IP Library › Granted Patent US 12,552,777
Granted Patent B2
US 12,552,777 · App. 18/660,668 · Granted Feb 17, 2026

Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof

Inventors: Guoqiang Wang (Belmont, MA); Ruichao Shen (Belmont, MA); Jiang Long (Wayland, MA); Jun Ma (Wayland, MA); Xuechao Xing (Wilmington, MA); Yong He (Lexington, MA); Brett Granger (Sudbury, MA); Jing He (Somerville, MA); Bin Wang (Newton, MA); Yat Sun Or (Waltham, MA)
Assignee: Enanta Pharmaceuticals, Inc.
C07D401/14C07D403/12C07D403/14C07D405/14C07D413/14C07D417/14
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Quick Facts
Patent No.
US 12,552,777
App. No.
18/660,668
Granted
Feb 17, 2026
Kind
B2
Abstract

The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, ester, stereoisomer, tautomer, solvate, hydrate, or combination thereof: which inhibit the Apoptosis signal-regulating kinase 1 (ASK-1), which associated with autoimmune disorders, neurodegenerative disorders, inflammatory diseases, chronic kidney disease, cardiovascular disease. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from ASK-1 related disease. The invention also relates to methods of treating an ASK-1 related disease in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The present invention specifically relates to methods of treating ASK-1 associated with hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD) and non-alcohol steatohepatitis disease (NASH).

Claims (33)

1 . A method of producing a compound of Formula (IIa-1),

wherein

X 1 is N, C(F) or C(OMe);

R 1 is

R 2 is selected from the groups below:

 and

R 3 is selected from the groups below

comprising the step of

reacting a compound of Formula (1),

with the compound

in the presence of a coupling agent and an organic base,

thereby producing the compound of Formula (IIa-1).

2 . The method of claim 1 , wherein the coupling agent is selected from the group consisting of bis(2-oxo-3-oxazolidinyl) phosphinic chloride; carbonyldiimidazole; N,N′-dicyclohexylcarbodiimide; 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride; 1-[bis(dimethylamino) methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxide hexafluorophosphate; 7-azabenzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate; and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.

3 . The method of claim 1 , wherein the organic base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine and N-methylmorpholine.

4 . The method of claim 1 , wherein R 3 is

5 . The method of claim 1 , wherein R 2 is methyl, hydroxymethyl, difluoromethyl or trifluoromethyl.

6 . The method of claim 1 , wherein the compound of Formula (IIa-1) is selected from the compounds set forth in the table below:

Compound

Structure

 7a

28a

30a

32a

33a

49a

51a

53a

55a

58a

6la

7 . The method of claim 1 , wherein the compound of Formula (IIa-1) is

8 . The method of claim 1 , wherein the compound of Formula (IIa-1) is

9 . The method of claim 1 , wherein the compound of Formula (IIa-1) is

Continuity (8)
Continuation 18073728 · Dec 2, 2022
Continuation 17197399 · Mar 10, 2021
Continuation 16866778 · May 5, 2020
Continuation 15979128 · May 14, 2018
Provisional Application 62550960 · Aug 28, 2017
Provisional Application 62523472 · Jun 22, 2017
Provisional Application 62505202 · May 12, 2017
Related Publication 20240376079A1 · Nov 14, 2024
References Cited (124)
US 6140347A · Castro et al. · 2000 [cited by applicant]
US 6534651B2 · Jagtap et al. · 2003 [cited by applicant]
US 7678792B2 · Chianelli et al. · 2010 [cited by applicant]
US 8378108B2 · Corkey et al. · 2013 [cited by applicant]
US 8653075B2 · Grundl et al. · 2014 [cited by applicant]
US 8895745B2 · Berdini et al. · 2014 [cited by applicant]
US 9067933B2 · Corkey et al. · 2015 [cited by applicant]
US 9132140B2 · Reddy et al. · 2015 [cited by applicant]
US 9254284B2 · Notte · 2016 [cited by applicant]
US 9751885B2 · Tomita et al. · 2017 [cited by applicant]
US 10246439B2 · Granger et al. · 2019 [cited by applicant]
US 10253018B2 · Wang et al. · 2019 [cited by applicant]
US 10450301B2 · Granger et al. · 2019 [cited by applicant]
US 10597382B2 · Wang et al. · 2020 [cited by applicant]
US 10683279B2 · Wang et al. · 2020 [cited by applicant]
US 10683289B2 · Granger et al. · 2020 [cited by applicant]
US 10988458B2 · Wang et al. · 2021 [cited by applicant]
US 11560368B2 · Wang et al. · 2023 [cited by applicant]
US 11834436B2 · Wang et al. · 2023 [cited by applicant]
US 20050113450A1 · Thorarensen et al. · 2005 [cited by applicant]
US 20070027156A1 · Nakai et al. · 2007 [cited by applicant]
US 20090318425A1 · Chang et al. · 2009 [cited by applicant]
US 20100029619A1 · Uchikawa et al. · 2010 [cited by applicant]
US 20100261687A1 · Grundl et al. · 2010 [cited by applicant]
US 20110009410A1 · Corkey et al. · 2011 [cited by applicant]
US 20120004267A1 · Corkey et al. · 2012 [cited by applicant]
US 20130203731A1 · Chang et al. · 2013 [cited by applicant]
US 20130210810A1 · Singh et al. · 2013 [cited by applicant]
US 20140018370A1 · Corkey et al. · 2014 [cited by applicant]
US 20140179663A1 · Notte · 2014 [cited by applicant]
US 20140249135A1 · Burger et al. · 2014 [cited by applicant]
US 20140329850A1 · Chang · 2014 [cited by applicant]
US 20150005280A1 · Sasmal et al. · 2015 [cited by applicant]
US 20150175597A1 · Notte · 2015 [cited by applicant]
US 20160166556A1 · Budas et al. · 2016 [cited by applicant]
US 20170210748A1 · Witty et al. · 2017 [cited by applicant]
US 20180327388A1 · Wang et al. · 2018 [cited by applicant]
US 20180362501A1 · Wang et al. · 2018 [cited by applicant]
US 20180362502A1 · Granger et al. · 2018 [cited by applicant]
US 20180362503A1 · Granger et al. · 2018 [cited by applicant]
US 20190062310A1 · Wang et al. · 2019 [cited by applicant]
US 20190337923A1 · Wang et al. · 2019 [cited by applicant]
US 20190337935A1 · Granger et al. · 2019 [cited by applicant]
US 20200062727A1 · He et al. · 2020 [cited by applicant]
US 20200157095A1 · Granger et al. · 2020 [cited by applicant]
US 20200308193A1 · Granger et al. · 2020 [cited by applicant]
US 20200331890A1 · Wang et al. · 2020 [cited by applicant]
CN 107793400A · 2018 [cited by applicant]
JP 2013530240A · 2013 [cited by applicant]
JP 2016503801A · 2016 [cited by applicant]
WO 2004018428A1 · 2004 [cited by applicant]
WO 2005009470A1 · 2005 [cited by applicant]
WO 2005103288A1 · 2005 [cited by applicant]
WO 2007000339A1 · 2007 [cited by applicant]
WO 2008082579A1 · 2008 [cited by applicant]
WO 2008106692B1 · 2008 [cited by applicant]
WO 2009011850A2 · 2009 [cited by applicant]
WO 2009027283A1 · 2009 [cited by applicant]
WO 2009123986A1 · 2009 [cited by applicant]
WO 2010008843A1 · 2010 [cited by applicant]
WO 2011008709A1 · 2011 [cited by applicant]
WO 2011041293A1 · 2011 [cited by applicant]
WO 2011097079A1 · 2011 [cited by applicant]
WO 2012003387A1 · 2012 [cited by applicant]
WO 2012011548A1 · 2012 [cited by applicant]
WO 2012080735A1 · 2012 [cited by applicant]
WO 2013112741A1 · 2013 [cited by applicant]
WO 2014100541A1 · 2014 [cited by applicant]
WO 2014106019A2 · 2014 [cited by applicant]
WO 2014137728A1 · 2014 [cited by applicant]
WO 2015095059A1 · 2015 [cited by applicant]
WO 2015187499A1 · 2015 [cited by applicant]
WO 2016049069A1 · 2016 [cited by applicant]
WO 2016049070A1 · 2016 [cited by applicant]
WO 2016105453A1 · 2016 [cited by applicant]
WO 2016106384A1 · 2016 [cited by applicant]
WO 2018090869A1 · 2018 [cited by applicant]
WO 2018133856A1 · 2018 [cited by applicant]
WO 2018133865A1 · 2018 [cited by applicant]
WO 2018133866A1 · 2018 [cited by applicant]
WO 2018148204A1 · 2018 [cited by applicant]
WO 2018149284A1 · 2018 [cited by applicant]
WO 2018151830A1 · 2018 [cited by applicant]
WO 2018157277A1 · 2018 [cited by applicant]
WO 2018157856A1 · 2018 [cited by applicant]
WO 2018157857A1 · 2018 [cited by applicant]
WO 2018160406A1 · 2018 [cited by applicant]
WO 2018169742A1 · 2018 [cited by applicant]
WO 2018183122A1 · 2018 [cited by applicant]
WO 2018187506A1 · 2018 [cited by applicant]
WO 2018209354A1 · 2018 [cited by applicant]
WO 2018218051A1 · 2018 [cited by applicant]
WO 2018233553A1 · 2018 [cited by applicant]
WO 2019034096A1 · 2019 [cited by applicant]
WO 2019050794A1 · 2019 [cited by applicant]
WO 2019051265A1 · 2019 [cited by applicant]
WO 2019070742A1 · 2019 [cited by applicant]
WO 2020198214A1 · 2020 [cited by applicant]
Pubmed Compound Summary for CID 53276841, ‘2-Methyl-1, 1,3-trioxo-N-pyridin-2-yl-1,2-benzolhiazole-6-carboxamide’, U.S. National library of Medicine, Aug. 1, 2011 (Aug. 1, 2011), p. 1-7; p. 2 (https:/lpubchem.ncbi.nlm.n… [cited by applicant]
Ali , et al., “Recent advances in the development of farnesoid X receptor agonists”, Ann Transl Med, 3(1), 2015, 1-16. [cited by applicant]
Burger, A. , et al., “Isosteric Compounds. I. Acyl Derivatives of Dibenzothiophene”, J. Am. Chem. Soc., 60(11), 1938, 2628-2630. [cited by applicant]
Dorwald, F. A, “Side Reactions in Organic Synthesis: A Guide to Successful Synthesis Design”, Wiley: VCH, Weinheim pg. IX of Preface, 2005, 1-15. [cited by applicant]
Dudkin, V. Y, “Bioisosteric Equivalence of Five-Membered Heterocycles”, Chemistry of Heterocyclic Compounds, 48(1), 2012, 27-32. [cited by applicant]
Gibson, T. S, et al., “Structure-based drug design of novel ASK1 inhibitors using an integrated lead optimization strategy”, Bioorg & Med Chem Lett.. 27(8), Apr. 2017, 1-5. [cited by applicant]
Jordan, V. , “Tamoxifen: A Most Unlikely Pioneering Medicine”, Nature Reviews, Mar. 2, 2003, 205-213. [cited by applicant]
Kawarazaki , et al., “Apoptosis signal-regulating kinase 1 as a therapeutic target”, Expert Opinion on Therapeutic Targets, 18(6), 2014, 651-664. [cited by applicant]
Kharkevich, D. A, “”, Pharmacology, 10th ed. M .: Geotar-Media, 2010, 73-74. [cited by applicant]
Lanier, M., et al., “Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure”, ACS Medicinal Chemistry Letters, 8, 2017, 316-320. [cited by applicant]
Loomba , et al., “The ASK1 Inhibitor Selonsertib in Patients with Nonalcoholic Steatohepatitis: A Randomized, Phase 2 Trial”, Hepatology 67(2), 2018, 549-559. [cited by applicant]
Lovering , et al., “Rational approach to highly potent and selective apoptosis signal regulating kinase 1 (ASK1) inhibitors”, Euro J Med Chem., 145, 2018, 606-621. [cited by applicant]
Monastyrsky , et al., “Discovery of 2-arylquinazoline derivatives as a new class of ASK1 inhibitors”, Bioorg & Med Chem Lett., 28, 2018, 400-404. [cited by applicant]
Ogier, J. M, et al., “ASK1 inhibition: a therapeutic strategy with multi-system benefits”, J. Mol. Med., 98https://doi.org/10.1007/s00109-020-01878-y, Feb. 14, 2020, 335-348. [cited by applicant]
Okamoto, M. , “Identification of novel ASK1 inhibitors using virtual screening”, Bioorg & Med Chem., 19, 2011, 486-489. [cited by applicant]
Patani, G. A., et al., “Bioisosterism: A Rational Approach in Drug Design”, Chem. Rev., 96, 1996, 3147-3176. [cited by applicant]
Sheridan, R. P., “The Most Common Chemical Replacements in Drug-Like Compounds”, J. Chem. Info. Comput. Sci., 42, 2002, 103-108. [cited by applicant]
Silverman, R. B, “The Organic Chemistry of Drug Design and Drug Action”, Second Edition, Chapter 2, Elsevier Academic Press, 2004, 29-32. [cited by applicant]
Starosyla, S. , et al., “ASK1 Pharmacophore Model Derived from Diverse Classes of Inhibitors”, Bioorg & Med Chem Lett., 24, 2014, 4418-4423. [cited by applicant]
Starosyla, S. , et al., “Identification of apoptosis signal-regulating kinase 1 (ASK1) inhibitors among the derivatives of benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one”, Bioorg & Med Chem., 23, 2015, 24… [cited by applicant]
Sumida, Y. , et al., “Current and Future Pharmacological Therapies for NAFLD/NASH”, J. Gastro., 53, Dec. 16, 2017, 362-376. [cited by applicant]
Terao , et al., “Design and biological evaluation of imidazo[1,2-a]pyridines as novel and potent ASK1 inhibitors”, Bioorg & Med Chem Lett., 22, 2012, 7326-7329. [cited by applicant]
Volynets , et al., “Identification of 3H-Naphtho[1,2,3-de]quinoline-2,7-diones as Inhibitors of Apoptosis Signal-Regulating Kinase 1 (ASK1)”, J Med Chem., 54, 2011, 2680-2686. [cited by applicant]
Volynets , et al., “Rational design of apoptosis signal-regulating kinase 1 inhibitors: Discovering novel structural scaffold”, Euro J Med Chem., 61, 2013, 104-115. [cited by applicant]
Wermuth, C. G, “Molecular Variations Based on Isosteric Replacements”, in “The Practice of Medicinal Chemistry”, Academic Press Limited, 1996, 203-237. [cited by applicant]
Zhulenko, V. N, et al., “”, Pharmacology. M.: KolosS, 2008, 34-35. [cited by applicant]