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( 12 ) United States Patent ( 10 ) Patent No .: US 10,858,376 B2 Alley Et Al

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( 12 ) United States Patent ( 10 ) Patent No .: US 10,858,376 B2 Alley Et Al US010858376B2 ( 12 ) United States Patent ( 10 ) Patent No .: US 10,858,376 B2 Alley et al . ( 45 ) Date of Patent : * Dec . 8 , 2020 ( 54 ) TRICYCLIC BENZOXABOROLE ( 56 ) References Cited COMPOUNDS AND USES THEREOF U.S. PATENT DOCUMENTS ( 71 ) Applicants :GlaxoSmithKline Intellectual 7,205,425 B2 4/2007 Shibasaki et al . Property ( No. 2 ) Limited , Brentford 7,446,236 B2 11/2008 Naud et al . ( GB ) ; Anacor Pharmaceuticals , Inc. , 7,816,344 B2 10/2010 Baker et al . Palo Alto , CA ( US ) 8,530,452 B2 9/2013 Gordeev et al . 8,703,742 B2 4/2014 Hernandez et al . ( 72 ) Inventors: Michael Richard Kevin Alley , Santa 2009/0227541 A1 9/2009 Baker et al . Clara , CA (US ); Vincent S. 2010/0048570 A1 2/2010 Kim et al . 2012/0115813 A1 5/2012 Hernandez et al . Hernandez , Watsonville, CA ( US ) ; 2013/0035501 A1 2/2013 Conde et al . Jacob J. Plattner , Palo Alto , CA ( US ) ; 2013/0064783 A1 3/2013 Baker et al . Xianfeng Li , Cupertino, CA ( US ) ; 2013/0165411 A1 6/2013 Gordeev et al. David Barros - Aguirre , Madrid ( ES ) ; 2016/0168167 Al 6/2016 Kim et al . Ilaria Giordano , Hertfordshire ( GB ) FOREIGN PATENT DOCUMENTS ( 73 ) Assignees : GlaxoSmithKline Intellectual Property ( No.2 ) Limited , Brentford WO WO2006096131 9/2006 WO WO2008157726 12/2008 ( GB ) ; Anacor Pharmaceuticals , Inc. , WO WO2011127143 10/2011 Palo Alto , CA ( US ) WO WO2012033858 3/2012 WO WO2013093615 6/2013 ( * ) Notice : Subject to any disclaimer , the term of this WO WO2015016558 2/2015 patent is extended or adjusted under 35 WO WO2015021396 2/2015 U.S.C. 154 ( b ) by 0 days. This patent is subject to a terminal dis OTHER PUBLICATIONS claimer . Adamczyk -Wozniak et al . , “ Benzoxaboroles — Old Compounds with new applications, ” J. Organometallic Chem ., vol . 694 , Issue 22 , ( 21 ) Appl . No .: 16 / 695,253 2009 , pp . 3533-3541 . ( 22 ) Filed : Nov. 26 , 2019 (Continued ) ( 65 ) Prior Publication Data Primary Examiner Karen Cheng US 2020/0095266 A1 Mar. 26 , 2020 ( 74 ) Attorney, Agent, or Firm Dority & Manning, P.A. Related U.S. Application Data ( 57 ) ABSTRACT ( 63 ) Continuation of application No. 16 / 385,547 , filed on Compounds of Formula II , Apr. 16 , 2019 , now Pat . No. 10,526,352 , which is a continuation of application No. 1 / 792,251 , filed on Oct. 24 , 2017 , now Pat . No. 10,308,668 , which is a R1 continuation of application No. 14 / 387,384 , filed as R2 application No. PCT /US2014 / 050370 on Aug. 8 , 2014 , now abandoned . B ( 60 ) Provisional application No. 61 / 918,976 , filed on Dec. 20 , 2013 , provisional application No. 61 / 864,496 , filed on Aug. 9 , 2013 . X NH2 ( 51 ) Int . Ci . A61K 31/69 ( 2006.01 ) CO7F 5/04 ( 2006.01 ) wherein X is selected from chloro , fluoro , bromo and iodo , CO7F 5/02 ( 2006.01 ) R and R2 are each independently selected from H , CH3 , A61K 45/06 ( 2006.01 ) CH2CH3 , — CH2CH2CH3, or CH ( CH3 ) 2 ; compositions ( 52 ) U.S. CI . containing them , their use in therapy, including their use as ??? C07F 5/04 ( 2013.01 ) ; A61K 31/69 anti- mycobacterial agents , for example in the treatment of a ( 2013.01 ) ; A61K 45/06 ( 2013.01 ) ; C07F 57025 mycobacterial infection in a mammal , and methods for the ( 2013.01 ) preparation of such compounds , are provided . ( 58 ) Field of Classification Search CPC A61K 31/69 See application file for complete search history . 18 Claims, 4 Drawing Sheets US 10,858,376 B2 Page 2 ( 56 ) References Cited OTHER PUBLICATIONS Canadian Office Action dated May 23 , 2017 for Canadian Appli cation No. 2,794,684 . English translation of Saudi Arabian Office Action , dated Jan. 11 , 2017 , for Saudi Arabian Application No. 516370551 . Hernandes et al . , “ Halogen Atoms in the Modern Medicinal Chem istry: Hints for the Drug Design , ” Current Drug Targets , vol . 11 , No. 3 , Mar. 2010 , pp . 303-314 . King , “ Bioisosteres , Conformational Restriction , and Pro -drugs Case History : An Example of a Conformational Restriction Approach , " Med Chem : Principle and Practice , Chapter 14 , XP 002033086 , 1994 , pp . 206-208 . U.S. Office Action Related to U.S. Appl. No. 14 / 969,467 dated Jul. 19 , 2017 . U.S. Office Action issued in U.S. Appl. No. 15 / 550,693 , dated Mar. 19 , 2018 U.S. Office Action issued in U.S. Appl. No. 15 / 550,658 , dated Jul. 6 , 2018 Vippagunta et al . , “ Crystalline solids, ” Elsevier Science B.V., Advanced Drugs Delivery Reviews 48 ( 2001 ) , pp . 3-26 . U.S. Patent Dec. 8 ,2 2020 Sheet 1 of 4 US 10,858,376 B2 GLOBAL XDR - TB + 69 untress have reported at WORLD HEALTH sast one case of ASSEMBLY RESOLUTION : end 07 2010 ) The 2009 resolution There urged all WHO Member estimated 25,400 States to achieve cases of XOR - TO universal access to emerging every diagnosis and year treatment of MDR - TB and XDR - TB * Countries that have reported XOR - 76 FIGURE 1 U.S. Patent Dec. 8 ,2 2020 Sheet 2 of 4 US 10,858,376 B2 al FIGURE 2 U.S. Patent Dec. 8 ,2 2020 Sheet 3 of 4 US 10,858,376 B2 80 70 ********************* 4444444444444 60 50 w 40 Strainnumber 30 20 ** 14 : 44 10 30.02 0.04 0.08 0.16 0.31 MIC ( M ) 1991YYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYY FIGURE 3 U.S. Patent Dec. 8 ,2 2020 Sheet 4 of 4 US 10,858,376 B2 ??- ???? -8 ?????????????????????????????????? Espositowie ***** WWWWWW FIGURE 4 US 10,858,376 B2 1 2 TRICYCLIC BENZOXABOROLE one quinolone and one aminoglycoside. As can be seen in COMPOUNDS AND USES THEREOF FIG . 1 , XDR M. tuberculosis has been reported across much of the globe. PRIORITY Add to these issues the ease of transmission , as shown in 5 FIG . 2 , the globalization of travel, and the ongoing reloca This application is a continuation of and claims priority to tion and emigration of many segments of the world's U.S. application Ser. No. 16 / 385,547 filed Apr. 16 , 2019 , population and it is apparent that MTB is becoming a global which is a continuation of and claims priority to U.S. crisis. application Ser . No. 15 / 792,251 filed Oct. 24 , 2017 , which Synthetic drugs for treating tuberculosis ( TB ) have been is a continuation of and claims priority to U.S. application 10 available for over half a century, but incidences of the Ser. No. 14 / 387,384 filed Sep. 23 , 2014 pursuant to 35 disease continue to rise world - wide . More than 2 billion U.S.C. § 371 as a United States National Phase Application people are currently infected with M. tuberculosis most of International Patent Application Serial No. PCT US2014/ / being latent cases , and it is estimated that over 9 million new 050370 filed Aug. 8 , 2014 , which claims priority to U.S. 15 nearlycases occur 2 million each deathsyear, worldwide per year ., Inresulting 2004 alone in from approxi 1.7 to Provisional Application No. 61 / 864,496 filed Aug. 9 , 2013 mately 24,500 new infections and close to 5,500 deaths were and U.S. Provisional Application No. 61 / 918,976 filed Dec. recorded , each day . See Zignol , M et al . , M. Surveillance of 20 , 2013 , and the entire contents of each of the foregoing anti - tuberculosis drug resistance in the world : an updated applications are hereby incorporated by reference . analysis , 2007-2010 . Bull . World Health Organ 2012 , 90 ( 2 ) , 20 111-119D ) Co - infection with HIV is driving the increase in FIELD OF THE INVENTION incidence ( Williams, B. G .; Dye C. Science, 2003 , XI, 1535 ) and the cause of death in 31 % of AIDS patients in This invention relates to compounds, compositions con- Africa can be attributed to TB . See Corbett , E. L et al . , Arch . taining them , their use in therapy, including their use as Intl. Med . , 2003 , 163 , 1009 , Septkowitz , A et al . , Clin . anti -mycobacterials , for example in the treatment of tuber- 25 Microbiol. Rev. 1995 , 8 , 180 ) . culosis , and methods for the preparation of such compounds. The limitations of tuberculosis therapy and prevention are well known . The current available vaccine , BCG was intro BACKGROUND OF THE INVENTION duced in 192l and fails to protect most people past child hood . According to a 2006 report— " International Standards Mycobacterium is a genus in the class of bacteria called 30 for Tuberculosis Care ” , a document developed by the Tuber Actinobacteria with its own distinct family known as Myco- culosis Coalition for Technical Assistance ( TBCTA ) which bacteriacae . Mycobacterium contains various obligate and partners include Centers for Disease Control, American opportunistic pathogens of animals, which may also be Thoracic Society , Tuberculosis oundation , KNCV, the transmitted to humans and cause disease in humans, thus World Health Organization and the International Union exhibiting a considerable zoonotic potential. During the past 35 Againstbecome Tuberculosisinfected with andactive Lung disease Disease currently patients endure who two do few decades , members of the Mycobacterium avium - intra months of combination therapy with medicines introduced cellulare complex ( MAIC ) emerged as pathogens of human between 50 and 60 years ago — isoniazid ( 1952 ) , rifampin diseases , including lymphadenitis in children , pulmonary ( 1963 ) , pyrazinamide ( 1954) and ethambutol (1961 ) fol tuberculosis - like disease , and disseminated infections (oc 40 lowed by another 4 months of isoniazid and rifampin ( also curring predominantly in immunocompromised persons, known as rifampicin ) Alternatively the continuation phase particularly AIDS patients ). Similarly, important animal could include Isoniazid and ethambutol for six months when diseases result from infections in an animal by members of adherence cannot be assessed , but according to this report, this group , e.g. , avian tuberculosis and paratuberculosis in a longer continuation phase is associated with a higher rate ruminants . MAIC includes M. intracellulare and 4 subspe- 45 of failure and relapse, especially in patients with HIV cies of M.
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