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(12) STANDARD PATENT (11) Application No. AU 2003270783 B2 (19) AUSTRALIAN PATENT OFFICE

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(12) STANDARD PATENT (11) Application No. AU 2003270783 B2 (19) AUSTRALIAN PATENT OFFICE (12) STANDARD PATENT (11) Application No. AU 2003270783 B2 (19) AUSTRALIAN PATENT OFFICE (54) Title Octahydro-2-H-naphtho[1,2-F] indole-4-carboxamide derivatives as selective glucocorticoid receptor modulators (51) International Patent Classification(s) C07D 417/00 (2006.01) C07D 231/44 (2006.01) (21) Application No: 2003270783 (22) Date of Filing: 2003.09.17 (87) WIPO No: W004/026248 (30) Priority Data (31) Number (32) Date (33) Country 60/412,231 2002.09.20 US 60/476,079 2003.06.05 us (43) Publication Date: 2004.04.08 (43) Publication Journal Date: 2004.05.20 (44) Accepted Journal Date: 2009.12.24 (71) Applicant(s) Merck & Co., Inc. (72) Inventor(s) Graham, Donald W.;Tata, James R.;Goulet, Joung L.;Sinclair, Peter J.;Aster, Susan D.;Taylor, Gayle E.;Hunt, Julianne A.;Balkovec, James M.;Ali, Amjad;Kallashi, Florida (74) Agent / Attorney Spruson & Ferguson, Level 35 St Martins Tower 31 Market Street, Sydney, NSW, 2000 (56) Related Art CA 1 178 965 US 4 307 102 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property O organization 11111|111||1 111 |1111 |||111| 111 |11111 111111 ||11111111 1 11 International Bureau 1111111 111111 111111 I 11 11 11 11 11 ii1111li iili (43) International Publication Date (10) International Publication Number 1 April 2004 (01.04.2004) PCT W O 2004/026248 A3 (51) International Patent Classification 7: C07D 417/00, 07065-0907 (US). TATA, James, R. [US/US]; 126 East 231/44 Lincoln Avenue, Rahway, NJ 07065-0907 (US). TAYLOR, Gayle, E. [US/US]; 126 East Lincoln Avenue, Rahway, (21) International Application Number: NJ 07065-0907 (US). GOULET, Joung, L. [US/US]; 126 PCT/US2003/029494 East Lincoln Avenue, Rahway, NJ 07065-0907 (US). (22) International Filing Date: (74) Common Representative: MERCK & CO., INC.; 126 17 September 2003 (17.09.2003) East Lincoln Avenue, Rahway, NJ 07065-0907 (US). (81) Designated States (national): AE, AG, AL, AM, AT, AU, (25) Filing Language: English AZ, BA, BB, BG, BR, BY, BZ, CA, CI, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, F, GB, GD, GE, (26) Publication Language: English GI, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, (30) Priority Data: MX, MZ, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, 60/412,231 20 September 2002 (20.09.2002) US SD, SE, SG, SK, SL, SY, TJ, TM, TN, TR, TT, TZ, UA, 60/476,079 5 June 2003 (05.06.2003) US UG, US, UZ, VC, VN, YU, ZA, ZM, ZW. (71) Applicant (for all designated States except US): MERCK (84) Designated States (regional): ARIPO patent (GIL GM, & CO., INC. [US/US]; 126 East Lincoln Avenue, Rahway, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW), NJ 07065-0907 (US). Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE, BG, ClI, CY, CZ, DE, DK, EE, , FR, GB, GR, , I, I, LU, MC, NL, PT, RO, (72) Inventors;- andES,(7) Iventrs;andSE, SI, SK, IR), GAPI patent (BF, BJ, CF, CG, CI, CM, (75) Inventors/Applicants (for US only): ALI, Amjad GA, GN, GQ, GW, ML, MR, NE, SN, ID, TG). [GB/US]; 126 East Lincoln Avenue, Rahway, NJ 07065-0907 (US). ASTER, Susan, D. [US/US]; 126 East Lincoln Avenue, Rahway, NJ 07065-0907 (US). Pubihe BALKOVEC, James, M. [US/US]; 126 East Lincoln Avenue, Rahway, NJ 07065-0907 (US). GRAHAM, Donald, W. [US/US]; 126 East Lincoln Avenue, Rahway, (88) Date of publication of the international search report: NJ 07065-0907 (US). HUNT, Julianne, A. [US/US]; 15 July 2004 126 East Lincoln Avenue, Rahway, NJ 07065-0907 (US). KALLASHI, Florida [US/US]; 126 East Lincoln For two-letter codes and other abbreviations, refer to the "Guid Avenue, Rahway, NJ 07065-0907 (US). SINCLAIR, dance Notes on Codes andAbbreviations"appearing at the begin S Peter, J. [US/US]; 126 East Lincoln Avenue, Rahway, NJ ning of each regular issue of the PCT Gazette. (54) Title: OCTAHYDRO-2-H-NAPHTHO[ 1,2-F] INT)OLE-4-CARBOXAMJDE DERIVATIVES AS SELECTIVE GLUCOCOR ~)TICOID RECEPTOR MODULATORS 16 (57) Abstract: The present invention encompasses compounds of For R mula 1: or pharmaceutically acceptable salts or hydrates thereof, which ('Y are useful as selective glucocorticoid receptor ligands for treating a va 12 y12riety of autoimmune and inflammatory diseases or conditions. Pharma S (R)6 2 7 r m Y3 ceutical compositions and methods of use are also included. 8 L R pDa ( BZ, K XR1 1 (R1 )0-3 WO 2004/026248 PCT/US2003/029494 TITLE OF THE INVENTION OCTAHYDRO-2-H-NAPHTHO[1,2-F] INDOLE-4-CARBOXAMIDE DERIVATIVES AS SELECTIVE GLUCOCORTICOID RECEPTOR MODULATORS 5 BACKGROUND OF THE INVENTION Intracellular receptors (IR's) are a class of structurally related proteins involved in the regulation of gene expression. The steroid hormone receptors are a subset of this superfamily whose natural ligands are typically comprised of 10 endogenous steroids such as estradiol, progesterone, and cortisol. Man-made ligands to these receptors play an important role in human health and, of these receptors, the glucocorticoid receptor has an essential role in regulating human physiology and immune response. Steroids that interact with the glucocorticoid receptor have been shown to be potent antfinflammatory agents. The present invention is directed to a 15 novel class of compounds that are selective glucocorticoid receptor modulators that have potent ani-inflammatory and immunosupresive activity and possess advantages over steroidal glucocorticoid ligands with respect to side effects, efficacy, toxicity and/or metabolism. 20 SUMMARY OF THE INVENTION The present invention encompasses compounds of Formula I: R1 6 1 0 (R -2 M Y2 R7 r D 3 I R K XR10 J ' (R1 1)0.3 25 1 or pharmaceutically acceptable salts or hydrates thereof, which are useful as selective glucocorticoid receptor ligands for treating a variety of autoimmune and inflammatory diseases or conditions. Pharamaceutical compositions and methods of use are also included. WO 2004/026248 PCT/US2003/029494 DETAILED DESCRIPTION OF THE INVENTION The present invention encompasses compounds of Formula I R16 (R 2)0-2 47^ R D Y3 LR K/ XR10 (R )n 5 or a pharmaceutically acceptable salt or hydrate thereof, wherein: n and m are each independently 0, 1 or 2; 10 J is selected from NR 1 or C(RI)(R2 ); K is selected from NR 3 or C(R3)(R4); L is selected from NR5 or C(R5)(R6); 15 X is a bond, -C(O), -N(R 14 )-, -N(R 14)-C(O)-, -C(O)-N(R1 4 )-, -N(R14 )-S(O)k-, -N(R 14)-C(O)-NH- or -S(O)k-N(R 14 ); k is 0, 1 or 2; 20 R1 and R10 are each independently selected from the group consisting of: (1) Cl-6alkyl, (2) C2-6alkenyl, 25 (3) C2-6akynyl, (4) C3-6cycloalkyl, (5) Cl-6alkoxy, (6) CI-6alkyl-S(O)k-, wherein k is 0, 1 or 2, (7) aryl, -2- WO 2004/026248 PCT/US2003/029494 (8) aryl C1-6alkyl, (9) HET, (10) -C1-6alkyl-HET, (11) aryloxy, 5 (12) aroyloxy, (13) aryl C2-6alkenyl, (14) aryl C2-6alkynyl, (15) hydrogen, (16) hydroxyl and 10 (17) cyano, wherein items (1) to (6) above and the alkyl portions of items (8) and (10) above and the alkenyl portion of item (13) above and the alkynyl portion of item (14) above are optionally substituted from one up to the maximum number of substitutable positions 15 with a substituent independently selected from the group consisting of: halo, oxo, OR 13 , N(R1 4 )2, C3-6cycloalkyl and C1-6alkyl-S(O)k-, wherein k is 0, 1 or 2, and wherein items (7), (9), (11) and (12) above and aryl portion of items (8), (13) and (14) above and the HET portion of item (10) above are optionally substituted from one up 20 to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: (a) halo, (b) OR 13 , (c) N(R14 )2, 25 (d) C1-6alkyl, (e) C2-6alkenyl, (f) C2-6akynyl, (g) C1-6alkyl-S(O)k-, wherein k is 0, 1 or 2, (h) aryl, 30 (i) aryl-S(O)k-, wherein k is 0, 1 or 2, () HET, (k) aryl C1-6alkyl, (1) aroyl, (m) aryloxy, -3- WO 2004/026248 PCT/US2003/029494 (n) aryl C1-6alkoxy, (o) CN and (p) C3-6cycloalkyl, wherein items (d) to (g) and (p) above and the alkyl portions of item (k) above are 5 optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 and N(R1 4 )2, and wherein items (h), (i), (j), (1)and (m) above and the aryl portions of items (k) and (n) 10 above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 and C1-4alkyl, R2 , R3 , R4 , R5 and R6 are each independently selected from the group 15 consisting of: (1) hydrogen, (2) halo, (3) C1-6alkyl, (4) C2-6alkenyl, 20 (5) C2-6akynyl, (6) C3-6cycloalkyl, (7) C1-6alkoxy, (8) C1-6alkyl-S(O)k-, wherein k is 0, 1 or 2, (9) aryl, 25 (10) aryl C1-6alkyl, (11) HET and (12) -C1-6alkyl-HET, wherein items (3) to (8) above and the alkyl portions of items (10) and (12) above are optionally substituted from one up to the maximum number of substitutable positions 30 with a substituent independently selected from the group consisting of: halo, OR 13 , N(R 14 )2 and C1-6alkyl-S(O)k-, wherein k is 0, 1 or 2; and wherein items (9) and (11) and the aryl portion of items (10) and the NET portion of item (12) are optionally substituted from one up to the maximum number of -4- WO 2004/026248 PCT/US2003/029494 substituable positions with a substituent independently selected from the group consisting of: (a) halo, (b) OR 13, 5 (c) N(R14 )2, (d) C1-6alkyl, (e) C2-6alkenyl, (f) C2-6akynyl and (g) C1-6alkyl-S(O)k-, wherein k is 0, 1 or 2, 10 wherein items (d) to (g) above are optionally substituted
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