(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization z INO A {nterational Bureau = (10) International Publication Number = (43) International Publication Date 7 2013 (01082013) WIPOIPCT ee eee (1) International Patent Classification: (72) Inventors: RAO, Jagannath Madanahalli Ranganath; CU7D 471/08 (2006.01) A6IK 31/428 (2006.01) No49, Shilpa Vidya, First Main Road, J P Nagar 3nd AGIK 31/439 (2006.01) A6IK 31/437 (2006.01) Phase, Bangalore, INDIA 560078 (IN). VENKATE: AIK 31/404 2006.01) —_A6IP 3/04 (2006.01) SHAM, Uppala; No.9, Shilpa Vidya, Fist Main Road, J AGIK 31/416 (2006.01) _461P 306 2006.01) P Nagar 3rd Phase, Bangalore, India 360078 (IN). DOP- ‘AGIK 31/4184 (2006.01) 461 3/10 2006.01) PALAPUDI, Sivanageswara Rao; No.49, Shilpa Vidya, First Main Road, J P Nagar 3rd Phase, Bangalore, INDIA, 560078 (IN). KENCHEGOWDA, Bommegowda Yad- aganahall; No.49, Shilpa Vidya, First Main Road, 3 P 21) International Application Number: PCT/IN2012/000842 (22) International Ping Date: Netar Sni Phase, Bangalore, INDIA ScO078 (IN) 21 Decenber2012(21.122012) FERNAND, George: No.9, Shilpa, Vid, Fist Main Road, J P Nagar 3d Phase, Bangalore, INDIA, 560078 @s) ng Language: English, (IN). GEORGE, Jenson; No.49, Shilpa Vidya, First Main yeeros nats Roa, } P Nagar el Pace. Banglore, INDIA. $6008 . (IN), MADHAVAN, G I Now, Shia Via, Fst (80) Peoriy Dat sorta ten Ma Roaf, 7 P- Nagar Sd Phase, Bangalore, INDIA SSTWCHE2OL1 22 December 2011 22.12.2011) IN tg ean (71) Applicant: CONNEXIOS LIFE SCIENCES PVT. LTD. ‘Vidya, First Main Road, J P Nagar 3rd Phase, Bangalore, [INAN]; No.49, Shilpa Vidya, First Main Road, J P Nagar INDIA 560078 (IN), KADAMBARI, V. S. Naga Rajesh; Su Phase, Bangor 360078), No Shilpa Vidy Fit Main Road, P Nagar 3rd Phase, Bangalore, INDIA. 560078 (IN). JAGANNATH, S; No, Shilpa Vidya, First Main Road, JP Nagar 3rd Phase, Bangalore, INDIA 560078 (IN). MANIVANNAN, R; No49, Shilpa Vidya, First Main Road, J P Nogar 3rd Phase, Bangalore, INDIA, 560078 (IN). KUMAR, T Sen thil; No49, Shilpa Vidya, First Main Road, J P Nagar 3d Phase, Bangalore, INDIA 560078 (IN). KUMAR, B Siva Senthil; No.49, Shilpa Vidya, First Main Road, J P Nagar 31d Phase, Banglore, INDIA, 560078 (IN), MALLIKAR- SUNA, Rayl; No.49, Shilpa Vidya, First Main Road, JP Nagar 3 Phase, Bangalore, INDIA $60078 (IN. (74) Agent: KEWALRAMANI, Nishant; Brain League IP Services Pvt. Limited, #40,Ist Floor, 1C Industrial Estate, ‘Kanakapura Road, Bangalore 560062 (IN) (BI) Designated States (uriess otherwise indicated, for every Kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, FE, FG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, 1D, TL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA. LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX. MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG; PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK. SL, SM, ST, SV, SY, TH, TI, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, 2M. Ww (84) Designated States (urless otherwise indicated, for every lind of regional protection available): ARIPO (BW, GI GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, $2, TZ, {Continued on next page} 6 (57) Abstract: The preseat invention relates to certain amide derivatives that have the ability to inhibit L1-f-hydzoxysteroid dehy ogenase type | (IIPHISD-1) and which ate therefore useful in the reatment of certain disorders that can be prevented of treated by inhibition ofthis enzyme. In addition the invention relates to the compounds methods for their preparation, pharmaceutical compos itions containing the compounds and the uses of these compounds in the treatment of certain disorders. Its expected thatthe com: pounds of the invention will find application in the teatment 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, hy pertension and as well as other diseases and conditions. itle: DERIVATIVES OF AZA ADAMANTANE AND USES THEREOF = = z 5 R ° =WO 2013/111150 A1 MINNIE MN EAM 2M, ZW), Eursin (AM, AZ, BY, KG, KZ, RU, TH, Published wopem (AL, AT, BE, BG, CH, CY, CZ, DE, DK, _- S. Gi, Hig, HU, He, 18, 17, with international search report (Art 21(3)) before the expiration of the time limit for amending the claims and to be republished in the event of receipt of ‘amendments (Ral 8.20) GW, ML, MR, NE, SN, TD, TG) Declarations under Rule 4.17: of inventorship (Rule 4.17(0))10 15 20 25 30 35 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-B-hydroxysteroid dehydrogenase type 1 (11B-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. BACKGROUND OF THE INVENTION 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 (118-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 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 118-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 (11B-HSD-2), which converts cortisol into cortisone, is a unidirectional dehydrogenase mainly located in kidney and protects minerallocorticoid receptors from illicit activation by glucocorticoids. Multiple fines of evidence indicate that 118-HSD-1-mediated intracellular cortisol production may have a pathogenic role in Obesity, Type 2 Diabetes and its co-morbidities. 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, 118-HSD-1 activity was decreased in liver and increased in the adipose tissue of obese individuals. Similarly 11B-HSD-1 mRNA was found to be increased in both 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 118-HSD-1 and 1