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(12) Patent Application Publication (10) Pub. No.: US 2016/0122312 A1 Adonato Et Al US 2016O122312A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0122312 A1 adonato et al. (43) Pub. Date: May 5, 2016 (54) ANTI-VIRAL COMPOUNDS, A 6LX39/39 (2006.01) PHARMACEUTICAL COMPOSITIONS AND A 6LX39/55 (2006.01) METHODS OF USE THEREOF A639/13 (2006.01) (71) Applicant: KINETA, INC., Seattle, WA (US) A 6LX39/29 (2006.01) C07D 3L/22 (2006.01) (72) Inventors: Shawn P. Ladonato, Seattle, WA (US); A639/45 (2006.01) Kristin M. Bedard, Bellevue, WA (US); (52) U.S. Cl Kerry W. Fowler, Seattle, WA (US) AV e. we CPC ............ C07D 311/36 (2013.01); C07D 311/22 (21) Appl. No.: 14/895,899 (2013.01); A61K 39/21 (2013.01); A61 K 22) PCT Fled: Jul. 16, 2014 39/145 (2013.01); A6IK39/155 (2013.01); (22) 1C ul. 10, A6 IK39/13 (2013.01); A61K 39/29 (2013.01); (86). PCT No.: PCT/US1.4/46829 A6IK39/39 (2013.01); A61 K 2039/55511 S371 (c)(1), (2013.01) (2) Date: Dec. 3, 2015 (57) ABSTRACT Related U.S. Application Data (60) Provisional application No. 61/846,997, filed on Jul. Disclosedise osed hereinere1n are compounds,ds, pph armaceU ticalIca composi 16, 2013, provisional application No. 61/991,417 tions, and methods for the treatment of viral infection, includ filed O May 9, 2014. s I u. s ing RNA viral infection, as well as compounds, pharmaceu tical compositions, and methods for modulating the RIG-I Publication Classification pathway in a Subject and/or in cells. These compounds are (51) Int. Cl. isoflavone derivatives, typically substituted at the 3-position CO7D 3II/36 (2006.01) with an aryl group and at the 7-position with a heterofunc A639/2 (2006.01) tional group. Patent Application Publication May 5, 2016 Sheet 1 of 9 US 2016/O122312 A1 . logit) i? Compound F.G. 1. Patent Application Publication May 5, 2016 Sheet 2 of 9 US 2016/O122312 A1 A. RSVA2 KN101 (-75% death 48h) 8 RSV A2 wira RNA 48 hours post infection 's -, S X. a. & S is at KIN-t of FIG. 2. Patent Application Publication May 5, 2016 Sheet 4 of 9 US 2016/O122312 A1 A. Dengue Serotype 2 2. st 9000 E O S. 6000 A. 3000 a s & S ES P SE KENO al FG. 4. Patent Application Publication May 5, 2016 Sheet 5 of 9 US 2016/O122312 A1 uolu FIG. 4. (cont'd) Patent Application Publication May 5, 2016 Sheet 6 of 9 US 2016/O122312 A1 aea aga '8's SS it competiti as KN268 -- KN 34 rehee KN372 - KN328 -- XM38 n in MSO uM compound F.G. 5. Patent Application Publication May 5, 2016 Sheet 7 of 9 US 2016/O122312 A1 paz?euduou#Ádoo *«? FT2 RG- OASL OAS MX1 F.G. 6. Patent Application Publication May 5, 2016 Sheet 8 of 9 US 2016/O122312 A1 initienza iting tier MHV iung titer t s: S. t & t s: JS * s C. engue type 2 Pasna exposure KIN 269 KIN 269 P Ongkgiday is trait post airin. F.G. 7. Patent Application Publication May 5, 2016 Sheet 9 Of 9 US 2016/O122312 A1 40LX6uniuerbivnºn?sø?doo FIG. 7. (cont'd) US 2016/0122312 A1 May 5, 2016 ANTI-VIRAL COMPOUNDS, window of opportunity for treatment. High resistance to ada PHARMACEUTICAL COMPOSITIONS AND mantanes already restricts their use, and massive stockpiling METHODS OF USE THEREOF of neuraminidase inhibitors will eventually lead to overuse and the emergence of resistant strains of influenza. CROSS REFERENCES TO RELATED 0008 Most drug development efforts against viruses tar APPLICATIONS get viral proteins. This is a large part of the reason that current 0001. This application claims priority to U.S. Provisional drugs are narrow in spectrum and Subject to the emergence of Patent Application Ser. No. 61/846,997 filed Jul. 16, 2013, viral resistance. As most RNA viruses have Small genomes and U.S. Provisional Patent Application Ser. No. 61/991,417 and many encode less than a dozen proteins, viral targets are filed May 9, 2014, the entire contents of both of which are limited. Based on the foregoing, there is an immense and incorporated by reference herein. unmet need for effective treatments against viral infections, including RNA viral infections. STATEMENT OF GOVERNMENT INTEREST 0002 This invention was made with government support SUMMARY OF THE DISCLOSURE under National Institutes of Health Grant No. A1081335. The 0009. The compounds, pharmaceutical compositions, and government has certain rights in the invention. methods disclosed herein shift the focus of viral drug devel opment away from the targeting of viral proteins to the tar FIELD OF THE DISCLOSURE geting and enhancing of the hosts innate antiviral immune 0003. The disclosure provides compounds, pharmaceuti response. Such compounds, pharmaceutical compositions, cal compositions, and methods for treating viral infection, and methods are likely to be more effective, be less suscep among other uses. The compounds modulate the retinoic tible to the emergence of viral resistance, cause fewer side acid-inducible gene 1 (RIG-I) pathway. effects, and be effective against a range of different viruses. Tan, S. L., et al. (2007) Systems biology and the host response BACKGROUND OF THE DISCLOSURE to viral infection, Nat Biotechnol 25, 1383-1389. 0010. The retinoic acid-inducible gene 1 (RIG-I) pathway 0004 Viruses, such as RNA viruses, represent an enor is intimately involved in regulating the innate immune mous public health problem in the United States and world response to virus infections including RNA virus infections. wide. Well-known RNA viruses include influenza virus (in RIG-I agonists are expected to be useful for the treatment of cluding the avian and Swine isolates; also known as flu), many viruses including Hepatitis C Virus (HCV), influenza hepatitis C virus (HCV), West Nile virus (WNV), SARS virus, and West Nile virus (WNV), among others. Accord coronavirus (SARS), respiratory syncytial virus (RSV), and ingly, the present disclosure relates to compounds, pharma human immunodeficiency virus (HIV). ceutical compositions including the compounds, and associ 0005. As one example, more than 170 million people ated methods of use to treat viral infection, including RNA worldwide are infected by HCV, and 130 million of these are viral infection, wherein the compounds modulate the RIG-I chronic carriers at risk of developing chronic liver diseases pathway. (cirrhosis, carcinoma, and liver failure). As such, HCV is responsible for two thirds of all liver transplants in the devel 0011. The compounds have the following general chemi oped world. Recent studies show that the death rate from cal structure HCV infection is rising due to the increasing age of chroni cally infected patients. As a second example, seasonal flu infects 5-20% of the population annually resulting in 200,000 hospitalizations and 36,000 deaths each year. Y3 Z3 (A), 0006 Compared to HCV and influenza, WNV causes the lowest number of infections, 981 in the United States in 2010. R3 Y 2 x-7 Twenty percent of infected patients, however, develop a (A1 Ny. z \ severe form of the disease, resulting in a 4.5% mortality rate. (R), Unlike HCV and influenza, there are no approved therapies for the treatment of WNV infection, and it is a high-priority as described more fully in the Detailed Description. pathogen for drug development due to its potential as a biot errorist agent. BRIEF DESCRIPTION OF THE DRAWINGS 0007 Among the viruses listed, vaccines exist only for influenza virus. Accordingly, drug therapy is essential to miti (0012 FIGS. 1A, 1B, and 1C show the antiviral activity of gate the significant morbidity and mortality associated with the compounds KIN100 and KIN101 against HCV. (A) HCV these viruses. Unfortunately, the number of antiviral drugs is focus-forming assay done in Huh? cells pre-treated with limited, many are poorly effective, and nearly all are plagued KIN100 for 24 hours and infected with HCV2a at a multi by the rapid evolution of viral resistance and a limited spec plicity of infection (MOI) of 0.5 for 48 hours. HCV proteins trum of action. Moreover, treatments for acute HCV and were detected by immunofluorescent staining with viral-spe influenza infections are only moderately effective. The stan cific serum and foci were normalized to negative control cells dard of care for HCV infection, PEGylated interferon and that were not drug treated (equal to 1). (B) Quantitation of ribavirin, is effective in only 50% of patients, and there are a HCV viral RNA by real-time quantitative PCR (RT-qPCR) number of dose-limiting side effects associated with the com done in Huh7 cells pre-treated with KIN101 for 18 hours and bined therapy. Both classes of acute influenza antivirals, ada infected with HCV2a at MOI of 1.0 for 72 hours. Viral RNA mantanes and neuraminidase inhibitors, are only effective was isolated and quantitated in the Supernatant of infected within the first 48 hours after infection, thereby limiting the cultures. (C) A similar quantitation of HCV viral RNA by US 2016/0122312 A1 May 5, 2016 RT-qPCR done in Huh? cells infected with HCV2a at MOI of compositions, and methods are likely to be more effective, 1.0 for 4 hours and then treated with KIN101. less Susceptible to the emergence of viral resistance, cause 0013 FIGS. 2A and 2B show the antiviral activity of the fewer side effects, and be effective against a range of different compound KIN101 against RSV. (A) Cell viability following viruses. Tan, S. L., et al. (2007) Systems biology and the host infection with RSV A2 and treatment with KIN101. (B) response to viral infection, Nat Biotechnol 25, 1383-1389.
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