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(12) United States Patent (10) Patent No.: US 7,973,161 B2 WAFS E.W. E. W (US); (52) U.S. C...54

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(12) United States Patent (10) Patent No.: US 7,973,161 B2 WAFS E.W. E. W (US); (52) U.S. C...54 US007973161B2 (12) United States Patent (10) Patent No.: US 7,973,161 B2 Bruncko et al. (45) Date of Patent: *Jul. 5, 2011 (54) APOPTOSIS PROMOTERS (60) Provisional application No. 60/519,695, filed on Nov. 13, 2003. (75) Inventors: Milan Bruncko, Green Oaks, IL (US); Hong Ding, Gurnee, IL (US); Steven (51) Int. Cl. Elmore, Northbrook, IL (US); Aaron C07D 24I/02 (2006.01) Kunzer, Arlington Heights, IL (US); C07D 403/02 (2006.01) WAFS E.W. E. w (US); (52) U.S. C. ................................ 544/393; 54.4/121 (US);an Cheol-Min cellan, Park, waukegan, Singapore (SG); (58) Field of Classification Search ........................ None Andrew Petros, Mundelein, IL (US); See application file for complete search history. Xiaohong Song, Grayslake, IL (US); (56) References Cited Xilu Wang, Grayslake, IL (US); Noah Tu, Gurnee, IL (US); Michael Wendt, U.S. PATENT DOCUMENTS Vernon Hills, IL (US); Alexander 5,138,069 A 8, 1992 Carini et al. Shoemaker, Green Oaks, IL (US); 6,410,584 B1 6/2002 Pamukcu et al. Michael Mitten, Beach Park, IL (US) 6,720,338 B2 4/2004 Augeri et al. (73) Assignee: Abbott Laboratories, Abbott Park, IL (Continued) (US) FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this NZ 230 136 12/1991 patent is extended or adjusted under 35 (Continued) U.S.C. 154(b) by 1010 days. This patent is Subject to a terminal dis- OTHER PUBLICATIONS claimer. Thomas H. Corbett, et al., “Discovery and Preclinical Antitumor Efficacy Evaluations of LY32262 and LY33169. Investigational (21) Appl. No.: 11/600,445 New Drugs, Feb. 21, 2003, vol. 31: pp. 33-45. (22) Filed: Nov. 16, 2006 (Continued) (65) Prior Publication Data Primary Examiner — Zinna N Davis US 2007/0072860A1 Mar. 29, 2007 (74) Attorney, Agent, or Firm — Jones Day Related U.S. Application Data (57) ABSTRACT (63) Continuation-in-part of application No. 1 1/491,851, Disclosed are compounds which inhibit the activity of anti filed on Jul. 24, 2006, which is a continuation-in-part apoptotic protein family members, compositions containing of application No. 11/202,827, filed on Aug. 12, 2005, the compounds and uses of the compounds for preparing now Pat. No. 7,642,260, which is a medicaments for treating diseases during which occurs continuation-in-part of application No. 1 1/127,940, expression one or more than one of an anti-apoptotic protein filed on May 12, 2005, now Pat. No. 7,767,684, which family member. is a continuation-in-part of application No. 10/988,338, filed on Nov. 12, 2004, now abandoned. 5 Claims, 7 Drawing Sheets EXAMPLE 2 and Etoposide 4000 E 3000 -- -H EXAMPLE 2 2000 -A - Etoposide s - -O- EXAMPLE 2 + Etoposide s -(- Combinotion Vehicle 5 1000 S 3. O 14. 18 22 26 30 34 38 42 Days post inoculation US 7,973,161 B2 Page 2 U.S. PATENT DOCUMENTS ISA, PCT International Preliminary Report on Patentability dated 7,030,115 B2 4/2006 Elmore et al. May 15, 2006, in International Application No. PCT/US2004/ 7,358,251 B2 4/2008 Elmore et al. 037911, filed Nov. 12, 2004. 7,390,799 B2 6, 2008 Bruncko et al. ISA, PCT International Search Report dated May 13, 2005, in Inter 7,449,485 B2 11/2008 Elmore et al. national Application No. PCT/US2004/036770, filed Nov. 3, 2004. 7,504,512 B2 3/2009 Augeri et al. ISA, PCT International Search Report dated May 13, 2005, in Inter 7,585,858 B2 9, 2009 Elmore et al. 7,642,260 B2 1/2010 Bruncko et al. national Application No. PC1/US2004/037911, filed Nov. 12, 2004. 2002fOO86887 A1 7/2002 Augeri et al. Kutzki, et al., “Development of Potent Bcl-Xl Antagonist Based on 2003/01 19894 A1 6/2003 Murthy et al. O-Helix Mimicry,” J. Am. Chern. Soc., 2002, 124, 11838-11839. 2006/0258657 A1 11/2006 Bruncko et al. Tse et al., “ABT-263: A Potent and Orally Bioavailable Bcl-2 Family 2007, OO15787 A1 1/2007 Bruncko et al. Inhibitor.” May 1, 2008, Cancer Research 68(9):3421-3428. 2008/0076779 A1 3/2008 Elmore et al. Wang, et al., “Structure-based discovery of an organic compound that 2008/0287419 A1 11/2008 Bruncko et al. binds Bcl-2 protein and induces apoptosis of tumor cells.” PNAS, Jun. 20, 2000, vol.97, No. 13, pp. 7124-7129. FOREIGN PATENT DOCUMENTS Wang, et al., “A novel Small molecule inhibitor of Bcl-X inhibits WO O224636 A1 3, 2002 tumor growth in a human head and neck squamous cell carcinoma WO 02098.848 A1 12/2002 Xenograft model.” Proceedings of the American Association for Can WO O3040 107 A1 5, 2003 cer Research, vol. 44, 2" Ed., Jul. 2003, p. 942, #4740. WO WOO3O80586 A1 10, 2003 Amendment and Response filed on Oct. 8, 2009 in U.S. Appl. No. WO 2004.043950 A1 5, 2004 WO 2004.0483.29 A1 6, 2004 1 1/600,445. WO WO 2005/049594 6, 2005 Banker, Gilbert S. et al., “Modem Pharmaceutics, Marcel Dekker', 1996. WO WO2005049593 A2 6, 2005 Final Office Action dated Aug. 12, 2009 for U.S. Appl. No. OTHER PUBLICATIONS 12/120,914. Hattori et al., CAS Accession No. 2006: 298664, 2006. Degterev, et al., “Identification of small-molecule inhibitors of inter Non-final Office Action dated Nov. 28, 2008 for U.S. Appl. No. action between the BH3 domain and Bcl-X.” Nature Cell Biology, 12/120,914. vol. 3, Feb. 2001, pp. 173-182. Oltersdorf et al., “An inhibitor of Bcl-2 family proteins induces Enyedy, et al., “Discovery of Small-Molecule inhibitors of Bcl-2 regression of solid tumours.” Nature, 2005, 435. through Structure-Based Computer Screening.” J. Med. Chem. Wang G. et al., “An Efficient Synthesis of ABT-263, a Novel Inhibi 2001, 44, 4313-4324. tor of Antiapoptotic Bcl-2 Proteins”. Synthesis, 2008, 15, 2398-2404. ISA, PCT International Preliminary Report on Patentability dated Wolff, Mandred E. "Burger's Medicinal Chemistry and Drug Dis May 15, 2006, in International Application No. PCT/US2004/ covery.” Principles and Practice, 1995,975-977, 5th Ed, vol. 1, John 036770, filed Nov. 3, 2004. Wiley & Sons. U.S. Patent Jul. 5, 2011 Sheet 1 of 7 US 7,973,161 B2 99 09:9ZZZ 000; 000€ 000Z 000|| (ues Fuu) ION JOun '9NW U.S. Patent US 7,973,161 B2 09GW07ÇÇGZ U.S. Patent US 7,973,161 B2 d'OHO+ZBT1dWWX3 U.S. Patent Jul. 5, 2011 Sheet 4 of 7 US 7,973,161 B2 0009) 0 00çZ'+ 0091?i 000||E. ( B 33 ? G E 009? U.S. Patent Jul. 5, 2011 Sheet 5 Of 7 US 7,973,161 B2 000£ 0 00çZ'+ 000){ 0091?i 0001? 009» ( B % ? Q --| ço U.S. Patent Jul. 5, 2011 Sheet 6 of 7 US 7,973,161 B2 |DNAunS lueOued U.S. Patent Jul. 5, 2011 Sheet 7 Of 7 US 7,973,161 B2 X90 0"| (uu) bulleMS pDd 100 US 7,973,161 B2 1. APOPTOSIS PROMOTERS (I) This application is a continuation-in-part of U.S. patent V/ application Ser. No. 1 1/491,851, filed Jul. 24, 2006, now ly N Yl pending, which is a continuation-in-part of U.S. patent appli 5 cation Ser. No. 1 1/202,827, filed Aug. 12, 2005, now U.S. Pat. i | No. 7,642,260, which is a continuation-in-part of U.S. patent D1 Al B', application Ser. No. 11/127,940, filed May 12, 2005, now U.S. Pat. No. 7,767,684, which is a continuation-in-part of 10 wherein A' is N or C(A): U.S. patent application No. 10/988,338, filed Nov. 12, 2004, one or two or three or each of A, B, D" and E' are now abandoned, which claims priority to U.S. Provisional independently selected R', OR', SR', S(O)R', SOR', C(O) Application No. 60/519,695, filed Nov. 13, 2003. R", C(O)OR', OC(O)R', NHR', N(R'), C(O)NHR', C(O) The specifications of U.S. patent application Ser. Nos. N(R'), NHC(O)R', NHC(O)OR', NRC(O)NHR', NRC 11/202,827, U.S. patent application Ser. No. 11/127,940 and 15 (O)N(R'), SONHR', SON(R'), NHSOR', U.S. Provisional Application No. 60/519,695, are hereby NHSONHR' or N(CH)SON(CH)R', and the remainder incorporated by reference into this application. are independently selected H, F, Cl, Br, I, CN, CF, C(O)OH, C(O)NH, or C(O)OR'; and Y' is H, CN, NO, C(O)OH, F, Cl, Br, I, CF. OCF, FIELD OF THE INVENTION 2O CFCF. OCFCF, R7, OR'7, C(O)R'7, C(O)OR'7, SR'7, NH, NHR'7, N(R7), NHC(O)R'7,C(O)NHC(O)NHR'7, This invention pertains to compounds which inhibit the C(O)N(R'7). NHS(O)R7 or NHSOR'7; activity of anti-apoptotic protein family members, composi O tions containing the compounds, and methods of treating B' and Y', together with the atoms to which they are diseases during which are expressed of one or more than one attached, are imidazole or triazole; and of an anti-apoptotic protein family member. one or two or each of A, D" and E' are independently selected R', OR', SR', S(O)R, SOR', C(O)R', C(O)OR', BACKGROUND OF THE INVENTION OC(O)R', NHR', N(R'), C(O)NHR', C(O)N(R'), NHC 30 (O)R', NHC(O)OR, NHC(O)NHR', N(CH)C(O)N(CH.) R', SONHR', SON(R').
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