermediate 5 (3.0g, 21.6mmol), concentrated nitric acid (30 mL), and H 2
SO
4 (5 mL). The reaction mixture was stirred at 800C for 12 hours. Upon completion of the reaction (reaction was monitored by LC-MS) reaction mixture was quenched with water and basified with sodium carbonate. The aqueous layer 10 was washed with DCM (100 mL) and resulting aqueous layer was diluted with THF (200 mL) and cooled to 00C. The pH of the mixture was adjusted to basic using Triethyl amine (5 mL). To this reaction mixture Boc-anhydride (6.0 g, 27.52 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. Upon completion of the reaction (reaction was monitored by LC-MS) reaction mixture was extracted with Ethyl acetate (100 mL X 3). 15 Combined organic layer was washed with water and brine and the reaction mass was dried over sodium sulfate. Organic layer was concentrated to obtain a crude intermediate which was then purified by silica gel column chromatography eluting with 40 % of EtOAc to give Intermediate-6 (2.5g, yield = 50%). 20 Synthesis of 2-azatricyclo [3.3.1.13 ]decan-5-ol (Intermediate-7): A 100mL RB flask fitted with magnetic stirrer was charged with Intermediate-6 (5.5g, 21.5 mmol) in DCM (30 mL). The reaction mixture thus formed was cooled to 0*C to which trifluoroacetic acid (7.4 g, 65.2 mmol) was added and stirred for 4 hours. After completion of the reaction (reaction was monitored by LCMS) the reaction mixture was concentrated 25 followed by trituration with mixture of hexane : ether (1:1) to give Intermediate-7 (3.4g, yield = 100%). Synthesis of methyl 2-azatricyclo[3.3.1 .1 3
,
7 ]decane-5-carboxylate, intermediate - 8. To 2-azatricyclo [3.3.1.1 3
'
7 ]decan-5-ol (Intermediate-7) (1.5g, 5.9mmol, 1 eq), 98% formic acid 30 (9ml) was added drop wise with vigorous gas evolution for over 30 mintutes to a rapidly stirred 30% oleum (36 ml) heated to 60 0 C. Upon completion of this addition, 99% formic acid (9 ml) was slowly added for the next 30 mintutes. The reaction mixture was stirred for another 1 hr at 600C (monitored by LCMS). The reaction mixture thus formed was then slowly poured into vigorously stirred methanol (75 ml) cooled to 00C. The mixture was allowed to slowly 35 warm to room temperature while stirring the reaction mixture for 4 - 5 hrs. The mixture was then concentrated under vacuum. The residue was poured into ice (30 g) and basified with saturated Na 2
CO
3 solution. The aqueous layer was extracted with 5% methanol in DCM (3 x 74 WO 2013/111150 PCT/IN2012/000842 100 ml). Combined organic layer was washed with brine and dried over Na 2
SO
4 . The organic layer was finally concentrated to get intermediate - 8, (550 mg, 50% yield) as an oily mass. Synthesis of 2-tert-butyl 5-methyl 2-azatricyclo[3.3.1.1 3
'
7 ]decane-2,5-dicarboxylate, 5 intermediate - 9. Methyl 2-azatricyclo[3.3.1 .13.7]decane-5-carboxylate, Intermediate - 8 (0.32g, 1.6 mmol) was added into THF (5 mL) and cooled to 00C. Triethyl amine (1.3 mL) was added to the reaction mixture followed by addition of Boc-anhydride (0.5 g, 1.96 mmol). The resulting mixture was stirred at room temperature for 6 hours. Upon completion of the reaction (reaction was 10 monitored by LC-MS) reaction mixture was extracted with Ethyl acetate (100 mL X 3). Combined organic layer was washed with water and brine and was dried over sodium sulfate. Organic layer was concentrated to give crude intermediate - 9, which was purified by silica gel column chromatography eluting with 15% of EtOAc to give Intermediate-9 (0.32g, yield = 66%). 15 Synthesis of 2-(tert-butoxycarbonyl)-2-azatricyclo[3.3.1.13 ']decane-5-carboxylic acid, intermediate -10. To a 00C cooled stirred solution of 2-tert-butyl 5-methyl 2-azatricyclo[3.3.1.1 3
'
7 ]decane-2,5 dicarboxylate, intermediate - 9 (0.16g, 0.5mmol) dissolved in methanol (3 ml), THF (1 ml) 20 and water (1 ml), LiOH (50 mg, 2 mmol) was added and the resulting reaction mass was stirred at room temperature for 6 hrs. Upon completion of the reaction (reaction monitored by TLC), the solvent present in the reaction mixture was completely removed under vacuum and the crude residue was acidified with saturated citric acid solution and extracted with ethyl acetate (3 x 15 ml). The organic layer was then washed with brine solution and dried over 25 sodium sulfate and was finally concentrated under vacuum to get intermediate - 10 as an oily mass, 0.16g (95%). Synthesis of tert-butyl 5-carbamoyl-2-azatricyclo[3.3.1 .1 3 7 ]decane-2-carboxylate, intermediate -11. 30 A 50 mL RB flask fitted with magnetic stirrer was charged with 5 mL of acetonitrile and 2-(tert butoxycarbonyl)-2-azatricyclo[3.3.1.1 3 7 ]decane-5-carboxylic acid, Intermediate - 10 (0.16g, 0.56 mmol). Under N 2 atm, pyridine (60 mg, 0.6 mmol) and Boc - anhydride (0.148g, 0.6 mmol) was added to the reaction mixture and was stirred for 1 hr. After 1hr, ammonium bicarbonate solid (75 mg, 0.9 mmol) was added and the reaction mixture was stirred at room 35 temperature for 12 hours. After completion of the reaction (reaction was monitored by TLC), reaction mixture was concentrated under vacuum. The resulted crude material was extracted with ethyl acetate (25 ml X 3). The organic layer was washed with ammonium chloride 75 WO 2013/111150 PCT/IN2012/000842 solution and saturated sodium bi carbonate solution. It was then dried over anhydrous sodium sulfate and concentrated to give Intermediate - 11, as an oily mass (0.14g, yield = 87%). 5 Synthesis of 2-azatricyclo[3.3.1.1 3
'
7 ]decane-5-carboxamide, intermediate -12. To a 100mL RB flask fitted with magnetic stirrer was charged tert-butyl 5-carbamoyl-2 azatricyclo[3.3.1.1 3
'
7 ]decane-2-carboxylate, Intermediate - 11 (0.1g, 0.0357mmol) in DCM (5 mL). The reaction mixture was cooled to 00C and trifluoroacetic acetic anhydride (0.21g, 0.17 mmol) was added and stirred for 4 hours. After completion of the reaction (reaction was 10 monitored by LCMS) reaction mixture was concentrated followed by trituration with mixture of hexane : ether (1:1) to give Intermediate-12 (0.09g, yield = 90%). Synthesis of tert-butyl 5-cyano-2-azatricyclo[3.3.1 .1 3
'
7 ]decane-2-carboxylate, intermediate -13. 15 A 50 mL RB flask fitted with magnetic stirrer was charged with 5 mL of DCM and tert-butyl 5 carbamoyl-2-azatricyclo[3.3. 1.1 3
'
7 ]decane-2-carboxylate, Intermediate - 11 (0.8g, 2.8 mmol). Under N 2 atm, triethyl amine (1.15 g, 11.4 mmol) and trifluoroacetic anhydride (2.4g, 11.4 mmol) was added and stirred for 6 hr. After completion of the reaction (reaction was monitored by TLC), reaction mixture was quenched with KHSO4 solution and extracted with 20 DCM (50 ml X 3). The organic layer was washed with saturated sodium bi carbonate solution followed by brine solution. Finally the reaction mixture was dried over anhydrous sodium sulfate and concentrated to give crude Intermediate - 13, which was subjected to column chromatogram (10% EtOAc in PE) as a off-white solid (0.5g, yield=70%). 25 Synthesis of 2-azatricyclo[3.3.1 .1 3 ']decane-5-carbonitrile, intermediate -14. A 50mL RB flask fitted with magnetic stirrer was charged with tert-butyl 5-cyano-2 azatricyclo[3.3.1.1 3
'
7 ]decane-2-carboxylate, Intermediate - 13 (0.5g, 1.98 mmol) in DCM (5 mL). Then reaction mixture was cooled to 0*C and trifluoroacetic acid (1.1 g, 9.54 mmol) was added and stirred for 4 hours. After completion of the reaction (reaction was monitored by 30 LCMS) the reaction mixture was concentrated followed by the process of trituration with mixture of hexane : ether (1:1) to give Intermediate-14 (0.5 g, yield = 97%). Synthesis of tert-butyl 5-(hydroxymethyl)-2-azatricyclo[3.3.1 .13'7] decane-2-carboxylate, intermediate -15. 35 A 50 mL RB flask fitted with magnetic stirrer was charged with 5 mL of THF, 2-tert-butyl 5 methyl 2-azatricyclo[3.3.1.1 3
'
7 ]decane-2,5-dicarboxylate, Intermediate - 9 (0.15g, 0.5 mmol) and cooled to 0*C. Under N 2 atm, LAH was added portion wise (30 mg, 0.8 mmol) and stirred 76 WO 2013/111150 PCT/IN2012/000842 for 2 hr. After completion of the reaction (reaction was monitored by TLC), reaction mixture was quenched with ethyl acetate and washed with water followed by 1 N HCI solution. The organic layer was washed with brine solution. Finally the organic layer was dried over anhydrous sodium sulfate and concentrated to give crude Intermediate - 15, as an oily mass 5 (0.12g, yield = 88%). Synthesis of 2-azatricyclo[3.3.1.1 3 7 ]dec-5-ylmethanol, intermediate -16. To a 50mL RB flask fitted with magnetic stirrer tert-butyl 5-(hydroxymethyl)-2 azatricyclo[3.3.1.1 3 7 ]decane-2-carboxylate, Intermediate - 15 (0.12g, 0.45 mmol) in DCM (5 10 mL) was added. The reaction mixture was cooled to 0*C followed by addition of trifluoroacetic acid (0.26 g, 2.2 mmol). This mixture was stirred for 4 hours. After completion of the reaction (reaction was monitored by LCMS) reaction mixture was concentrated followed by trituration with mixture of hexane : ether (1:1) to give Intermediate-16 (0.12 g, yield = 97%) as an oily mass. 15 Synthesis of tert-butyl 5-methoxy-2-azatricyclo[3.3.1.13,7]decane-2-carboxylate, intermediate -17. A 15 mL seal tube fitted with magnetic stirrer was charged with 5 mL of THF, tert-butyl 5 hydroxy-2-azatricyclo[3.3.1.1 3
,
7 ]decane-2-carboxylate, Intermediate - 6 (0.15 g, 0.5 mmol). 20 Potassium hydride (47 mg, 1.1 mmol) was added to this mixture at 00C, under N 2 atm. The reaction mixture was then stirred at room temperature for 30 minutes. Methyl iodide was slowly added (0.12g, 0.8 mmol) at 0*C and the resulting reaction mass was refluxed at 600C under sealed condition for 12 hrs. After completion of the reaction (reaction was monitored by TLC), reaction mixture was quenched with cold water and extracted with ethyl acetate (25 25 ml X 3). The organic layer was washed with sodium chloride solution, was dried over anhydrous sodium sulfate and was concentrated to give crude Intermediate - 17, which was subjected to column chromatogram (22% EtOAc in PE) to obtain an oily mass (0.1 g, yield=70%). 30 Synthesis of 5-methoxy-2-azatricyclo[3.3.1.1 3 7 ]decane, intermediate -18: To a 50mL RB flask fitted with magnetic stirrer was charged tert-butyl 5-methoxy-2 azatricyclo[3.3.1.1 3
,
7 ]decane-2-carboxylate, Intermediate - 17 (0.1g, 0.037 mmol) in DCM (5 mL). Then reaction mixture was cooled to 00C and trifluoroacetic acid (0.22 g, 1.8 mmol) was added and stirred for 4 hours. After completion of the reaction (reaction was monitored by 35 LCMS) reaction mixture was concentrated followed by trituration with mixture of hexane ether (1:1) to give Intermediate-18 (0.09 g, yield = 95%) as an oily mass. 77 WO 2013/111150 PCT/IN2012/000842 Synthesis of tert-butyl 5-(cyclopropylmethoxy)-2-azatricyclo[3.3.1.13'7] decane-2 carboxylate, intermediate -19. A 15 mL seal tube fitted with magnetic stirrer was charged with 5 mL of THF, tert-butyl 5 hydroxy-2-azatricyclo[3.3.1.1 3
'
7 ]decane-2-carboxylate, Intermediate - 6 (50 mg, 0.2 mmol). To 5 the tube, potassium hydride (20 mg, 0.5 mmol) was added at 0*C, under N 2 atm. The reaction mass was stirred at room temperature for 30 minutes. To this mixture, cyclopropyl methyl bromide (40 mg, 0.3 mmol) was slowly added at 00C and the resulting reaction mass was refluxed at 600C under sealed condition for 12 hrs. After completion of the reaction (reaction was monitored by TLC), reaction mixture was quenched with cold water and extracted with 10 ethyl acetate (25 ml X 3). The organic layer was washed with sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give crude Intermediate - 17, which was subjected to column chromatogram (18% EtOAc in PE) to obtain an oily mass (50mg, yield=80%). 15 Synthesis of 5-(cyclopropylmethoxy)-2-azatricyclo[3.3.1 .1 3
'
7 ]decane, intermediate -20. To a 50mL RB flask fitted with magnetic stirrer was charged tert-butyl 5 (cyclopropylmethoxy)-2-azatricyclo[3.3.1.1 3
,
7 ]decane-2-carboxylate, Intermediate - 19 (50 mg, 0.016 mmol) in DCM (5 mL). Then reaction mixture was cooled to 0*C and trifluoroacetic acid (0.099 g, 0.084 mmol) was added and stirred for 4 hours. After completion of the reaction 20 (reaction was monitored by LCMS) the reaction mixture was concentrated followed by trituration with mixture of hexane : ether (1:1) to give Intermediate-20 (50 mg, yield = 95%) as an oily mass. EXAMPLE 1: 1-(2-azatricyclo[3.3.1.1 3
'
7 ]dec-2-y)-3-(1H-indol-3-yl) propan-1 -one (1) OND N 25 H (1) 78 WO 2013/111150 PCT/IN2012/000842 SYNTHETIC SCHEME 2 OH H0 .HCI + N H N H Starting material 5 Intermediate 5 EXAMPLE 1: 1-(2-azatricyclo[3.3.1 .1 3, 7 ]dec-2-yI)-3-(1 H-indol-3-yl)propan-1 -one (1) 5 Starting Material-2 (0.2mmol) was added to Intermediate-5 (0.2mmol) in dichloromethane (DCM), followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochcloride (EDCl) (0.26mmol) and 1-Hydroxybenztriazole (HOBt) (0.23mmol). The reaction mixture was cooled to 0*C and was maintained at the same temperature for 30 minutes. Further, Triethylamine (0.93mmol) was added to the reaction mixture, and the 10 resulting solution was stirred at room temperature for 15 hours. The reaction mass was then diluted with equal ratio of DCM and water, and was washed with 1 N HCI solution followed by NaHCO 3 and brine solution. The organic layer was separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate 15 (1:4) as eluent to obtain Compound (1) (9.5mg, gummy material). 1 H NMR (300MHz,CDC13): 6 7.91 (brs, 1H), 7.54 (d, 1H), 7.28 (d, 1H), 7.12 (t, 1H), 7.02 (t, 1H), 6.98 (s, 1H), 4.82 (s, 1H), 3.92 (s, 1H), 3.06 (t, 2H), 2.61 (t, 2H), 1.97-1.98 (m, 2H), 1.60 -1.75 (m, 10H). LC-MS (M+H)* = 309.2; HPLC purity = 92.94%. 20 EXAMPLE 2: 1-(2-azatricyclo[3.3. 1.1 7 ]dec-2-yl)-3-(4-methyl-1 H-indol-3-yl)propan-1 -one (2) o N H (2) 79 WO 2013/111150 PCT/IN2012/000842 SYNTHETIC SCHEME 3 Acrylic Acid OH
AC
2 0, AcOH HOBt, EDCI 6 N + TEA, DCM I N 0-H NN H H Starting material 3 Intermdiate 21 intermediate 22 (2) Synthesis of 4-methyl-IH-indole (Intermeditate-21): A 100 mL RB flask fitted with 5 magnetic stirrer and reflux condenser was charged with 60 mL of DMF. To the stirred solvent Starting Material-3 (5 g, 33 mmol) was added followed by Dimethyl formamide dimethyl acetal (13.1 mL, 99.2 mmol). To this Pyrrolidie (3.2 mL, 39.6 mmol) was added and the reaction mixture was heated at 120 0 C under Nitrogen atmosphere for 21 hours. After completion of the reaction the mixture was cooled to room temperature and the solvent was removed under 10 reduced pressure. The resulting crude mass was taken in ether (250 mL) and was washed with water (50 mLx3), saturated brine solution (50 mL) and the organic layer was dried over anhydrous sodium sulphate and concentrated. Resulted crude material was taken in Ethyl acetate (50 mL). To this 10%Pd/C (1.0 g, 10% w/w) was added and hydrogenated in a parr shaker for 2 hours. After completion of the reaction (reaction monitored by TLC), the mixture 15 was filtered through celite bed. Filtrate was concentrated to give crude product, which was purified by column chromatography on silica gel (120 meshe) using Petroleum ether (60-80) and ethyl acetate as eluent to give Intermediate-21 (1.2 g). Synthesis of.3-(4-methyl-1H-indol-3-yI)propanoic acid (Intermeditate-22): A 100 mL RB 20 flask fitted with magnetic stirrer was charged with 2.5 mL of acetic acid. To the stirred solvent acetic anhydride 2.0 mL was added followed by addition of acrylic acid (1.8 mL, 27.4 mmol). To this stirred mixture Intermediate-21 (1.2 g, 9.15mmol) was added and the reaction mixture was stirred at room temperature for 1 week. After completion of the reaction (reaction was monitored by TLC), reaction mass was basified using 5N NaOH (5 mL) and washed with 25 Ethyl acetate (100 mLX2). The aqueous layer was acidified with concentrated HCl (3ML) and was extracted using Ethyl acetate (100 mLX3). The combined ethyl acetate layer was washed with brine solution and was concentrated to give Intermediate-22 (350 mg). Synthesis of Compound (2): Compound (2) was synthesized by following the procedure 30 used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate as eluent to obtain Compound (2). 1 H NMR (300MHz,CDCl3) : 5 7.94 80 WO 2013/111150 PCT/IN2012/000842 (brs, 1H), 7.12 (d, 1H), 6.99 (t, 1H), 6.92 (s, 1H), 6.76 (d, 1H), 4.82 (s, 1H), 3.94 (s, 1H), 3.21 (t, 2H), 2.64 (s, 3H), 2.58 (t, 2H), 2.12-2.17 (m, 1H), 1.64-1.76 (m, 11H). LC-MS (M+H)* 323.2; HPLC purity: 71.84%. 5 EXAMPLE 3: 1-(2-azatricyclo[3.3.1 .1 3 ,]dec-2-yl)-3-(1,4-dimethyl-1 H-indol-3-yl)propan-1 one (3) N (3) Synthesis of Compound (3): Compound (3) was synthesized by following the procedure 10 used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate as eluent to obtain Compound (3). 1 H NMR (300MHz,CDCl3) : 6 6.98-7.05 (m, 2H), 6.75-6.78 (m, 2H), 4.82 (s, 1H), 3.93 (s, 1H), 3.63 (s, 3H), 3.16-3.22 (m, 2H), 2.64 (s, 3H), 2.55-2.61 (m, 2H), 1.97-2.01 (m, 2H), 1.75-1.79 (m, 2H), 1.70-1.72 (m, 3H), 15 1.59-1.65 (m, 5H). LC-MS (M+H)* = 337.2; HPLC purity: 79.30%. EXAMPLE 4: 3-(4-fluoro-1H-indol-3-yl)-l-(5-hydroxy-2-azatricyclo[3.3.1.1 3 ,]dec-2 yl)propan-1 -one (4) O NOH F N H 20 (4) 81 WO 2013/111150 PCT/IN2012/000842 SYNTHETIC SCHEME 4 0 0 F F 0 O O F I _ F A--N H H N H -N Starting material 4 Intermediate 23 H Intermediate 25 Intermediate 24 0 0 N OH OH F HOBt EDCI F TEA, DCM N N H H Intermediate 26 (4) 5 Synthesis of 4-fluoro-1H-indole-3-carbaldehyde (Intermediate-23): To a 25mL RB flask fitted with magnetic stirrer were added DMF (0.413 g) and POC 3 (0.623g, 4 mmol) at 00C under N 2 atmosphere and the resulting mixture was stirred for 30 minutes at same temperature. Then Starting Material-4 (500 mg, 3.7 mmol) in DMF was added to the mixture and stirred at 400C for 1 hour. After completion of the reaction the 10 reaction mixture was cooled to OC, quenched with NaOH solution and was extracted with ethyl acetate. Organic layers were concentrated to give crude material, which was then purified by silica-gel column chromatography eluting with hexane : EtOAc to give Intermediate-23 (230 mg) as brown material. LC-MS (M+H)* = 164.2. 15 Synthesis of ethyl (2E)-3-(4-fluoro-IH-indol-3-yl)prop-2-enoate (Intermediate-24): To a 100 mL RB flask fitted with magnetic stirrer was charged with Intermediate-23 (0.23g, 1.4 mmol), Ethyl Malonate (0.204g, 1.5 mmol) and Piperdine (0.011g, 0.13 mmol) in Pyridine (10 mL). Resulted reaction mixture was heated at 110*C for 14 hours. After completion of the reaction, the reaction mixture was concentrated to obtain a crude material which was then 20 dissolved in ethyl acetate and washed with water and brine. Organic layer was then concentrated to give crude material, which was purified by silica-gel column chromatography eluting with hexane : EtOAc to give Intermediate-24 (250 mg). Synthesis of ethyl 3-(4-fluoro-1H-indol-3-yl)propanoate 25 (Intermediate-25): Intermediate-24 (0.24 g, 1.0 mmol) was taken in EtOAc (10 mL) to which 10%Pd/C (50 mg) was added. The resulting reaction mass was stirred under H 2 atmosphere (30 psi) for 4 82 WO 2013/111150 PCT/IN2012/000842 hours. The reaction mass was filtered through celite bed and concentrated to give Intermediate-25 (240 mg). Synthesis of 3-(4-fluoro-1H-indol-3-yl)propanoic acid 5 (Intermediate-26): Intermediate -25 (100mg, 0.4mmol) was taken in EtOH: THF: H 2 0 (5 mL: 5 mL: 1mL). To this NaOH (51 mg, 1.2 mmol) was added. Resulting reaction mixture was refluxed for 4 hours. After completion of reaction (reaction monitored by TLC), the reaction mixture was concentrated which was diluted with water, acidified (pH = 1 to 2) with 1 N HCI, extracted with 10 EtOAc and concentrated to give Intermediate-26 (90 mg). Synthesis of Compound (4): Compound (4) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: 15 MeOH as eluent to obtain Compound (4). 1 H NMR (300MHz,CDCl3) : 6 8.04(s, 1H),6.97 7.07(m, 2H),6.94(s, 1H), 6.65-6.71(m, 1H),5.01(s, 1H), 4.21(s, 1H), 3.08-3.13(t, 2H), 2.62 2.67(t, 2H), 2.24(s, 1H),1.53-1.74(m, 10H)..LC-MS (M+H)* = 343.12; HPLC purity: 95.20%. EXAMPLE 5: 1-(2-azatricyclo[3.3.1.1 3
,
7 ]dec-2-yI)-3-(6-fluoro-1 H-indol-3-yl)propan-1-one 20 (5) oN@ F N H (5) Synthesis of Compound (5): Compound (5) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the 25 organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate as eluent to obtain Compound (5). 1 H NMR (300MHz,CDCl3) : 6 8.02(brs, 1H), 7.41-7.46(dd, 1H), 6.95-6.99(m, 2H), 6.78-6.85(m, 1H), 4.81(s, 1H), 3.90(s, 1H), 3.03 3.08(t, 2H), 2.63-2.68(t, 2H), 1.96-2.02(m, 2H), 1.56-1.76(m, 10H). ".LC-MS (M+H)* = 327.3; HPLC purity: 95.25%. 30 83 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 6: 3-(5-fluoro-1H-indol-3-yl)-1-(4-hydroxy-2-azatricyclo[3.3.1 .1 3
'
7 ]dec-2 yl)propan-1 -one (6) OH O , N F N H (6) 5 SYNTHETIC SCHEME 5 OH OH O H H / O HO t, EDCI N HN TEA, CM 0 HH. Intermediate 3 Intermediate 27 Intermediate 28 (6) Synthesis of methyl 4-hydroxy-2-azatricyclo[3.3.1 .1 3
'
7 ]decane-2-carboxylate 10 (Intermediate-27): To a 1OOmL RB flask fitted with magnetic stirrer was charged 25 mL of Dichloromethane. To this Intermediate-3 (0.5g, 2.5mmol), followed by m-CPBA (0.69g, 4.Ommol) were added at 00C. Then reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched using aqueous NaHCO 3 solution and was 15 extracted with dichloromethane. Organic layer was concentrated to give Intermediate 27(0.5g). Synthesis of 2-azatricyclo[3.3.1 .1 3 ']decan-4-ol hydrogen chloride salt (intermediate-28): 20 A 50mL pressurized seal tube fitted with magnetic stirrer was charged with Intermediate-27 (0.2g, 0.9mmol) in HCI containing 1,4-Dioxane (20 mL). Then reaction mixture was stirred at 900C for 8 hours. After completion of the reaction (reaction was monitored by LCMS), it was concentrated followed by trituration with mixture of hexane : ether (1:1) to give Intermediate 28 (0.2g). 25 Synthesis of Compound (6): Compound (6) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the 84 WO 2013/111150 PCT/IN2012/000842 organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (6). 'H NMR (300MHz,CDC3) : 6 7.97(brs, 1H), 7.17 7.23(d, 1H),7.14- 7.15(d, 1H), 7.02(s, 1H), 6.84-6.90(m, 1H), 4.67-4.73(d, 1H), 3.83 (brs, 0.5H), 3.68(s, 1H), 3.35 (brs, 1H), 2.98-3.03(t, 2H), 2.56-2.64(m, 2H), 2.07-2.11(m, 1H), 5 1.97(m, 1H), 1.61-1.69(m, 7H). LC-MS (M+H)* = 343.1; HPLC purity: 95.88%. EXAMPLE 7: 1-(2-azatricyclo[3.3.1.1 3 ' ]dec-2-yl)-3-(5-fluoro-1 H-indol-3-yl)propan-1 -one (7) F N H 10 (7) Synthesis of Compound (7): Compound (7) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate as eluent to obtain Compound (7). 'H NMR (300MHz,CDC3) : 6 7.94(s, 15 1H), 722(d, 1H), 7.16(s, 1H), 7.03(s, 1H), 6.86-6.87(t, 1H), 4.81(s, 1H), 3.91(s, 1H), 2.99 3.04(t, 2H), 2.57-2.62(t, 2H), 1.92-1.98(m, 2H), 1.58-1.75(m, 10H)..LC-MS (M+H)* = 327.2; HPLC purity: 96.53%. EXAMPLE 8: 3-(4-fluoro-1 -methyl-1 H-indol-3-yl)-1 -(5-hydroxy-2-azatricyclo 20 [3.3.1.1 3 ,7]dec-2-yl)propan-1-one (8) F N OH F N (8) Synthesis of Compound (8): Compound (8) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the 25 organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (8). 'H NMR (300MHz,CDCI3) : 6 6.96-7.07(m, 2H),6.78(s, 1H), 6.63-6.69(m, 1H),5.01(s, 1H), 4.21(s, 1H), 3.64(s, 3H), 3.05-3.10(t, 2H), 2.59-2.64(t, 2H), 2.24(s, 1H),1.53-1.74(m, 10H). LC-MS (M+H)* = 357.1; HPLC purity: 89.95%. 85 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 9: 3-(5-fluoro-1H-indol-3-yI)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3 7]dec-2 yl)propan-1-one (9) O N OH F N H (9) 5 Synthesis of Compound (9): Compound (9) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (9). 1 H NMR.(300MHz,CDCl3) : 6 7.94(brs, 1H), 7.19 7.22(d, 1H),7.15- 7.16(d, 1H), 7.02(s, 1H), 6.83-6.90(m, 1H),5.02(s, 1H), 4.01(s, 1H), 2.99 10 3.04(t, 2H), 2.57-2.62(t, 2H), 2.26(s, 1H), 1.61-1.97(m, 10H)..LC-MS (M+H)* = 343.1; HPLC purity: 93.42%. EXAMPLE 10: 1--(5-hydroxy-2-azatricyclo[3.3.1 .1 3 7]dec-2-yl)-3-methyl-3-(1 -methyl-I H indol-3-yl)butan-1 -one (10) O NOH N 15 (10) 86 WO 2013/111150 PCT/IN2012/000842 SYNTHETIC SCHEME 6 OH0 0 O H 0 HO &N &N N N H H Starting material 5 Intermediate 29 Intermediate 31 Intermediate 30 .. .O OH 9NN &NN N Intermediate 32 Intermediate 33 Intermediate 34 Intermediate 35 Synthesis of methyl 1H-indol-3-ylacetate (Intermediate-29): 5 A 100 mL RB flask fitted with magnetic stirrer was charged with 15 mL of Methanol. To the stirred solvent Starting Material-5 (2.0 g, 11.41mmol) was added. The resulting mixture was cooled to 0*C and concentrated H 2
SO
4 (0.5 mL) was added. The reaction mixture was then stirred at room temperature for 1 hour. After completion of the reaction (reaction monitored by TLC), solvent from the reaction mass was removed under reduced pressure. The resulting 10 crude mass was taken in Ethyl acetate (100 mL) and was washed with water (50 mL), Sodium bicarbonate solution (100 mLX2) and saturated brine solution (50 mL). The organic layer was then dried over anhydrous sodium sulphate. Then the solvent was removed under reduced pressure. The product Intermediate-29 was obtained as brown syrup. (2.1g). LC-MS (M+H)* = 190.2. 15 Synthesis of methyl 2-methyl-2-(1-methyl-IH-indol-3-yl)propanoate (Intermediate-30): A 100 mL 3 neck RB flask fitted with magnetic stirrer was charged with 1OmL of dry THF. To the stirred solvent diisopropyl amine (401.12 mg, 3.964mmol) was added and the resulting solution was cooled to -78*C. n-BuLi (2.5 mL, 3.964mmol) was added and stirred for 1 hour 20 at 0*C. The reaction mixture was again cooled to -78*C to which Intermediate-29 (150 mg, 0.7928 mmol) was added. The reaction mixture was then stirred for 1 hour. This was followed by addition of Methyl Iodide. The resulting mass was then stirred at room temperature for 15 hours. After completion of the reaction (reaction monitored by TLC), the reaction mass was quenched with saturated ammonium chloride and was extracted using 25 EtOAc (100 mLX3). The combined organic layers were washed with brine and dried after which the solvent was removed under reduced pressure. The resulting crude compound was 87 WO 2013/111150 PCT/IN2012/000842 purified by column chromatography on silica gel (120 meshes) using Petroleum ether (60-80) and ethyl acetate as eluent. The product Intermediate-30 was obtained as a brown syrup. (150mg). LC-MS (M+H)* = 232.2. 5 Synthesis of 2-methyl-2-(1 -methyl-I H-indol-3-yl)propan-1 -ol (intermediate-31): A 250 mL RB flask fitted with magnetic stirrer was charged with Lithium aluminum hydride (0.983 g, 25.951mmol) and THF (20 mL) was added to it at 00C. To this resulting suspension Intermediate-30 (2.0 g, 8.65mmol) in THF (20 mL) was added and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture 10 was diluted with EtOAc (50 mL) and then quenched with Na 2
SO
4 (5g). The resulting slurry was stirred at room temperature for 1 hour, filtered through celite and washed with ethyl acetate. The resulting filtrate was concentrated to give Intermediate-31 (0.9 g). 1 H NMR (300MHz,DMSO-d6) : 6 7.65-7.68(d,11H), 7.34-7.36(d,1H), 7.07-7.12(t,1H), 7.03(s,1H), 6,94 6.99(t, 1 H), 4.53-4.57(t, 1 H), 3.71 (s,3H), 3.54-3.56(d,2H), 1.31 (s,6H). 15 Synthesis of 2-methyl-2-(I-methyl-IH-indol-3-yl)propanal (Intermediate-32): A 100 mL RB flask fitted with magnetic stirrer was charged with 30 mL DCM to which Pyridinium chloro chromate (2.466g, 11.4419mmol) was added followed by the addition of Intermediate-31 (1.55 g, 7.627 mmol) in 10 mL of DCM. The resulting mixture was stirred at 20 room temperature for 2 hours. After completion of the reaction, the solvent from the reaction mass was removed under reduced pressure to yield the crude compound. Crude mass was purified by column chromatography using 60-120 silica gel and 9:1 Pet ether/ethyl acetate as eluent to give Intermediate-32 (0.79 g). 1 H NMR (300MHz,DMSO-d6) : 6 9.39(s,1H), 7.40 7.44(t,1H), 7.32(s,1H), 7.13-7.18(t,1H), 6.98-7.03(t,1H), 3.77(s,3H), 1.46(s,H). 25 Synthesis of 3-[(3E)-4-methoxy-2-methylbut-3-en-2-y]-1 -methyl-1 H-indole (Intermediate-33): A 100 mL RB flask fitted with magnetic stirrer was charged with 20 mL of dry THF and Methoxy methyl triphenyl phosphonium chloride (2.566 g, 7.487 mmol) followed by Potassium 30 tert butoxide (2.295 g, 20.451 mmol). The resulting mass was stirred at room temperature for 2 hours and then cooled to 0*C. Intermediate-32 (1.37 g, 6.807 mmol) in 10 mL of THF was added to the above reaction mass and was stirred at room temperature for 2 hours. After completion of the reaction the reaction mass was diluted with 10 mL of water and was extracted with ethyl acetate (100 mL X 3). The combined organic layers were washed with 35 brine solution and was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Crude product was purified by column chromatography using 60-120 silica gel and 6% of ethyl acetate in Pet ether as eluent to give Intermediate-33. Yield: 1.12 g (71.8%). 88 WO 2013/111150 PCT/IN2012/000842 'H NMR (300MHz,CDCI3) : 6 7.73-7.80(mlH), 7.33(s,1H), 7.16-7.21(t,1H), 7.03-7.08(t,1H), 6.81(s,11H), 5.79-6.34(m,1H), 4.58-5.15(m,1H), 3.73-3.74(d,3H), 3.49-3.53(d,3H), 1.55(s,6H). Synthesis of 3-methyl-3-(1-methyl-IH-indol-3-yl)butanal (Intermediate-34): 5 A 100 mL RB flask fitted with magnetic stirrer was charged with 50.4 mL of 1,4 dioxane and 12.76 mL of water. To this Intermediate-33 (1.12 g, 4.884 mmol) was added followed by addition of p-toluene sulphonic acid (0.0424 g, 0.2232 mmol). The resulting mass was heated at 600C for 16 hours. After completion of the reaction, the reaction mixture was quenched with 10 mL of water and extracted with ethyl acetate (100 mL X 3) and the combine organic 10 layer was washed with saturated sodium bicarbonate solution followed by brine solution and was dried over anhydrous sodium sulfate and was concentrated to obtain the crude product. The crude product was purified by column chromatography using 60-120 silica gel and 8% of ethyl acetate in Pet ether as eluent to give Intermediate-34. 1 H NMR (300MHz,DMSO-d6) : 6 9.47-9.49(t,1H), 7.73-7.76(d,1H), 7.37-7.40(d,1H), 7.11-7.16(t,1H), 7.10(s,11H), 6.99 15 7.04(t,1H) 3.72(s,3H), 2.78(s,2H), 1.49(s,6H). Synthesis of 3-methyl-3-(1-methyl-1H-indol-3-yl)butanoic acid (Intermediate-35): A 50 mL RB flask fitted with magnetic stirrer was charged with 10 mL of THF and was cooled to -78*C to which 2-methyl-2-butene (3 mL) was added and stirred for 15 minutes. Another 20 100 mL RB flask fitted with magnetic stirrer was charged with Intermediate-34 (557 mg, 2.59mmol) and tert butanol (15 mL) and was stirred at room temperature and the above prepared THF solution was added to it. Then the resulting mass was cooled to 00C to which NaH 2
PO
4 (1.42 g) in water was added followed by addition of NaCIO 2 (0.35g) in water. The resulting mixture was stirred at 0*C for 20 minutes and quenched with water. The pH of the 25 reaction mixture was adjusted to 1-2 using 1N HCl and the product was extracted with ethyl acetate and concentrated to give Intermediate-35 (480 mg). 1 H NMR (300MHz,DMSO-d6) : 6 11.82(s,11H), 7.69-7.71(d,1H), 7.35-7.38(d,1H), 7.09-7.14(t,1H), 7.05(s,1H), 6.96-7.01(t,1H), 3.71(s,3H), 2.66(s,2H), 1.48(s,6H) 30 Synthesis of Compound (10): Compound (10) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (10). 1 H NMR (300MHz,DMSO-d6) : 6 7.70-7.73(d,1H), 7.34-7.37(d, 1H), 7.10(t,1H),7.04(s,1H), 6.98-7.04(t, 1H), 4.75(brs, 1H), 35 4.54 (s, 1H), 3.99(brs, 1H), 3.70(s, 3H), 2.60-2.65(dd, 2H), 2.02 (s, 1H), 1.28-1.62 (m, 16H)LC-MS (M+H)* = 367.3; HPLC purity: 88.74%. 89 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 11: 1-(2-azatricyclo[3.3.1.1 3
'
7 ]dec-2-y)-3-(1,3-benzothiazol-2-yl)propan-1 -one (11) N 0 S N - (11) 5 SYNTHETIC SCHEME 7 0 N 0 + 0 SHs OH 0 Starting material 6 Starting material 7 Intermediate 36 Synthesis of 3-(1,3-benzothiazol-2-yl)propanoic acid (Intermediate-36): 10 Starting material-7 (3.97mmol) in benzene was added drop wise to the solution of Starting Material-6 (3.97mmol) in benzene. The resulting solution was heated to reflux for 2 hours. After 2 hours the reaction mass was cooled to room temperature and was extracted with 10% sodium hydroxide solution. The aqueous layer was acidified using Conc.HCI (3ml) at 00C. The resulting solids were filtered and dried at room temperature to get Intermediate-36 15 (660mg). Synthesis of Compound (11): Compound (11) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum 20 ether: Ethyl acetate (1:4) as eluent to obtain Compound (11). 1 H NMR (300 MHz, CDCI3) : 6 7.89-7.91 (d, 1H), 7.76-7.78 (d, 1H), 7.36-7.41 (t, 1H), 7.26-7.31 (t, 1H), 4.79 (s, 1H), 4.01 (s, 1H), 3.40-3.46 (t, 2H), 2.82-2.88 (t, 2H), 1.98-2.02 (m, 2H), 1.66-1.81 (m, 10H). LC-MS: (M+H)+ = 327.3; HPLC purity = 94.43 %. 90 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 12: 3-(1,3-benzothiazol-2-y)-1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3
,
7 ]dec-2 yl)propan-1 -one (12) N 0 s OH (12) 5 Synthesis of Compound (12): Compound (12) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (12). 1H NMR (300 MHz, CDCl3) : 5 7.91-7.93 (d, 1H), 7.76-7.79 (d, 1H), 7.37-7.43 (t, 1H), 7.28-7.33 (t, 1H), 4.99 (s, 1H), 4.28 (s, 10 1H), 3.42-3.47 (t, 2H), 2.88-2.93 (t, 2H), 2.28 (brs, 1H), 1.51-1.79 (m, 1OH). LC-MS: (M+H)+ = 343.1; HPLC purity = 99.27 %. EXAMPLE 13: 3-(1,3-benzothiazol-2-y)-1-[5-(difluoromethoxy)-2 azatricyclo[3.3.1.1 3
,
7 ]dec-2-yl]propan-1 -one (13) N o S N 0 F 15 F (13) SYNTHETIC SCHEME 8 N 0N 0 OH 0 (12) (13) F 20 F Synthesis of Compound (13): To a stirred solution of (80 mg, 0.28 mmol) in MeCN (3 riL) was added Cul (88 mg, 0.046 mmol) and heated to 45 0 C. To this difluoro(fluorosulfonyl)acetic acid (23 mg, 0.46 mmol) was added. The resultant mixture is allowed to stir at the same 25 temperature for 30 minutes. After completion of the reaction, the reaction mixture is 91 WO 2013/111150 PCT/IN2012/000842 quenched with water, extracted with EtOAc and concentrated. Resulted crude material was purified by silica gel column chromatography eluting with hexane: EtOAc to give Compound (13) (40 mg) as dark yellow gummy material. 1H NMR (300 MHz, CDCI3) : 5 7.87-7.89 (d, 1H), 7.76-7.78 (d, 1H), 7.35-7.40 (t, 1H), 7.26-7.31(t, 1H), 5.97-6.48(t, 1H), 5.03 (brs, 1H), 5 4.33 (brs, 1H), 3.39-3.44 (t, 2H), 2.85-2.89 (t, 2H), 2.33 (brs, 1H), 1.87-1.98 (m, 4H), 1.57 1.70 (m, 6H). LC-MS: (M+H)+ = 393.2; HPLC purity = 89.63 %. EXAMPLE 14: 1-(2-azatricyclo[3.3.1.13, 7]dec-2-yl)-3-(1 H-pyrrolo[2,3-b]pyridin-3 yl)propan-1 -one (14) oN N N 10 H (14) SYNTHETIC SCHEME 9 OH H o N .HCI N N HOBt, EDCI N NH H N N Intermediate 37 (14) 15 Synthesis of 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoic acid (Intermediate-37): Intermediate-37 was synthesized by following the procedure used to make Intermediate-26 (Scheme 4). Synthesis of Compound (14): Compound (14) was synthesized by following the procedure 20 used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (14). 1H NMR (300 MHz, CDCI3) : 6 8.99(brs, 1H), 8.22-8.21(d, 1H), 7.9- 7.88(d, 1H), 7.07(s, 1H), 7.03-6.99(t, 1H), 4.81(s, 1H), 3.92(s, 1H), 3.07-3.02(t, 2H), 2.62-2.57(t, 2H), 1.97-1.98(m, 3H), 1.76-1.56(m, 11H).. LC-MS: 25 (M+H)+ = 310.2; HPLC purity = 98.28%. 92 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 15: 1-(5-hydroxy-2-azatricyclo[3.3.1.13, 7 ]dec-2-yl)-3-(1 H-pyrrolo[2,3-b]pyridin 3-yl)propan-1 -one (15) O N OH N N H (15) 5 Synthesis of Compound (15): Compound (15) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (15). -1H NMR (300 MHz, CDCl3) : 6 9.02 (brs,1H), 8.20-8.22(d, 1H), 7.86-7.88(d, 1H), 7.07(brs, 1H), 6.99-7.03 (dd, 1H), 5.00(bs, 10 1H), 4.10(brs, 1H), 3.02-3.07(t,2H), 2.57-2.62(t,2H) , 2.22 (brs, 1H), 1.45-1.73(m,1OH).. LC MS: (M+H)+ = 326.1; HPLC purity = 98.04%. EXAMPLE 16: 3-(1H-benzotriazol-1-yl)-l-(5-hydroxy-2-azatricyclo[3.3.1.1 3 7 ]dec-2 yl)propan-1-one (16) N@ OH N N 15 N (16) SYNTHETIC SCHEME 10 H Et OH H N NN N N - N Starting Material 8 Intermediate 38 Intermediate 39 20 Synthesis of ethyl 3-(1H-benzotriazol-1-yl)propanoate (Intermediate-38): The starting material-8 (4.1mmol) in dry THF (5ml) was cooled to 00C, followed by the addition of NaH (6.Ommol). The reaction mixture was gradually warmed to room temperature and allowed to react for 20 minutes. The reaction mixture was again cooled to 00C, followed 93 WO 2013/111150 PCT/IN2012/000842 by the drop wise addition of ethyl 3-bromopropanoate (4.6mmol) in THF (2.5ml). The reaction was allowed for 12 hours at room temperature. After 12 hours the reaction mixture was quenched with ice cooled water and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO 4 , and concentrated to obtain Intermediate-38 (70mg). 1H NMR 5 (300MHz, CDC13) : 6 7.98-8.01(1H,d),7.55-7.58(d,1H),7.41-7.46(t,1H),7.28-7.33(t,1H),4.82 4.87 (t,2H), 4.00-4.07(t,2H),3.00-3.05(t,2H), 1.08-1.1(t,3H). Synthesis of 3-(1H-benzotriazol-1-yl)propanoic acid (Intermediate-39): At 0C, LiOH (1.5mmol) in water (Iml) was added to Intermediate-38 in the solvent THF: 10 MeOH (1:1, 3ml each). The reaction was allowed for 12 hours at room temperature. After 12 hours the reaction mixture was concentrated, further acidified with 1N HCI (pH = 2). The reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO 4 , and evaporated under reduced pressure to obtain Intermediate-39 (60mg). 1H NMR (300MHz, CDC13): 6 7.29-8.00(4H,m),4.82-4.87(t,2H),3.09-3.14 (t,2H). 15 Synthesis of Compound (16): Compound (16) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (16). 1H NMR (300 MHz, CDC13) : 6 20 7.23-7.97(m,4H), 4.81-4.92(m, 3H), 4.10 (brs, 1H), 3.01-3.05(t, 2H), 2.21 (brs, 1H), 1.40 1.78(m, 10H).. LC-MS: (M+H)+ = 327.2; HPLC purity = 98.35%. EXAMPLE 17: 1-(2-azatricyclo[3.3.1 .1 3 7 ]dec-2-yl)-3-(1H-indol-3-yl)butan-1 -one (17) N H 25 (17) 94 WO 2013/111150 PCT/IN2012/000842 SYNTHETIC SCHEME 11 0 H O o H N H Starting Starting Starting material 9 material 10 material 11 Intermediate 40 o 0 0 - OH N N H H lntermediate42 Intermediate4l Synthesis of 5-[1 -(1 H-indol-3-yl)ethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 5 40): A 100mL RB flask fitted with magnetic stirrer was charged with Starting Material-9 (4.Og, 34mmol), Starting Material-10 (4.92, 34mmol) and Starting Material-11 (3g, 68mmol) in 75mL of acetonitrile. The resulting solution was stirred at room temperature overnight. After completion of the reaction (reaction monitored by TLC), the solvent was removed under 10 reduced pressure, and the resulting crude compound was purified by column chromatography on silica gel (230-400 mesh) using Petroleum ether (60-80) and ethyl acetate as eluent. The product (intermediate-40) was obtained as a brown liquid (2.51g). LC-MS (M-H)* = 286. Synthesis of ethyl 3-(1H-indol-3-yl)butanoate (Intermediate-41): 15 A 100 mL RB flask fitted with magnetic stirrer was charged with intermediate-40 (2.5g, 8.7mmol) in 5OmL of pyridine and 8 ml of ethanol. To this mixture copper powder (0.4g, 5mol%) was added. Then the resulting reaction mass was refluxed at 1100 C for 3 hours. After completion of the reaction (reaction monitored by TLC), solvent was removed from the reaction mass and the reaction mass was diluted with 100mL of ethyl acetate. This was 20 followed by washing of the reaction mass with 50mL 1.5N HCI (2X25mL) and brine solution. Then the organic layer was dried over 10g of anhydrous MgSO 4 . The solvent was removed under reduced pressure, and the resulting crude compound was purified by column chromatography on silica gel (230-400 mesh) using Petroleum ether (60-80) and ethyl acetate as eluent. The product (intermediate-41) was obtained as a brown liquid. (0.380g). 25 LC-MS (M+H)* = =232. 95 WO 2013/111150 PCT/IN2012/000842 Synthesis of ethyl 3-(1H-indol-3-yl)butanoic acid (Intermediate-42): A 50 mL RB flask fitted with magnetic stirrer was charged with 6mL of methanol and 2 mL of water. To the stirred solvent intermediate-41 (0.145g, 0.62mmol) and KOH (0.098g, 5 2.54mmol) was added. Then the resulting reaction mass was refluxed at 700C for 3 hours. After completion of the reaction (reaction monitored by TLC), solvent was removed from the reaction mass and the reaction mass was diluted with 20mL of water. The aqueous layer was washed with 20 mL of diethylether and was acidified by 1NHCI to pH 5.5. The product was then extracted with ethyl acetate and the solvent was removed under reduced pressure. The 10 product (intermediate-42) was obtained as a brown liquid (0.115g). The product obtained above was directly taken for next step without any purification. Synthesis of Compound (17): Compound (17) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the 15 organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (17). 1H NMR (300 MHz, CDC13) : 6 7.91(brs, 1H), 7.60-7.63(d, 1H), 7.27-7.30(d, 1H), 7.09-7.13(t, 1H), 7.01-7.03(t, 1H), 6.96(s, 1H), 4.80(s, 1H), 3.93(s, 1H), 3.54-3.61(m, 1H), 2.72-2.79(m, 1H), 2.45-2.50(m, 1H), 2.10(brs, 1H), 1.88-1.97(m, 1H), 1.66-1.74(m, 5H), 1.47-1.59(m, 5H), 1.38-1.41(d, 3H). LC-MS: (M+H)+ 20 = 323.3; HPLC purity = 90.83 %. EXAMPLE 18: 1-(4-hydroxy-2-azatricyclo[3.3.1.1 3 ' ]dec-2-yI)-3-(1H-indol-3-yl)butan-1 one (18) OH N H 25 (18) Synthesis of Compound (18): Compound (18) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (18). 1H NMR (300 MHz, CDC13) : 6 30 7.92(brs, 1H),7. 75-7.54(m, 1H), 7.35-7.27(m, 1H), 7.14-7.01(m, 2H), 6.96(brs, 1H), 4.73 4.64(d, 1H),3.89(s, 1H), 3.67(s, 1H), 3.37-3.60(m,1H), 2.67-2.79(m,1H),2.59-2.46(m,1H), 96 WO 2013/111150 PCT/IN2012/000842 2.08-1.86(m,3H),1.75-1.60(m,5H), 1.53-1.44(m, 2H), 1.38-1.42 (m, 3H). LC-MS: (M+H)+ = 339.2; HPLC purity = 98.80 %. EXAMPLE 19: 1-(4-hydroxy-2-azatricyclo[3.3.1.13, 7 ]dec-2-yI)-3-(1H-indol-3-yI)-4 5 methylpentan-1-one (19) OH N H (19) Synthesis of Compound (19): Compound (19) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the 10 organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (19). 1H NMR (300 MHz, CDCl3) : 6 8.06- 7.98(d, 1H),7.70-7.56(d, 1H), 7.36-7.24(m, 1H), 7.16-7.01(m, 2H), 6.98- 6.91(d, 1H), 4.57-4.56(d, 1H), 3.83- 3.39(m, 2H), 3.25-2.90(m, 2H), 2.80-2.66(m, 1H),2.16-2.02(m, 1H),1.98-1.66(m,4H), 1.54-1.08(m, 6H), 0.961-0.89 (d, 6H). LC-MS: (M+H)+ = 367.3; HPLC 15 purity = 98.74 %. EXAMPLE 20: 1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3
'
7 ]dec-2-yI)-3-(1 H-indol-3-yl)butan-1 one (20) 0 NOH N H 20 (20) Synthesis of Compound (20): Compound (20) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (20). 1H NMR (300 MHz, CDCl3) : 6 25 7.99(brs, 1H), 7.59-7.62(d, 1H), 7.27-7.29(d, 1H), 7.08-7.13(t, 1H), 7.01-7.06 (t, 1H), 6.96(brs, 1H), 4.98(brs, 1H), 4.09(brs, 1H), 3.56-3.61(q, 1H), 2.73-2.78(t, 1H), 2.43-2.50 (m, 1H), 1.94 1.97 (m, 1H), 1.42-1.68(m, 10H), 1.40 (d, 3H). LC-MS: (M+H)+ = 339.2; HPLC purity = 94.22%. 97 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 21: 1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
'
7 ]dec-2-yi)-3-(1H-indol-3-yl)butan-1 one (21) O N@ OH N H 5 (21) Synthesis of Compound (21) (peak-1): Racemate of Compound (20) was separated by using HPLC to give enantiomer Compound (21) (peak-1). 1H NMR (300 MHz, CDC13) : 7.99(brs, 1H), 7.59-7.62(d, 1H), 7.27-7.29(d, IH), 7.08-7.13(t, 1H), 7.01-7.06 (t, 1H), 6.96(brs, 1H), 4.98(brs, 1H), 4.09(brs, 1H), 3.56-3.61(q, 1H), 2.73-2.78(t, 1H), 2.43-2.50 (m, 1H), 1.94 10 1.97 (m, 1H), 1.42-1.68(m, 1OH), -1.40 (d, 3H). LC-MS: (M+H)+ = 339.2; HPLC purity = 98.2 %, Chiral purity: (RT = 19.9 min). EXAMPLE 22: 1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
,
7 ]dec-2-yl)-3-(1H-indol-3-yl)butan-1 one (22) O N@ OH N 15 H (22) Synthesis of Compound (22) (peak-1): Racemate of Compound (20) was separated by using HPLC to give enantiomer Compound (22) (peak-2). 1 H NMR (300 MHz, CDC13) : 7.99(brs, 1H), 7.59-7.62(d, 1H), 7.27-7.29(d, 1H), 7.08-7.13(t, 1H), 7.01-7.06 (t, IH), 6.96(brs, 20 1H), 4.98(brs, 1H), 4.09(brs, 1H), 3.56-3.61(q, 1H), 2.73-2.78(t, 1H), 2.43-2.50 (m, 1H), 1.94 1.97 (m, 1H), 1.42-1.68(m, 10H), 1.40 (d, 3H). LC-MS: (M+H)+ = 339.2; HPLC purity = 97.8 %; Chiral purity: (RT = 22.28 min). 98 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 23: 1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
,
7 ]dec-2-yl)-3-(1 H-indol-3-yl)-4 methylpentan-1 -one (23) O N OH N H (23) 5 Synthesis of Compound (23): Compound (23) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain (23). 1H NMR (300 MHz, DMSO-d6) : 6 10.77(s,1H), 7.50-7.53(d,1H), 7.28-7.31(d,1H), 7.07(s,1H), 6.99-7.04(t,1H), 6.90-6.95(t,1H), 10 4.67(s,1H), 4.55-4.62(d,1H), 4.26-4.29(d,1H), 3.22-3.26(m,1H), 2.65-2.67(m,2H), 1.98(m,2H), 1.55-1.62(d,5H), 1.36-1.48(m,3H), 1.15-1.19(m,1H), 1.01-1.06(m,1H), 0.77-0.87(m,6H). LC MS: (M+H)+ = 367.2; HPLC purity = 85.41%. EXAMPLE 24: 1-(5-fluoro-2-azatricyclo[3.3.1.1 3
,
7 ]dec-2-yI)-3-(1 H-indol-3-yi)-4 15 methylpentan-1 -one (24) O N@ _ F N H (24) SYNTHETIC SCHEME 12 0 Na OH ON0 F N H~ N H 20 (23) (24) 99 WO 2013/111150 PCT/IN2012/000842 Synthesis of Compound (24): Under N 2 atmosphere to a stirred solution of Compound (23) (0.035g, 0.09mmol), DAST (0.015g, 0.09mmol) was added at -78*C. The reaction mixture was stirred for 2h at same temperature. After completion of the reaction (reaction monitored by TLC), reaction mass was 5 quenched with NaHSO 3 Solution and extracted with DCM (3x25 mL). The organic layer was washed with saturated brine solution (15mL), and concentrated to obtain the crude product. The crude product was loaded on Prep TLC plate (97:3. Chloroform: Methanol) and Compound (24) (12 mg) was collected as pale yellow solid. 1H NMR (300 MHz, CDCI3) : 6 7.94(s, 1H),7.57-7.59(d, 1H), 7.25-7.30(m, 1H),6.99-7.12(m, 2H), 6.93(s, 1H), 4.95(s, 10 1H),4.09(s, 1H),3.12-3.21(m, 1H), 2.72-2.82(m, 1H) 2.63-2.67(m, 1H), 2.08-2.25(m, 3H), 1.72-1.79(m, 2H), 1.61-1.69(m, 7H), 0.96-.98 (d,3H),.0.71-.81(d,3H).. LC-MS: (M+H)+ = 369.1; HPLC purity = 96.16%. EXAMPLE 25: 3-(4-fluoro-1H-indol-3-yl)-1-(5-hydroxy-2-azatricyclo[3.3.1 .13,' 7 ]dec-2-yl)-4 15 methylpentan-1-one (25) F0 OH F N H (25) Synthesis of Compound (25): Compound (25) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the 20 organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (25). 1H NMR (300 MHz, CDCI3) : 6 8.29-8.26(d, 1H), 7.14-7.02(m, 2H), 6.98(s, 1H), 6.77-6.71(t, 1H), 4.93(s, 1H), 4.21(s, 1H), 3.25(m, 1H), 2.91-2.66(m, 2H), 2.25(s, 1H), 2.16-2.05(m,2H), 1.72-1.34(m, 9H), 0.79 0.81(d,6H). LC-MS: (M+H)+ = 385.2; HPLC purity = 98.37 %. 25 100 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 26: 3-(4-fluoro-IH-indol-3-yl)-1-(5-hydroxy-2-azatricyclo[3.3. 1.1 3
'
7 ]dec-2 yl)butan-1 -one (26) F OOH F N H (26) 5 Synthesis of Compound (26): Compound (26) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (26). 1 H NMR (300 MHz, CDCI3) : 6 8.15(brs, 1H), 7.00-7.09(m, 3H), 6.67-6.73(t, 1H), 4.99(s, 1H), 4.25(s, 1H), 3.59(m, 1H), 10 2.90(s, 1H), 2.63-2.70(s, 1H), 2.26-2.31(m,2H), 1.85(m, 3H), 1.60-1.72(m,6H), 1.35 1.40(d,3H). LC-MS: (M+H)+ = 357.2; HPLC purity = 97.11 %. EXAMPLE 27: 3-(4-fluoro-1H-indol-3-yl)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
'
7 ]dec-2 yl)butan-1 -one (27) F OOH N 15 H (27) Synthesis of Compound (27) (peak-1): Racemate of Compound (26) was separated by using chiral HPLC to give enantiomer, Compound (27) (peak-1). 1H NMR (300 MHz, CDCI3): 6 8.15(brs, 1H), 7.00-7.09(m, 3H), 6.67-6.73(t, 1H), 4.99(s, 1H), 4.25(s, 1H), 3.59(m, 1H), 20 2.90(s, 1H), 2.63-2.70(s, 1H), 2.26-2.31(m,2H), 1.85(m, 3H), 1.60-1.72(m,6H), 1.35 1.40(d,3H). LC-MS: (M+H)+ = 357.2; HPLC purity = 99.60%; Column: Chiralpak IA. 4.6mmX250mm, mobile phase: Hexanes: EtOH (8:2), chiral purity 92.25% (RT 12.52 min). 101 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 28: 3-(4-fluoro-1H-indol-3-yl)-1 -(5-hydroxy-2-azatricyclo[3.3.1.1 3
'
7 ]dec-2 yI)butan-1 -one (28) F OOH F N H (28) 5 Synthesis of Compound (28) (peak-2): Racemate of Compound (26) was separated by using chiral HPLC to give enantiomer, Compound (28) (peak-2). 1H NMR (300 MHz, CDCI3) : 6 8.15(brs, 1H), 7.00-7.09(m, 3H), 6.67-6.73(t, 1H), 4.99(s, 1H), 4.25(s, 1H), 3.59(m, 1H), 2.90(s, 1H), 2.63-2.70(s, 1H), 2.26-2.31(m,2H), 1.85(m, 3H), 1.60-1.72(m,6H), 1.35 1.40(d,3H). LC-MS: (M+H)+ = 357.2; HPLC purity = 94.43 %; Column: Chiralpak IA. 10 4.6mmX250mm, mobile phase: Hexanes: EtOH (8:2), Chiral purity = 99.69% (RT= 11.13 min). EXAMPLE 29: 3-(4-fluoro-1H-indol-3-yl)-1-(5-methoxy-2-azatricyclo[3.3.1.1 3 ']dec-2 yl)butan-1-one (29) F N H 15 (29) Synthesis of Compound (29): Compound (29) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (29). 1H NMR (300 MHz, CDCl3) 20 68.06(brs, 1H), 7.02-7.07(m, 1H), 6.97-7.01(m, 1H), 6.94-6.95(d, 1H), 6.66-6.72(dd,1H), 4.26(brs, 1H), 4.26(brs, 1H), 3.5-3.6(m, 1H), 3.05-3.12(d, 3H), 2.8-2.89(m, 1H), 2.41-2.48(m, 1H), 2.17-2.23(m, 1H), 1.48-1.72 (m, 10H), 1.36-1.38(d, 3H). LC-MS: (M+H)+ = 371.2; HPLC purity = 97.80 %. 102 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 30: 3-(4-fluoro-1H-indol-3-yl)-1-(5-methoxy-2-azatricyclo[3.3.1.1 3 '7]dec-2 yl)butan-1-one (30) 0~ o N O F N H (30) 5 Synthesis of Compound (30) (peak-1): Racemate of Compound (29) was separated by using chiral HPLC to give enantiomer Compound (30) (peak-1). 1H NMR (300 MHz, CDCI3): 68.06(brs, 1H), 7.02-7.07(m, 1H), 6.97-7.01(m, 1H), 6.94-6.95(d, 1H), 6.66-6.72(dd,1H), 4.26(brs, 1H), 4.26(brs, 1H), 3.5-3.6(m, 1H), 3.05-3.12(d, 3H), 2.8-2.89(m, 1H), 2.41-2.48(m, 1H), 2.17-2.23(m, 1H), 1.48-1.72 (m, 10H), 1.36-1.38(d, 3H). LC-MS: (M+H)+ = 371.2; HPLC 10 purity = 99.56 %; Chiral purity = 99.75% (RT=13.52 min, Column: Chiral pack IA, 4.6mmX250mm, mobile phase: MTBE:MeOH (98:02). EXAMPLE 31: 3-(4-fluoro-1H-indol-3-yl)-I-(5-methoxy-2-azatricyclo[3.3.1.13,']dec-2 yl)butan-1-one (31) o N O F N 15 H (31) Synthesis of Compound (31) (peak-2): Racemate of Compound (29) was separated by using chiral HPLC to give enantiomer Compound (31). 1H NMR (300 MHz, CDCI3) : 6 68.06(brs, IH), 7.02-7.07(m, 1H), 6.97-7.01(m, IH), 6.94-6.95(d, 1H), 6.66-6.72(dd,1H), 20 4.26(brs, 1H), 4.26(brs, 1H), 3.5-3.6(m, 1H), 3.05-3.12(d, 3H), 2.8-2.89(m, 1H), 2.41-2.48(m, 1H), 2.17-2.23(m, 1H), 1.48-1.72 (m, 10H), 1.36-1.38(d, 3H). LC-MS: (M+H)+ = 371.2; HPLC purity = 95.79%; Chiral purity = 99.88% (RT=16.37 min, Column: Chiral pack IA, 4.6mmX250mm, mobile phase: MTBE:MeOH (98:02). 103 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 32: 1-(5-chloro-2-azatricyclo[3.3.1 .1 3
'
7 ]dec-2-yl)-3-(4-fluoro-1 H-indol-3 yl)butan-1 -one (32) O N cl F N H (32) 5 SYNTHETIC SCHEME 13 O NOH O NC 0 X lntermdiate 6 Intermediate 43 Intermdiate 44 Synthesis of tert-butyt 5-chloro-2-azatricyclo(3.3.1.1 3
'
7 ]decane-2-carboxylate 10 (Intermediate-43): To a stirred solution of Intermediate-6 (70 mg, 0.19mmol) in CC14 (3 mL), SOC12 (1.5 mL) was added and the reaction mixture was heated at 800C for 15 hours. After reaction was completed (reaction was monitored by LC-MS), reaction mass was concentrated to give Intermediate-43 (60 mg). 15 Synthesis of 5-chloro-2-azatricyclo[3.3.1 .1 3
'
7 ]decane, trifluoroacetic acid salt (Intermediate-44): Intermediate-44 was synthesized by following the procedure used to make Intermediate-20 (Scheme 1). 20 Synthesis of Compound (32): Compound (32) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate as eluent to obtain Compound (32).1H NMR (300 MHz, 25 CDC13) : 6 8.02-8.06(d, 1H), 7.01-7.09(m, 2H),6.94(s,1H), 6.67-6.73(m, 1H), 4.95(s, 1H), 4.20(s, 1H), 3.54-3.61(m, 1H), 2.79-2.88(m, 1H), 2.40-2.49(m, 1H), 2.12-2.26(m,4H), 1.81 2.02(m, 3H), 1.58(m,4H), 1.36-1.43(d,3H).. LC-MS: (M+H)+ = 376.1; HPLC purity = 90.30%. 104 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 33: 1 -[5-(cyclopropylmethoxy)-2-azatricyclo[3.3.1 .1 3
'
7 ]dec-2-yl]-3-(4-fluoro 1H-indol-3-yl)butan-1 -one (33)
-
/ N N H (33) 5 Synthesis of Compound (33): Compound (33) was synthesized by using intermediate 20 and following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (33). 1 H NMR (300 MHz, CDCl3) : 68.07(s, 1H), 6.97-7.07(m, 2H),6.95-6.94(d,1H), 6.66-6.72(t, 1H), 10 4.97(s, 1H), 4.25(s, 1H), 3.53-3.60(m, 1H),3.00-3.12(dd, 2H), 2.79-2.89(m, 1H), 2.40-2.50(m, 1H), 2.16-2.25(d,1H),2.13-2.26(d,1H), 1.54-1.74(m,8H), 1.36-1.38(d,3H), 0.87-.89(m,1H) 0.41-0.47(m,2H), 0.07(m,2H). LC-MS: (M+H)+ = 411.2; HPLC purity = 96.10 %. EXAMPLE 34: 3-(1H-indol-3-yl)-1-(5-methoxy-2-azatricyclo[3.3. 1.13'] dec-2-yl)butan-1 15 one (34) 0 N O N H (34) Synthesis of Compound (34): Compound (34) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating 20 the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (34). 1H NMR (300 MHz, CDCl3) : 6 7.95(brs, 1H), 7.59-7.62(d, 1H), 7.26-7.29(d, 1H) 7.07(m, 2H), 6.95(s, 1H), 4.99(brs, 1H), 4.10(brs, 1H), 3.50-3.67(m, 1H), 3.00-3.12(d, 3H), 2.74-2.82(m, 1H), 2.42 2.52(m, 1H), 2.15-2.12(m, 1H), 1.46-1.72 (m, 6H), 1.36-1.38(d, 3H), 0.99-1.46 (m, 4H). LC 25 MS: (M+H)+ = 353.2; HPLC purity = 90.44 %. 105 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 35: 3-(4-chloro-1 H-indol-3-yl)-1 -(5-hydroxy-2-azatricyclo[3.3. 1.13'] dec-2 yl)butan-1 -one (35) 0 NOH CI N H (35) 5 Synthesis of Compound (35): Compound (35) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (35). 1H NMR (300 MHz, CDC13) : 6 8.44(brs, 1H), 7.01-7.19(m, 1H), 6.95-7.011(m, 3H),4.99(brs, 1H), 4.23(brs, 1H), 3.99-4.06(m, 10 1H), 2.82-2.87(m, 1H), 2.40-2.50(m, 1H), 1.34-2.22(m, 14H). LC-MS: (M+H)+ = 373.2; HPLC purity = 93.64 %. EXAMPLE 36: 3-(4-chloro-IH-indol-3-yl)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
,
7 ]dec-2 yl)butan-1 -one (36) 0 OH O N o ci N 15 H (36) Synthesis of Compound (36) (peak-1): Racemate of Compound (35) was separated by using chiral HPLC to give enantiomer Compound (36) (peak-1). 1H NMR (300 MHz, CDC13) 6 8.44(brs, 1H), 7.01-7.19(m, 1H), 6.95-7.011(m, 3H),4.99(brs, 1H), 4.23(brs, 1H), 3.99-4.06(m, 20 1H), 2.82-2.87(m, 1H), 2.40-2.50(m, 1H), 1.34-2.22(m, 14H). LC-MS: (M+H)+ = 373.2; HPLC purity = 91.31 %; Chiral purity = 98.36% (RT = 17.89 min). 106 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 37: 3-(4-chloro-1H-indol-3-yI)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
'
7 ]dec-2 yl)butan-1 -one (37) O NOH ci N H (37) 5 Synthesis of Compound (37) (peak-2): Racemate of Compound (35) was separated by using chiral HPLC to give enantiomer Compound (37) (peak-2). I H NMR (300 MHz, CDCl3) 6 8.44(brs, 1H), 7.01-7.19(m, IH), 6.95-7.011(m, 3H),4.99(brs, 1H), 4.23(brs, 1H), 3.99-4.06(m, 1H), 2.82-2.87(m, 1H), 2.40-2.50(m, IH), 1.34-2.22(m, 14H). LC-MS: (M+H)+ = 373.2; HPLC purity = 97.96 %; Chiral purity = 99.11% (RT = 15.94 min). 10 EXAMPLE 38: 1 -[5-(cyclopropylmethoxy)-2-azatricyclo[3.3.1 .1 3
'
7 ]dec-2-yl]-3-(1 H-indol-3 yl)butan-1 -one (38) o N o0 N H (38) 15 Synthesis of Compound (38): Compound (38) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (38). 1H NMR (300 MHz, CDC13) : 6 7.92(brs, 1 H), 7.59-7.62(d, 1H), 7.26-7.29(d,2H), 7.01-7.02(m,2H), 4.98(brs,1H), 20 4.09(brs,1H), 3.45-3.61(m, 1H), 3.08-3.16(dd, 2H), 2.55-2.64(m, 2H), 2.09-2.36(m,2H), 1.61 1.82(m, 9H), 1.41-1.43(d,3H), 0.86-0.89(m,1H), 0.41-0.47(m,2H), 0.07(m,2H). LC-MS: (M+H)+ 393.3; HPLC purity = 95.10 %. 107 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 39: 3-(4-chloro-1H-indol-3-yl)-1-[5-(difluoromethoxy)-2-azatricyclo [3.3.1.1 3 ,7]dec-2-yl]butan-1 -one (39) O N D O _F cl F N H (39) 5 Synthesis of Compound (39): Compound (39) was synthesized by following the procedure used to make and Compound (1) (Scheme 2) and Compound (13) (Scheme 8). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate as eluent to obtain Compound (39). 1H NMR (300 MHz, CDCI3) : 6 8.22(brs, 1H), 7.06(brs, 2H), 6.99-7.01(m, 10 2H), 5.9-6.4(t, 1H), 5.03(brs, 1H), 4.26(brs, 1H), 4.03-4.04(m, 1H), 2.83-2.87(m, 1H), 2.49 2.57(m, 1H), 2.28(brs, 1H), 1.93(m, 1H), 1.62-2.01 (m, 10H), 1.38-1.41(d, 3H). LC-MS: (M+H)+ = 423.2; HPLC purity = 92.19 %. EXAMPLE 40: 3-(4-bromo-1 H-indol-3-yl)-1 -(5-hydroxy-2-azatricyclo[3.3.1 .1 3
'
7 ]dec-2 15 yl)butan-1-one (40) 0 OH Br N H (40) Synthesis of Compound (40): Compound (40) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the 20 organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (40). 1 H NMR (300 MHz, DMSO-d6) 6 11.21 (brs, 1H), 7.32-7.36 (m, 2H), 7.14-7.17 (d, 1H), 6.92-6.97 (t, 1H), 4.80(brs, 1H), 4.66 (s, 1H), 4.33(brs, 1H), 3.99-4.06 (m, 1H), 2.50-2.55 (m, 1H), 2.19(brs, 1H), 1.69(brs, 2H), 1.62-2.01 (m, 8H), 1.38-1.41(d, 3H). LC-MS: (M+H)+ = 418.1; HPLC purity = 92.77%. 25 108 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 41: 3-(4-cyclopropyl-1 H-indol-3-yi)-1 -(5-hydroxy-2-azatricyclo[3.3.1 .1 3
'
7 ]dec 2-yl)butan-1 -one (41) 0 N OH N N H (41) 5 Synthesis of Compound (41): Compound (41) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (41). 1H NMR (300 MHz, CDC13) : 6 7.97(brs, 1H), 7.01-7.1 (d, 1H), 6.97-7.02 (m, 2H, 6.66-6.68 (d, 1H), 5.03(brs, 1H), 4.19(brs, 10 2H), 2.77-2.83(m, 1H), 2.35-2.44(m, 2H), 2.24(brs, 1H), 1.75(brs, 2H), 1.57-1.66 (m, 8H), 1.36-1.38(d, 3H), 0.73-0.94 (m, 4H). LC-MS: (M+H)+ 379.2; HPLC purity = 97.64%. EXAMPLE 42: 3-[4-(5-hydroxy-2-azatricyclo[3.3.1 1 3
'
7 ]dec-2-yl)-4-oxobutan-2-yl]-1 H indole-4-carbonitrile (42) 0 NOH CN N 15 H (42) Synthesis of Compound (42): Compound (42) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using 20 Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (42). 1 H NMR (300 MHz, CDC13) : 68.97(s,1H), 7.47-7.50(d,1H), 7.38-7.40(d,IH), 7.18(m,1H), 7.07-7.13(m,1H), 4.95(s,1H), 4.30(s,1H), 3.86-3.93(m,1H), 2.81-2.91(m,1H), 2.56-2.66(m,1H), 2.23(s,1H), 1.57 1.74(m,10H), 1.39-1.41(d,3H). LC-MS: (M+H)+ = 364.2; HPLC purity = 97.36%. 109 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 41: 3-(4-cyclopropyl-1H-indol-3-yl)-1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3 '7]dec 2-yl)butan-1 -one (41) O N@ OH N H (41) 5 Synthesis of Compound (41): Compound (41) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (41). 1H NMR (300 MHz, CDCl3) : 6 7.97(brs, 1H), 7.01-7.1 (d, 1H), 6.97-7.02 (m, 2H, 6.66-6.68 (d, 1H), 5.03(brs, 1H), 4.19(brs, 10 2H), 2.77-2.83(m, 1H), 2.35-2.44(m, 2H), 2.24(brs, 1H), 1.75(brs, 2H), 1.57-1.66 (m, 8H), 1.36-1.38(d, 3H), 0.73-0.94 (m, 4H). LC-MS: (M+H)+ = 379.2; HPLC purity = 97.64%. EXAMPLE 42: 3-[4-(5-hydroxy-2-azatricyclo[3.3.1.13, 3 7 ]dec-2-yl)-4-oxobutan-2-yl]-1 H indole-4-carbonitrile (42) C OOH cN CN 15 H (42) Synthesis of Compound (42): Compound (42) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using 20 Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (42). 1H NMR (300 MHz, CDC13) : 58.97(s,1H), 7.47-7.50(d,1H), 7.38-7.40(d,1H), 7.18(m,1H), 7.07-7.13(m,1H), 4.95(s,1 H), 4.30(s,IH), 3.86-3.93(m, 1 H), 2.81-2.91(m, 1H), 2.56-2.66(m,1 H), 2.23(s,1 H), 1.57 1.74(m,10H), 1.39-1.41(d,3H). LC-MS: (M+H)+ = 364.2; HPLC purity 97.36 %. 109 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 43: 2-[3-(4-chloro-1H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1 .1 3
'
7 ]decane-5 carboxylic acid (43) OH 0 N O Cl N H (43) 5 SYNTHETIC SCHEME 14 0 OH 0 N O NO CI Cl N N H H Intermediate 45 (43) Synthesis of Compound (43): Compound (43) was synthesized by following the procedure used to make Intermediate-26 (Scheme 4). The crude product was obtained by evaporating 10 the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (43). 1H NMR (300 MHz, CDC3) : 6 12.25(s,1H), 11.20(s,1H), 7.29-7.31(m,2H), 6.96-7.04(m,2H), 4.78(s,1H), 4.28(s,1H), 3.92-3.99(m,1H), 2.55-2.76(m,2H), 2.11(s,1H), 1.59-1.89(m,10H), 1.26-1.28(d,3H). LC-MS: (M+H)+ = 401.1; HPLC purity = 89.33 %. 15 EXAMPLE 44: 3-[4-(4-chlorophenoxy)-1H-indol-3-yl]-1-(5-hydroxy-2 azatricyclo[3.3.1.1 3
,
7 ]dec-2-yl)butan-1 -one (44) Cl N' OH N H (44) 20 Synthesis of Compound (44): Compound (44) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum 110 WO 2013/111150 PCT/IN2012/000842 ether: Ethyl acetate (1:4) as eluent to obtain Compound (44). 1H NMR (300 MHz, CDCl3) : 5 8.12(s,1H), 7.21-7.24(m,2H), 7.04-7.07(m,2H), 6.94-7.01(m,2H), 6.92-6.93(m,1H), 6.40 6.43(d,1H), 4.94(s,1H), 4.11(s,1H), 3.57-3.63(m,1H), 2.78-2.85(m,1H), 2.32-2.42(m,1H), 2.16(s,1H), 1.66-1.69(d,3H), 1.43-1.47(m,7H), 1.38-1.39(d,3H). LC-MS: (M+H)+ = 465.2; 5 HPLC purity = 99.73 %. EXAMPLE 45: 2-[3-(4-chloro-1H-indol-3-yl)butanoyl]-N-(4-fluorophenyl)-2 azatricyclo[3.3.1 .1 3 7 ]decane-5-carboxamide (45) F NH CI o N O N 10 H (45) SYNTHETIC SCHEME 15 F OH NH 0 0 CIS ) NO
NH
2 HOBt, EDCI CI O NO C1TEA, 0CM C1 N N H F H (43) Starting Material 12 (45) 15 Synthesis of Compound (45): Compound (45) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (45). 1H NMR (300 MHz, CDCl3): 5 20 8.21-8.24(d,1H), 7.34-7.42(m,2H), 7.19(m,2H), 6.91-7.04(m,5H), 4.96(s,1H), 4.18(s,1H), 4.01-4.12(m,1H), 2.80-2.89(m,1H), 2.41-2.59(m,1H), 2.19-2.26(m,1H), 1.60-1.97m,1OH), 1.37-1.40(m,3H). LC-MS: (M+H)+ = 494.2; HPLC purity = 98.06%. 111 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 46: 3-[4-chloro-1-(methylsulfonyl)-1H-indol-3-yI]-1-(5-hydroxy-2 azatricyclo[3.3.1.1 3 ']dec-2-yI)butan-1 -one (46) 0 Na OH c N (46) 5 Synthesis of Compound (46): Compound (46) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (46). 1H NMR (300 MHz, CDCI3) : 6 7.74-7.77(m, 1H), 7.20-7.22(m, 3H), 5.01(s, 1H), 4.22(s, 1H), 4.08(s, 1H), 3.02(s,3H), 2.73 10 2.802(m,1H), 2.33-2.42(m,1H), 2.28(s,1H), 1.77(s,2H), 1.60-1.66(m,9H), 1.34-1.36(d,3H). LC MS: (M+H)+ = 451.1; HPLC purity = 94.52 %. EXAMPLE 47: 2-[3-(4-chloro-1H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1.1 3
,
7 ]decane-5 carboxamide (47) 0 O N NH 2 ci N 15 H (47) SYNTHETIC SCHEME 16 N N OH N N NH2 H O (43) (47) Intermediate 46 20 112 WO 2013/111150 PCT/IN2012/000842 Synthesis of tert-butyl 3-(4-(5-carbamoyl-2-azaadamantan-2-y)-4-oxobutan-2-y)-4 chloro-1H-indole-1-carboxylate (Intermediate-46): To a stirred solution of compound 43 (0.070 g, 0.17 mmol) in MeCN (2 mL), pyridine (0.016 g, 0.21 mmol) was added, followed by di-tert-butyl dicarbonate (0.045 g, 0.21 mmol) and stirred for 1 hour at room temperature. To 5 this solution solid ammonium bicarbonate (0.021 g, 0.27 mmol) was added and stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was quenched with H 2 0 and extracted with EtOAc and concentrated to give Intermediate-46 (30 mg) as white solid. 10 Synthesis of Compound (47): To a stirred solution of Intermediate-46 (0.030 g, 0.017 mmol) in DCM (1 mL), TFA (0.013 g, 0.11 mmol) was added at 0*C and stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated to remove DCM and TFA. The reaction mixture was further diluted with H 2 0 and extracted with EtOAc and was then concentrated to give crude material which was purified by 15 using Silica-gel column chromatography eluting with mixture of hexanes: EtOAc to give Compound (47) (145 mg) as white solid. 1H NMR (300 MHz, CDC13) : 611.20(s,1H), 7.29 7.31(d,2H), 6.96-7.04(m,3H), 6.81(s,1H), 4.74(s,1H), 4.28(s,1H), 3.89-4.02(m,1H), 2.68 2.72(m,2H), 2.10(s,1H), 1.62-1.85(m,10H), 1.26-1.28(d,3H). LC-MS: (M+H)+ = 400.2; HPLC purity = 99.92 %. 20 EXAMPLE 48: 1 -(5-hydroxy-2-azatricyclo[3.3.1.1 3 7 ]dec-2-yI)-3-(4-methyl-1H-indol-3 yl)butan-1 -one (48) N OH N H (48) 25 113 WO 2013/111150 PCT/IN2012/000842 SYNTHETIC SCHEME 17 0 0 0 0 0 OH Br N N N H H H Intermediate 47 Intermediate 48 Intermediate 49 5 Synthesis of ethyl 3-(4-bromo-1H-indol-3-yl)butanoate (Intermediate-47): Intermediate-47 was synthesized by following the procedure used to make Intermediate-41 (Scheme 11). 10 Synthesis of ethyl 3-(4-methyl-1,H-indol-3-yl)butanoate (Intermediate-48): A 100 mL RB flask fitted with magnetic stirrer and reflux condenser was charged with 25 mL of toluene and 5 mL of water. To the stirred solvent Intermediate-47 (4.4 g, 14.185 mmol) was added followed by the addition of methyl boronic acid (1.696 g, 28.37 mmol), Potassium phosphate tribasic (10.535 g, 49.647 mmol) and tricyclohexyl phosphine (0.397 g, 1.4185 15 mmol). The resulting mass was stirred at room temperature under argon purging for 30 minutes. Then Palladium acetate (0.159, 0.7092 mmol) was added and the resulting mixture was stirred at 100*C for 16 hours. After completion of the reaction reaction mass was diluted with 10 mL of water and was extracted with ethyl acetate (100 mL X 3) and the combine organic layer was washed with brine solution and was dried over anhydrous sodium sulfate 20 and solvent from the organic layer was removed under reduced pressure to yield the crude compound. Crude mass was purified by column chromatography using 60-120 silica gel and 8% of ethyl acetate in Pet ether as eluent to give Intermediate-48 (2.55 g). Synthesis of 3-(4-methyl-1H-indol-3-yl)butanoic acid (Intermediate-49): 25 Compound Intermediate-49 was synthesized by following the procedure used to make Intermediate-42(Scheme 11). Synthesis of Compound (48): Compound (48) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the 30 organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (48). 1 H NMR (300 MHz, DMSO-d6) 114 WO 2013/111150 PCT/IN2012/000842 6 10.78(s,1H), 7.12-7.15(d,2H), 6.87-6.92(t,1H), 6.67-6.69(d,1H), 4.80(s,1H), 4.64 4.65(d,1H), 4.33(s,1H), 3.69-3.76(m,1H), 2.63-2.68(m,2H), 2.60(s,3H), 2.15-2.19(d,1H), 1.68(s,2H), 1.42-1.63(m,8H), 1.23-1.25(d,3H). LC-MS: (M+H)+ = 353.2; HPLC purity = 98.43 %. 5 EXAMPLE 49: 1 -(5-hydroxy-2-azatricyclo[3.3. 1.13 ,7 ]dec-2-yl)-3-(4-methyl-1 H-indol-3 yl)butan-1 -one (49) 0 NOH N H (49) 10 Synthesis of Compound (49) (Peak-1): Racemate of Compound (48) was separated by using chiral HPLC to give enantiomer Compound (49) (peak-1). 1H NMR (300 MHz, DMSO d6) : 6 10.78(s,1H), 7.12-7.15(d,2H), 6.87-6.92(t,1H), 6.67-6.69(d,1H), 4.80(s,1H), 4.64 4.65(d,1H), 4.33(s,1H), 3.69-3.76(m,1H), 2.63-2.68(m,2H), 2.60(s,3H), 2.15-2.19(d,1H), 1.68(s,2H), 1.42-1.63(m,8H), 1.23-1.25(d,3H). LC-MS: (M+H)+ = 353.2; HPLC purity = 95.87 15 %; Chiral purity = 100% (RT = 17.45 min), Column: Chiralpak IC 4.6mmX250mm, Mobile phase, hexane :IPA:DCM (75:15:10). EXAMPLE 50: 1-(5-hydroxy-2-azatricyclo[3.3.1.1 3 ' ]dec-2-yl)-3-(4-methyl-1 H-indol-3 yl)butan-1-one (50) o N OH N 20 H (50) Synthesis of Compound (50) (peak-2): Racemate of Compound (48) was separated by using chiral HPLC to give enantiomer, Compound (50) (peak-2). 1H NMR (300 MHz, DMSO d6) : 6 10.78(s,1H), 7.12-7.15(d,2H), 6.87-6.92(t,1H), 6.67-6.69(d,1H), 4.80(s,1H), 4.64 25 4.65(d,1H), 4.33(s,1H), 3.69-3.76(m,1H), 2.63-2.68(m,2H), 2.60(s,3H), 2.15-2.19(d,1H), 1.68(s,2H), 1.42-1.63(m,8H), 1.23-1.25(d,3H). LC-MS: (M+H)+ = 353.2; HPLC purity = 98.64 %; Chiral purity = 100% (RT = 21.17 min), Column: Chiralpak IC 4.6mmX250mm, Mobile phase, hexane :IPA:DCM (75:15:10). 115 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 51: 2-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]-2 azatricyclo[3.3.1.1 3
'
7 ]decane-5-carboxylic acid (51) OH 0 N N H (51) 5 Synthesis of Compound (51): Compound (51) was synthesized by following the procedure used to make Compound 43 (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum DCM: MeOH as eluent to obtain Compound (51). 1H NMR (300 MHz, DMSO-d6) : 6 12.23(s,1H), 10.801(s,1H), 7.11-7.17(m,2H), 6.88-6.93(t,1H), 6.55-6.58(d,1H), 4.75(s,1H), 10 4.26(s,1H), 4.01-4.04(m,1H), 3.37-3.41(m,2H), 2.68-2.73(m,1H), 2.09(s,1H), 1.62 1.88(m,13H), 0.85-00.91(m,2H), 0.70-0.77(m,2H). LC-MS: (M+H)+ = 407.2; HPLC purity = 91.19%. EXAMPLE 52: 2-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]-2 15 azatricyclo[3.3.1 .1 3
'
7 ]decane-5-carboxylic acid (52) OH 0 N O N H (52) Synthesis of Compound (52) (peak-1): Racemate of Compound (51) was separated by using chiral HPLC to give enantiomer Compound (52) (peak-1) . 1H NMR (300 MHz, DMSO 20 d6) : 6 12.23(s,1H), 10.801(s,1H), 7.11-7.17(m,2H), 6.88-6.93(t,1H), 6.55-6.58(d,1H), 4.75(s,1 H), 4.26(s,1 H), 4.01-4.04(m,1 H), 3.37-3.41 (m,2H), 2.68-2.73(m, 1 H), 2.09(s,1 H), 1.62 1.88(m,13H), 0.85-00.91(m,2H), 0.70-0.77(m,2H). LC-MS: (M+H)+ = 407.3; HPLC purity = 89.77 %; Chiral purity = 100% (RT = 8.29 min), Column: Chiralpak IC 4.6mmX250mm, Mobile phase, hexane :IPA:DCM (75:15:10). 25 116 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 53: 2-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]-2 azatricyclo[3.3.1.13, 7 ]decane-5-carboxylic acid (53) OH 0 N O N H (53) 5 Synthesis of Compound (53) Peak-2: Racemate of Compound (51) was separated by using chiral HPLC to give enantiomer, Compound (53) (peak-2). 1H NMR (300 MHz, DMSO-d6) : 5 12.23(s,1H), 10.801(s,1H), 7.11-7.17(m,2H), 6.88-6.93(t,1H), 6.55-6.58(d,1H), 4.75(s,1H), 4.26(s,1H), 4.01-4.04(m,1H), 3.37-3.41(m,2H), 2.68-2.73(m,1H), 2.09(s,1H), 1.62 1.88(m,13H), 0.85-00.91(m,2H), 0.70-0.77(m,2H). LC-MS: (M+H)+ = 407.3; HPLC purity = 10 86.37%; Chiral purity = 94.78% (RT = 11.60 min), Column: Chiralpak IC 4.6mmX250mm, Mobile phase, hexane :IPA:DCM (75:15:10). EXAMPLE 54: 2-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]-2 azatricyclo[3.3.1.1 3
'
7 ]decane-5-carboxylic acid sodium salt (sodium salt) (54) O-Na* 0 N o N 15 H (54) SYNTHETIC SCHEME 18 OH ONa* NS0 N N N H H (51) (54) 20 Synthesis of Compound (54) (Sodium salt): To a stirred solution of Compound (51) (306 mg, 0.72 mmol) in THF: MeOH: H 2 0 (2 mL: 3mL: 1mL), sodium hydroxide (26 mg, 0.65 117 WO 2013/111150 PCT/IN2012/000842 mmol) was added at 00C. Resulted reaction mixture was allowed to stir at room temperature for 16 hours. Then reaction mixture was concentrated, followed by trituration with mixture of hexane : ether to give Compound (54) (sodium salt) (25 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) : 6. 10.92 (s,1H), 7.12-7.15(m,2H), 6.87-6.92(t,1H), 6.54-6.57(d,1H), 5 4.69(s,1 H), 4.1 7(s,1 H), 4.02-4.03(m,1 H), 3.39-3.41(m,2H), 2.61-2.7(m,2H), 1.28 1.79(m,13H), 0.89-0.92(m,2H), 0.70-0.76(m,2H)LC-MS: (M+H)+ = 407.3; HPLC purity = 96.31 %. EXAMPLE 55: 2-[3-(4-bromo-1 H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1.1 ']decane-5 10 carboxylic acid (55) OH 0 N O Br N H (55) Synthesis of Compound (55): Compound (55) was synthesized by following the procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating 15 the organic layer under reduced pressure and was purified by silica gel column using Petroleum DCM: MeOH as eluent to obtain Compound (55). 1H NMR (300 MHz, DMSO-d6) 6 12.25(s,1H), 11.20(s,1H), 7.32-7.36(m,2H), 7.14-7.17(d,1H), 6.92-6.97(t,1H), 4.74(s,1H), 4.28(s,1H), 4.01-4.05(m,1H), 2.70-2.77(m,2H), 2.11(s,2H), 1.60-1.89(m,9H), 1.26-1.28(d,3H). LC-MS: (M+H)+ = 445.1; HPLC purity = 90.50 %. 20 EXAMPLE 56: 2-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]-2 azatricyclo[3.3.1 .13 7]decane-5-carboxamide (56)
NH
2 O N o N H (56) 25 Synthesis of Compound (56): Compound (56) was synthesized by following the procedure used to make Compound (47) (Scheme 16). The crude product was obtained by. evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (56). 1H NMR (300 MHz, 118 WO 2013/111150 PCT/IN2012/000842 DMSO-d6) 6 10.79(s, 1H), 9.50(s, 2H), 7.01-7.17(m, 1H), 6.88-6.93(m, 1H), 6.79(s, 1H), 6.55-6.58(d, 1H), 4.74(s,1H), 4.26(s,1H), 4.01-4.04(d,1H), 2.6-2.8(m,3H), 2.07-2.08(m,2H), 1.15-1.98(m,12H), 0.83-0.95(m,2H), 0.70-0.95(m,2H). LC-MS: (M+H)+ = 406.2; HPLC purity = 88.73 %. 5 EXAMPLE 57: 2-[3-(4-methyl-1H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1.1 3
'
7 ]decane-5 carboxylic acid (57) OH 0 N O N H (57) 10 Synthesis of Compound (57): Compound (57) was synthesized by following the procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (57). 1H NMR (300 MHz, DMSO-d6) : 6 12.25(s,1H), 10.78(s,1H), 7.12-7.15(m,2H), 6.87-6.92(t,1 H), 6.67-6.69(d,1 H), 4.74(s,1 H), 4.28(s,1 H), 3.76 15 3.80(m,1H), 2.61-2.68(m,5H), 2.08-2.11(m,1H), 1.48-1.88(m,10H), 1.24-1.26(d,3H). LC-MS: (M+H)+ = 381.2; HPLC purity = 99.05 %. EXAMPLE 58: 3-(4-chloro-1 H-indol-3-yl)-1 -[5-(hyd roxymethyl)-2 azatricyclo[3.3.1 .1 3 ,7]dec-2-yl]butan-1 -one (58) OH 0 oN ci N 20 H (58) Synthesis of Compound (58): Compound (58) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using 25 Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (58). 1H NMR (300 MHz, CDCl3) : 6 11.19(s,1H), 7.28-7.31(m,2H), 6.96-7.04(m,2H), 4.72(s,IH), 4.42-4.45(m,1H), 4.24(s,1 H), 3.91-3.95(m,1 H), 2.99-3.01(m,2H), 2.67-2.75(m,3H), 2.07(s,1 H), 1.42 1.63(m,9H), 1.25-1.28(d,3H). LC-MS: (M+H)+ = 387.1; HPLC purity = 97.41 %. 119 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 59: 2-[3-(4-chloro-1H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1.1 3
,
7 ]decane-5 carbonitrile (59) ON CN ci N H 5 (59) Synthesis of Compound (59): Compound (59) was synthesized by following the procedure used to make Compound (1)-(Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (59). 1H NMR (300 MHz, 10 CDCI3) : 6 8.10(s,1H), 7.21-7.25(m,1H), 7.00-7.03(m,3H), 4.90(s,1H), 4.02-4.12(m,2H), 2.77 2.87(m,1H), 2.37-2.49(m,1H), 2.06-2.12(m,3H), 1.60-1.94(m,8H), 1.37-1.40(m,3H). LC-MS: (M+H)+ = 382.3; HPLC purity = 97.62 %. EXAMPLE 60: 3-(4-chloro-2-methyl-1H-indol-3-yI)-1-(5-hydroxy-2 15 azatricyclo[3.3.1 .1 3 ']dec-2-yl)butan-1 -one (60) o N OH ci N H (60) Synthesis of Compound (60): Compound (60) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating 20 the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (60). 1H NMR (300 MHz, CDCl3) : 6 7.86-7.89(d,1H), 7.08-7.10(d,1H), 6.99-7.03(m,1H), 6.88-6.94(t,1H), 4.91 5.00(m,1H), 4.00-4.33(m,2H), 2.56-2.67(m,1H), 2.40(s,3H), 2.21-2.24(m,1H), 1.74 1.80(m,2H), 1.54(m,9H), 1.36-1.38(d,3H). LC-MS: (M+H)+ = 387.1; HPLC purity = 98.42%. 25 120 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 61: 2-[3-(1H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1.13,' 7 ]decane-5-carboxylic acid (61) OH 0 O N O N H (61) 5 Synthesis of Compound (61): Compound (61) was synthesized by following the procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (61). 1H NMR (300 MHz, DMSO-d6) : 6 12.21(s,1H), 10.77(s,1H), 7.51-7.54(d,1H), 7.29-7.32(m,1H), 7.12-7.13(d,1H), 7.01-7.06(t,1H), 6.92 10 6.97(t,1H), 4.72(s,1H), 4.20(s,1H), 3.39-3.45(m,1H), 2.65-2.72(m,1H), 2.09(s,1H), 1.85(s,2H), 1.73-1.77(d,3H), 1.43-1.66(m,6H), 1.29-1.31(d,3H). LC-MS: (M+H)+ = 367.2; HPLC purity = 93.96 %. EXAMPLE 62: 2-{3-[4-(4-fluorophenyl)-1H-indol-3-yl]butanoyl}-2 15 azatricyclo[3.3.1.1 3 7 ]decane-5-carboxylic acid (62) F OH NN 0 N H (62) Synthesis of Compound (62): Compound (62) was synthesized by following the procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating 20 the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (62). 1H NMR (300 MHz, CDCI3) : 6 8.30(s,1H), 7.31 7.39(m,2H), 7.25-7.29(d,1H), 7.08-7.12(t,1H), 7.04-7.05(m,3H), 6.82-6.85(d,1H), 4.75(s,1H), 3.56-3.68(t,1H), 3.13-3.14(d,1H), 2.25-2.30(m,2H), 1.88-1.92(m,3H), 1.71-1.75(m,6H), 1.58(s,3H), 1.48-1.54(d,2H). LC-MS: (M+H)+ = 461.2; HPLC purity = 95.42 %. 25 121 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 63: 4-{[({2-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]-2 azatricyclo[3.3.1.1 3 ']dec-5-yl)carbonyl)amino]methyl}benzoic acid (63) 0 OH NH O N O N H (63) 5 SYNTHETIC SCHEME 19 0 0 OOH 0 NH NHP N NNH H Intermediate 50 (63) Synthesis of Compound (63): Compound (63) was synthesized by following the procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating 10 the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (63). 1H NMR (300 MHz, DMSO-d6) : 6 12.80(s,1H), 10.81(s,1H), 8.12-8.20(m,1H), 7.86-7.89(d,2H), 7.28-7.31(m,2H), 7.12-7.17(t,2H), 6.88 6.93(t,1H), 6.55-6.58(d,1H), 4.77(s,1H), 4.30(s,2H), 4.04(s,1H), 2.61-2.80(m,1H),2.50 2.54(m,2H), 2.08-2.13(t,1 H), 1.86-1.91(m,4H), 1.63-1.78(m,6H), 1.50-1.55(d, 1 H), 1.28-1.31(d, 15 3H), 0.89-0.91(m,2H), 0.69-0.74(m,2H). LC-MS: (M+H)+ = 540.3; HPLC purity = 95.62 %. 122 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 64: 1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
,
7 ]dec-2-yl)-3-(1 H-indol-3-yl)pentan-1 one (64) 0 Na OH N H (64) 5 Synthesis of Compound (64): Compound (64) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (64). 1 H NMR (300 MHz, CDC13) : 6 8.03(s,1H), 7.58-7.61(d,1H), 7.26-7.29(d,1H), 7.07-7.12(t,1H), 6.99-7.04(t,1H), 10 6.94(s1 H), 4.93(s,1 H), 4.01-4.04(d,1 H), 3.25-3.35(m,1 H), 2.70-2.79(m, 1 H), 2.56-2.59(m,1 H), 2.03-2.17(d,1H), 1.75-1.85(m,2H), 1.56-1.65(m,5H), 1.31-1.45(m,3H), 1.18-1.22(m,2H), 0.77 0.82(m,3H) LC-MS: (M+H)+ = 353.2; HPLC purity = 94.01 %. EXAMPLE 65: 2-[3-(1H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1 .1 3
'
7 ]decane-5 15 carbonitrile (65) o N C N N H (65) Synthesis of Compound (65): Compound (65) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating 20 the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (65). 1 H NMR (300 MHz, CDC13) : 6 7.92-7.95(d,1H), 7.58-7.61(d,1H), 7.27-7.32(t,1H), 7.09-7.13(t,1H), 7.01 7.06(t,1H), 6.95(d,1H), 4.83-4.87(d,1H), 3.83-3.94(d,1H), 3.55-3.62(m,1H), 2.69-2.77(m,1H), 2.42-2.50(m,1H), 2.07-2.10(m,1H), 1.93-2.00(m,4H), 1.86(s,1H), 1.74-1.79(d,1H), 1.57 25 1.64(m,4H), 1.40-1.43(m,3H). LC-MS: (M+H)+ = 348.2; HPLC purity = 91.69 %. 123 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 66: 3-cyclopropyl-1-(5-hydroxy-2-azatricyclo[3.3.1.13,' 7 ]dec-2-yI)-3-(1 H-indol 3-yI)propan-1 -one (66) o N OH N H (66) 5 Synthesis of Compound (66): Compound (66) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (66). 1 H NMR (300 MHz, CDC13) : 6 8.01-8.05(m,1H), 7.59-7.62(d,1H), 7.26-7.29(d,1H), 7.07-7.12(t,1H), 6.98 10 7.04(m,2H), 4.93(s,1 H), 4.60-4.61 (d,1 H), 4.08-4.11 (d,1 H), 2.84-2.91(m, 1 H), 2.65-2.78(m,2H), 2.04-2.18(s,1H), 1.65(s,2H), 1.57(s,2H), 1.44(m,2H), 1.32-1.34(m,3H), 0.47-0.56(m,1H), 0.35 0.39(m,1H), 0.25-0.32(m,1H), 0.06-0.13(m,2H). LC-MS: (M+H)+ = 365.2; HPLC purity = 93.07 %. 15 EXAMPLE 67: 1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
'
7 ]dec-2-yl)-3-(1 H-indol-3-yl)-3 phenylpropan-1 -one (67) /0 NT OH N H (67) 20 SYNTHETIC SCHEME 20 / OH HN OH 0 N OH .HCI HOBt, EDCI N TEA, DCM H N H Intermediate 51 (67) 124 WO 2013/111150 PCT/IN2012/000842 Synthesis of 3-(1H-indol-3-yl)-3-phenylpropanoic acid (intermediate-51): Intermediate-51 was synthesized by following the procedure used to make Intermediate-42 (Scheme 11). 5 Synthesis of Compound (67): Compound (67) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (67). 1H NMR (300 MHz, DMSO-d6) : 6 10.85(s,1H), 7.28-7.33(m,5H), 7.18-7.23(t,2H), 7.07-7.12(t,1H), 6.97 10 7.02(t,1H), 6.83-6.88(t,1H), 4.67-4.71(m,1H), 4.62-4.65(m,1H), 4.56(s,1H), 4.35(s,1H), 3.01 3.08(m,2H), 1.98-2.13(d,1H), 1.63(s,2H), 1.55(s,1H), 1.47-1.50(d,3H), 1.38-1.41(m,2H), 1.25 1.28(m,2H). LC-MS: (M+H)+ = 401.2; HPLC purity = 94.67 %. EXAMPLE 68: 3-(5-chloro-1H-indol-3-yl)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
,
7 ]dec-2 15 yl)butan-1-one (68) o N OH ci N H (68) Synthesis of Compound (68): Compound (68) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating 20 the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (68). 1H NMR (300 MHz, CDCI3) : 6 8.10(s,1H), 7.55-7.56(d,1H), 7.21-7.25(d,1H), 7.04-7.07(d,1H), 6.99(s,1H), 4.97(s,1H), 4.03-4.13(m,1H), 3.54-3.62(m,IH), 2.64-2.72(d,1H), 2.44-2.54(d,1H), 2.15 2.30(m,2H), 1.76(s,4H), 1.70(s,3H), 1.62(s,2H), 1.38-1.40(d,3H) .LC-MS: (M+H)+ = 373.1; 25 HPLC purity = 92.50 %. 125 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 69: 3-(6-chloro-1H-indol-3-yI)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
'
7 ]dec-2 yl)butan-1 -one (69) O Na OH H (69) 5 Synthesis of Compound (69): Compound (69) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (69). 1H NMR (300 MHz, CDCl3) : 6 8.03(s,1H), 7.49-7.51(d,1H), 7.27(s,1H), 6.95-7.01(m,2H), 4.91-5.01(s,1H), 10 4.08(s,1H), 3.56-3.58(m,1H), 2.69-2.73(d,1H), 2.54(s,1H), 2.11-2.27(m,1H), 1.8(s,1H), 1.68(s,9H), 1.37-1.40(d,3H). LC-MS: (M+H)+ = 373.1; HPLC purity = 91.91 %. EXAMPLE 70: 2-[3-(4-methyl-1H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1 .13 3 7 ]decane-5 carbonitrile (70) O0 CN N 15 H (70) Synthesis of Compound (70): Compound (70) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum 20 ether: Ethyl acetate (1:4) as eluent to obtain Compound (70). 1H NMR (300 MHz, CDC3) : 6 7.94(s,1H), 7.12-7.14(d,1H), 6.96-7.02(m,2H), 6.77-6.79(d,1H), 4.91(s,1H), 4.04(s,1H), 3.89(s,1H), 2.65(s,3H), 2.37-2.48(m,1H), 2.25-2.30(m,1H), 2.12(s,2H), 2.06(s,2H), 1.98 2.02(d,2H), 1.86-1.94(s,2H), 1.71-1.77(m,3H), 1.34-1.36(d,3H). LC-MS: (M+H)+ = 362.2; HPLC purity = 95.85 %. 25 126 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 71: 3-(4-chlorophenyl)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
'
7 ]dec-2-yl)-3-(1 H indol-3-yi)propan-1 -one (71) ci O N@ OH N H (71) 5 Synthesis of Compound (71): Compound (71) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (71). 1H NMR (300 MHz, CDCl3) : 6 8.01-8.13(t,1H), 7.25-7.28(d,2H), 7.18(m,4H), 7.05-7.10(t,1H), 6.93-6.96(d,2H), 10 4.92(s,1H), 4.79(s,1H), 4.11(s,1H), 2.97-3.05(m,2H), 2.15(s,1H), 1.69(s,7H), 1.45(d,3H). LC MS: (M+H)+ = 435.1; HPLC purity = 95.96 %. EXAMPLE 72: 1-(5-hydroxy-2-azatricyclo[3.3. 1.1 3
-
7 ]dec-2-yl)-3-(4-methyl-1H-indol-3-yI) 3-phenylpropan-1 -one (72) N OH
N
15 H (72) Synthesis of Compound (72): Compound (72) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using 20 Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (72). 1H NMR (300 MHz, CDCl3) : 6 8.13-8.21(d,1H), 7.14-7.15(d,4H), 7.04-7.11(m,2H), 6.99(s,1H), 6.90-6.96(m,1H), 6.64-6.66(d,1H), 5.08-5.13(t,1H), 4.92(s,1H), 4.13(s,1H), 2.89-3.02(m,2H), 2.4(d,3H), 2.08 2.21(m,1H), 1.81(s,1H), 1.68(s,2H), 1.62(s,2H), 1.39(s,2H), 0.78-0.90(m,3H). LC-MS: (M+H)+ = 415.2; HPLC purity = 99.51 %. 25 127 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 73: 3-(4-fluorophenyl)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3, 7 ]dec-2-yl)-3-(1 H indol-3-yl)propan-1 -one (73) F 0 OH /N N N H (73) 5 Synthesis of Compound (73): Compound (73) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (73). 1 H NMR (300 MHz, DMSO-d6) : 6 10.87(s,1H), 7.28-7.31(m,5H), 6.98-7.05(m,3H), 6.84-6.89(t,1H), 4.58 10 4.71(m,3H), 4.36(s,1H), 2.97-3.12(m,2H), 2.08-2.13(d,1H), 1.64(s,2H), 1.41-1.55(m,6H), 1.20.-1.35(m,2H). LC-MS: (M+H)+ = 419.2; HPLC purity = 95.83%. EXAMPLE 74: 1.-(5-hydroxy-2-azatricyclo[3.3.1.1 3 ']dec-2-yi)-4-methyl-3-(4-methyl-1 H indol-3-yl)pentan-1 -one (74) 0 NOH N 15 H (74) Synthesis of Compound (74): Compound (74) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using 20 Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (74). 1 H NMR (300 MHz, DMSO-d6) : 5 10.77(s,1H), 7.11-7.13(d,2H), 6.85-6.90(t,1H), 6.64-6.66(d,1H), 4.66(s,1H), 4.58-4.62(d,IH), 4.38-4.40(d,1H), 3.70(s,1H), 2.67-2.76(m,2H), 2.64(s,3H), 2.05-2.16(d,1H), 1.84-1.86(m,1H), 1.52-1.64(m,5H), .1.36-1.48(m,5H), 0.82-0.90(m,6H). LC-MS: (M+H)+ = 381.2; HPLC purity = 97.77 %. 25 128 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 75: 3-(5-fluoro-1H-indol-3-yI)-1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3 ']dec-2 yl)butan-1 -one (75) 0 N@ OH F N H (75) 5 Synthesis of Compound (75): Compound (75) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (75). 1H NMR (300 MHz, DMSO-d6) : 6 10.88(s, 1H), 7.28-7.32(m, 2H), 7.21-7.24(m, 1H), 6.85-6.91(m, 1H), 10 4.78(s,1H), 4.58-4.64(d,1H), 4.23-4.25(d,1H), 3.16-3.39(m,2H), 2.53-2.69(m,2H), 2.15 2.17(m,1H), 1.65(s,2H), 1.54-1.57(m,3H), 1.36-1.49(m,4H), 1.29-1.30(d,3H). LC-MS: (M+H)+ = 356.1; HPLC purity = 98.0%. EXAMPLE 76: 3-(4-chloro-1H-indol-3-yl)-1-[5-(1H-tetrazol-5-yl)-2 15 azatricyclo[3.3.1.1 3
-
7 ]dec-2-yl]butan-1 -one (76) 0N N H N ci N H (76) Synthesis of Compound (76): Compound (76) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating 20 the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (76). 1H NMR (300 MHz, CD30D) : 6 7.10-7.21(m,3H), 6.93(s,2H), 4.30-4.35(d,1H), 4.08(s,1H), 2.89(s,1H), 2.54 2.61(m,2H), 1.90-1.94(m,4H), 1.74-1.77(m,5H), 1.24-1.37(m,6H). LC-MS: (M+H)+ = 426.1; HPLC purity = 99.36%. 25 129 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 77: 3-(4-methyl-1H-indol-3-yI)-1-[5-(1H-tetrazol-5-yI)-2 azatricyclo[3.3.1.13, 7 ]dec-2-yl]butan-1 -one (77) HN--N 0 N NN N H (77) 5 SYNTHETIC SCHEME 21 HN-N N NN NN N N H H (77) Intermediate 52 Synthesis of Compound (77): To a stirred solution of Intermediate-52 (20 mg, 0.05 mmol) 10 in toluene (10 mL) NaN 3 (37 mg, 0.5 mmol) was added along with trimethyltin chloride (49mg, 0.25mmol) under N 2 atmosphere,. Resulted reaction mixture was heated at 110*C for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water and was extracted with ethyl acetate (3 x 10 mL). The combined organic layer was concentrated to obtain a crude product. The resulted crude product was purified by 15 prep. TLC eluted with DCM: MeOH to give Compound (77) (8 mg) as white solid. 1H NMR (300 MHz, CD30D) : 6 7.06-7.15(m,2H), 6.84-6.94(m,1H), 6.67-6.72(m,1H), 4.69-4.81(m,1H), 4.30-4.35(d,1H), 3.92-3.98(m,1H), 2.82-2.90(m,1H), 2.68(d,3H), 2.57-2.64(m,IH), 2.21(s,1H), 1.96-2.11 (m,5H), 1.8(s,3H), 1.70-1.74(m,2H), 1.57-1.61(d,1H), 1.38-1.40(d,3H). LC-MS: (M+H)+ 405.2; HPLC purity = 98.31 %. 20 130 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 78: 1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
,
7 ]dec-2-yl)-3-(7-methyl-1H-indol-3 yl)butan-1 -one (78) 0 NOH N H (78) 5 Synthesis of Compound (78): Compound (78) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (78). 1H NMR (300 MHz, CDCl3) : 5 7.88(s,1H), 7.44-7.46(d,1H), 6.90-7.03(m,3H), 3.52-3.61(m,1H), 2.72-2.79(m,1H), 10 2.40-2.50(m,1H), 2.40(m,3H), 2.22-2.23(m,1H), 1.70(s,3H), 1.49-1.61(m,6H), 1.45(s,3H), 1.40-1.43(m,3H). LC-MS: (M+H)+ = 353.2; HPLC purity = 97.30 %. EXAMPLE 79: 3-(6-fluoro-1H-indol-3-yl)-1 -(5-hydroxy-2-azatricyclo[3.3.1.1 3
'
7 ]dec-2 yl)butan-1 -one (79) 0 NOH F N 15 H (79) Synthesis of Compound (79): Compound (79) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using 20 Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (79). 1H NMR (300 MHz, CDCI3) : 6 7.99(s,1H), 7.55-7.60(m,1H), 6.98-7.04(m,2H), 6.84-6.91(m,1H), 5.04(s,1H), 4.15(s,1H), 3.56-3.68(m,1H), 2.74-2.82(m,1H), 2.48-2.55(m,1H), 2.29-2.18(s,1H), 1.76(s,2H), 1.67(s,2H), 1.57-1.62(m,4H), 1.48-1.50(m,2H), 1.43-1.46(m,3H). LC-MS: (M+H)+ = 357.2; HPLC purity = 91.94 %. 25 131 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 80: 3-[4-cyclopropyl-1 -(2-hydroxyethyl)-1 H-indol-3-yl]-1 -(5-hydroxy-2 azatricyclo[3.3.1.1 3
'
7 ]dec-2-yl)butan-1 -one (80) 0 OH N OH (80) 5 Synthesis of Compound (80): Compound (80) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (80). 1 H NMR (300 MHz, CDC13) : 6 7.14-7.19(m,IH), 7.06-7.11(m,1H), 7.00(s,1H), 6.73-6.75(d,1H), 5.06(s,1H), 10 4.27(s,1H), 4.20-4.24(m,3H), 3.91-3.95(m,2H), 2.76-2.90(m,1H), 2.56-2.64(m,1H), 2.43 2.51(m,1H), 2.31(s,1H), 1.79(s,2H), 1.68(s,2H), 1.63-1.65(d,4H), 1.57(s,3H), 1.42 1.46(m,3H), 0.97-1.02(m,2H), 0.79-0.90(m,2H). LC-MS: (M+H)+ = 423.2; HPLC purity = 97.26 %. 15 EXAMPLE 81: 3-(4-fluorophenyl)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3 ']dec-2-yl)-3-(1 H indol-3-yl)propan-1 -one (81) F 0 Na OH N H (81) Synthesis of Compound (81) (peak-1): Racemate of Compound (73) was separated by 20 using chiral HPLC to give enantiomer Compound (81) (peak-1) 1H NMR (300 MHz, CDC13) : 6 10.87(s, I H), 7.20(m,5H), 7.00-7.05(m,3H), 6.83(m, 1 H), 4.66-4.68(m, 1 H), 4.58(m,2H), 4.40(s,IH), 3.10(s,2H), 2.08-2.13(d,1H), 1.61.23-1.55(m,8H), 1.11-1.15(m,2H). LC-MS: (M+H)+ = 419.2; HPLC purity = 94.26 %; Chiral purity = 100% (RT=8.57 min), Chiral column: Chiralpak IC 4.6mmX250mm, Mobile phase hexane:EtbH:DCM (75:15:10). 25 132 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 82: 3-(4-fluorophenyl)-1-(5-hydroxy-2-azatricyclo[3.3. 1.1 3
'
7 ]dec-2-yl)-3-(1H indol-3-yl)propan-1 -one (82) F 0 OH N H (82) 5 Synthesis of Compound (82) (peak-2): Racemate of Compound (73) was separated by using chiral HPLC to give enantiomer Compound (82) (peak-2). 1H NMR (300 MHz, CDCI3)': 6 10.87(s,1H), 7.20(m,5H), 7.00-7.05(m,3H), 6.83(m,1H), 4.66-4.68(m,1H), 4.58(m,2H), 4.40(s,1H), 3.10(s,2H), 2.08-2.13(d,1H), 1.61.23-1.55(m,8H), 1.11-1.15(m,2H). LC-MS: (M+H)+ = 419.2; HPLC purity = 97.71 %; Chiral purity = 100% (RT=10.56 min), Chiral 10 column: Chiralpak IC 4.6mmX250mm, Mobile phase hexane:EtOH:DCM (75:15:10). EXAMPLE 83: 3-(4-fluoro-1H-indol-3-yl)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3 ']dec-2-yl)-3 phenylpropan-1 -one (83) F N H 15 (83) Synthesis of Compound (83): Compound (83) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (83). 1 H NMR (300 MHz, 20 DMSO-d6) : 611.17(s,1H), 7.35-7.37(m,1H), 7.14-7.27(m,4H), 7.06-7.11(m,2H), 6.93 7.00(m,1 H), 6.58-6.64(m, 1 H),. 4.80-4.85(t,1 H), 4.70(s,1 H), 4.60-4.65(d, 1 H), 4.37(s, 1 H), 2.93 3.17(m,2H), 2.07-2.27(m,2H), 1.64(s,2H), 1.40-1.53(m,3H), 1.36(m,2H), 1.23-1.28(m,2H). LC MS: (M+H)+ = 419.2; HPLC purity = 96.72 %. 25 133 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 84: 3-(1,3-benzothiazol-2-yl)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3 ']dec-2 yI)butan-1 -one (84) N 0 S N OH (84) 5 SYNTHETIC SCHEME 22 N, H + H OH S ON OH1 + HOBt, EDCl Intermediate 53 TEA, DCM (84) OH Synthesis of Compound (84): Intermediate-53 was synthesized by following the procedure 10 used to make Intermediate-36 (Scheme 7). Compound (84) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain (84). 1H NMR (300 MHz, CDC13) : 5 7.90-7.93(d,1H), 7.76-7.79(d,1H), 7.36-7.41(t,1H), 7.26-7.31(t,1H), 4.96(s,1H), 4.33(s,1H), 3.84-3.86(d,1H), 15 3.04-3.11(m,1H), 2.58-2.73(m,1H), 2.23-2.27(d,1H), 1.72-1.76(d,4H), 1.55-1.65(m,6H), 1.45 1.47(d,3H). LC-MS: (M+H)+ = 357.1; HPLC purity = 98.96 %. EXAMPLE 85: 1-(2-azatricyclo[3.3.1.1 3
'
7 ]dec-2-yI)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)butan 1-one (85) 20 N N H (85) 134 WO 2013/111150 PCT/IN2012/000842 SYNTHETIC SCHEME 23 0 O OH O HNO .HCI N N H HOBt, EDCI N N TEA, DCM H Intermediate 54 (84) Synthesis of 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)butanoic acid (Intermediate-54): 5 Intermediate-54 was synthesized by following the procedure used to make Intermediate-42 (Scheme 11). Synthesis of Compound (85): Compound (85) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating 10 the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate as eluent to obtain Compound (85). 1H NMR (300 MHz, CDCl3) : 6 9.29(s,1H), 8.19-8.21(m,1H), 7.93-7.96(m,1H), 7.07(s,1H), 6.97-7.01(m,1H), 4.76(s,1H), 3.89(s,1H), 3.52-3.66(m,1H), 2.65-2.73(m,1H), 2.42-2.49(m,1H), 1.97(s,1H), 1.84(s,1H),1.65-1.68(m,4H), 1.61-1.65(m,3H), 1.56-1.57(d,2H), 1.41-1.49(m,1H), 1.35(d,3H). 15 LC-MS: (M+H)+ = 324.2; HPLC purity = 94.58 %. EXAMPLE 86: 1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
,
7 ]dec-2-yl)-3-(1 H-pyrrolo[2,3-b]pyridin 3-yl)butan-1 -one (86) O NOH N 20 (86) Synthesis of Compound (86): Compound (86) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (86). 1H NMR (300 MHz, CDCl3) : 6 8.82-9.01(m,1H), 25 8.19-8.21(d,1H), 7.94-7.96(m,1H), 7.05(s,1H), 6.98-7.02(m,1H), 4.96(s,1H), 4.08(s,1H), 3.55 3.62(m,1H), 2.65-2.72(m,1H), 2.42-2.55(m,1H), 2.09-2.29(m,1H), 1.69(s,3H), 1.50(s,2H), 1.18-1.44(m,5H), 1.18(s,1H), 0.78-0.98(m,2H). LC-MS: (M+H)+ = 340.2; HPLC purity = 99.20 %. 135 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 87: 3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-y)-1-(5-hydroxy-2 azatricyclo[3.3.1 .1 3 ']dec-2-yl)butan-1 -one (87) 0 OH ci N N H 5 (87) Synthesis of Compound (87): Compound (87) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (87). 1H NMR (300 MHz, DMSO-d6) : 611.77(s,1H), 10 8.09-8.11(d,1H), 7.38-7.43(m,1H), 7.10-7.11(d,1H), 4.80(s,1H), 4.66(s,1H), 4.35(s,1H), 3.84(s,1H), 2.69(m,3H),2.18(s,1H), 1.45-1.68(m,9H), 1.23-1.30(m,3H). LC-MS- (M+H)+ 374.2; HPLC purity = 96.68%. EXAMPLE 88: 1-(5-hydroxy-2-azatricyclo[3.3.1.13'
]
dec-2-yl)-3-(4-methyl-1 H-pyrrolo[2,3 15 b]pyridin-3-yl)butan-1 -one (88) 0 OH N N H (88) Synthesis of Compound (88): Compound (88) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating 20 the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (88). 1H NMR (300 MHz, CDCl3) : 611.91-11.95(d,1H), 7.97-7.99(d,1H), 7.26-7.29(d,1H), 7.05-7.06(d,1H), 4.89 4.94(d,1H), 4.26(s,1H), 3.91(s,1H) , 3.04-3.06 (m,1H), 2.90(s,3H), 2.50-2.66(m,2H)(, 2.27(s,1H), 1.36-1.78(m,9H), 1.29-1.32(d,3H). LC-MS: (M+H)+ = 354.2; HPLC purity = 25 99.38%. 136 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 89: 1-(5-hydroxy-2-azatricyclo[3.3.1.1 3 ,7]dec-2-yl)-3-phenyl-3-(1 H-pyrrolo[2,3 b]pyridin-3-yl)propan-1 -one (89) 0 OH N~j N N H (89) 5 Synthesis of Compound (89): Compound (89) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (89). LC-MS: (M+H)+ = 402.2; HPLC purity = 95.83%. 10 EXAMPLE 90: 1-(5-hydroxy-2-azatricyclo[3.3.1.1 3 '7]dec-2-yl)-4-methyl-3-(1 H-pyrrolo[2,3 b]pyridin-3-yl)pentan-1 -one (90) o N OH N N H (90) 15 Synthesis of Compound (90): Compound (90) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1:4) as eluent to obtain Compound (90). 1H NMR (300 MHz, CDCl3) : 511.48-11.50(d,1H), 8.28-8.33(t,1H), 8.14-8.16(d,1H), 7.22(m,2H), 4.75-4.80(d,1H), 20 4.13(s,1H), 3.32-3.37(m,1H), 2.63-2.69(m,3H), 2.12-2.20(d,1H), 1.95-2.04(m,IH), 1.36 1.70(m,9H), 0.89-0.93(m,3H), 0.77-0.81(m,3H). LC-MS: (M+H)+ = 368.2; HPLC purity = 94.67%. 137 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 91: 2-[3-(1H-pyrrolo[2,3-b]pyridin-3-yl)butanoyl]-2 azatricyclo[3.3.1 .1 3
,
7 ]decane-5-carboxylic acid (91) OH 0 N O N N H (91) 5 Synthesis of Compound (91): Compound (91) was synthesized by following the procedure used to make Intermediate-26 (Scheme 4). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (91). IH NMR (300 MHz, CDCl3) : 611.09(s,1H), 8.08 8.13(m,2H), 7.06-7.10(m,2H), 4.71(s;1H), 3.64-3.72(m,2H), 2.66-2.74(t,1H), 2.36-2.41(m,1H), 10 2.01-2.04(d,1H), 1.80-1.84(d,1H), 1.48-1.70(m,8H), 1.43-1.45(d,3H), 1.18-1.22(m,1H). LC MS: (M+H)+ = 368.2; HPLC purity = 98.93%. EXAMPLE 92: 2-[4-methyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)pentanoyl]-2 azatricyclo[3.3.1.13,7]decane-5-carbonitrile (92) o NT - CN N N 15 H (92) Synthesis of Compound (92): Compound (92) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: 20 MeOH as eluent to obtain Compound (92). 1H NMR (300 MHz, CDCl3): 6 10.75-10.78(d,1H), 8.18-8.25(m,2H), 7.19-7.20(m,2H), 4.72(s,1H), 4.03(s,1 H), 3.33-3.35(m,1 H), 2.61 2.70(m,2H), 2.13(s,1H), 1.97-2.02(m,4H), 1.81-1.90(m,2H), 1.09-1.68(m,5H), 0.90 0.92(m,3H), 0.77-0.79(d,3H). LC-MS: (M+H)* = 377.2; HPLC purity = 97.71%. 138 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 93: 3-(4-fluorophenyl)-1-(5-hydroxy-2-azatricyclo[3.3.1 .13'7] dec-2-yl)-3-(4 methyl-I H-indol-3-yl)propan-1 -one (93) *F -F o0 OH N H (93) 5 Synthesis of Compound (93): Compound (93) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (93). 1H NMR (300 MHz, DMSO-d6) : 6 10.91(s, 1H), 10 7.36(m, 1H), 7.18-7.23(m, 2H), 7.12-7.15(d, 1H), 7.01-7.06(t, 2H), 6.85-6.902(t, 1H), 6.58 6.60(d,1H), 4.99-5.02(m,1H), 4.74(m,1H), 4.58-4.66(d,1H), 4.36(m,1H), 2.95-2.97(m,2H), 2.42(s,3H), 2.07-2.17(m,1H), 1.28-1.65(m,10H). LC-MS: (M+H)* = 433.2; HPLC purity = 94.79%. 15 EXAMPLE 94: 3-(6-fluoro-IH-indol-3-yI)-I-(5-hydroxy-2-azatricyclo[3.3.1 .1 3 '7]dec-2-yl)-3 phenylpropan-1-one (94) / N@ OH F N H (94) Synthesis of Compound (94): Compound (94) was synthesized by following the procedure 20 used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (94). 1H NMR (300 MHz, DMSO-d6) : 6 10.94(s,1H), 7.30-7.32(m,4H), 7.19-7.26(m,2H), 7.04-7.13(m,2H), 6.69-6.75(t,1H), 4.71(s,1H), 4.56 4.65(m,2H), 4.35(s,1H), 3.02-3.05(m,2H), 2.06-2.13(d,1H), 1.63(s,2H), 1.20-1.59(m,8H). LC 25 MS: (M+H)* = 419.1; HPLC purity = 93.86%. 139 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 95: 3-cyclopropyl-3-(4-fluoro-1H-indol-3-yl)-1-(5-hydroxy-2 azatricyclo[3.3.1 .13,7]dec-2-yl)propan-1 -one (95) F OOH F N H (95) 5 Synthesis of Compound (95): Compound (95) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (95). 1H NMR (300 MHz, CDCI3) : 6 8.13(s,1H), 6.93 7.08(m,3H), 6.66-6.73(m,1H), 4.93(s,1H), 4.24(s,1H), 2.94-3.04(m,1H), 2.66-2.75(m,1H), 10 2.60(s,1H), 2.08-2.20(d,1H), 1.21-1.67(m,10H), 0.76-0.97(m,1H), 0.49-0.53(m,1H), 0.26 0.32(m,2H), 0.05-0.07(m,1H). LC-MS: (M+H)* = 383.1; HPLC purity = 96.02%. EXAMPLE 96: 3-(2,4-difluorophenyl)-1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3 ']dec-2-yl)-3 (1 H-indol-3-yl)propan-1 -one (96) F F O N OH F N 15 H (96) Synthesis of Compound (96): Compound (96) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: 20 MeOH as eluent to obtain Compound (96). 1H NMR (300 MHz, DMSO-d6) : 6 10.90(s, 1H), 7.36-7.41(m, 1H), 7.32(m, 2H), 7.29(m, 1H), 7.11-7.15(t, 1H), 6.97-7.05(t, 1H), 6.88-6.95(m, 2H), 4.93(t,1H), 4.69(s,1H), 4.62-4.64(d,1H), 4.40(s,1H), 2.72-3.11(m,2H), 2.14-2.27(m,1H), 1.24-1.66(n,10H). LC-MS: (M+H)* = 437.1; HPLC purity = 92.20%. 140 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 97: 3-(6-fluoro-IH-indol-3-yI)-1-(5-hydroxy-2-azatricyclo[3.3.1 .13,7]dec-2 yl)butan-1 -one peak-I (97) O NOH F ~ N H (97) 5 Synthesis of Compound (97) (peak-1): Racemate of (79) was separated by chiral HPLC column chromatography to give Compound (97) (peak-1). 1H NMR (300 MHz, CDC13) : 6 7.90(S,1H), 7.48-7.53(m,1H), 6.92-6.97(m,2H), 6.78-6.84(t,1H), 4.97(s,1H), 4.09(s,1H), 3.52 3.96(m,1H), 2.67-2.75(m,1H), 2.41-2.48(m,1H), 2.11-2.22(d,1H), 1.60(m,6H), 1.36 1.39(m,6H). LC-MS: (M+H)* = 357.1; HPLC purity = 93.22%; Chiral purity: 100% (RT = 15.45 10 min); Column: Chiralpak IC, 4.6mmX250mm; Mobile phase: hexanes: i-PrOH: DCM (7.5:1.5:1.0). EXAMPLE 98: 3-(6-fluoro-1H-indol-3-yl)-I-(5-hydroxy-2-azatricyclo[3.3.1.1 3
'
7 ]dec-2 yl)butan-1-one peak-) (98) o N' OH F N 15 H (98) Synthesis of Compound (98) (peak-2): Racemate of Compound (79) was separated by chiral HPLC column chromatography to give Compound (98) (peak-2). 1H NMR (300 MHz, CDCl3) : 6 7.89(S,1H), 7.48-7.53(m,1H), 6.93-6.97(m,2H), 6.78-6.84(t,1H), 4.97(s,1H), 20 4.08(s,1H), 3.52-3.59(m,1H), 2.67-2.75(m,1H), 2.41-2.48(m,1H), 2.11-2.22(d,1H), 1.54 1.69(m,9H), 1.36-1.38(d,3H). LC-MS: (M+H)* = 357.2; HPLC purity = 95.14%; Chiral purity: 99.35% (RT = 19.0 min); Column: Chiralpak IC, 4.6mmX250mm; Mobile phase: hexanes: i PrOH: DCM (7.5:1.5:1.0). 141 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 99: 3-(4-fluoro-1 H-indol-3-yl)-3-(4-fluorophenyl)-1 -(5-hydroxy-2 azatricyclo[3.3.1.1 3 ']dec-2-yl)propan-1 -one (99) F 0 OH F N H (99) 5 Synthesis of Compound (99): Compound (99) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain 10 Compound (99). 1H NMR (300 MHz, DMSO-d6): 6 11.19-11.23(d,1H), 7.37(s,1H), 7.27 7.29(t,2H), 7.12-7.14(d,1H), 6.93-7.05(m,3H), 6.58-6.65(m,1H), 4.80-4.84(m,1H), 4.70(s,1H), 4.59-4.65(d,1H), 4.37(s,1H), 2.96-3.11(m,2H), 2.08-2.16(d,1H), 1.29-1.65(m,10H). LC-MS: (M+H)* = 437.1; HPLC purity = 99.01%. 15 EXAMPLE 100: 2-[3-(4-chloro-1H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1.1 3
'
7 ]decane-5 carbonitrile peak-1 (100): o N cN ci N H (100) Synthesis of Compound (100) (peak-1): Racemate of Compound (59) was separated by 20 preparative chiral column to give Compound (100) (peak-1). 1H NMR (300 MHz, CDCl3): 6 8.06(s,1H), 7.32(m,1H), 7.00-7.02(m,3H), 4.90(s,1H), 3.96-4.11(m,2H), 2.77-2.87(m,1H), 2.40-2.48(m,1H), 1.60-2.12(m,11H), 1.37-1.40(m,3H). LC-MS: (M+H)* = 382.1; HPLC purity = 98.74%; Chiral purity: 100% (RT = 16.17 min); Column: Chiralpak IC, 4.6mmX250mm; Mobile phase: hexanes: i-PrOH: DCM (7.5:1.5:1.0). 25 142 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 101: 2-[3-(4-chloro-1H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1 .1 3
,
7 ]decane-5 carbonitrile peak-2 (101): 0 N CN CI N H (101) 5 Synthesis of Compound (101) (peak-2): Racemate of Compound (59) was separated by preparative chiral column to give Compound (101) (peak-2). 1H NMR (300 MHz, CDC3): 6 8.07(s,1 H), 7.00-7.04(m,4H), 4.90(s,1H), 3.96-4.11 (m,2H), 2.77-2.87(m, 1 H), 2.40 2.48(m,1H), 1.60-2.12(m,11H), 1.37-1.40(m,3H). LC-MS: (M+H)* = 382.1; HPLC purity = 98.08%; Chiral purity: 100% (RT = 30.89 min); Column: Chiralpak IC, 4.6mmX250mm; Mobile 10 phase: hexanes: i-PrOH: DCM (7.5:1.5:1.0). EXAMPLE 102: 3-(4-cyclopropyl-1H-indol-3-yl)-1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3
-
7 ]dec 2-yl)butan-1-one peak-1 (102): 0 NOH N H 15 (102) Synthesis of Compound (102) (peak-1): Racemate of Compound (41) was separated by preparative chiral column to give Compound (102) (peak-1). 1H NMR (300 MHz, DMSO-d6): 6 10.80(s,1H), 7.12-7.16(m,2H), 6.88-6.963(t,1H), 6.55-6.58(d,1H), 4.81(s,1H), 4.65(d,1H), 4.32(s,1H), 4.01-4.06(m,1H), 2.67-2.72(m,2H), 2.17(s,1H), 1.43-1.68(m,11H), 1.27 20 1.30(d,3H), 0.89-0.95(m,2H), 0.73-0.86(m,2H). LC-MS: (M+H)* = 379.2; HPLC purity = 98.53%; Chiral purity: 100% (RT = 15.36 min); Column: Chiralpak IC, 4.6mmX250mm; Mobile phase: hexanes: i-PrOH: DCM (7.5:1.5:1.0). 143 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 103: 3-(4-cyclopropyl-1H-indol-3-yI)-1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3
,
7 ]dec 2-yl)butan-1-one peak-2 (103): 0 NOH N H (103) 5 Synthesis of Compound (103) (peak-2): Racemate of Compound (41) was separated by preparative chiral column to give Compound (103) (peak-2). 1H NMR (300 MHz, DMSO-d6): 6 10.80(s,1H), 7.12-7.16(m,2H), 6.88-6.93(t,1H), 6.55-6.58(d,1H), 4.81(s,1H), 4.65(d,1H), 4.32(s,1H), 3.97-4.05(m,1H), 2.67-2.72(m,2H), 2.17(s,1H), 1.43-1.68(m,11H), 1.27 1.30(d,3H), 0.83-0.95(m,2H), 0.70-0.74(m,2H). LC-MS: (M+H)* = 379.2; HPLC purity = 10 99.43%; Chiral purity: 100% (RT = 22.17 min); Column: Chiralpak IC, 4.6mmX250mm; Mobile phase: hexanes: i-PrOH: DCM (7.5:1.5:1.0). EXAMPLE 104: 1-(5-fluoro-2-azatricyclo[3.3.1.1 3 ']dec-2-yl)-3-(4-methyl-1 H-indol-3 yl)butan-1 -one (104): o N F N 15 H (104) Synthesis of Compound (104): Compound (104) was synthesized by following the procedure used to make Compound (24) (Scheme 12). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 20 using hexane: EtOAc as eluent to obtain Compound (104). 1H NMR (300 MHz, DMSO-d6): 6 10.79(s,11H), 7.12-7.16(m,2H), 6.87-6.92(mt,1H), 6.67-6.69(d,1H), 4.92(s,1H), 4.48(s,1H), 3.73-3.80(m,1H), 2.65-2.72(m,1H), 2.61(s,3H), 2.27-2.36(m,2H), 1.42-1.93(m,10H), 1.24 1.26(d,3H). LC-MS: (M+H)* = 355.2; HPLC purity = 98.31%. 144 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 105: 1-(2-azatricyclo[3.3.1.1 3
,
7 ]dec-2-yI)-3-(1,3-benzothiazol-2-yl)butan-1 -one (105): N O s (105) 5 Synthesis of Compound (105): Compound (105) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using hexane : EtOAc as eluent to obtain Compound (105). 1H NMR (300 MHz, CDC13): 5 7.87-7.89(d,1H), 7.74-7.77(d,1H), 7.33-7.38(tmlH), 7.23-7.28(t,1H), 4.77(s,1H), 4.05(s,1H), 10 3.65-3.89(m,1H), 2.96-3.03(m,1H), 2.55-2.57(m,1H), 1.66-2.01(m,12H), 1.33-1.35(d,3H). LC MS: (M+H)* = 341.1; HPLC purity = 98.67%. EXAMPLE 106: 3-(1,3-benzothiazol-2-yl)-1-(5-fluoro-2-azatricyclo[3.3.1.1 3
'
7 ]dec-2 yl)butan-1 -one (106): 0 15 F (106) Synthesis of Compound (106): Compound (106) was synthesized by following the procedure used to make Compound (24) (Scheme 12). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 20 using hexane: EtOAc as eluent to obtain Compound (106). 1H NMR (300 MHz, CDC13): 5 7.85-7.88(d,1H), 7.75-7.78(m,1H), 7.33-7.39(m,1H), 7.23-7.29(m,1H), 5.04(s,1H), 4.40(s,1H), 3.79-3.88(m,1H), 3.01-3.09(m,1H), 2.53-2.61(m,1H), 2.36(d,1H), 1.50-1.88(m,10H), 1.42 1.47(d,3H). LC-MS: (M+H)* = 359.1; HPLC purity = 95.97%. 145 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 107: 3-(1,3-benzothiazol-2-y)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
,
7 ]dec-2-yi)-3 phenylpropan-1 -one (107): N 0 OH (107) 5 Synthesis of (107): Compound (107) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (107). 1H NMR (300 MHz, DMSO-d6): 6 7.91 8.00(m,2H), 7.22-7.50(m,7H), 4.95-5.00(m,1H), 4.64-4.69(m,2H), 4.43(s,1H), 3.52 10 3.59(m,1H), 2.95-3.04(m,1H), 2.08-2.20(m,1H), 1.23-1.79(m,10H). LC-MS: (M+H)* = 419.1; HPLC purity = 99.70%. EXAMPLE 108: 3-(1 ,3-benzothiazol-2-y)-1-(5-fluoro-2-azatricyclo[3.3.1 .1 3 ']dec-2-yl)-3 phenylpropan-1 -one (108): N 0 s N 15 F (108) Synthesis of Compound (108): Compound (108) was synthesized by following the procedure used to make Compound (24) (Scheme 12). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 20 using hexane: EtOAc as eluent to obtain Compound (108). 1H NMR (300 MHz, DMSO-d6): 67.90-8.00(m,2H), 7.22-7.50(m,7H), 4.95-5.01(m,1H), 4.82(s,1H), 4.60(s,1H), 3.53 3.61(m,1H), 2.96-3.09(m,IH), 2.27-2.35(m,1H), 1.23-1.79(m,10H). LC-MS: (M+H)* = 421.1; HPLC purity = 92.61%. 146 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 109: 1-(5-hydroxy-2-azatricyclo[3.3.1 .13,7]dec-2-yl)-3-(5-methoxy-1 H-indol-3 yl)butan-1 -one (109): 0o N OH 0 N H (109) 5 Synthesis of Compound (109): Compound (109) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (109). 1H NMR (300 MHz, DMSO-d6): 6 10.61(s,1H), 7.18-7.22(d,1H), 7.09(s,1H), 6.96(s,1H), 6.68-6.71(m,1H), 4.79(s,1H), 4.59 10 4.64(d,1H), 4.25-4.28(m,1H), 3.74(s,3H), 3.37-3.40(m,1H), 2.63-2.72(m,2H), 2.07 2.37(m,1H), 1.27-1.65(m,13H). LC-MS: (M+H)* = 369.2; HPLC purity = 98.14%. EXAMPLE 110: 1-(5-hydroxy-2-azatricyclo[3.3.1.1 3 ']dec-2-yl)-3-(5-methyl-1 H-indol-3 yl)butan-1 -one (110): 0 N OH N 15 H (110) Synthesis of Compound (110): Compound (110) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 20 using DCM: MeOH as eluent to obtain Compound (110). 1H NMR (300 MHz, DMSO-d6): 6 10.62(s,1H), 7.29(s,1H), 7.18-7.21(d,1H), 7.06(s,1H), 6.85-6.88(d,1H), 4.80(s,1H), 4.61 4.65(d,1H), 4.28(s,1H), 3.39(m,1H), 2.62-2.72(m,2H), 2.36(s,3H), 2.10-2.27(m,1H), 1.27 1.66(m,13H). LC-MS: (M+H)* = 353.2; HPLC purity = 95.0%. 147 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 111: 2-[3-(4-fluoro-1H-indol-3-yI)-3-phenylpropanoyl]-2 azatricyclo[3.3.1 .1 3 ']decane-5-carboxylic acid (111): OH 0 F N H (111) 5 Synthesis of Compound (111): Compound (111) was synthesized by following the procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (111).1H NMR (300 MHz, DMSO-d6): 6 12.17(s,1H), 11.1.8(s,1H), 7.37(s,1H), 7.17-7.31(m,4H), 7.05-7.14(m,2H), 6.92-6.99(m,1H), 10 6.57-6.64(m,1H), 4.81-4.86(t,1H), 4.64(s,1H), 4.31(s,1H), 3.00-3.07(m,2H), 1.30 2.07(m,11H). LC-MS: (M+H)* = 447.3; HPLC purity = 98.60%. EXAMPLE 112: 2-[3-(6-fluoro-1H-indol-3-yl)-3-phenylpropanoyl]-2 azatricyclo[3.3.1.13,]decane-5-carboxylic acid (112): OH / N O F N 15 H (112) Synthesis of Compound (112): Compound (112) was synthesized by following the procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 20 using DCM: MeOH as eluent to obtain Compound (112). 1H NMR (300 MHz, DMSO-d6): 6 12.19(s,1H), 10.94(s,1H), 7.30-7.33(m,4H), 7.18-7.27(m,2H), 7.03-7.13(m,2H), 6.69 6.74(m,1H), 4.61-4.66(m,2H), 4.29(s,1H), 3.02-3.05(d,2H), 2.72(m,2H), 1.32-2.08(m,9H). LC MS: (M+H)* = 447.2; HPLC purity = 96.93%. 148 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 113: 3-(5-fluoro-2-methyl-1 H-indol-3-yl)-1 -(5-hydroxy-2 azatricyclo[3.3.1.1 3
'
7 ]dec-2-yl)butan-1 -one (113): O NOH F N H (113) 5 Synthesis of Compound (113): Compound (113) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (113). 1H NMR (300 MHz, DMSO-d6): 6 10.74(s,1H), 7.26-7.31(m,1H), 7.15-7.20(m,1H), 6.73-6.80(m,1H), 4.72(s,1H), 4.51 10 4.61(m,1H), 4.09(s,1H), 3.35-3.39(m,1H), 2.70-2.80(m,2H), 2.29(s,3H), 1.97-2.14(d,1H), 0.74-1.60(m,13H). LC-MS: (M+H)* = 371.2; HPLC purity = 97.40%. EXAMPLE 114: 3-(1,3-benzothiazol-2-y)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
'
7 ]dec-2 yl)butan-1-one Peak-I (114): N 0 15 OH (114) Synthesis of Compound (114) (peak-1): Racemate of Compound (84) was separated by preparative chiral HPLC column to give Compound (114) (peak-1). 1H NMR (300 MHz, CDCl3): 6 7.86-7.89(d,1H), 7.75-7.78(d,1H), 7.34-7.39(t,1H), 7.24-7.29(t,1H), 4.96(s,1H), 20 4.31(s,1H), 3.79-3.86(m,IH), 2.99-3.07(m,1H), 2.54-2.62(m,1H), 2.22-2.27(m,1H), 1.43 1.75(m,14H). LC-MS: (M+H)* = 357.1; HPLC purity = 99.8%; Chiral purity: 100% (RT = 16.99 min); Column: Chiralpak IC, 4.6mmX250mm; Mobile phase: hexanes: i-PrOH: DCM (7:2:1). 149 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 115: 3-(1,3-benzothiazol-2-yi)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
,
7 ]dec-2 yl)butan-1 -one Peak-2 (115): N 0 OH (115) 5 Synthesis of Compound (115) (peak-2): Racemate of Compound (84) was separated by preparative chiral HPLC column to give Compound (115) (peak-2).1H NMR (300 MHz, CDCI3): 6 7.86-7,89(d,1H), .7.75-7.78(d,1H), 7.34-7.39(t,1H), 7.24-7.29(t,1H), 4.96(s,1H), 4.31(s,1H), 3.79-3.86(m,1H), 2.99-3.07(m,1H), 2.54-2.62(m,1H), 2.22-2.27(m,1H), 1.43 1.76(m,14H). LC-MS: (M+H)* = 357.1; HPLC purity = 99.85%; Chiral purity: 100% (RT = 10 23.47 min); Column: Chiralpak IC, 4.6mmX250mm; Mobile phase: hexanes: i-PrOH: DCM (7:2:1). EXAMPLE 116: 1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3
,
7 ]dec-2-yl)-3-(4-methyl-1 H-indol-3 yl)propan-1-one (116): 0 N OH N 15 H (116) Synthesis of Compound (116): Compound (116) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 20 using DCM: MeOH as eluent to obtain Compound (116).1H NMR (300 MHz, CDCl3): 6 7.90(s,1H), 7.10-7.13(d,1H), 6.96-7.01(t,1H), 6.92(d,1H), 6.76-6.78(d,1H), 5.02(s,1H), 4.13(s,1H), 3.18-3.23(m,2H), 2.64(s,3H), 2.58-2.63(m,2H), 2.24(s,1H), 1.49-1.74(m,11H). LC MS: (M+H)* = 339.3; HPLC purity = 91.46%. 150 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 117: 3-(6-chloro-5-methoxy-1H-indol-3-yI)-1-(5-hydroxy-2 azatricyclo[3.3.1.1 3 ,7]dec-2-yl)butan-1 -one (117): o N / OH 00 ci N H (117) 5 Synthesis of Compound (117): Compound (117) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (117). 1H NMR (300 MHz, CDCl3): 6 7.85 (brs, 1H), 7.30-7.31 (d, 1H), 7.09 (brs, 1H), 6.92-6.93 (m, 1H), 4.98 (brs, 1H), 4.09 (brs, 1H), 10 3.87 (s, 3H), 3.52-3.59 (m, 1H), 2.63-2.71 (m, 1H), 2.40-2.44 (m, 1H), 2.10 (brs, 1H), 1.41 1.70 (m, 10H), 1.35-1.38 (d, 3H). LC-MS: (M+H)* = 403.2; HPLC purity = 99.36%. EXAMPLE 118: 2-[3-(1,3-benzothiazol-2-yl)butanoyl]-2-azatricyclo[3.3.1.1 3
,
7 ]decane-5 carbonitrile (118): N 0 15 CN (118) Synthesis of Compound (118): Compound (118) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 20 using DCM: MeOH as eluent to obtain Compound (118). 1 H NMR (300 MHz, CDCl3) : 6 7.84 7.89 (dd, 1H), 7.76-7.78 (d, 1H), 7.34-7.40 (m, 1H), 7.25-7.30 (m, 1H), 4.86 (brs, 1H), 4.23 (brs, 1H), 3.79-3.87 (m, 1H), 3.00-3.09 (m, 1H), 2.49-2.59 (m, 1H), 1.90-2.18 (m, 8H), 1.63 1.76 (m, 3H), 1.45 (d, 3H). LC-MS: (M+H)* = 366.2; HPLC purity = 93.68%. 151 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 119: 1-(2-azatricyclo[3.3.1 .13,7]dec-2-yl)-3-(4-chloro-1,3-benzothiazol-2 yl)butan-1-one (119): ci N 0 s (119). 5 Synthesis of Compound (119): Compound (119) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using hexane : EtOAc as eluent to obtain Compound (119). 1H NMR (300 MHz, CDC3) : 6 7.64-7.67 (d, 1H), 7.36-7.39 (d, 1H), 7.15-7.21 (dd, 1H), 4.74 (brs, IH), 4.10 (brs, 1H), 3.85 10 3.92 (q, IH), 3.04-3.11 (dd, 1H), 2.53-2.61 (dd, 1H), 1.98-2.02 (m, 2H), 1.65-1.79 (m, 10H), 1.45 (d, 3H). LC-MS: (M+H)* = 375.1; HPLC purity = 98.71%. EXAMPLE 120: 3-(4-chloro-1,3-benzothiazol-2-y)-1-(5-hydroxy-2-azatricyclo [3.3.1.1 3 ,7]dec-2-yl)butan-1 -one (120): ci CI N 0 N 15 OH (120) Synthesis of Compound (120): Compound (120) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 20 using DCM: MeOH as eluent to obtain Compound (120). 1H NMR (300 MHz, DMSO-d6): 6 8.02-8.05(d,1H), 7.56-7.58(d,1H), 7.36-7.41(t,1H), 4.65-4.72(m,2H), 4.34(s,1H), 3.80(m,1H), 2.80-3.20(m,2H), 1.45-2.22(m,11H), 1.39-1.42(d,3H). LC-MS: (M+H)* = 391.1; HPLC purity = 98.58%. 152 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 121: 3-(1H-benzotriazol-1-yl)-1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3
,
7 ]dec-2-yl)-3 phenylpropan-1 -one (121): Q N OH N (121) 5 SYNTHETIC SCHEME 24 O H OH N OH OH(): - N N N N. + ,N,N 'N ~ H N N N Starting Material 13 Starting Material 8 Intermediate 55 (121) 10 Synthesis of 3-(1H-benzotriazol-1-yl)-3-phenylpropanoic acid (intermediate-55): A 30mL ACE pressure tube fitted with magnetic stirrer was charged with Starting Material-13 (2 g, 13.4 mmol) and Starting Material-8 (4.8 g, 40.4 mmol). Reaction mixture was heated at 1500C for 12 hours. After completion of reaction, the mixture was diluted with ethyl acetate and concentrated. Resulted crude product was purified by Combiflash column 15 chromatography eluting with hexanes: EtOAc to give Intermediate-55 (2.1 g). Synthesis of Compound (121): To a stirred solution of Intermediate-55 (75mg, 0.28 mmol) in THF (4 mL) Intermediate-7 (43 mg, 0.28 mmol) and HBTU (126mg, 0.3 mmol) was added. This was followed by addition of DIPEA (108mg, 0.84 mmol) at 0*C. Resulted reaction 20 mixture was stirred at room temperature for 1 hour. After completion of reaction, the resultant mass was first quenched with water, then extracted with ethyl acetate and then concentrated. Resulted crude product was purified by preparative TLC eluting with hexanes: EtOAc to give compound compound (121)(40 mg) as white solid. 1H NMR (300 MHz, DMSO-d6): 6 7.99 8.02(d,1H), 7.88-7.91(d,1H), 7.45-7.52(m,3H), 7.24-7.39(m,3H), 6.52-6.54(d,1H), 4.66 25 4.67(d,1H), 4.62(s,1H), 4.46(s,1H), 4.01-4.10(m,1H), 3.23-3.25(m,1H), 2.16(s,1H), 1.23 1.67(m,11H). LC-MS: (M+H)+ = 403.2; HPLC purity = 93.95 %. 153 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 122: 2-[3-(4-fluoro-1H-indol-3-yI)-3-(thiophen-2-yl)propanoyl]-2 azatricyclo[3.3.1 .13,]decane-4-carboxylic acid (122): HO 0 7~0 O N F N H 5 (122) SYNTHETIC SCHEME 25 H0 o 0 HOA O- OA O-A O OH N -N Intermediate 27 Intermediate 56 Intermediate 57 Intermediate 58 O HO 0 0 0 0 NS 0 O0 N / ON HN ~ F F Intermediate 59 NN H H Intermediate 60 (122) 10 Synthesis of methyl 4-oxo-2-azatricyclo[3.3.1.13,' 7 ]decane-2-carboxylate (Intermediate-56): To a stirred solution of Intermediate-27 (0.5g, 2.3mmol) in DCM (10 mL), PCC (1.01g, 4.7 mmol) was added. The reaction mixture was then stirred at room temperature for 16 hours. After completion of reaction, the resultant mass was quenched with water and extracted with 15 DCM. Organic layer was washed with 10%NaHCO 3 solution and concentrated. Resulted crude material was purified by silica gel column chromatography eluting with hexanes: EtOAc to give Intermediate-56 (230 mg). Synthesis of methyl 4-cyano-2-azatricyclo[3.3.1 .1 3 ']decane-2-carboxylate 20 (Intermediate-57): To a stirred solution of Intermediate-56 (0.23g, 1.1 mmol) and Tos MIC (0.3g, 1.5mmol) in DME: EtOH (5 mL: 0.2 mL), t-BuOK (0.37 g, 3.30 mmol) was added at 00C. The reaction 154 WO 2013/111150 PCT/IN2012/000842 mixture was stirred at room temperature for 2 hours. Then reaction mixture was filtered. Filtrate portion was concentrated to give Intermediate-57 (230 mg). Synthesis of 2-tert-butyl 4-ethyl 2-azatricyclo[3.3.1.13,']decane-2,4-dicarboxylate 5 (intermediate-58) A 1 O0mL RB fitted with magnetic stirrer was charged with Intermediate-57 (0.23g, 1.04mmol), and 5N H 2
SO
4 (25 mL). The reaction mixture was heated at 1000C for 36 hours. After completion of reaction (monitored by LC-MS), the mixture was cooled to 0*C. Conc. HCI was added to the cooled mixture, followed by addition of EtOH. The mixture was then heated at 10 90 0 C for 16 hours. The resultant mass was quenched with water, basified with sodium carbonate and washed with DCM. The aqueous layer was diluted with THF (40 mL) to which TEA (5 mL) and Boc-anhydride (0.360 g, 1.4 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. Then reaction mixture was extracted with ethyl acetate and concentrated. Resulted crude material was purified by silica gel column 15 chromatography eluting with hexanes: EtOAc to give Intermediate-58 (130 mg). Synthesis of ethyl 2-azatricyclo[3.3.1.13, 7 ]decane-4-carboxylate. Trifluoroacetic acid salt (intermediate-59): To a stirred solution of Intermediate-58 (0.13g, 0.4 mmol) in DCM (5 mL), TFA (0.1 g, 0.8 20 mmol) was added at 00C. Resulted reaction mixture was stirred for 4 hours at room temperature. After completion of the reaction (reaction was monitored by LC-MS), the resultant mass was concentrated followed by trituration with mixture of hexanes: ether (1:1) to give Intermediate-59 (130 mg). 25 Synthesis of ethyl 2-[3-(4-fluoro-1H-indol-3-yl)-3-(thiophen-2-yl)propanoyl]-2 azatricyclo[3.3.1.1 3 ,7]decane-4-carboxylate (Intermediate-60): Intermediate-60 was synthesized by following the procedure used to make Compund (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using hexanes: EtOAc as eluent to obtain 30 Intermediate-60. Synthesis of Compound (122): Compound (122) was synthesized by following the procedure used to make Compound (43) (Scheme 14). 1H NMR (300 MHz, CDCI3): 6 8.30-9.30(m, 1H), 7.00-7.02(m, 2H), 6.87 35 6.89(m, 1H), 6.77-6.79(m, 2H), 6.62-6.65(m, 1H), 6.46-6.56(m, 1H), 5.02-5.33(m,1H), 4.34 4.73(m,1 H), 3.99-4.12(m,1 H), 2.92-3.61(m,2H), 1.45-2.64(m, 11 H). LC-MS: (M+H)+ = 453.2; HPLC purity = 98.96%. 155 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 123: 2-[3-(4-chloro-1,3-benzothiazol-2-yl)butanoyl]-2 azatricyclo[3.3.1 .13, 7 ]decane-5-carbonitrile (123): ci N' 0 S NN CN 5 (123) Synthesis of Compound (123): Compound (123) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using hexanes: EtOAc as eluent to obtain Compound (123). 1H NMR (300 MHz, CDCl3): 6 10 7.65-7.67(d,1H), 7.36-7.40(m,1H), 7.22(m,1H), 4.84(s,1H), 4.26(s,1H), 3.84-3.91(m,1H), 3.11-3.20(m,1H), 2.48-2.58(m,1H), 1.55-2.15(m,11H), 1.45-1.47(m,3H). LC-MS: (M+H)+ = 400.1; HPLC purity = 96.66%. EXAMPLE 124: 2-[3-(4-chloro-1,3-benzothiazol-2-yl)butanoyl]-2 15 azatricyclo[3.3.1 .1 3
'
7 ]decane-5-carbonitrile Compound (124) peak 1: ci s N CN (124) Peak 1 Synthesis of Compound (124) (peak-1): Racemic compound Compound (123) was separated by chiral preparative HPLC to give Compound (124) (peak-1). LC-MS: (M+H)+ = 20 400.1; HPLC purity = 91.31%; Chiral column, Chiralpak IC, 4.6mmX250m; Mobile Phase:hexane:i-PrOH:DCM (7:2:1); RT = 23.47 minutes. EXAMPLE 125: 2-[3-(4-chloro-1,3-benzothiazol-2-yl)butanoyl]-2 azatricyclo[3.3.1.1 3 7 ]decane-5-carbonitrile Compound (125) peak 2: CI Cl N 0 s 25 cN (125) peak 2 156 WO 2013/111150 PCT/IN2012/000842 Synthesis of Compound (125) (peak-2): Racemate of Compound (123) was separated by chiral preparative HPLC to give Compound (125) peak-2 (125). LC-MS: (M+H)+ = 400.1; HPLC purity = 97.74%; Chiral column, Chiralpak IC, 4.6mmX250m; Mobile Phase:hexane:i PrOH:DCM (7:2:1); RT = 27.72 minutes. 5 EXAMPLE 126: 3-(4-cyclopropyl-1H-indol-3-yI)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
'
7 ]dec 2-yl)propan-1-one (126): 0 NOH N H (126) 10 Synthesis of Compound (126): Compound (126) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (126). 1H NMR (300 MHz, CDCI3): 6 8.00 (brs, 1H), 7.09-7.12 (d, 1H), 6.96-7.01 (t, 1H), 6.93-6.94 (d, 1H), 6.64-6.66 (1H, d), 5.01 (brs, 15 1H), 4.14 (brs, 1H), 3.31-3.36 (t, 2H), 2.65-2.70 (m, 2H), 2.32-2.41 (m, 1H), 2.23 (brs, 1H), 1.45-1.73 (m, 10H), 0.88-0.94 (m, 2H), 0.74-0.81 (M, 2H). LC-MS: (M+H)+ = 365.2; HPLC purity = 98.22%. EXAMPLE 127: 3-(4-fluoro-1H-indol-3-yI)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
'
7 ]dec-2-yl) 20 3-(thiophen-2-yl)propan-1 -one (127): F o N OH F /N H (127) Synthesis of Compound (127): Compound (127) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by 25 evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (127). 1H NMR (300 MHz, CDC3): 6 8.34 (brs, 0.5H), 8.30 (brs, 0.5H), 6.99-7.06 (m, 2H), 6.96-6.97 (m, 2H), 6.81-6.83 (m, 2H), 6.61 6.68 (m, 1H), 5.14-5.20 (m, 1H), 4.94 (brs, 1H), 4.23 (brs, 1H), 3.02-3.20 (m, 2H), 2.14 (brs, 1H), 1.35-1.70 (m, 1OH). LC-MS: (M+H)+ = 425.2; HPLC purity = 99.56%. 157 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 128: 1-(5-hydroxy-2-azatricyclo[3.3.1.1' 3 7]dec-2-yI)-3-(4-propyl-1H-indol-3 yl)propan-1 -one (128): 0 NOH N H 5 (128) Synthesis of Compound (128): Compound (128) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (128). 1H NMR (300 MHz, CDCl3): 6 7.99 10 (brs, 1H), 7.10-7.13 (d, 1H), 6.99-7.04 (t, 1H), 6.91-6.92 (d, 1H), 6.80-6.82 (d, 1H), 5.02 (brs, 1H), 4.13 (brs, 1H), 3.14-3.19 (t, 2H), 2.87-2.92 (t, 2H), 2.59-2.64 (m, 2H), 2.24 (brs, 1H), 1.53-1.74 (m, 12H), 0.93-0.98 (t, 3H). LC-MS: (M+H)+ = 367.2; HPLC purity = 96.54%. EXAMPLE 129: 3-(6-chloro-5-methoxy-1H-indol-3-yl)-1-(5-hydroxy-2-azatricyclo 15 [3.3.1.1 3
,
7 ]dec-2-yl)butan-1 -one (129) peak 1: O NOH c NX 0 H (129) peak I Synthesis of Compound (129) (Peak-1): Racemate of Compound (117) was separated by chiral preparative HPLC to give Compound (129) (peak-1). IH NMR (300 MHz, CDCI3) : 6 20 7.85 (brs, 1H), 7.30-7.31 (d, 1H), 7.09 (brs, 1H), 6.92-6.93 (m, 1H), 4.98 (brs, 1H), 4.09 (brs, IH), 3.87 (s, 3H), 3.52-3.59 (m, 1H), 2.63-2.71 (m, 1H), 2.40-2.44 (m, 1H), 2.10 (brs, 1H), 1.41-1.70 (m, 10H), 1.35-1.38 (d, 3H). LC-MS: (M+H)+ = 403.2; HPLC purity = 99.32%; Chiral Column: Chiralpak IC, 4.6mmX250mm; Mobile phase: hexane: i-PrOH: DCM (7:2:1); RT 11.65 minutes. 25 158 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 130: 3-(6-chloro-5-methoxy-1H-indol-3-yl)-1-(5-hydroxy-2 azatricyclo[3.3.1 .1 3
,
7 ]dec-2-yl)butan-1 -one (130) peak 2: 0 NOH 0 ci N H (130) peak2 5 Synthesis of Compound (130) (peak-2): Racemate of compound (117) was separated by chiral preparative HPLC to give Compound (130) (peak-2). 1H NMR (300 MHz, CDC13) 6 7.85 (brs, 1H), 7.30-7.31 (d, 1H), 7.09 (brs, 1H), 6.92-6.93 (m, 1H), 4.98 (brs, 1H), 4.09 (brs, 1H), 3.87 (s, 3H), 3.52-3.59 (m, 1H), 2.63-2.71 (m, 1H), 2.40-2.44 (m, 1H), 2.10 (brs, 1H), 1.41-1.70 (m, 10H), 1.35-1.38 (d, 3H). LC-MS: (M+H)+ = 403.2; HPLC purity = 99.76%; Chiral 10 Column: Chiralpak IC, 4.6mmX250mm; Mobile phase: hexane: i-PrOH: DCM (7:2:1); RT = 14.60 minutes. EXAMPLE 131: 1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3
,
7 ]dec-2-yl)-4-methyl-3-(4-methyl-1 H benzotriazol-1-yl)pentan-1-one (131): N ) OH 15 N N 15 (131) Synthesis of Compound (131): Compound (131) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 20 using DCM: MeOH as eluent to obtain Compound (131). 1H NMR (300 MHz, CDC13): 6 7.37 7.40 (d, 1H), 7.26-7.31 (t, 1H), 7.02-7.04 (d, 1H), 5.00-5.06 (m, 1H), 4.81 (brs, 1H), 4.25 (brs, 1H), 3.47-3.65 (m, 2H), 2.72 (s, 3H), 2.28-2.34 (m, 1H), 2.10 brs, 1H), 1.35-1.75 (m, 1OH), 0.96-0.98 (d, 3H), 0.72-0.74 (d, 3H). LC-MS: (M+H)+ = 383.2; HPLC purity = 94.65%. 159 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 132: 3-(4-cyclopropyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-1 -(5-hydroxy-2 azatricyclo[3.3.1.1 3
,
7 ]dec-2-yl)butan-1 -one (132): O NOH N N H (132) 5 Synthesis of Compound (132): Compound (132) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (132). 1H NMR (300 MHz, CDCI3): 6 9.30 (brs, 1H), 8.03-8.05 (d, 1H), 7.03 (s, 1H), 6.47-6.49 (d, 1H), 5.02 (brs, 1H), 4.21 (brs, 1H), 10 4.01 (brs, 1H), 2.73-2.78 (m, 1H), 2.33-2.49 (m, 2H), 2.26 (brs, 1H), 1.42-1.75 (m, 10H), 1.35 1.37 (d, 3H). LC-MS: (M+H)+ = 380.2; HPLC purity = 98.45%. EXAMPLE 133: 3-(6-chloro-5-fluoro-1H-indol-3-yI)-1-(5-hydroxy-2-azatricyclo [3.3.1.1 3
'
7 ]dec-2-yl)butan-1 -one (133): O Na OH F 15 H (133) Synthesis of Compound (133): Compound (133) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 20 using DCM: MeOH as eluent to obtain Compound (133). 1H NMR (300 MHz, CDC3) : 6 7.91 (brs, 1H), 7.31-7.34 (d, 1H), 7.28-7.30 (d, 1H), 6.99-7.00 (d, 1H), 4.98 (brs, 1H), 4.10 (brs, 1H), 3.47-3.54 (q, 1H), 2.63-2.71 (m, 1H), 2.40-2.44 (m, 1H), 2.15 (brs, 1H), 1.40-1.71 (m, 10H), 1.34-1.36 (d, 3H). LC-MS: (M+H)+ = 391.2; HPLC purity = 97.57%. 160 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 134: 2-[3-(6-chloro-1H-indol-3-yl)-3-phenylpropanoyl]-2-azatricyclo [3.3.1.1 3
,
7 ]decane-5-carboxylic acid (134): 0 / N OH N H 5 (134) Synthesis of Compound (134): Compound (134) was synthesized by following the procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (134). 1H NMR (300 MHz, DMSO-d6): . 6 10 12.34 (brs, 1H), 11.03 (s, 1H), 7.10-7.40 (m, 8H), 6.84-6.91 (m, 1H), 4.66 (brs, 2H), 4.30 (brs, 1H), 3.01-3.10 (m, 2H), 2.05 (brs, 1H), 1.55-1.98 (m, 1OH). LC-MS: (M+H)+ = 463.2; HPLC purity = 99.58%. EXAMPLE 135: 3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-y)-1-(5-hydroxy-2 15 azatricyclo[3.3.1.1 3
'
7 ]dec-2-yl)butan-1-one (135): 0 Ne OH ci N N H (135) Synthesis of Compound (135): Compound (135) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by 20 evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (135). 1H NMR (300 MHz, CDCI3): .6 9.15 (brs, 0.5H), 9.01 (brs, 1H), 8.15-8.16(d, 1H), 7.91 (s, 1H), 7.09-7.10 (d, 1H), 4.97 (brs, 1H), 4.10 (brs, 1H), 3.51-3.58 (q, 1H), 2.61-2.68 (dd, 1H), 2.42-2.50 (dd, 1H), 2.24 (brs, 0.5H), 2.14 (brs, 0.5H), 1.44 (1.71 (m, 10H), 1.35-1.38 (d, 3H). LC-MS: (M+H)+ = 374.2; HPLC purity 25 = 98.36%. 161 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 136: 2-[3-(4-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)butanoyl]-2 azatricyclo[3.3.1 .1 3 ']decane-5-carbonitrile (136): N CN N N N H 5 (136) Synthesis of Compound (136): Compound (136) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (136). 1H NMR (300 MHz, DMSO-d6): .6 10 11.28 (brs, 1H), 7.99-8.00 (d, 1H), 7.25 (s, 1H), 6.52-6.53 (d, 1H), 4.72 (brs, 1H), 4.29 (brs, 1H), 3.85-3.89 (m, 1H), 2.55.-2.72 (m, 3H), 2.09 (brs, 1H), 1.45-1.99 (m, 10H), 1.28-1.30 (d, 3H), 1.00-1.05 (m, 2H), 0.83-0.88 (m, 2H). LC-MS: (M+H)+ = 389.3; HPLC purity = 98.69%. EXAMPLE 137: 2-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)butanoyl]-2-azatricyclo 15 [3.3.1.1 37 ]decane-5-carbonitrile (137): O N cN ci N N H (137) Synthesis of Compound (137): Compound (137) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by 20 evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (137). 1H NMR (300 MHz, CDC3): .6 8.98 (brs, 0.5H), 8.88 (brs, 0.5H), 8.15-8.20 (m, 1H), 7.90 (s, 1H), 7.10 (s, 1H), 4.90 (brs, 1H), 4.00 (brs, IH), 3.50-3.60 (m, 1H), 2.58-2.62 (dd, 1H), 2.40-2.45 (m, 1H), 2.13-2.16 (m, 1H), 1.60 1.93 (m, 10H), 1.38-1.40 (d, 3H). LC-MS: (M+H)+ = 383.2; HPLC purity 97.99%. 25 162 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 138: 3-(6-chloro-5-cyclopropyl-1H-indol-3-yI)-1-(5-hydroxy-2-azatricyclo [3.3.1.1 3
'
7 ]dec-2-yl)butan-1 -one (138): 0 OH cN N C, H (138) 5 Synthesis of Compound (138): Compound (138) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (138). 1H NMR (300 MHz, CDCl3): .6 7.98 (brs, 0.5H), 7.95 (brs, 0.5H), 7.29 (s, 1H), 7.23 (s, 1H), 6.88 (s, 1H), 4.96 (brs, 1H), 4.09 (brs, 10 1H), 3.46-3.52 (q, 1H), 2.64-2.72 (dd, 1H), 2.38-2.45 (dd, 1H), 2.21-2.24 (m, 1H), 2.08-2.14 (m, 2H), 1.40-1.70 (m, 9H), 1.34-1.36 (d, 3H), 0.83-0.95 (m, 2H), 0.58-0.63 (m, 2H). LC-MS: (M+H)+ = 413.3; HPLC purity = 95.14%. EXAMPLE 139: 3-(5-fluoro-4-methyl-1H-indol-3-yl)-1-(5-hydroxy-2-azatricyclo 15 [3.3.1 .1 3
,
7 ]dec-2-yI)butan-1 -one Compound (139): F 0 N H (139) Synthesis of Compound (139): Compound (139) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 20 using DCM: MeOH as eluent to obtain Compound (139). 1H NMR (300 MHz, CDCI3) : 6 7.89 (br s, 1H), 7.00-7.05 (dd, IH), 6.98-6.99 (d, 1H), 6.81-6.87 (t, 1H), 5.04 (br s, 1H), 4.20 (br s, 1H), 3.84-3.93 (m, 1H), 2.65-2.71 (dd, 1H), 2.54-2.55 (d, 3H), 2.37-2.48 (dd, 1H), 2.26 (br s, 1H), 1.54-1.66 (m, 8H), 1.75 (br s, 2H), 1.39-1.43 (d, 3H). LC-MS: (M+H)+ = 371.2; HPLC purity = 96.42%. 25 163 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 140: 2-[3-(6-chloro-1H-indol-3-yI)-3-phenylpropanoyl]-2 azatricyclo[3.3.1 .1 3 ']decane-5-carboxylic acid (peak-1) (140): 0 OH N NH O (140) Synthesis of Compound (140): Racemate of compound (134) was separated by chiral 5 preparative HPLC to give Compound (140). 1H NMR (300 MHz, DMSO-d6): . 6 12.34 (brs, 1H), 11.03 (s, 1H), 7.10-7.40 (m, 8H), 6.84-6.91 (m, 1H), 4.66 (brs, 2H), 4.30 (brs, 1H), 3.01 3.10 (m, 2H), 2.05 (brs, 1H), 1.55-1.98 (m, 10H). LC-MS: (M+H)+ = 463.1; HPLC purity = 99.56%; Chiral RT = 7.95 min [column: ChiralPak IC, Mobile phase: hexane: IPA: DCM (7:2:1)]. 10 EXAMPLE 141: 2-[3-(6-chloro-1H-indol-3-yl)-3-phenylpropanoyl]-2 azatricyclo[3.3.1 .13, 7 ]decane-5-carboxylic acid (peak-2) (141): 0 OH N NH 0 (141) Synthesis of Compound (141): Racemate of compound (134) was separated by chiral 15 preparative HPLC to give Compound (141). 1H NMR (300 MHz, DMSO-d6): . 6 12.34 (brs, 1H), 11.03 (s, 1H), 7.10-7.40 (m, 8H), 6.84-6.91 (m, 1H), 4.66 (brs, 2H), 4.30 (brs, 1H), 3.01 3.10 (m, 2H), 2.05 (brs, 1H), 1.55-1.98 (m, 10H). LC-MS: (M+H)+ = 463.1; HPLC purity = 99.15%; Chiral RT = 11.99 min [column: ChiralPak IC, Mobile phase: hexane: IPA: DCM (7:2:1)]. 20 164 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 142: 2-[3-(5-phenyl-1H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1.1 37 ]decane-5 carboxylic acid (142): 0 NO H OH (142) Synthesis of Compound (142): Compound (142) was synthesized by following the 5 procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (142). 1H NMR (300 MHz, CDC13): 6 7.96 (br s, 1H), 7.80 (br s, 1H), 7.56-7.59 (d, 2H), 7.32-7.39 (m, 4H), 7.24-7.29 (dd, 1H), 6.97-6.99 (m, 1H), 4.89 (br s, 1H), 4.04 (br s, 1H), 3.61-3.63 (m, 1H), 2.75-2.81 (dd, 1H), 2.48-2.52 (dd, 10 1H), 1.54-2.09 (m, 11H), 1.41-1.44 (dd, 3H). LC-MS: (M+H)+ = 443.2; HPLC purity = 98.51%. EXAMPLE 143: 2-[3-(5-chloro-1H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1.1 3
'
7 ]decane-5 carboxylic acid (143): Cl 0 No N 0 H OH (143) 15 Synthesis of Compound (143): Compound (143) was synthesized by following the procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (143). 1H NMR (300 MHz, DMSO-d6): 6 20 12.20 (br s, 1H), 11.00 (br s, 1H), 7.54 (br s, 1H), 7.30-7.34 (dd, 1H), 7.23 (br s, 1H), 7.01 7.05 (m, 1H), 4.71 (br s, 1H), 4.18 (br s, 1H), 3.67-3.78 (m, 1H), 2.62-2.68 (m, 1H), 2.43-2.47 (m, 1H), 1.39-1.97 (m, 11H), 1.29-1.31 (d, 3H). LC-MS: (M+H)+ = 401.2; HPLC purity = 97.21%. 165 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 144: 3-(5-chloro-4-methyl-1H-indol-3-yl)-1-(5-hydroxy-2 azatricyclo[3.3.1.1 3
'
7 ]dec-2-yl)butan-1 -one (144): Cl 0 Noa N OH H (144) 5 Synthesis of Compound (144): Compound (144) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (144). 1H NMR (300 MHz, CDC13): 6 7.95 (br s, 1H), 7.09-7.12 (d, 1H), 7.03-7.06 (d, 1H), 6.93-6.98 (d, 1H), 5.03 (br s, 1H), 4.19 (br s, 10 1H), 3.88-3.90 (m, 1H), 2.68 (s, 3H), 2.62-2.65 (m, 1H), 2.37-2.45 (m, 1H), 2.27 (br s, 1H), 1.54-1.76 (m, 10H), 1.32-1.34 (d, 3H). LC-MS: (M+H)+ = 387.2; HPLC purity = 97.47%. EXAMPLE 145: {2-[3-(4-chloro-1H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1.1 3
,
7 ]dec-5 yl}acetic acid (145): Cl N N H HO 0 15 (145) Synthesis of Compound (145): Compound (145) was synthesized by following the procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column -using DCM: MeOH as eluent to obtain Compound (145). 1H NMR (300 MHz, CDC3): 6 8.39 20 (br s, 1H), 7.16-7.20 (m, 1H), 6.92-6.97 (m, 3H), 4.88 (br s, 1H), 4.20 (br s, 1H), 3.98-4.13 (m, 1H), 2.78-2.94 (m, 1H), 2.52-2.59 (m, 1H), 2.08 (br s, 2H), 2.04 (br s, 1H), 1.52-1.68 (m, 10H), 1.37-1.39 (d, 3H).LC-MS: (M+H)+ = 415.2; HPLC purity = 97.51%. 166 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 146: 3-{2-[3-(4-cyclopropyl-1 H-indol-3-yl)butanoyl]-2 azatricyclo[3.3.1.1 3 ']dec-5-yl}propanoic acid (146): O N N H O (146) OH Synthesis of Compound (146): Compound (146) was synthesized by following the 5 procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (146). 1H NMR (300 MHz, DMSO-d6): 6 12.01 (br s, 1H), 10.81 (br s, 1H), 7.17 (br s, 1H), 7.12-7.15 (d, 1H), 6.88-6.93 (t, 1H), 6.56 6.58 (d, 1H), 4.71 (br s, 1H), 4.20 (br s, 1H), 4.02-4.04 (m, 1H), 2.26-2.28 (m, 1H), 2.06-2.16 10 (m, 5H), 1.32-1.60 (m, 12H), 1.25-1.29 (d, 3H). LC-MS: (M+H)+ = 435.2; HPLC purity = 98.38%. EXAMPLE 147: 3-(5-fluoro-4-methyl-1H-indol-3-yl)-1-(5-hydroxy-2 azatricyclo[3.3.1.13, 7 ]dec-2-yl)butan-1 -one (peak-1) (147): F 0 NN N~ OH H (147) 15 Synthesis of Compound (147): Racemic compound (139) was separated by using chiral preparative column chromatography to give Compound (147). 1H NMR (300 MHz, CDCl3): 6 7.89 (br s, 1H), 7.00-7.05 (dd, 1H), 6.98-6.99 (d, 1H), 6.81-6.87 (t, 1H), 5.04 (br s, 1H), 4.20 (br s, 1H), 3.84-3.93 (m, 1H), 2.65-2.71 (dd, 1H), 2.54-2.55 (d, 3H), 2.37-2.48 (dd, 1H), 2.26 20 (br s, 1H), 1.54-1.66 (m, 8H), 1.75 (br s, 2H), 1.39-1.43 (d, 3H). LC-MS: (M+H)+ =371.2; HPLC purity = 96.98%. Chiral RT = 10.82 min [Column: ChiralPak IC, Mobile phase: hexane: THF (7:3)]. 167 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 148: 3-(5-fluoro-4-methyl-1H-indol-3-yI)-1-(5-hydroxy-2 azatricyclo[3.3.1.1 3
'
7 ]dec-2-yl)butan-1-one (peak-2) (148): F 0 NN N~ OH H (148) Synthesis of Compound (148): Racemic compound (139) was separated by using chiral 5 preparative column chromatography to give Compound (148). 1H NMR (300 MHz, CDCi3) : 6 7.89 (br s, 1H), 7.00-7.05 (dd, 1H), 6.98-6.99 (d, 1H), 6.81-6.87 (t, 1H), 5.04 (br s, 1H), 4.20 (br s, 1H), 3.84-3.93 (m, 1H), 2.65-2.71 (dd, IH), 2.54-2.55 (d, 3H), 2.37-2.48 (dd, 1H), 2.26 (br s, 1H), 1.54-1.66 (m, 8H), 1.75 (br s, 2H), 1.39-1.43 (d, 3H). LC-MS: (M+H)+ = 371.2; HPLC purity = 99.16%; Chiral RT = 9.69 min [Column: ChiralPak IC, Mobile phase: hexane: 10 THF (7:3)]. EXAMPLE 149: 3-(4-cyclopropyl-1H-indol-3-yI)-1-[5-(1H-tetrazol-5-yl)-2 azatricyclo[3.3.1.13, 7 ]dec-2-yl]butan-1 -one (149): N 'N NH HN/ 0 (149) 15 Synthesis of Compound (149): Compound (149) was synthesized by following the procedure used to make Compound (77) (Scheme 21). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (149). 1H NMR (300 MHz, CDC13): 6 8.38 (br s, 0.5H), 8.25 (br s, 0.5H), 7.02-7.07 (t, 1H), 6.98-7.00 (d, 1H), 6.89-6.94 (m, 1H), 6.56 20 6.66 (dd, 1H), 4.88-4.92 (d, 1H), 4.20 (br s, 1H), 3.47-3.50 (m, 1H), 2.78-2.85 (m, 1H), 2.46 2.59 (m, 1H), 2.29-2.34 (m, IH), 2.17-2.19 (m, IH), 1.61-2.01 (m, IOH), 1.32-1.38 (m, 3H), 0.72-0.79 (m, 2H), 0.63-0.65 (m, 2H). LC-MS: (M+H)+ = 431.2; HPLC purity = 92.97%. 168 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 150: 3-(4-cyclopropyl-5-fluoro-1H-indol-3-yI)-1-(5-hydroxy-2 azatricyclo[3.3.1.1 3
'
7 ]dec-2-yl)butan-1 -one (150): F 0 N~J N H (150) Synthesis of Compound (150): Compound (150) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (150). 1H NMR (300 MHz, CDCl3): 5 7.93 (br s, 1H), 7.04-7.06 (d, 1H), 7.01-7.02 (d, 1H), 6.74-6.84 (dd, 1H), 5.02 (br s, IH), 4.21-4.24 (m, 1H), 4.20 (br s, 1H), 2.68-2.75 (dd, 1H), 2.34-2.43 (dd, 1H), 2.22-2.25 (m, 1H), 2.00-2.09 10 (m, 1H), 1.52-1.75 (m, 10H), 1.31-1.34 (d, 3H), 0.99-1.03 (m, 2H), 0.83-0.87 (m, 2H). LC-MS: (M+H)+ = 397.2; HPLC purity = 97.0%. EXAMPLE 151: 3-(5-chloro-4-cyclopropyl-1H-indol-3-yI)-1-(5-hydroxy-2 azatricyclo[3.3.1.1 3 ,7]dec-2-yl)butan-1-one (151): Cl 0 CI H OH (151) 15 Synthesis of Compound (151): Compound (151) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (151). 1H NMR (300 MHz, DMSO-d6): 6 20 11.04 (br s, 1H), 7.29 (br s, 1H), 7.17-7.20 (d, 1H), 6.98-7.00 (d, 1H), 4.79 (br s, 1H), 4.64 4.65 (d, 1H, OH group), 4.31 (br s, 1H), 4.22-4.23 (m, 1H), 2.60-2.72 (m, 2H), 2.07-2.27 (m, 2H), 1.38-1.68 (m, 10H). 1.24-1.27 (d, 3H), 0.80-0.85 (m, 2H), 0.70-0.75 (m, 2H). LC-MS: (M+H)+ = 413.1; HPLC purity = 95.99%. 169 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 152: {2-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1.1 3 ']dec 5-yl}acetic acid (152): OH HNq N _ 0 (152) Synthesis of Compound (152): Compound (152) was synthesized by following the 5 procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (152). 1H NMR (300 MHz, DMSO-d6): 6 10.82 (br s, 1H), 7.17 (br s, 1H), 7.12-7.15 (d, 1H), 6.88-6.93 (t, 1H), 6.56-6.58 (d, 1H), 4.72 (br s, 1H), 4.22 (br s, IH), 4.00-4.06 (m, 1H), 2.68-2.73 (m, 2H), 2.43-2.46 (m, 3H), 1.99-2.05 10 (m, 1H), 1.45-1.68 (m, 10H), 1.28-1.30 (d, 3H), 0.85-0.90 (m, 2H), 0.70-0.75 (m, 2H). LC-MS: (M+H)+ = 421.2; HPLC purity = 98.6 %. EXAMPLE 153: 1-(5-hydroxy-2-azatricyclo[3.3.1 .13, 7 ]dec-2-yl)-3-[4-(thiophen-2-y)-1H indol-3-yl]butan-1 -one (153): S N N OH H (153) 15 Synthesis of Compound (153): Compound (153) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (153). 1H NMR (300 MHz, CDC3): 6 8.16 20 (br s, 1H), 7.31-7.34 (d, 1H), 7.23-7.26 (m, 1H), 7.10-7.15 (t, 1H), 7.02-7.08 (m, 4H), 4.89 (br s, 1H), 3.80 (br s, 1H), 3.38-3.40 (m, 1H), 2.38-2.43 (m, 1H), 2.19-2.22 (m, 1H), 1.97-2.01 (m, 1H), 1.45-1.71 (m, 10H), 1.37-1.39 (d, 3H). LC-MS: (M+H)+ = 421.1; HPLC purity = 96.43%. 170 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 154: (2-{3-[4-(thiophen-2-y)-1 H-indol-3-yl]butanoyl}-2 azatricyclo[3.3.1.1 3
,
7 ]dec-5-yl)acetic acid (154): S OOH H N 1~ N 0 (154) Synthesis of Compound (154): Compound (154) was synthesized by following the 5 procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (154). 1H NMR (300 MHz, CDC3): 6 8.68 (br s, 0.5H), 8.57 (br s, 0.5H), 7.22-7.30 (m, 2H), 7.01-7.09 (m, 5H), 4.77 (br s, 1H), 3.46 (br s, 1H), 3.31-3.35 (m, 1H), 2,35-2.48 (m, 2H), 2.07 (br s, 1H), 1.40-1.78 (m, 13H). LC-MS: 10 (M+H)+ = 463.1; HPLC purity = 92.86%. EXAMPLE 155: {2-[3-(4-cyclopropyl-1 H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1.13 a]dec 5-yl)acetic acid (peak-1) (155): OH H N N 0 0 (155) 15 Synthesis of Compound (155): Racemic compound (152) was purified by using chiral preperative HPLC chromatography to give Compound (155). 1H NMR (300 MHz, CDCl3): 6 7.98 (br s, 1H), 7.09-7.12 (d, 1H), 6.99-7.01 (d, 1H), 6.97 (br s, 1H), 6.66-6.78 (d, 1H), 4.89 (br s, 1H), 4.14-4.16 (m, 1H), 4.06 (br s, 1H), 2.75-2.82 (dd, 1H), 2.37-2.45 (m, 2H), 2.08 (s, 2H), 2.04 (br s, 1H), 1.52-1.71 (m, 10H), 1.36-1.38 (d, 3H), 0.90-0.95 (m, 2H), 0.76-0.81 (m, 20 2H). LC-MS: (M+H)+ = 421.2; HPLC purity = 98.67%; Chiral RT = 9.07 min [column: ChiralPak IC, mobile phase: hexane: IPA: DCM (7.5:1.5:1)]. 171 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 156: {2-[3-(4-cyclopropyl-1 H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1.1 3 ']dec 5-yl}acetic acid (peak-2) (156): OH H N N 0 (156) 5 Synthesis of Compound (156): Racemic compound (152) was purified by using chiral preparative HPLC chromatography to give Compound (156). 1H NMR (300 MHz, DMSO-d6): 6 10.82 (br s, 1H), 7.17 (br s, 1H), 7.12-7.15 (d, 1H), 6.88-6.93 (t, 1H), 6.56-6.58 (d, 1H), 4.72 (br s, 1H), 4.22 (br s, 1H), 4.00-4.06 (m, 1H), 2.68-2.73 (m, 2H), 2.43-2.46 (m, 3H), 1.99-2.05 (m, 1H), 1.45-1.68 (m, 1OH), 1.28-1.30 (d, 3H), 0.85-0.90 (m, 2H), 0.70-0.75 (m, 2H). LC-MS: 10 (M+H)+ = 421.2; HPLC purity = 99.66%; Chiral RT = 12.93 min [column: ChiralPak IC, mobile phase: hexane: IPA: DCM (7.5:1.5:1)]. EXAMPLE 157: 3-(4-cyclopropyl-5-fluoro-1H-indol-3-yl)-1-(5-hydroxy-2 azatricyclo[3.3.1.1 3
,
7 ]dec-2-yl)butan-1 -one (peak-1) (157): F 0 * N N H OH (157) 15 Synthesis of Compound (157) (peak-1): Racemic compound (150) was purified by using chiral preparative HPLC chromatography to give Compound (157). LC-MS: (M+H)+ = 397.2; Chiral RT 10.98 min [column: ChiralPak IC, mobile phase: hexane: IPA: DCM (7.5:1.5:1)]. 172 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 158: 3-(4-cyclopropyl-5-fluoro-1H-indol-3-yl)-1-(5-hydroxy-2 azatricyclo[3.3.1.1 3 ']dec-2-yl)butan-1 -one (peak-2) (158): F 0 *N N H OH (158) Synthesis of Compound (158) (peak 2): Racemic compound (150) was purified by using 5 chiral preparative HPLC chromatography to give Compound (157). LC-MS: (M+H)+ = 397.2; HPLC purity = 98.48%; Chiral RT = 14.93 min [column: ChiralPak IC, mobile phase: hexane: IPA: DCM (7.5:1.5:1)]. EXAMPLE 159: {2-[3-(4-fluoro-1 H-indol-3-yl)-3-(thiophen-2-yl)propanoyl]-2 10 azatricyclo[3..1.1 3 ']dec-5-yl}acetic acid (159): F OH HN N O S 0 (159) Synthesis of Compound (159): Compound (159) was synthesized by following the procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced:pressure and was purified by silica gel column 15 using DCM: MeOH as eluent to obtain Compound (159). 1H NMR (300 MHz, DMSO-d6): 5 11.93 (br s, 1H), 11.21 (br s, 1H), 7.35 (s, 1H), 7.21-7.23 (m, IH), 7.15-7.18 (d, 1H), 6.97 7.04 (m, 1H), 6.85-6.88 (m, 1H), 6.81-6.83 (m, 1H), 6.63-6.70 (dd, 1H), 5.09-5.11 (t, 1H), 4.65 (br s, 1H), 4.27 (br s, 1H), 3.10-3.17 (m, 1H), 2.95-3.05 (m, 1H), 2.01 (s, 2H), 1.97 (s, 2H), 1.40-1.66 (m, 10H). LC-MS: (M+H)+ = 467.1; HPLC purity = 99.63%. 20 173 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 160: 3-(4-cyclopropyl-5-methyl-1 H-indol-3-yI)-1 -(5-hydroxy-2 azatricyclo[3.3.1 .1 3
'
7 ]dec-2-yl)butan-1 -one (160): 0 N OH H (160) Synthesis of Compound (160): Compound (160) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (160). 1H NMR (300 MHz, CDCI3): 6 7.84 (br s, 1H), 7.04-7.07 (d, 1H), 6.97 (br s, 1H), 6.88-6.91 (d, 1H), 5.00 (br s, 1H), 4.34-4.47 (m, 1H), 4.20 (br s, 1H), 2.67-2.73 (dd, 1H), 2.43 (s, 3H), 2.29-2.37 (dd, 1H), 2.15-2.22 (m, 1H), 10 2.00-2.05 (m, 1H), 1.45-1.78 (m, 10H), 1.33-1.36 (m, 3H), 1.04-1.10 (M, 2H), 0.64-0.69 (m, 2H). LC-MS: (M+H)+ = 393.3; HPLC purity = 98.30%. EXAMPLE 161: 3-(4-chloro-5-cyclopropyl-1H-indol-3-yl)-1-(5-hydroxy-2 azatricyclo[3.3.1 .1 3 ,7]dec-2-yl)butan-1 -one (161): 15 Cl 0 N N N OH H (161) Synthesis of Compound (161): Compound (161) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 20 using DCM: MeOH as eluent to obtain Compound (161). 1H NMR (300 MHz, CDCl3): 5 8.03 (br s, 1H), 7.08-7.10 (d, IH), 7.01-7.01 (d, 1H), 6.74-6.77 (d, 1H), 5.02 (br s, 1H), 4.26 (br s, 1H), 4.10-4.12 (m, 1H), 2.37-2.46 (m, 1H), 2.26-2.29 (m, 1H), 2.15-2.24 (m, 1H), 1.45-1.75 (m, 11H), 1.36-1.39 (d, 3H), 0.89-0.96 (m, 2H), 0.59-0.62 (m, 2H). LC-MS: (M+H)+ = 413.1; HPLC purity = 98.97%. 25 174 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 162: {2-[3-(4-bromo-5-chloro-1H-indol-3-yl)butanoyl]-2 azatricyclo[3.3.1 .1 3
'
7 ]dec-5-yl}acetic acid (162): Cl Br N N ( H HO 0 (162) 5 Synthesis of Compound (162): Compound (162) was synthesized by following the procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (162). 1H NMR (300 MHz, CDCl3): 6 8.70 (br s, 0.5H), 8.62 (br s, 0.5H), 7.12-7.15 (d, 1H), 7.07-7.09 (d, 1H), 7.01 (s, 1H), 4.87 (br s, 10 1H), 4.15-4.21 (m, 1H), 4.01 (br s, 1H), 2.72-2.85 (m, 1H), 2.45-2.60 (m, 1H), 2.29 (s, 2H), 2.04 (s, 1H), 1.50-1.75 (m, 10H). LC-MS: (M+H)+ = 493.2; HPLC purity = 91.99%. EXAMPLE 163: 3-(5-chloro-4-cyclopropyl-1H-indol-3-yI)-1-(5,7-dihydroxy-2 azatricyclo[3.3.1.1 3
'
7 ]dec-2-yl)butan-1 -one (163): Cl O0 OH NNg N OH H 15 (163) Synthesis of Compound (163): Compound (163) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (163). 1H NMR (300 MHz, CDC3): 6 8.01 20 (br s, 1H), 7.06 (s, 2H), 7.01-7.02 (d, 1H), 4.27-4.42 (m, 1H), 3.50 (br s, 1H), 3.43 (br s, 1H), 2.62-2.77 (dd, 1H), 2.37-2.46 (dd, 1H), 2.11-2.13 (m, 1H), 1.83-1.98 (m, 4H), 1.62-1.68 (m, 4H), 1.55-1.58 (m, 2H), 1.33-1.35 (d, 3H), 1.12-1.16 (m, 2H), 0.76-0.84 (m, 2H). LC-MS: (M+H)+ = 429.1; HPLC purity = 99.90%. 175 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 164: 3-(4,5-dimethyl-1H-indol-3-yI)-1 -(5-hydroxy-2- azatricyclo[3.3.1 .137]dec 2-yl)butan-1 -one (164): 0 N N OH H (164) Synthesis of Compound (164): Compound (164) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (164). 1H NMR (300 MHz, CDCl3): 6 7.92 (br s, 1H), 7.01-7.03 (d, 1H), 6.91-6.93 (d, 1H), 6.90 (s, 1H), 5.03 (br s, 1H), 4.18 (br s, 1H), 3.92-3.95 (m, IH), 2.68-2.74 (dd, 1H), 2.54 (s, 3H), 2.35-2.43 (dd, 1H), 2.29 (s, 3H), 2.20 10 2.25 (m, 1H), 1.52-1.75 (m, 11H), 1.33-1.35 (d, 3H). LC-MS: (M+H)+ = 367.2; HPLC purity = 97.04%. EXAMPLE 165: 1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3 7 ]dec-2-yI)-3-(5-methoxy-4-methyl-1 H indol-3-yl)butan-1 -one (165): 15 0 0 H L ;Z OH (165) Synthesis of Compound (165): Compound (165) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 20 using DCM: MeOH as eluent to obtain Compound (165). 1H NMR (300 MHz, CDCl3): 6 7.77 (br s, 1H), 7.05-7.08 (d, 1H), 6.95-6.96 (d, 1H), 6.82-6.85 (d, 1H), 5.04 (br s, 1H), 4.19 (br s, 1H), 3.87-3.89 (m, 1H), 3.77 (s, 3HO, 2.67-2.73 (dd, 1H), 2.54 (s, 3H), 2.36-2.44 (dd, 1H), 2.24-2.26 (m, 1H), 1.55-1.75 (m, 10H), 1.33-1.35 (d, 3H). LC-MS: (M+H)+ = 383.2; HPLC purity = 95.78%. 25 176 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 166: 3-(4-chloro-5-methyl-1H-indol-3-yl)-1-(5-hydroxy-2 azatricyclo[3.3.1 .1 3 7 ]dec-2-yl)butan-1 -one (166): Cl 0 N N& OH H (166) 5 Synthesis of Compound (166): Compound (166) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (166). 1H NMR (300 MHz, CDC13): 6 8.00 (br s, 1H), 7.08-7.10 (d, 1H), 6.98-7.00 (d, 1H), 6.95 (s, 1H), 5.02 (br s, 1H), 4.25 (br s, 1H), 10 4.09-4.11 (m, 1H), 2.82-2.87 (m, 1H), 2.40-2.44 (m, 1H), 2.38 (s, 3H), 2.23-2.25 (m, 1H), 1.55-1.78 (m, 11 H). LC-MS: (M+H)+ = 388.2; HPLC purity = 99.97%. EXAMPLE 167: 2-{2-[3-(4-cyclopropyl-1H-indol-3-yl)butanoyl]-2 azatricyclo[3.3.1 .1 3
,
7 ]dec-5-yl}propanoic acid (167): HN N O 0 (167) 15 Synthesis of Compound (167): Compound (167) was synthesized by following the procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (167). 1H NMR (300 MHz, DMSO-d6): 6 20 12.01 (br s, 1H), 10.81 (s, 1H), 7.16-7.17 (d, 1H), 7.12-7.15 (d, 1H), 6.88-6.93 (t, 1H), 6.55 6.58 (d, 1H), 4.72 (br s, 1H), 4.24 (br s, 1H), 4.02-4.04 (m, 1H), 2.67-2.723 (m, 2H), 2.38-2.43 (m, 1H), 2.05-2.07 (m, 1H), 1.99-2.02 (m, 1H), 1.46-1.74 M, 10H), 1.28-1.30 (d, 3H), 0.95 0.98 (d, 3H), 0.83-0.88 (m, 2H), 0.70-0.74 (m, 2H). LC-MS: (M+H)+ = 435.2; HPLC purity = 96.54%. 25 177 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 168: 3-(4,5-dichloro-1H-indol-3-yI)-1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3 7 ]dec-2 yl)butan-1-one (168): Cl C 0 N OH H (168) Synthesis of Compound (168): Compound (168) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (168). 1H NMR (300 MHz, CDCI3): 5 8.18 (br s, 1H), 7.10-7.13 (d, 2H), 7.06-7.07 (d, 1H), 5.00 (br s, 1H), 4.24 (br s, 1H), 4.04-4.07 (m, 1H), 2.78-2.84 (m, 1H), 2.37-2.47 (dd, 1H), 2.24-2.26 (m, 1H), 1.73-1.78 (m, 3H), 1.61-1.65 10 (m, 7H), 1.35-1.38 (d, 3H). LC-MS: (M+H)+ = 407.1; HPLC purity = 99.28% EXAMPLE 169: 3-(4,5-dimethyl-1 H-indol-3-yl)-1 -(5-hydroxy-2-azatricyclo[3.3.1 .1 3
,
7 ]dec-2 yl)butan-1 -one (peak-1) (169): 0 N * N H H (169) 15 Synthesis of Compound (169): Racemic compound (164) was purified by using chiral preparative HPLC chromatography to give Compound (169). 1H NMR (300 MHz, CDC3): 6 7.92 (br s, 1H), 7.01-7.03 (d, 1H), 6.91-6.93 (d, 1H), 6.90 (s, 1H), 5.03 (br s, 1H), 4.18 (br s, 1H), 3.92-3.95 (m, 1H), 2.68-2.74 (dd, 1H), 2.54 (s, 3H), 2.35-2.43 (dd, 1H), 2.29 (s, 3H), 20 2.20-2.25 (m, 1H), 1.52-1.75 (m, 11H), 1.33-1.35 (d, 3H). LC-MS: (M+H)+ = 367.2; HPLC purity = 93.27%; Chiral RT = 20.93 min [column: ChiralPak IC, mobile phase: hexane: IPA: DCM (7.5:1.5:1)]. 178 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 170: 3-(4,5-dimethyl-1H-indol-3-yl)-1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3
'
7 ]dec-2 yl)butan-1 -one (peak-2) (170): 0 N H (170) Synthesis of Compound (170): Racemic compound (164) was purified by using chiral 5 preperative HPLC chromatography to give Compound (170). 1H NMR (300 MHz, CDCl3): 5 7.92 (br s, 1H), 7.01-7.03 (d, 1H), 6.91-6.93 (d, 1H), 6.90 (s, 1H), 5.03 (br s, 1H), 4.18 (br s, 1H), 3.92-3.95 (m, 1H), 2.68-2.74 (dd, 1H), 2.54 (s, 3H), 2.35-2.43 (dd, 1H), 2.29 (s, 3H), 2.20-2.25 (m, 1H), 1.52-1.75 (m, 11H), 1.33-1.35 (d, 3H). LC-MS: (M+H)+ = 367.2; HPLC purity = 99.81%; Chiral RT ='25.61 min [column: ChiralPak IC, mobile phase: hexane: IPA: 10 DCM (7.5:1.5:1)]. EXAMPLE 171: 3-(4-cyclopropyl-5-methoxy-1H-indol-3-yl)-1-(5-hydroxy-2 azatricyclo[3.3.1.1 3 ,7]dec-2-yl)butan-1-one (171): 0 0 N N-OH H (171) 15 Synthesis of Compound (171): Compound (171) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (171). 1H NMR (300 MHz, CDC13): 5 7.83 (br s, 1H), 7.06-7.09 (d, 1H), 6.98-6.99 (d, i H), 6.78-6.81 (d, 1H), 5.02 (br s, 1H), 4.26-4.29 20 (m, 1H), 4.19 (br s, 1H), 3.78 (s, 3H), 2.69-2.76 (dd, 1H), 2.31-2.39 (dd, 1H), 2.22-2.25 (m, 1H), 1.95-1.99 (m, 2H), 1.45-1.75 (m, 9H), 1.34-1.36 (d, 3H), 0.99-1.01 (m, 2H), 0.79-0.81 (m, 2H). LC-MS: (M+H)+ = 409.2; HPLC purity = 92.57%. 179 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 172: 3-(4,5-dichloro-1H-indol-3-yI)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3 ']dec-2 yl)butan-1 -one (peak-1) (172): Cl C 0 N OH H (172) Synthesis of Compound (172): Racemic compound (168) was purified by using chiral 5 preparative HPLC chromatography to give Compound (172). 1H NMR (300 MHz, CDCl3): 6 8.18 (br s, 1H), 7.10-7.13 (d, 2H), 7.06-7.07 (d, 1H), 5.00 (br s, 1H), 4.24 (br s, 1H), 4.04-4.07 (m, 1H), 2.78-2.84 (m, 1H), 2.37-2.47 (dd, 1H), 2.24-2.26 (m, 1H), 1.73-1.78 (m, 3H), 1.61 1.65 (m, 7H), 1.35-1.38 (d, 3H). LC-MS: (M+H)+ = 407.0; HPLC purity = 94.74%; Chiral RT = 8.15 min [column: ChiralPak IC, mobile phase: hexane: IPA: DCM (7:2:1)]. 10 EXAMPLE 173: 3-(4,5-dichloro-1H-indol-3-yI)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
'
7 ]dec-2 yl)butan-1 -one (peak-2) (173): CI Cl NNH H (173) Synthesis of Compound (173): Racemic compound (168) was purified by using chiral 15 preparative HPLC chromatography to give Compound (173). 1H NMR (300 MHz, CDCl3): 6 8.18 (br s, 1H), 7.10-7.13 (d, 2H), 7.06-7.07 (d, 1H), 5.00 (br s, 1H), 4.24 (br s, 1H), 4.04-4.07 (m, 1H), 2.78-2.84 (m, 1H), 2.37-2.47 (dd, 1H), 2.24-2.26 (m, 1H), 1.73-1.78 (m, 3H), 1.61 1.65 (m, 7H), 1.35-1.38 (d, 3H). LC-MS: (M+H)+ = 407.0; HPLC purity = 99.34%; Chiral RT = 11.31 min [column: ChiralPak IC, mobile phase: hexane: IPA: DCM (7:2:1)]. 20 EXAMPLE 174: 3-(4-chloro-5-methyl-1 H-indol-3-yl)-1 -(5-hydroxy-2 azatricyclo[3.3.1.13, ]dec-2-yl)butan-1 -one (peak-1) (174): CI O H * NOH (174) 180 WO 2013/111150 PCT/IN2012/000842 Synthesis of Compound (174): Racemic compound (166) was purified by using chiral preperative HPLC chromatography to give Compound (174). 1H NMR (300 MHz, CDCl3): 6 8.00 (br s, 1H), 7.08-7.10 (d, 1H), 6.98-7.00 (d, 1H), 6.95 (s, 1H), 5.02 (br s, 1H), 4.25 (br s, 1H), 4.09-4.11 (m, 1H), 2.82-2.87 (m, 1H), 2.40-2.44 (m, 1H), 2.38 (s, 3H), 2.23-2.25 (m, 1H), 5 1.55-1.78 (m, 11H). LC-MS: (M+H)+ = 387.1; HPLC purity = 95.57%; Chiral RT = 15.30 min [column: ChiralPak IC, mobile phase: hexane:THF (7:3)]. EXAMPLE 175: 3-(4-chloro-5-methyl-1H-indol-3-yl)-1-(5-hydroxy-2 azatricyclo[3.3.1 .1 3 ']dec-2-yl)butan-1 -one (peak 2) (175): CI N '_ N OH H 10 (175) Synthesis of Compound (175): Racemic compound 166) was purified by using chiral preperative HPLC chromatography to give Compound (175). 1H NMR (300 MHz, CDCl3): 6 8.00 (br s, 1H), 7.08-7.10 (d, 1H), 6.98-7.00 (d, 1H), 6.95 (s, 1H), 5.02 (br s, 1H), 4.25 (br s, IH), 4.09-4.11 (m, 1H), 2.82-2.87 (m, 1H), 2.40-2.44 (m, 1H), 2.38 (s, 3H), 2.23-2.25 (m, 1H), 15 1.55-1.78 (m, 11H). LC-MS: (M+H)+ = 387.1; HPLC purity = 98.33%; Chiral RT = 17.15 min [column: ChiralPak IC, mobile phase: hexane:THF (7:3)]. EXAMPLE-176: 3-(4,5-dimethyl-1 H-indol-3-yl)-1 -(5-fl uoro-2-azatricyclo[3.3.1.1 3 ']dec-2 yl)butan-1-one (176): 0 N H (176) 20 Synthesis of Compound (176): Compound (176) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (176). 1 H NMR (300 MHz, CDCl3): 6 8.06 25 (br s, 1H), 8.02-8.04 (d, 1H), 7.31-7.34 (d, 1H), 7.11-7.13 (d, 1H), 4.99-5.05 (m, 1H), 4.70 4.71 (m, 1H), 4.61-4.62 (m, 1H), 2.57-2.62 (m, 1H), 2.33-2.41 (m, 1H), 2.25 (s, 3H), 2.10 (s, 3H), 1.33-1.87 (m, 14H). LC-MS: (M-19)+ = 413.3; HPLC purity = 90.92%. 181 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 177: 1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
,
7 ]dec-2-yl)-3-[4-(propan-2-yloxy)-1H indol-3-yl]butan-1-one (177): 0 0 NN H OH (177) Synthesis of Compound (177): Compound (177) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (177). 1H NMR (300 MHz, CDCl3): 6 7.91 (br s, 1H), 7.03-7.08 (t, 1H), 6.91-6.93 (d, 1H), 6.90 (s, 1H), 6.46-6.49 (d, 1H), 5.06 (br s, 1H), 4.74-4.80 (m, 1H), 4.22 (br s, 1H), 3.76-3.88 (m, 1H), 2.97-3.06 (m, 1H), 2.52-2.56 (m, 1H), 10 2.22-2.27 (m, 1H), 1.55-1.77 (m, 10H), 1.42-1.45 (m, 9H). LC-MS: (M+H)+ = 397.2; HPLC purity = 90.56%. EXAMPLE 178: 1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3
'
7 ]dec-2-yI)-3-[4-(propan-2-yloxy)-1 H indol-3-yl]butan-1 -one (peak-1) (178): 0 0 NN H (178) 15 Synthesis of Compound (178): Racemic compound (177) was purified by using chiral preperative HPLC chromatography to give Compound (178). LC-MS: (M+H)+ = 397.2; HPLC purity = 99.12%. Chiral RT = 9.72 min [column: ChiralPak IC, mobile phase: hexane:IPA:DCM (8:1:1)]. 20 182 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 179: 1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3
,
7 ]dec-2-yl)-3-[4-(propan-2-yloxy)-1 H indol-3-yl]butan-1 -one (peak-2) (179): 0 0 N H OH (179) Synthesis of Compound (179): Racemic compound (177) was purified by using chiral 5 preperative HPLC chromatography to give Compound (179). LC-MS: (M+H)+ = 397.2; HPLC purity = 99.65%. Chiral RT = 11.97 min [column: ChiralPak IC, mobile phase: hexane:IPA:DCM (8:1:1)]. EXAMPLE 180: 1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
'
7 ]dec-2-yl)-3-[4-(piperidin-1-yl)-1H 10 indol-3-yl]butan-1 -one (180): NN 0 H NOH (180) Synthesis of Compound (180): Compound (180) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 15 using DCM: MeOH as eluent to obtain Compound (180). 1 H NMR (300 MHz, CDCl3): 6 7.90 (br s, 1H), 7.00-7.04 (m, 2H), 6.90-6.94 (m, 1H), 6.73-6.76 (m, 1H), 5.03 (br s, IH), 4.13 (br s, 1H), 3.76-3.79 (m, 1H), 3.64-3.66 (m, 1H), 3.15-3.25 (m, 2HO, 2.86-2.92 (m, 1H), 2.76-2.77 (m, 1H), 2.37-2.41 (m, 1H), 2.19-2.21 (m, 1H), 1.34-1.98 (m, 19H). LC-MS: (M+H)+ = 422.2; HPLC purity = 97.45%. 20 183 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 181: 1-(2-azatricyclo[3.3.1.1 7 ]dec-2-yl)-3-[4-(propan-2-yloxy)-1 H-indol-3 yI]butan-1 -one (181): 0 N H (181) Synthesis of Compound (181): Compound (181) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (181). 1H NMR (300 MHz, CDCl3): 6 7.85 (br s, 1H), 7.04-7.07 (m, 1H), 6.89-6.92 (m, 2H), 6.46-6.48 (m, 1H), 4.87 (br s, 1H), 4.75-4.79 (m, 1H), 4.04 (br s, 1H), 3.80-3.84 (m, 1H), 2.49-2.54 (m, 1H), 2.31-2.35 (m, 1H), 2.00-2.05 10 (m, 1H), 1.55-1.80 (m, 11H), 1.42-1.45 (m, 9H). LC-MS: (M+H)+ = 381.2; HPLC purity 99.41% EXAMPLE 182: 1-(5-fluoro-2-azatricyclo[3.3.1.1 3
,
7 ]dec-2-yl)-3-[4-(propan-2-yloxy)-1 H indol-3-yl]butan-1 -one (182): 0 N H (182) 15 Synthesis of Compound (182): Compound (182) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (182). 1H NMR (300 MHz, CDCl3): 6 7.82 20 (br s, 1H), 6.97-7.02 (t, 1H), 6.84-6.86 (d, 1H), 6.83 (s, 1H), 6.40-6.42 (d, 1H), 5.07 (br s, 1H), 4.65-4.73 (m, 1H), 4.21 (br s, 1H), 3.71-3.78 (m, 1H), 2.90-3.00 (m, 1H), 2.39-2.50 (m, 1H), 2.21-2.24 (m, 1H), 1.53-1.90 (m, 10H), 1.35-1.39 (m, 9H). LC-MS: (M+H)+ = 399.2; HPLC purity = 93.52%. 184 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 183: 1-{3-[4-(2-azatricyclo[3.3.1.1 3 ']dec-2-yl)-4-oxobutan-2-y]-1H-indol-4 yl}piperidine-4-carboxylic acid (183): 0 OH N 0 H (183) Synthesis of Compound (183): Compound (183) was synthesized by following the 5 procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (183). LC-MS: (M+H)+ = 450.2; HPLC purity = 97.82%. 10 EXAMPLE 184:.1-(5-fluoro-2-azatricyclo[3.3.1.13, ]dec-2-yl)-3-[4-(propan-2-yloxy)-1 H indol-3-yl]butan-1 -one (peak-1) (184): 0 0 NN F H (184) Synthesis of Compound (184): Racemic compound (182) was purified by using chiral preparative HPLC chromatography to 15 give Compound (184). LC-MS: (M+H)+ = 399.2; HPLC purity = 95.51%. Chiral RT = 13.60 min [column: ChiralPak IC, mobile phase: hexane:IPA:DCM (8:1:1)]. 185 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 185: 1-(5-fluoro-2-azatricyclo[3.3.1.1 3
'
7 ]dec-2-yl)-3-[4-(propan-2-yloxy)-1 H indol-3-yl]butan-1 -one (peak-2) (185): 0 NN F H (185) Synthesis of Compound (185): Racemic compound 182) was purified by using chiral 5 preparative HPLC chromatography to give Compound (185). LC-MS: (M+H)+ = 399.2; HPLC purity = 97.38%. Chiral RT = 18.54 min [column: ChiralPak IC, mobile phase: hexane:IPA:DCM (8:1:1)]. EXAMPLE 186: 2-{2-[3-(4-chloro-1H-indol-3-yl)butanoyl]-2-azatricyclo[3.3.1 .1 3 '7]dec-5 10 yl}propanoic acid (186): HN / N OH 0 (186) Synthesis of Compound (186): Compound (186) was synthesized by following the procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 15 using DCM: MeOH as eluent to obtain Compound (186). LC-MS: (M+H)+ = 429.13; HPLC purity = 90.92%. 186 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 187: 1-(5-hydroxy-2-azatricyclo[3.3.1.1 3
,
7 ]dec-2-yI)-3-[4-(thiophen-3-y)-1 H indol-3-yl]butan-1 -one (187): S 0 N~PN OOH H (187) Synthesis of Compound (187): Compound (187) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (187). LC-MS: (M+H)+ = 421.1; HPLC purity = 96.22%. 10, EXAMPLE 188: 1-(5-hydroxy-2-azatricyclo[3.3.1 .13, 7 ]dec-2-yl)-3-[4-(thiophen-2-y)-1H indol-3-yl]butan-1 -one (peak-1) (188): S 0 N"< OO N , NOH H (188) Synthesis of Compound (188): Racemic compound (153) was purified by using chiral preparative HPLC chromatography to 15 give Compound (188). LC-MS: (M+H)+ = 421.1; HPLC purity = 92.0%; Chiral RT = 6.57 min [column: ChiralPak IC, mobile phase: hexane:THF:EtOH (8:1:1)]. 187 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 189: 1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3
-
7 ]dec-2-yl)-3-[4-(thiophen-2-y)-1 H indol-3-yl]butan-1 -one (peak-2) (189): S 0 N * NOH H (189) Synthesis of Compound (189): Racemic compound (153) was purified by using chiral 5 preparative HPLC chromatography to give Compound (189). LC-MS: (M+H)+ = 421.1; HPLC purity = 93.52%; Chiral RT = 9.17 min [column: ChiralPak IC, mobile phase: hexane:THF:EtOH (8:1:1)]. EXAMPLE 190: 3-(5-chloro-1,3-benzothiazol-2-y)-1-(5-hydroxy-2 10 azatricyclo[3.3.1 .1 3 ']dec-2-yl)butan-1 -one (190): OH CI N 0 (190) Synthesis of Compound (190): Compound (190) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 15 using DCM: MeOH as eluent to obtain Compound (190). LC-MS: (M+H)+ = 391.1; HPLC purity = 96.40%. 188 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 191: 2-[3-(5-chloro-1,3-benzothiazol-2-yl)butanoyl]-2 azatricyclo[3.3. 1.1 3
-
7 ]decane-5-carbonitrile (191): N // N (191) Synthesis of Compound (191): Compound (191) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (191). LC-MS: (M+H)+ = 400.1; HPLC purity = 97.71%. 10 EXAMPLE 192: 3-(6-chloro-1,3-benzothiazol-2-y)-1 -(5-hydroxy-2 azatricyclo[3.3.1 .1 3 ']dec-2-yI)butan-1 -one (192): 0 NNO CI (192) Synthesis of Compound (192): Compound (192) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by 15 evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (192). LC-MS: (M+H)+ = 391.1; HPLC purity 94.40%. 189 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 193: 2-[3-(6-chloro-1,3-benzothiazol-2-yl)butanoyl]-2 azatricyclo[3.3.1.1 3
'
7 ]decane-5-carbonitrile (193): 0 N N Cl (193) Synthesis of Compound (193): Compound (193) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (193). LC-MS: (M+H)+ = 400.1; HPLC purity = 94.39%. 10 EXAMPLE 194: 3-(6-chloro-1,3-benzothiazol-2-yl)-1-(5-hydroxy-2 azatricyclo[3.3.1.1 3
'
7 ]dec-2-yl)butan-1 -one (peak-1) (194): 0 NNO Cl (194) Synthesis of Compound (194): Racemic compound (192) was purified by using chiral preparative HPLC chromatography to 15 give Compound (194). LC-MS: (M+H)+ = 391.1; HPLC purity = 99.6%. EXAMPLE 195: 3-(6-chloro-1,3-benzothiazol-2-y)-1-(5-hydroxy-2 azatricyclo[3.3.1.13, 7 ]dec-2-yl)butan-1 -one (peak-2) (195): 0 N OH Cl (195) 20 Synthesis of Compound (195): Racemic compound (192) was purified by using chiral preparative HPLC chromatography to give Compound (195). LC-MS: (M+H)+ = 391.1; HPLC purity = 99.56%. 190 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 196: 2-[3-(6-chloro-1,3-benzothiazol-2-yl)butanoyl]-2 azatricyclo[3.3.1 .1 3
,
7 ]decane-5-carboxamide (196): 0 N NO
NH
2 Cl (196) Synthesis of Compound (196): Compound (196) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (196). LC-MS: (M+H)+ = 418.1; HPLC purity = 97.62%. 10 EXAMPLE 197: 3-(4,5-dichloro-1H-pyrrolo[2,3-b]pyridin-3-y)-1-(5-hydroxy-2 azatricyclo[3.3.1.1 3
'
7 ]dec-2-yl)butan-1 -one (197): Cl CI NN H OH (197) Synthesis of Compound (197): Compound (197) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by 15 evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (197). LC-MS: (M+H)+ = 408.1; HPLC purity = 94.42%. EXAMPLE 198: 3-(5-chloro-4-cyclopropyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-1 -(5-hydroxy-2 20 azatricyclo[3.3.1 .1 3 ']dec-2-yl)butan-1 -one (198): Cl N~NOH H (198) Synthesis of Compound (198): Compound (198) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by 191 WO 2013/111150 PCT/IN2012/000842 evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (198). LC-MS: (M+H)+ = 414.2; HPLC purity = 98.68%. 5 EXAMPLE 199: 3-(5-chloro-4-cyclopropyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-1 -(5-hydroxy-2 azatricyclo[3.3.1 .13, 7 ]dec-2-yl)butan-1 -one (peak-1) (199): Cl 0 N * N' OH H (199) Synthesis of Compound (199): Racemic compound (198) was purified by using chiral preparative HPLC chromatography to give Compound (199). LC-MS: (M+H)+ = 414.2; HPLC 10 purity = 94.06%. Chiral RT = 15.94 min [column: ChiralPak IC, mobile phase: hexane:IPA:DCM (7.5:1.5:1)].
EXAMPLE 200: 3-(5-chloro-4-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-y)-1-(5-hydroxy-2 azatricyclo[3.3.1 .1 3
'
7 ]dec-2-yl)butan-1 -one (peak-2) (200): 15 Cl NN N OH H (200) Synthesis of Compound (200): Racemic compound (198) was purified by using chiral preperative HPLC chromatography to give Compound (200). LC-MS: (M+H)+ = 414.2; HPLC purity = 98.40%. Chiral RT = 20.09 min [column: ChiralPak IC, mobile phase: 20 hexane:IPA:DCM (7.5:1.5:1)]. 192 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 201: 3-(4,5-dicyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-y)-1-(5-hydroxy-2 azatricyclo[3.3.1.1 3 ,7]dec-2-yl)butan-1-one (201): 0 NN H H (201) Synthesis of Compound (201): Compound (201) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (201). LC-MS: (M+H)+ = 420.2; HPLC purity = 90.88%. 10 EXAMPLE 202: 3-(6-chloro-1H-benzimidazol-2-yl)-1-(5-hydroxy-2 azatricyclo[3.3.1 .13, 7 ]dec-2-yl)butan-1 -one (202): OH 0 ci N N H (202) Synthesis of Compound (202): Compound (202) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by 15 evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (202). LC-MS: (M+H)+ = 372.1; HPLC purity = 84.69%. 193 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 203: 3-(6-cyclopropyl-1H-benzimidazol-2-yl)-1-(5-hydroxy-2 azatricyclo[3.3.1 .1 3 ']dec-2-yl)butan-1 -one (203): 0 N N OH (203) Synthesis of Compound (203): Compound (203) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (203). LC-MS: (M+H)+ = 380.1; HPLC purity = 98.88%. 10 EXAMPLE 204: {2-[3-(4-cyclopropyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)butanoyl]-2 azatricyclo[3.3.1 .1 3 ']dec-5-yl}acetic acid (204): O N-N N OH H (204) Synthesis of Compound (204): Compound (204) was synthesized by following the 15 procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (204). LC-MS: (M+H)+ = 422.2; HPLC purity = 99.63%. 194 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 205: 3-(I-cyclopropyl-4-methyl- H-indol-3-yl)-1-(5-hydroxy-2 azatricyclo[3.3.1.1 3 ']dec-2-yl)butan-1 -one (205): OO N *~ (205) Synthesis of Compound (205): Compound (205) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (205). LC-MS: (M+H)+ = 393.2; HPLC purity = 99.04%. 10 EXAMPLE 206: 3-(1,4-dimethyl-1H-indol-3-yl)-1-(5-hydroxy-2-azatricyclo[3.3.1.1 3 ']dec-2 yl)butan-1 -one (206): OH (206) Synthesis of Compound (206): Compound (206) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by 15 evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (206). LC-MS: (M+H)+ = 367.2; HPLC purity = 98.36%. EXAMPLE 207: 3-(4-chloro-I -methyl-1 H-indol-3-yl)-1 -(5-hydroxy-2 20 azatricyclo[3.3.1.13, 7 ]dec-2-yl)butan-I -one (207): / Cl N OH _N NNQ (207) Synthesis of Compound (207): Compound (207) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by 195 WO 2013/111150 PCT/IN2012/000842 evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (207). LC-MS: (M+H)+ = 387.1; HPLC purity = 99.49%. 5 EXAMPLE 208: 3-[4-chloro-5-(furan-2-y)-1H-indol-3-yl]-1-(5-hydroxy-2 azatricyclo[3.3.1 .1 3
,
7 ]dec-2-yl)butan-1 -one (208): OOH HN N 0 (208) Synthesis of Compound (208): Compound (208) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by 10 evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (208). LC-MS: (M+H)+ = 439.1; HPLC purity = 91.39%. EXAMPLE 209: 1-(5-hydroxy-2-azatricyclo[3.3.1 .1 3 ,7]dec-2-yl)-3-(4-methoxy-5-methyl-1 H 15 indol-3-yl)butan-1 -one (209): OH / 0 HN ~ 0 (209) Synthesis of Compound (209): Compound (209) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 20 using DCM: MeOH as eluent to obtain Compound (209). LC-MS: (M+H)+ = 383.2; HPLC purity = 93.48%. 196 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 210: 1-(5-hydroxy-2-azatricyclo[3.3.1.13,7]dec-2-yl)-3-[5-methyl-4-(thiophen 2-yI)-1H-indol-3-yl]butan-1-one (210): 0 OO N N OH H (210) Synthesis of Compound (210): Compound (210) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (210). LC-MS: (M+H)+ = 435.2; HPLC purity = 91.98%. 10 EXAMPLE 211: 4-chloro-3-[4-(5-hydroxy-2-azatricyclo[3.3.1.1 3 7 ]dec-2-yl)-4-oxobutan-2 yl]-5-methyl-1,3-dihydro-2H-indol-2-one (211): Cl O N N S OH (211) SYNTHETIC SCHEME 26 15 Cl Cl 0 N OH O N OH H H 0 (166) (211) Synthesis of Compound (211): To a stirred solution of Compound (166) (15 mg, 0.03 mmol) in DMF (2 mL) was added pyridinium tribromide (16 mg, 0.050 mmol) at 0*C. Resulted 20 reaction mixture was stirred at room temperature for 3 hours. After reaction quenched with
H
2 0 (10 mL), extracted with ether (2X20 mL).The combined organic layers were washed with 197 WO 2013/111150 PCT/IN2012/000842 brine and concentrated. Resulted crude material was purified by preparative TLC eluting with DCM: MeOH (95:05) to give Compound (211) (5.5 mg, off white solid). EXAMPLE 212: 4-cyclopropyl-3-[4-(5-hydroxy-2-azatricyclo[3.3.1.1 3 ']dec-2-yI)-4 5 oxobutan-2-yl]-1,3-dihydro-2H-indol-2-one (212): 0 N H O OH (212) Synthesis of Compound (212): Compound (212) was synthesized by following the procedure used to make Compound (211) (Scheme 26). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column 10 using DCM: MeOH as eluent to obtain Compound (212). 1H NMR (300 MHz, CDC13) : 6 7.50 (br s, 1H), 7.07-7.12 (t, IH), 6.59-6.62 (d, 1H), 6.48-6.51 (d, 1H), 5.11 (br s, 1H), 4.54 (br s, 1H), 3.81 (br s, 1H), 3.79-3.81 (m, 1H), 2.37-2.41 (m, 2H), 2.21-2.23 (m, 1H), 1.43-1.88 (m, 11H), 1.06-1.08 (m, 2H), 0.83-0.88 (m, 2H), 0.72-0.74 (d, 3H).LC-MS: (M+H)+ = 395.2; HPLC purity = 99.65%. 15 EXAMPLE 213: 3-(4-cyclopropyl-1H-indol-3-yl)-1-(5-fluoro-7-hydroxy-2 azatricyclo[3.3.1 .1 3 '7]dec-2-yl)butan-1 -one (213): 0 F N H OH (213) Synthesis of Compound (213): Compound (213) was synthesized by following the 20 procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (213). 1H NMR (300 MHz, CDC13): 6 8.06 (br s, 1H), 7.18-7.20 (d, 1H), 7.05-7.10 (t, 1H), 7.04 (s, 1H), 6.74-6.76 (d, 1H), 5.26 (br s, 1H), 4.40 (br s, 1H), 4.23-4.25 (m, 1H), 2.85-2.90 (m, 1H), 2.45-2.53 (m, 2H), 1.99 (br s, 2H), 1.62 25 1.81 (m, 8H), 1.44-1.46 (d, 3H), 0.95-0.99 (m, 2H), 0.81-0.85 (m, 2H). LC-MS: (M+H)+ = 397.3; HPLC purity = 93.84%. 198 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 214: 1-(5-hydroxy-7-methyl-2-azatricyclo[3.3. 1.1 3
,
7 ]dec-2-yl)-3-[4-(propan-2 yloxy)-1H-indol-3-yl]butan-1-one (214): 0 PI NL0' N OH (214) 5 Synthesis of Compound (214): Compound (214) was synthesized by following the procedure used to make Compound (1) (Scheme 2). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (214). 1H NMR (300 MHz, CDC13): 5 7.86 (br s, 1H), 6.96-7.01 (t, 1H), 6.84-6.86 (d, 1H), 6.83 (s, 1H), 6.39-6.42 (d, 1H), 5.00 (br s, 1H), 10 4.67-4.72 (m, 1H), 4.20 (br s, 1H), 3.72-3.79 (m, 1H), 2.89-3.01 (m, 1H), 2.39-2.51 (m, IH), 1.25-1.65 (m, 19H). LC-MS: (M+H)+ = 411.3; HPLC purity = 90.45%. EXAMPLE 215: 2-(2-(3-(4-(5-fluorofuran-2-yl)-1H-indol-3-yl)butanoyl)-2-azaadamantan-5 yl)acetic acid (215): F 0 0 N N OH H (215) 15 Synthesis of Compound (215): Compound (215) was synthesized by following the procedure used to make Compound (43) (Scheme 14). The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using DCM: MeOH as eluent to obtain Compound (215). LC-MS: (M+H)+ = 465.4; HPLC 20 purity = 99.37%. 199 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 216: 1-(5-hydroxy-2-azaadamantan-2-y)-3-(4-methyl-1-(quinolin-8 ylsulfonyl)-1H-indol-3-yl)butan-1 -one (216): 0 N OH N SZO (216) Synthesis of Compound (216): Compound (216) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). LC-MS: (M+H)+ = 544.3; HPLC purity = 98.61%. EXAMPLE 217: 4-chloro-3-(4-(5-hydroxy-2-azaadamantan-2-yl)-4-oxobutan-2-yl)-5 methyl-IH-indole-2-carbonitrile (217): Cl 0 N N OH H "~N (217) 10 Synthesis of Compound (217): Compound (217) was synthesized by following the procedure used to make Compound (1) (Scheme 2). LC-MS: (M+H)+ = 412.3. EXAMPLE 218: 4-chloro-3-(4-(5-hydroxy-2-azaadamantan-2-yl)-4-oxobutan-2-yl)-1 H 15 indole-2-carbonitrile (218): Cl 0 N N H H N (218) Synthesis of Compound (218): Compound (218) was synthesized by following the procedure used to make Compound (1) (Scheme 2). LC-MS: (M+H)+ = 398.2; HPLC purity = 98.47%. 20 200 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 219: 3-(4-chloro-5-methyl-1H-indol-3-yl)-1-(5-hydroxy-7-methyl-2 azaadamantan-2-yl)butan-1 -one (219): Cl 0 N H OH (219) Synthesis of Compound (219): Compound (219) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). LC-MS: (M+H)+ = 401.2; HPLC purity = 89.36%. EXAMPLE 220: 4-cyclopropyl-3-(4-(5-hydroxy-2-azaadamantan-2-yI)-4-oxobutan-2-yl) I H-indole-2-carbonitrile (220): 0 N H N (220) 10 Synthesis of Compound (220): Compound (220) was synthesized by following the procedure used to make Compound (1) (Scheme 2). LC-MS: (M+H)+ = 404.3; HPLC purity = 98.29%. 15 EXAMPLE 221: 2-(3-(4,5-dimethyl-1H-indol-3-yl)butanoyl)-2-azaadamantanecarbonitrile (221): 0 N H N (221) Synthesis of Compound (221): Compound (221) was synthesized by following the procedure used to make Compound (1) (Scheme 2). LC-MS: (M+H)+ 376.3; HPLC purity 20 85.11%. 201 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 222: 2-(3-(4-(furan-2-yI)-1H-indol-3-yl)butanoyl)-2-azaadamantane-5 carboxylic acid (222): 0 N O H OH (222) Synthesis of Compound (222): Compound (222) was synthesized by following the 5 procedure used to make Compound (43) (Scheme 14). LC-MS: (M+H)+ = 433.3; HPLC purity = 98.85%. EXAMPLE 223: 4-cyclopropyl-3-(4-(5-hydroxy-2-azaadamantan-2-yI)-4-oxobutan-2-yl) 1H-indole-2-carboxylic acid (223): 0 N 0 H HO (223) 10 SYNTHETIC SCHEME 27 0 NN H '>N NN 0 H HO (220) (223) 15 Synthesis of Compound (223): Compound 220 (0.070 g, 0.17 mmol) was taken in a sealed tube and MeOH (3 mL) was added to it followed by addition of 50% aqueous KOH solution (2 mL). The reaction mixture was then heated at 1 10*C for 24 hours and concentrated to give crude material, which was diluted with H 2 0, acidified with 2N HCI (PH = 2), extracted with 202 WO 2013/111150 PCT/IN2012/000842 EtOAc and concentrated to give crude product. The crude product was then purified by using silica gel column chromatography eluting with mixture of DCM: MeOH to give 30 mg of Compound (223) as brown solid. LC-MS: (M+H)+ = 423.1; HPLC purity = 98.09%. 5 EXAMPLE 224: 1-(5-fluoro-2-azaadamantan-2-y)-3-(5-methoxy-1H-indol-3-yl)butan-1 one (224): 0 0 N H (224) Synthesis of Compound (224): Compound (224) was synthesized by following the procedure used to make Compound (1) (Scheme 2). LC-MS: (M+H)+ = 371.2; HPLC purity = 10 92.10%. EXAMPLE 225: 3-(4-(5-bromo-2-azaadamantan-2-y)-4-oxobutan-2-y)-1H-indol-5-yI trifluoromethanesulfonate (225): F F OS F 0' '0 0 N H (225) 15 Synthesis of Compound (225): Compound (225) was synthesized by following the procedure used to make Compound (1) (Scheme 2). LC-MS: (M+H)+ = 549.2; HPLC purity = 92.61%. EXAMPLE 226: 1-(2-azaadamantan-2-y)-3-(5-methoxy-1 H-indol-3-yl)butan-1 -one (226): 0 0 NN H 20 (226) 203 WO 2013/111150 PCT/IN2012/000842 Synthesis of Compound (226): Compound (226) was synthesized by following the procedure used to make Compound (1) (Scheme 2). LC-MS: (M+H)+ = 353.2; HPLC purity 90.02%. 5 EXAMPLE 227: 3-(6-methoxy-1H-indol-3-yI)-1-(5-methyl-2-azaadamantan-2-yl)butan-1 one (227): 0 0 N H (227) Synthesis of Compound (227): Compound (227) was synthesized by following the procedure used to make Compound (1) (Scheme 2). LC-MS: (M+H)+ = 367.3; HPLC purity = 10 92.59%. EXAMPLE 228: 3-(4-(2-azaadamantan-2-y)-4-oxobutan-2-y)-1H-indol-5-yI trifluoromethanesulfonate (228): 0,.CF3 'S 0'0 0 N H (228) 15 Synthesis of Compound (228): Compound -(228) was synthesized by following the procedure used to make Compound (1) (Scheme 2). 1 H NMR (300 MHz, DMSO-d6): 5 11.24 (br s, 1H), 7.59 (s, 1H), 7.44-7.47 (d, 1H), 7.36 (s, 1H), 7.11-7.14 (d, 1H), 4.62 (br s, 1H), 4.01 (br s, 1H), 3.43-3.48 (m, 1H), 2.62-2.65 (m, 1H), 2.43.2.47 (m, 1H), 2.10 (s, 1H), 2.00 (s, 1H), 1.44-1.86 (m, 10H), 1.30-1.33 (d, 3H). LC-MS: (M+H)+ = 471.1; HPLC purity = 89.84%. 20 204 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 229: 3-(4-(2-azaadamantan-2-yI)-4-oxobutan-2-yl)-1H-indol-5-yi methanesulfonate (229): 0,/ O / O' '0 0 N H (229) Synthesis of Compound (229): Compound (229) was synthesized by following the 5 procedure used to make Compound (1) (Scheme 2). 1H NMR (300 MHz, CDCI3) : 6 8.37 (br s, 1H), 7.50 (s, 1H), 7.23-7.26 (d, 1H), 6.98-7.05 (m, 2H), 4.74 (br s, 1H), 3.92 (br s, 1H), 3.51-3.58 (m, 1H), 3.08 (s, 1H), 2.68-2.75 (m, 1H), 2.41-2.48 (m, 1H), 1.96 (br s, IH), 1.84 (br s, 1H), 1.45-1.72 (m, 1OH), 1.39-1.42 (d, 3H).LC-MS: (M+H)+ = 417.1; HPLC purity = 92.90%. 10 EXAMPLE 230: 2-(3-(5-methoxy-1H-indol-3-yl)butanoyl)-2-azaadamantane-5-carbonitrile (230): -0 0 N& N HN N (230) Synthesis of Compound (230): Compound (230) was synthesized by following. the procedure used to make Compound (1) (Scheme 2). 1H NMR (300 MHz, CDCl3) : 6 7.95 (br 15 s, IH), 7.22-7.28 (m, 1H), 7.09-7.12 (m, 1H), 6.99-7.00 (d, 1H), 6.83-6.89 (m, 1H), 4.91-4.95 (d, 1H), 3.97-4.03 (d, 1H), 3.86 (s, 3H), 3.61-3.67 (m, 1H), 2.72-2.81 (m, 1H), 2.45-2.55 (m, 1H), 2.13-2.16 (m, 1H), 1.58-2.05 (m, 1OH)1.48-1.51 (d, 3H). LC-MS: (M+H)+ = 378.3; HPLC purity = 99.49%. 20 205 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 231: 1-(5-amino-2-azaadamantan-2-yl)-3-(4-cyclopropyl-1H-indol-3-yl)butan 1-one (231):
NH
2 N NH 0 (231) 5 SYNTHETIC SCHEME 28 H NH C NH 2 N9 No N NH N NH NH 0 ~00 (41) Intermediate-61 (231) Synthesis of Intermediate-61: To a stirred solution of compound-41 (0.10g, 0.26mmol) in 10 DCM (5 mL) in AcOH (2 mL), chloroaceto nitrile (117 mg, 1.56 mmol) was added at 0*C. The reaction mixture was then treated with sulfuric acid (0.75 mL). The reaction mixture was stirred at 0*C for 1 hour and continued to stir at room temperature for 12 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NaHCO 3 solution and extracted with EtOAc to give Intermediate-61 (90 mg). It was used for 15 next step without any purification. Synthesis of Compound 231: A stirred solution of Intermediate-61 (0.090 g, 0.19 mmol)) and thiourea (0.028 g, 0.38 mmol) in EtOH (5 mL) at 00C was treated with acetic acid (0.5 mL). The reaction mixture was heated to reflux for 12 hours. After completion of the reaction, 20 the reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with DCM and concentrated to give Compound 231 (30 mg). 206 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 232: 3-(4-cyclopropyl-1H-indol-3-yI)-1-(5-(methylamino)-2-azaadamantan-2 yl)butan-1 -one (232) NH N NH 0 (232) 5 SYNTHETIC SCHEME 29
NH
2 NH NH NHN 0 0 (231) (232) Synthesis of 232: To a stirred solution of Compound 231 (0.020 g, 0.053 mmol)) in DMF, 10 K 2
CO
3 (14.6 mg, 0.16 mmol) was added at 00C. To this solution Mel was added and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched with H 2 0, extracted with EtOAc, and concentrated to give crude product, which was purified by using prep TLC to give Compound 232 (5 mg). 15 EXAMPLE 233: 3-(4-cyclopropyl-1H-indazol-3-yl)-1-(5-hydroxy-2-azatricyclo (3.3.1.1 3 7 ]dec-2-yI)propan-1 -one (233): 0 NL H (233) 20 207 WO 2013/111150 PCT/IN2012/000842 SYNTHETIC SCHEME 30 Br -Br Br Br Br O NH 2 N-N N-N N-N Starting Material-14 H H Intermediate-62 Boc Intermediate-63 Intermediate-64 Intermediate-65 Br 0 0 0 0 OH N-N K.NN e N.N N /N N'N N'N N'N Boc H H H Intermediate-66 Intermediate-67 Intermediate-68 Intermediate-69 0 N N-N I H OH (233) 5 Synthesis of Intermediate-62: To a stirred solution of Starting Material-14 (2.0 g, 8.6 mmol) in THF: MeOH (40 mL, 1:1), activated Zn powder (3.71 g, 69.5 mmol) was added, followed by saturated NH 4 CI solution and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture it was concentrated and diluted with H 2 0, extracted with EtOAc and concentrated to give Intermediate-62 (1.7 g) as pale yellow solid. 10 Synthesis of Intermediate-63: To a stirred solution of Intermediate-62 (1.8 g, 9.7 mmol) in chloroform (20 mL), Ac 2 0 (2.25 mL, 22.0 mmol) was added at 00C. The resulted reaction mixture was stirred at room temperature for 24 hours. Then KOAc (0.28 g, 2.9 mmol), followed by isoamylnitrile (2.44 g, 20 mmol) were added, and heated at 60 *C for 18 hours. 15 After completion of the reaction, the reaction mixture quenched with H 2 0 and concentrated, to this conc HCI (5 mL) was added and heated at 60 *C for 2 hours. The reaction mixture was then basified with 50%aqueous NaOH solution and extracted with EtOAc and concentrated to give Intermediate-63 (420 mg) as brown solid. 20 Synthesis of Intermediate-64: To a stirred solution of Intermediate-63 (0.50 g, 2.5 mmol) in DMF (5 mL), KOH (0.28 g, 5.0 mmol) was added and stirred at room temperature for 20 minutes. To the reaction mixture iodine (0.26 g, 5.0 mmol) in DMF was added and the reaction was continued at room temperature for 12 hours. After completion of the reaction the reaction mixture was quenched with H 2 0, extracted with EtOAc and concentrated to give 208 WO 2013/111150 PCT/IN2012/000842 Intermediate-64 (750 mg) as brown solid, which was used in next step without any purification. Synthesis of Intermediate-65: To a stirred solution of Intermediate-64 (0.75 g, 2.3 mmol) in 5 MeCN (5 mL), TEA (0.696 g, , 6.9 mmol), DMAP (0.024 g, 0.2 mmol) and (Boc) 2 0 (1.00 g, 4.6 mmol) were added at 0*C. The resulted reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was quenched with H 2 0, extracted with EtOAc and concentrated to give crude material. The crude material was purified by using silica gel column chromatography eluting with mixtrure of hexane: EtOAc to 10 give Intermediate-65 (700 mg) as white solid. Synthesis of Intermediate-66: To a stirred solution of Intermediate-65 (0.25 g, 0.7 mmol) in DMF (5 mL), TEA (0.31 mL, , 2.3 mmol), ethyl crotanoate (0.11 g, 1.1 mmol) and TBAI (0.05 g, 0.14 mmol) were added, and purged with argon gas for 15 minutes. To the reaction mixture 15 PdCl 2 (dppf) (0.06 g, 0.07 mmol) was added. The resulted reaction mixture was kept under micro wave conditions at 100*C for 2 hours. After completion of the reaction, the reaction mixture was filtered through celite and concentrated, resulted crude material was purified by using silica gel column chromatography eluting with mixture of hexanes: EtrOAc to give Intermediate-66 (20 mg) as white solid. 20 Synthesis of Intermediate-67: To a stirred solution of Intermediate-66 (0.05 g, 0.12 mmol) in dioxane: H20 (4 mL, 3:1) cyclopropyl boronic acid (0.02 g, 0.25 mmol), Cs 2
CO
3 (0.136 g, 0.42 mmol) were added, and purged with argon gas for 10 minutes. To the reaction mixture PdCl 2 (dppf) 0.009 g, 0.012 mmol) was added. The resulted reaction mixture was kept under 25 micro wave conditions at 120 *C for 1 hour. After completion of the reaction, the reaction mixture was quenched with H 2 0, extracted with EtOAc and concentrated. The resulted reaction mixture was purified by using silica gel column chromatography eluting with mixture of hexane: EtOAc to give Intermediate-67 (30 mg) as brown gummy material. 30 Synthesis of Intermediate-68: To a stirred solution of Intermediate-67 (0.030 g, 0.11 mmol) in DMF: MeOH (2 mL, 1:1), NaBH 4 (0.006 g, 0.17 mmol) was added, followed by cobalt chloride (0.002 g, 0.022 mmol). The resulted reaction mixture was stirred at rt for 45 min. After completion of ther reaction, the reaction mixture was quenched with H 2 0, extracted with EtOAc and concentrated to give Intermediate-68 (25 mg) as brown gummy material. 35 Synthesis of Intermediate-69: Intermediate-69 was synthesized by following the procedure used to make Intermediate-26 (scheme-4). 209 WO 2013/111150 PCT/IN2012/000842 Synthesis of Compound (233): Compound (233) was synthesized by following the procedure used to make Compound (1) (Scheme 2). 1H NMR (300 MHz, CDCI3) : 6 7.22 7.33 (m, 2H), 6.75-6.78 (m, 1H), 5.09 (br s, 1H), 4.40 (br s, 1H), 3.61-3.66 (t, 2H), 2.93-2.98 5 (t, 2H), 2.18-2.22 (t, 1H), 1.60-2.04 (m, 11H), 1.06-1.08 (m, 2H), 0.86-0.88 (m, 2H). LC-MS: (M+H)+ = 366.1. EXAMPLE 234: 2-(3-(4-fluoro-5-methyl-1H-indol-3-yl)butanoyl)-2-azaadamantane-5 carbonitrile (234): 10 F O NI N& HN N (234) Synthesis of Compound (234): Compound (234) was synthesized by following the procedure used to make Compound (1) (Scheme 2). 1H NMR (300 MHz, CDCI3) : 6 7.97 (br s, 1H), 7.02-7.06 (m, 1H), 6.93-6.99 (m, 2H), 4.96 (br s, 1H), 4.17-4.21 (m, 1H), 3.60-3.68 (m, 15 1H), 2.84-2.88 (m, 1H), 2.47-2.56 (m, 1H), 2.36 (s, 3H), 2.10-2.13 (m, 1H), 1.61-2.05 (m, 10H), 1.45-1.48 (d, 3H). LC-MS: (M+H)+ = 380.2. HPLC purity = 99.13%. EXAMPLE 235: 2-(4-cyclopropyl-1H-indol-3-yl)-1-(5-hydroxy-2-azaadamantan-2 yl)propan-1 -one (235): 20 0 OH (235) 210 WO 2013/111150 PCT/IN2012/000842 SYNTHETIC SCHEME 31 Ts NH Br0 0 0 0 0 BrBr 0Br N Br N ~ N -N - N N ~ Starting H H H Material-15 Intermediate-70 Intermediate-71 Intermediate-72 Intermediate-73 0 0 0 0 O 0 OH OH N ~ N N N ~ N Boc BOc Boc H Intermediate-74 Intermediate-75 Intermediate-76 Intermediate-77 0 H OH 5 (235) Synthesis of Intermediate-70: To a stirred solution of Starting Material-15 (40 g, 206 mmol) in ether (400 mL), oxalyl chloride (23.2 mL, 268 mmol) was added at 0*C, and stirred at room temperature for 5 hours. The reaction mixture was then filtered and washed with ether to get 10 solid materilal (42 g), which was treated with MeOH (28 mL) in ether (200 mL) at 0*C to room temperature for 5 hours. After completion of the reaction the reaction mixture was diluted with hexanes, resulted precipitate was filtered and dried to get Intermediate-70 (35 g) as yellow solid. 15 Synthesis of Intermediate-71: To a stirred solution of Intermediate-70 (35 g, 129 mmol) in MeOH (350 mL), tosyl hydrazine (23.1 g, 129 mmol) was added and refluxed for 4 hours. After completion of the reaction, the reaction mixture was concentrated to give crude mixture, which is diluted with H 2 0, extracted with DCM and concentrated to give Intermediate-69 (35 g) as pale yellow solid. 20 Synthesis of Intermediate-72: To a stirred solution of Intermediate-71 (14 g, 31 mmol) in THF (140mL), NaBH 4 (1.8 g, 46 mmol) was added at 0*C and continued to stir at room temperature for 6 hours. After completion of the reaction, the reaction mixture was quenched with H 2 0, extracted with DCM and concentrated. The resulted crude product was purified by 211 WO 2013/111150 PCT/IN2012/000842 using silica gel column chromatography elutive with mixture of hexanes, EtOAc to give Intermediate-72 (3 g) as pale yellow liquid. Synthesis of Intermediate-73: Intermediate-73 was synthesized by following the procedure 5 used to make Intermediate-67 (Scheme 30). Synthesis of Intermediate-74: Intermediate-74 was synthesized by following the procedure used to make Intermediate-65 (Scheme 30). 10 Synthesis of Intermediate-75: Intermediate-75 was synthesized by following the procedure used to make Intermediate-30 (Scheme 6). Synthesis of Intermediate-76: Intermediate-76 was synthesized by following the procedure used to make Intermediate-26 (Scheme 4). 15 Synthesis of Intermediate-77: Intermediate-77 was synthesized by following the procedure used to make Intermediate-7 (Scheme 1). Synthesis of Compound (233): Compound (233) was synthesized by following the 20 procedure used to make Compound (1) (Scheme 2). 1H NMR (300 MHz, CDCl3): 6 8.13 (br s, 1H), 7.13-7.16 (d, 1H), 6.96-7.04 (m, 2H), 6.75-6.78 (d, 1H), 5.08 (br s, 1H), 4.62-4.67 (m, IH), 4.32 (br s), 2.25-2.30 (m, 1H), 2.05-2.08 (m, 1H), 1.53-1.79 (m, 1OH), 1.46-1.49 (d, 3H), 0.93-0.98 (m, 2H), 0.83-0.88 (m, 2H). LC-MS: (M+H)+ = 365.2. HPLC purity = 95.44%. 25 EXAMPLE 236: 3-(4-cyclopropyl-1-methyl-IH-indazol-3-yl)-I-(5-hydroxy-2 azaadamantan-2-yl)propan-1 -one (236): 0 N~I N-N (236) 30 Synthesis of Compound 236: Compound (236) was synthesized by following the procedure used to make Compound (233) (Scheme 30). LC-MS: (M+H)+ = 380.3. HPLC purity 99.86%. 212 WO 2013/111150 PCT/IN2012/000842 EXAMPLE 237: 1-(2-azaadamantan-2-yl)-3-(4-cyclopropyl-1-methyl-IH-indazol-3 yl)propan-1-one (237): 0 N-N (237) 5 Synthesis of Compound (237): Compound (237) was synthesized by following the procedure used to make Compound (233) (Scheme 30). LC-MS: (M+H)+ = 364.3. HPLC purity = 91.66%. 10 EXAMPLE 238: 1-(2-azaadamantan-2-yl)-2-(4-cyclopropyl-I H-indol-3-yl)propan-I -one (238): 0 N H (238) Synthesis of Compound (238): Compound (238) was synthesized by following the procedure used to make Compound (233) (Scheme 27). LC-MS: (M+H)+ = 349.2. 15 Biological activity In vitro HSDI P1 inhibition assay: CHO cells were maintained in Dulbecco's modified Eagle's medium/nutrient mixture F 12 containing 5% fetal bovine serum (v/v) and 2 mM glutamine. Cells were cultured at 37 0 C 20 with 5% CO 2 . For transient expression of human full length HSD11 I expression vector (OriGene Technologies), cells were seeded at a density of 2 x1 05 cells/well in a 6-well plate. Transfection was done using Turbofectin8 reagent (OriGene Technologies), according to the protocol provided with the reagent. After 24hours post-transfection, cells were trypsinized and pooled together before they were re-seeding to 96-well plate at a density of 40000 25 cells/well. 24 hours after re-seeding, cells were incubated with 200 nM cortisone + 5OuM NADPH (or along with small molecule inhibitors) overnight. The enzymatic activity or inhibition of enzyme activity was measured by estimating the conversion of cortisone to 213 WO 2013/111150 PCT/IN2012/000842 cortisol by LC/MS-MS method. The IC50 in nM was calculated from a 8 point log scale of concentration versus inhibition. The results of the biological testing are shown in table 1: Cmpd No 11pHSD1 Cmpd No 11pHSD1 Cmpd No 11pHSDI (IC50) (IC50) (IC50) 1 * 80 * 159 2 **** 81 * 160 3 * 82 ***** 161 4 * 83 ***** 162 5 ** 84 ** 163 * 6 * 85 ****** 164 7 * 86 * 165 * 8 * 87 *** 166 9 * 88 * 167 ** 10 * 89 * 168 11* 90 * 169 12 * 91 * 170 * 13 * 92 * 171 ** 14 **** 93 * 172 * 15 * 94 ***** 173 16 * 95 **** 174 * 17 **** 96 **** 175 18 **** 97 * 176 * 19 ** 98 ***** 177 20 * 99 ***** 178 21 * 100 ***** 179 * 22 * 101 ** 180 * 23 * 102 ***** 181 * 24 * 103 * 182 25 * 104 183 * 26 ** 105 ****** 184 27 * 106 185 * 28 ** 107 * 186 * 29 108 * 187 30* 109 * 188 214 WO 2013/111150 PCT/IN2012/000842 Cmpd No IIpHSDI Cmpd No 11pHSD1 Cmpd No 11pHSDI (IC50) (IC50) (IC50) 31 110 * 189 * 32 *** * 190 33 * 112 ** 191 * 34 * 113 * 192 35 114 * 193 36 ** 115 ** 194 37 ***** 116 ** 195 * 38 * 117 * 196 * 39 **** 118 * 197 40 ***** 119 ***** 198 41 ***** 120 * 199 42 *121 200 43 *122 201 44 **23 202 45 *124 203 46 *125 204 47 *** 126 ***** 205 * 48 ***** 127 ***** 206 * 49 ***** 128 * 207 50 * 129 * 208 51 * 130 ***** 209 ** 52 * 131 * 210 53 * 132 ***** 211 54 * 133 **** 212 * 55 * 134 *** 213 56 ***** 135 * 214 57 * 136 ***** 215 * 58 ***** 137 * 216 * 59 138 **** 217 * 60 * 139 218 * 61 * 140 * 219 62 * 141 220 * 63 * 142 * 221 * 64 **** 143 * 222 * 215 WO 2013/111150 PCT/IN2012/000842 Cmpd No 11pHSDI Cmpd No 11PHSD1 Cmpd No 11 pHSD1 (IC50) (IC50) (IC50) 65 ** 144 223 * 66 * 145 **** 224 * 67 146 * 225 * 68 * 147 **** 226 69 148 ***** 227 70 *** 149 * 228 71 * 150 ***** 229 * 72 * 151 ***** 230 * 73 ****** 152 74 * 153 75 ** 154 * 76 * 155 77 * 156 * 78 * 157 79 **** 158 * = <lOOnM = lOOnM< and <150 nM = l50nM< and <200 nM 5 **=200nM< and <250 nM * = 250nM< 216

权利要求:
Claims (36)
[1] 1. A compound of formula (I): O Rla A (R 2 )a Ar A B N Rila R1 5 R1 Formula (1) wherein: each R 1 , Rl" and R 2 is independently selected from the group consisting of H, 10 halogen, OH, NO 2 , CN, SH, NH 2 , CF 3 , OCF 3 , OCH 3 , CH 2 OH,CH 2 CO 2 H, CH 2 CH 2 CO 2 H, CH 2 NH 2 , optionally substituted Ci-C 12 alkyl, optionally substituted C-C 12 haloalkyl optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C2 C 1 2 heteroalkyl, optionally substituted C 3 -Cl 2 cycloalkyl, optionally substituted C3 C 1 2 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C2 15 C 1 2 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, optionally substituted C1 C 18 heteroaryl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C 2 -C 1 2 alkenyloxy, optionally substituted C 2 -C 12 alkynyloxy, optionally substituted C 2 -C 1 oheteroalkyloxy, optionally substituted C 3 -C 12 cycloalkyloxy, optionally substituted C 3 -C 1 2 cycloalkenyloxy, optionally substituted C 2 -C 12 heterocycloalkyloxy, optionally substituted C2-C12 heterocycloalkenyloxy, 20 optionally substituted C 6 -C 1 3aryloxy, optionally substituted C 1 -C 18 heteroaryloxy, optionally substituted C-C 12 alkylamino, SR , SO 3 H, SO 2 NR 3 R 4 , S0 2 R 3 , SONR 3 R 4 , SOR, COR, COOH, COOR 3 , CONR 3 R 4 , NR 3 COR 4 , NR 3 COOR 4 , NR 3 SO 2 R 4 , NR3CONR 3 R 4 , and NR 3 R 4 ; Ar is an optionally substituted C-C 18 heteroaryl group or an optionally substituted C2 25 C 1 2 heterocycloalkyl group; A is selected from the group consisting of S, SO, SO 2 , 0, and -CRaRb_; B is a group of the formula -(CR*R )n-; 30 217 WO 2013/111150 PCT/IN2012/000842 wherein each R", Rb, Rc and Rd is independently selected from the group consisting of H, halogen, OH, NO 2 , CN, SH, NH 2 , CF 3 , OCF 3 , optionally substituted C-C 12 alkyl, optionally substituted C 2 -C 1 oheteroalkyl, optionally substituted C-C 12 haloalkyl, optionally substituted C3 C 1 2 cycloalkyl, optionally substituted C 6 -C 15 aryl, optionally substituted C-C 18 heteroaryl; SR 3 , 5 SO 3 H, SO 2 NR 3 R 4 , SO 2 R 3 , SONR 3 R 4 , SOR 3 , COR 3 , COOH, COOR 3 , CONR 3 R 4 , NR3COR4 3 , NR 3 COOR 4 , NR 3 SO 2 R 4 , NR3CONR 3 R 4 , NR 3 R 4 ; or any two R", Rb, Rc and Rd on the same carbon atom when taken together may form a substituent of the formula: 10 R 5 wherein each R 3 and R 4 is independently selected from the group consisting of H, optionally substituted Cl-Cl 2 alkyl, optionally substituted C 2 -C 1 oheteroalkyl, optionally 15 substituted C-C 12 haloalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C6 C 1 8 aryl, and optionally substituted C-C 1 heteroaryl; R 5 is selected from the group consisting of 0, S, and NR 6 ; 20 R3 is selected from the group consisting of H, OR 7 , optionally substituted C-C 1 2 alkyl, optionally substituted C-C 1 2 haloalkyl optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 1 2 alkynyl, optionally substituted C-C 12 alkyloxy, optionally substituted C C 1 2 haloalkyloxy, optionally substituted C 2 -Cloheteroalkyl, optionally substituted C3 C 1 2 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C2-C12 25 heterocycloalkyl, optionally substituted C 2 -C 12 heterocycloalkenyl, optionally substituted C6 C 1 8 aryl, and optionally substituted C-C 18 heteroaryl; R 7 is selected from the group consisting of H, optionally substituted C-C 1 2 alkyl, optionally substituted C 2 -Cloheteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally 30 substituted C 6 -C1 8 aryl, and optionally substituted C-C 1 8 heteroaryl; or any two or more Ra, Rb, Rc and Rd may join together to form a multiple bond between adjacent carbon atoms such as a double or triple bond, or a cyclic moiety connecting the carbon atoms to which they are attached; 35 218 WO 2013/111150 PCT/IN2012/000842 n is an integer selected from the group consisting of 0, 1, 2, 3, and 4; a is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; 5 or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof.
[2] 2. A compound according to claim 1 wherein B is CH 2 .
[3] 3. A compound according to claim 1 or 2 wherein A is CR"R . 10
[4] 4. A compound according to claim 3 wherein Ra and Rb are different.
[5] 5. A compound according to claim 4 wherein one of Ra and Rb is H and the other is optionally substituted alkyl. 15
[6] 6. A compound according to claim 5 wherein Rb is H and R" is optionally substituted alkyl.
[7] 7. A compound according to claim 6 wherein R8 is selected from the group consisting of 20 methyl, ethyl, propyl, isopropyl and butyl.
[8] 8. A compound according to any one of claims 1 to 6 wherein Ar is a group of the formula: V V 3 V 2 V5V V6%, u 25 wherein each V 1 , V 2 , V 3 , V 4 , V 5 and V 6 is independently selected from the group consisting of N and CR 8 ; U is selected from the group consisting of NR 9 , 0, S and CR 9 2 , 30 wherein each R 8 is independently selected from the group consisting of H, halogen, OH, NO 2 , CN, SH, NH 2 , CF 3 , OCF 3 , optionally substituted C 1 -C 2 alkyl, optionally substituted C 1 -C 12 haloalkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -Cl 2 alkynyl, optionally substituted C 2 -Cl 2 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally 219 WO 2013/111150 PCT/IN2012/000842 substituted C 3 -C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 -C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 1 8 heteroaryl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C2 C 12 alkenyloxy, optionally substituted C 2 -Cl 2 alkynyloxy, optionally substituted C2 5 C 10 heteroalkyloxy, optionally substituted C 3 -C 12 cycloalkyloxy, optionally substituted C3 C 12 cycloalkenyloxy, optionally substituted C 2 -Cl 2 heterocycloalkyloxy, optionally substituted C 2 -Cl 2 heterocycloalkenyloxy, optionally substituted C 6 -C 18 aryloxy, optionally substituted C C 1 heteroaryloxy, optionally substituted C-Cl 2 alkylamino, SR' 0 , SO 3 H, S0 2 NR 0 R", S0 2 R', OS0 2 R4, SONR 0 R", SOR 0 , COR'4, COOH, COOR'4, CONR 1 R' 1 , NR 10 COR 11 , 10 NR"COOR", NR 10 S0 2 R", NR'CONR 0 R, and NR 1 R 11 ; wherein R 9 is selected from the group consisting of H, optionally substituted C1 C 12 alkyl, optionally substituted C 2 -Cl 2 alkenyl, optionally substituted C 2 -Cl 2 alkynyl, optionally substituted C 2 -Cl 2 heteroalkyl, optionally substituted C 3 -Cl 2 cycloalkyl, optionally substituted C 2 -Cl 2 heterocycloalkyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 15 C 18 heteroaryl, SO 3 H, SO 2 NR' R", S0 2 R 1 , SONR'R 11 , SOR' 0 , COR 10 , COOH, COOR 0 , and CONR 0 R"; wherein each R'* and R" is independently selected from the group consisting of H, optionally substituted C-C 12 alkyl, optionally substituted C 2 -C 1 oheteroalkyl, optionally 20 substituted C-Cl 2 haloalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C6 C 1 8 aryl, and optionally substituted C-C 1 8 heteroaryl.
[9] 9. A compound according to claim 8 wherein Ar is selected from the group consisting of: (R 8 )e (R8)f (R")e R8 R8 N N N N R9 R R 9 (Ra)e NR N (Ra)e N N S 'I N 25 R 220 WO 2013/111150 PCT/IN2012/000842 (R 8 ). and wherein R 8 and R' are as defined in claim 8; 5 e is an integer selected from the group consisting of 0, 1, 2, 3, and 4; f is an integer selected the group consisting of 0, 1, 2, and 3.
[10] 10. A compound according to claim 9 wherein the R 8 substituent is located in the 4 or the 10 5 position of the six membered ring.
[11] 11. A compound according to claim 9 or 10 wherein each R 8 is independently selected from the group consisting of CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , Cl, Br, F, 1, OH, NO 2 , NH 2 , CN, SO 3 H, OCH 3 , OCH 2 CH 2 CH 3 , CF 3 , and OCF 3 . 15
[12] 12. A compound according to any one of claims 1 to 11 wherein a is 0.
[13] 13. A compound according to any one of claims 1 to 12 wherein each R'" is H. 20
[14] 14. A compound according to any one of claims 1 to 13 wherein each R 1 is independently selected from the group consisting of H, OH, F, Cl, Br, CO 2 H, CONH 2 , CH 2 OH, CN, OCH 3 , and OCHF 2 .
[15] 15. A compound according to any one of claims 1 to 14 wherein one R' is H and the other 25 R 1 is OH.
[16] 16. A compound according to claim 1 selected from the group consisting of: N N N N H H 221 WO 2013/111150 PCT/IN2012/000842 N OH F N N H N OON F N H F N H O NH N OH N N F F N N H O0 ' OH 0 ' OH N N H N 0 N 0 OH SN 0 00 F -- N N F H 0 OH 'YN'- OH N',,N N N N H 222 WO 2013/111150 PCT/1N2012/000842 0 OH NN NN X5 NN H H OHH OHO N N H HH 0 a OH 0 N OH H N H O N@ F 0N'a OH F. N N H H F a OH 0N'a 2 H N H N H F ~ ' F N ' ~ O NN H H F N 'X 0 F vvK; N N H H 223 WO 2013/111150 PCT/IN2012/000842 O N O O N OH CI N N H H N OH C O O C1 cF C O NO N N H H O C 0: OH Ci F Br N N H H 0A OH 0 ' OH CN N N H H 0OH CIrO N2 0 N N H H F 0 N 'e - OH CI NH N H 224 WO 2013/111150 PCT/1N2012/000842 00 0o N OH NS NH 2 Cil N N H H " 'o-OHOH N 0 NN H -~N H OH O-Na+ NJJoN 0 N N N H H OH NH 2 Br N N H H OH OH 0 0 N N H H ONT N N N H H 225 WO 2013/111150 PCT/1N2012/000842 OH F OH 0N 0 o 0 S o NN N H OH N NH--$ AJ N 0 NS H N H N N H H NI NT / N N H H 0 NT - OH 0 NT -~ ON clN N CIH H CI 0 OH N~ H H 226 WO 2013/111150 PCT/1N2012/000842 F O OH o " ) OH N / N~ N N H H N O HN--N O a N N F cI N HN H 0N NN NN N H H 0 / ~OH H F N N H OH F O OH 0 N -O NN H N 0 ~OHI N N H 227 WO 2013/111150 PCT/1N2012/000842 0 OH 0 ' OH N N N N H H O0 ' OH 0 OHo NN N N H H OH OH N@ ' N NI HN N H 0 CN F N 0 NQJO N NI H N H 0 NOH 0 N OH F F; /N -N H H F O OH 0 N -O F 11 NF N N H H F /I - OH N F N ' N H 228 WO 2013/111150 PCT/IN2012/000842 OH 0 F jNN@ N N H H N 0 N 0 F N 0 N 0 N N OH OH FF OHO -a N' OH F N H H OHO O0 NS \ Ns"' N F HC H OH 0 a OH0N aO N ol H OH 229 WO 2013/111150 PCT/IN2012/000842 N 0 No sN NSO CN OH N OH CN N: HO cI 0 N 0 *FF 0l No_ N'@ OH ON N H 7 0 N OH0 a O F0 N NC N H 0 a OH0 NT - OH 0F NI N i N HH 230 WO 2013/111150 PCT/IN2012/000842 CIN' OH C N OH CI N N CO N H H C CN OH CN N N N N H H 0 N OH O N F H N Cl N H HH 0 0 O 0 / NJJ'o H NT O ci ci N - N H H 0 0 NS o - rj~iOH ci HO N N H H O NT - OH 0 H NrN F -~N H - N H 231 WO 2013/111150 PCT/IN2012/000842 F N D OH C0 OH HO F CI N OO N H H N OH N OH -~ N -~ N H H N OH N OOH CI N -~ N H H 0 OH 0 O Br 0 _ a CI OI 23 N H H 0OH 0 N OH N N@ -~ N -~ N H H 0NO OH CI 0 H~N N H H 0 N@- OH 0 N@- OH CI -~ N -~ N H H 232 WO 2013/111150 PCT/1N2012/000842 0 F 0 ' OH N N H H 0 -~OH0 N a1 N N H H O N F 0 OH NN NN NN H N OH s O cI 0 N H HH N N, 0 S S N OH N N, 0 N 0 O H N N, 0 0 OOH -~ N X LS N ci NH, 0 N N H 233 WO 2013/111150 PCT/IN2012/000842 C N OH 0 OH OX N O cI N N N N H H N N0 /l x NH / NH OH OH N OH N/ OH 0 L N ;N H O OH O NOH N& N''N N -5 N H HO O cl N) OH N/a O N N HH s NN HH OH 0 N N H H 234 WO 2013/111150 PCT/1N2012/000842 a OH F 0O NNO H H 0OH 0' OH N N -s-O H /N/ I N N H H 0OT -O 0 N NN N N H H 0 oO 0 N/QJt 1 OH 0NT - O 0/ 0 N OH N H H 0 NT - F /'- Br 0 0 \ o K' '~-F 3 C N 0N H H 235 WO 2013/111150 PCT/1N2012/000842 0 0~ - N -~ N H H 0 0 o 0 o0 - N 0 ~ N H H 0-N 0 O N -- NK 0/ 0 - N N H H F 0 N@-S OH F 0 O 0/ N@ IC30 @ O N N N H N N H H OH- / ~ NH 2 0 N -~ N H H 2NH6 WO 2013/111150 PCT/IN2012/000842 OHO 0 N N H F 2 HCN" OH 0 ~ 0 O OI N N N N H O O~ H H o-NN O-NN F Oi OOH3C'\ O N Hi F F0 N HC N H H N Fo F F 0 1 0 1 N N N H H 0 N 0 -@ F 0 0 H 3 C \ I - N 0 N H H N ~ND FH 3 C F F O H 3 Cj 0 -~ N N H H 237 WO 2013/111150 PCT/IN2012/000842 O N O-NN 0 0 Na F F CF 3 0 CF 3 0 N N H H -NN O N O N cI F CF 3 O CHFO N N H H 0 N 0 CH 3 0 CH 3 0 N N N H H 0 F0 N N F F CH 3 0 CH 3 0 N N N N H H 0 N 0 F 0 CH 3 0 -o H 3 C \ 0 N N N N H H 0 0 N N 038 CH3SOICH 3 0 N N N N H H 0230 WO 2013/111150 PCT/IN2012/000842 CH 3 0 NN N N N O NN H H o 0' F N N N/ N o a 0 N IN H N O N H H 0 rY 0 NNO OH ' N NN HH cl Na O '0 0Na OH N ,/N N'N N N H H O N' N'23O WO 2013/111150 PCT/IN2012/000842 N N N N cI F 0 0 O N' O NN H H -N N N F F O NN NN H H O NF N N O O OH N N N OH- NN H H F F F N N N OH l N' N H H Na OH O N N 0 0 F0Na -N F 0 N e-OH 0 0 F 0 Na OH IF ON NSC -=N 0 0 NN H H 240 WO 2013/111150 PCT/1N2012/000842 O 0 N N H H F 0NaOH FI cl N = N N H H o 0 F N~OHC N N H H ~ 0 0 N N H H o 0 NNyN H H 0 0 N N H H 241 WO 2013/111150 PCT/1N2012/000842 ol0Na Hc 0 N 0 0 I N N H H F 0Na 7 -H CI a 0I 0 N N H H 0 0 NN H H 1 F Na0H o-l 0a = N N H H o 0 NN H H 0 0 N N H H 0 0 N NN N H H 242 WO 2013/111150 PCT/1N2012/000842 ol0Na Hc 0 a = 0 0 N NN N H H 0 0 fF .0 NaH /l 0 Na = 0j 0 NN N N H H 0 0 NN N N H H 00 6 F N~-H F0 r ~Naj=N NN N NN H H 0 0 F 0N"K-H I F 0Na N NN N H H o240 WO 2013/111150 PCT/1N2012/000842 0 0 N NN N H H F 0Na-OH Ci a = N NN N H H 0 0 NN N N H H 0 O-~0 F 6F Na OH Ql Na -= N N N N H H F 0N"KaOH IF 0Na 0i 0 N N N N H H O 0 O 0 I NN N N H H c 1 0N OH F O N-OH N N NI N 244 WO 2013/111150 PCT/1N2012/000842 O N' D N 0 N5-N N N' N NN N F L N eN F"~ N N N' N 'l N0 N )-N N 0N Na-OH F N0 N 1 N *N N N* 0 0 N N N N N N N N 1 N N N ~24* WO 2013/111150 PCT/1N2012/000842 F Na O lN N N N' N'N N NN Ne-N N N cIl N&§~OH F Ne-OH N N' N N NN N N'N N*N F F N N N' N O 0 N ~N N N' 24 WO 2013/111150 PCT/1N2012/000842 O 0 F 0NOH 0I Nb- N N N O 0 Fl OH -= N N N N N' O 0 0 N N N0 O 0 0Nt-OH CI NJ&OH N N 0 0 6F Naj~OH N5- N N N 247 WO 2013/111150 PCT/1N2012/000842 0l 0 FN N I N N . NF .l Na O NI N"" 7 OHO F N' F Fl N / N N O 0 NNN q N *N N N' 0 1 N -OH F ~ - OH N N NI'-O N '~ ~~ N N F O d - 0 -O N ~N N NN N N -2N8 WO 2013/111150 PCT/1N2012/000842 O 0 Nt-O CI FF NN - N *N N N II N & N Ni NOH 00 NN qN'N N N N N' N N F0Nd-OHF ci 0NJt -OH N N N' N N 24 WO 2013/111150 PCT/1N2012/000842 0 0 N OH 0 0 N_ N 00 OH N-N OH H0H F 0 NN N N HH OH 0 0 N-N N-N / Na OH /. 60 F F' F 1 OH NN H F N N H N F F, F 0 F 0I T F N H HH F<,o N~- F50 WO 2013/111150 PCT/1N2012/000842 o, a F0 0 6 0 o N OH c Ii NN H N H F FNY >-O0H Na 7 OH c I F 0 1 N N N N H H F F F 0, 0 FV F0 F N~O oNvOH N N H H F 1 N NN HN H F 0 0 s Na OH N N H H .0 0 F F 0 N N H H F F A NN N N H H WO 2013/111150 PCT/1N2012/000842 40 q0 0 NA N N H H 40 Na 7 OH 440 0N OH F cI N N H A H Oq 0 J N0 77 0 F N 1 N H H 0 NN 0 0 N N - N H HO N 0 H HO F CI 0 00 N N N 0 N 0 H HO H HO 252 WO 2013/111150 PCT/IN2012/000842 F SO N 0 N N O H HO N O H HO Cl 0 CI O S N N N N H HN0 H HO F S F N 0 N N N H HN N H HN I 0 "N H or pharmaceutically acceptable salt, isomer or prodrug thereof. 5
[17] 17. A pharmaceutical composition including a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable diluent, excipient or carrier.
[18] 18. A method of prevention or treatment of a condition in a mammal, the method comprising administering an effective amount of a compound according to any one of claims 10 1 to 16.
[19] 19. A method according to claim 18 wherein the condition can be prevented or treated by inhibition of 11 p-HSD1. 15
[20] 20. A method according to claim 19 wherein the condition is selected from the group consisting of Metabolic syndrome, type 2 diabetes, diabetes as a consequence of obesity, 253 WO 2013/111150 PCT/IN2012/000842 insulin resistance, hyperglycemia, prandial hyperglycemia, hyperinsulinemia, Inappropriately low insulin secretion, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), increased hepatic glucose production, pediatric diabetes, dyslipidemia, diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, decreased 5 HDL cholesterol, impaired LDL/HDL ratio, other disorders of lipid metabolism, obesity, visceral obesity, hypertension, diabetic late complications, micro-/macroalbuminuria, nephropathy, retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases, arteriosclerosis, atherosclerosis, coronary artery disease, cardiac hypertrophy, myocardial ischemia, heart insufficiency, congestional heart failure, stroke, myocardial infarction, 10 arrhythmia, decreased blood flow, myopathy, loss of muscle tissue, muscle wasting, muscle catabolism and osteoporosis.
[21] 21. A method according to claim 19 wherein the condition is selected from the group consisting of metabolic syndrome, diabetes, diabetic late complications, hyperglycemia, low 15 glucose tolerance (IGT), impaired fasting glucose (IFG) hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity, abdominal obesity, glaucoma, hypertension, cardiovascular diseases, arteriosclerosis, atherosclerosis and its sequelae, myopathy, muscle wasting, osteoporosis, glaucoma and dysregulation of intraocular pressure, disorders of lipid metabolism, polycystic ovaries syndrome, retinopathy, 20 nephropathy, neuropathy, osteoporosis, osteoarthritis, dementia, depression, neurodegenerative disease, psychiatric disorders, Cushing's Disease, Cushing's syndrome, viral diseases, and inflammatory diseases.
[22] 22. A method according to claim 21 wherein the condition is diabetes. 25
[23] 23. A method according to claim 21 wherein the condition is type I diabetes.
[24] 24. The method of claim 24, wherein the compound is administered in combination with an adjuvant. 30
[25] 25. The method of claim 24, wherein the adjuvant is selected from the group consisting of dipeptidyl peptidase-IV (DP-IV) inhibitors; (b) insulin sensitizing agents; (c) insulin and insulin mimetics; (d) sulfonylureas and other insulin secretagogues; (e) alpha-glucosidase inhibitors; (f) GLP-1, GLP-1 analogs, and GLP-1 receptor agonists; and combinations thereof. 35 254 WO 2013/111150 PCT/IN2012/000842
[26] 26. The method of claim 25, wherein the insulin sensitizing agents are selected from the group consisting of (i) PPAR-gamma-agonists, (ii) PPAR-alpha-agonists, (iii) PPAR alpha/gamma-dual agonists, (iv) biguanides, and combinations thereof. 5
[27] 27. Use of a compound according to claim 1 in the preparation of a medicament.
[28] 28. A use according to claim 27 wherein the medicament is for treatment of a condition that can be prevented or treated by inhibition of 11 p-HSD1. 10
[29] 29. A use according to claim 28 wherein the condition is selected from the group consisting of Metabolic syndrome, type 2 diabetes, diabetes as a consequence of obesity, insulin resistance, hyperglycemia, prandial hyperglycemia, hyperinsulinemia, Inappropriately low insulin secretion, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), increased hepatic glucose production, pediatric diabetes, dyslipidemia, diabetic dyslipidemia, 15 hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, decreased HDL cholesterol, impaired LDL/HDL ratio, other disorders of lipid metabolism, obesity, visceral obesity, hypertension, diabetic late complications, micro-/macroalbuminuria, nephropathy, retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases, arteriosclerosis, atherosclerosis, coronary artery disease, cardiac hypertrophy, myocardial 20 ischemia, heart insufficiency, congestional heart failure, stroke, myocardial infarction, arrhythmia, decreased blood flow, myopathy, loss of muscle tissue, muscle wasting, muscle catabolism and osteoporosis.
[30] 30. A use according to claim 28 wherein the condition is selected from the group 25 consisting of metabolic syndrome, diabetes, diabetic late complications, hyperglycemia, low glucose tolerance (IGT), impaired fasting glucose (IFG) hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity, abdominal obesity, glaucoma, hypertension, cardiovascular diseases, arteriosclerosis, atherosclerosis and its sequelae, myopathy, muscle wasting, osteoporosis, glaucoma and dysregulation of 30 intraocular pressure, disorders of lipid metabolism, polycystic ovaries syndrome, retinopathy, nephropathy, neuropathy, osteoporosis, osteoarthritis, dementia, depression, neurodegenerative disease, psychiatric disorders, Cushing's Disease, Cushing's syndrome, viral diseases, and inflammatory diseases. 35
[31] 31. A use according to claim 28 wherein the condition is diabetes.
[32] 32. A use according to claim 28 wherein the condition is type Il diabetes. 255 WO 2013/111150 PCT/IN2012/000842
[33] 33. A use according to claim 27 or 28, wherein the medicament contains an adjuvant.
[34] 34. A use according to claim 33, wherein the adjuvant is selected from the group 5 consisting of dipeptidyl peptidase-IV (DP-IV) inhibitors; (b) insulin sensitizing agents; (c) insulin and insulin mimetics; (d) sulfonylureas and other insulin secretagogues; (e) alpha. glucosidase inhibitors; (f) GLP-1, GLP-1 analogs, and GLP-1 receptor agonists; and combinations thereof. 10
[35] 35. A use according to claim 34 wherein the insulin sensitizing agents are selected from the group consisting of (i) PPAR-gamma-agonists, (ii) PPAR-alpha-agonists, (iii) PPAR alpha/gamma-dual agonists, (iv) biguanides, and combinations thereof.
[36] 36. A compound according to claim 1 substantially as hereinbefore described with 15 reference to any of the examples. 256

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法律状态:
2017-08-03| FGA| Letters patent sealed or granted (standard patent)|

优先权:

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申请号 | 申请日 | 专利标题

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IN4526/CHE/2011||2011-12-22||

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IN4526CH2011||2011-12-22||

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PCT/IN2012/000842|WO2013111150A1|2011-12-22|2012-12-21|Derivatives of aza adamantane and uses thereof|

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