Substituted hydantoin compounds, processes for their preparation, and their use in the treatment and / or prevention of coronavirus diseases

Abstract

The present disclosure provides compounds of formula (II), where R1 is an optionally substituted monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl containing at least one nitrogen atom, and other variables are as defined herein. The compounds are intended to inhibit the activity of coronavirus main protease (M PRO ). Methods for the preparation of the compounds and uses of the compounds, for example in the treatment and / or prevention of coronavirus diseases, such as COVID-19, are also disclosed. [Formula 1] TIFF2024517740000062.tif26170

Description

[Technical field]

[0001] The present disclosure relates to substituted hydantoin derivatives. More specifically, the present disclosure relates to substituted 5,7-diazaspiro[3.4]octane-6,8-diones, methods for their preparation, and their use in the treatment and / or prevention of coronavirus diseases, e.g., COVID-19, as well as the use of substituted hydantoin derivatives ... pro ) and its use as an inhibitor of [Background technology]

[0002] Novel coronavirus disease 2019 (abbreviated COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (abbreviated SARS-CoV-2). The SARS-CoV-2 virus has caused the largest health crisis in this generation, with COVID-19 already causing over 3 million deaths worldwide. Despite promising vaccination efforts, antiviral drugs will likely be important to control future coronavirus epidemics. SARS-CoV-2 is the third deadliest coronavirus in recent history, and therefore will likely continue to circulate and pose a major threat to our society. Antiviral agents are needed to treat infected patients as well as to administer prophylactically to patients at high risk of infection.

[0003] WO 02 / 06333 relates to inhibitors of viral replication. A preferred embodiment provides compounds of formula (I) that include a hydantoin moiety.

[0004] Non-patent literature 1 (Nature, Vol. 258, 11 June 2020, 289) describes the M pro The crystal structure and docketing data support the discovery of the SARS-CoV-2 M inhibitors, which are highly conserved among all coronaviruses. proIt has been stated that the results show that the hydantoin can bind to the substrate binding pocket of 2,2,2-trifluoroethyl carbamates and α-aminoesters. Non-patent literature 2 (ACS Comb. Sci. 2018, 20, 35-43) relates to the parallel synthesis of a hydantoin library by in situ generation of 2,2,2-trifluoroethyl carbamates and α-aminoesters. A library of 1158 hydantoins designed according to lead similarity criteria (MW 200-350, cLogP 1-3) was prepared. Non-patent literature 3 (J. Am. Chem. Soc. 2022, 144, 2905-2929) relates to ultra-large scale virtual screening for the identification of SARS-CoV.2 main protease inhibitors with broad-spectrum activity against coronaviruses.

[0005] Among the proteins encoded by the SARS-CoV-2 genome, chymotrypsin-like main protease (abbreviated as M pro ) has emerged as a promising drug target. Inhibition of this enzyme blocks the processing of polypeptides generated by translation of viral RNA that are essential for viral replication. Following the 2002 SARS-CoV epidemic, M pro Inhibitors of MHC have been identified, some of which have recently been confirmed to be active against the SARS-CoV-2 protease, which shows a high degree of homology. However, many of these are covalent modifiers reacting with the active site cysteine, which may be peptidomimetics or promiscuous inhibitors with limited drug similarity. Thus, it is important to identify MHC inhibitors with favorable physiochemical properties. pro There is a need for novel non-covalent inhibitors of SARS-CoV-2 main protease (M pro The present invention provides compounds which are inhibitors of the . [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. WO2017 / 047146 A2 [Non-patent literature]

[0007] [Non-Patent Document 1] Nature,Vol.258,11 June 2020,289 [Non-Patent Document 2] ACS Comb. Sci. 2018, 20, 35-43 [Non-Patent Document 3] J.Am.Chem.Soc.2022,144,2905-2929 Summary of the Invention [Problem to be solved by the invention]

[0008] It is an object of the present disclosure to fulfill the above-mentioned needs and / or to provide advantages and aspects not offered by the heretofore known art. [Means for solving the problem]

[0009] The above mentioned objects are achieved in whole or at least in part as set forth in the attached independent claims 1, 14, 15, 16, 18 and 20. Embodiments are set forth in the attached dependent claims and in the following description and examples. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The present disclosure provides a compound of formula II, or a pharma- ceutically acceptable salt or composition thereof; [ka] During the ceremony, R1 is a monocyclic or bicyclic heterocyclyl containing at least one nitrogen atom, and the monocyclic or bicyclic heterocyclyl is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of: a) C1-C4 alkyl substituted with 0, 1, 2 or 3 F; b) C1-C4 alkoxy substituted with 0, 1, 2 or 3 F; c) CN; d) OH, e) oxo, f) NO2, g) NRaRb, where Ra is selected from H, C1-C3 alkyl, and cyclopropyl; Rb is selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, phenyl, or heterocyclyl, and the phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, wherein Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, wherein Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclic ring, or Ra and Rb, together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclic ring; h) 5-6 membered monocyclic saturated, partially unsaturated, or aromatic heterocyclyl substituted with 0, 1, or 2 substituents, the substituents being each independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra is selected from H, C1-C3 alkyl, and cyclopropyl, and Rb is selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, phenyl, or heterocyclyl, the phenyl and heterocyclyl being substituted with 0, 1, or 2 substituents, and the substituents being 5-6 membered monocyclic saturated, partially unsaturated, or aromatic heterocyclyl, each independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclic ring, or Ra and Rb, together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclic ring; i) F, Cl, Br, I, j) C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, phenyl, heterocyclyl, and the phenyl and heterocyclyl may be substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb. wherein Ra is selected from H, C1-C3 alkyl, and cyclopropyl; Rb is selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc; wherein Rc is H, C1-C3 alkyl, phenyl, or heterocyclyl; phenyl and heterocyclyl are preferred. is substituted with 0, 1, or 2 substituents each independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is , H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb are bonded together with the nitrogen atom to which they are bonded to form a 4-6 membered heterocycle, or Ra and Rb are bonded together with the nitrogen atom to which they are bonded to form a 4-6 membered heterocycle, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, k) phenyl substituted with 0, 1, 2, 3, or 4 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra is selected from H, C1-C3 alkyl, and cyclopropyl, and Rb is selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, and S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, or cyclopropyl; alkyl, phenyl, or heterocyclyl, wherein the phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is selected from H, C1-C3 alkyl, phenyl, or heterocyclyl, and phenyl and heterocyclyl are preferred. cryl is substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb arephenyl, and R2 is selected from the group consisting of: a) H, b) F, Cl or Br, c) C1-C4 alkyl substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, OH, C3-C6 cycloalkyl, phenyl, monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, where the phenyl and heterocyclyl are substituted with 0, 1, 2, 3, or 4 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, NRaRb, where Ra is selected from H, C1-C3 alkyl, and cyclopropyl, and Rb is H, C1-C3 alkyl; aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, phenyl, or heterocyclyl, and the phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, the substituents being each independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, Rc is selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Rb and Rb are bonded together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, or Rb and Rb are bonded together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, and C(=O)Rc, C(=O)ORc, C(=O)NRaRc , C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is selected from H, C1-C3 alkyl, phenyl, or heterocyclyl, and phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc,C1-C4 alkyl selected from C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle; d) C1-C4 alkoxy substituted with 0, 1, 2, or 3 substituents, each of which is independently F, OH, C3-C6 cycloalkyl, phenyl, monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, wherein the phenyl and heterocyclyl are substituted with 0, 1, 2, 3, or 4 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, NRaRb, where Ra is selected from H, C1-C3 alkyl, and cyclopropyl, and Rb is H, C1-C3 alkyl. , aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, phenyl, or heterocyclyl, and the phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, the substituents being each independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, and C(=O)Rc, C(=O)ORc, C(=O)NRaRc , C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is selected from H, C1-C3 alkyl, phenyl, or heterocyclyl, and phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc,C1-C4 alkoxy selected from C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle; e) C3-C6 cycloalkyl substituted with 0, 1, 2 or 3 F, Cl, Br, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; f) phenyl substituted with 0, 1, 2, 3, or 4 substituents, each independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, NRaRb, where Ra is selected from H, C1-C3 alkyl, and cyclopropyl; Rb is selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, R a and R b are each independently selected from H, C1-C3 alkyl, aryl, C(=O)R c, C(=O)OR c, C(=O)NRaR c, C(=S)NRaR c, C(=S)OR c, C(=O)SR c, S(=O)R c, S(=O)R c, S(=O)NRaR c, and R b are each independently selected from H, C1-C3 alkyl, aryl, C(=O)R c, C(=O)OR c, C(=O)NRaR c, C(=S)OR c, C(=O)SR c, S(=O)R c, S(=O)NRaR c, and or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic ring, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is selected from H, C1-C3 alkyl, phenyl, or heterocyclyl, and phenyl and heterocyclyl are preferred. cryl is substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb arephenyl, g) C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, phenyl, heterocyclyl, and the phenyl and heterocyclyl may be substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb. wherein Ra is selected from H, C1-C3 alkyl, and cyclopropyl; Rb is selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc; wherein Rc is H, C1-C3 alkyl, phenyl, or heterocyclyl; phenyl and heterocyclyl are preferred. is substituted with 0, 1, or 2 substituents each independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is , H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb are bonded together with the nitrogen atom to which they are bonded to form a 4-6 membered heterocycle, or Ra and Rb are bonded together with the nitrogen atom to which they are bonded to form a 4-6 membered heterocycle, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, h) monocyclic or bicycyclic saturated, partially unsaturated or aromatic heterocyclyl, which is substituted with 0, 1, 2, 3, or 4 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, NRaRb, where Ra is selected from H, C1-C3 alkyl, and cyclopropyl, and Rb is H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRa Rc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, phenyl, or heterocyclyl, and phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, the substituents being each independently selected from F, Cl, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc; C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, wherein Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, and C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O) Rc, S(=O)2NRaRc, where Rc is selected from H, C1-C3 alkyl, phenyl, or heterocyclyl, and phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc;S(═O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic ring; R3 is selected from the group consisting of: a) F, Cl or Br, b) C1-C4 alkyl substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, OH, C3-C6 cycloalkyl, phenyl, monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, where the phenyl and heterocyclyl are substituted with 0, 1, 2, 3, or 4 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, NRaRb, where Ra is selected from H, C1-C3 alkyl, and cyclopropyl, and Rb is H, C1-C3 alkyl, aryl, Rc is H, C1-C3 alkyl, phenyl, or heterocyclyl, and the phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, the substituents being each independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, and Rb is each independently selected from H, C1-C3 alkyl, aryl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, , C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, wherein Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, and C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S) NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is selected from H, C1-C3 alkyl, phenyl, or heterocyclyl, and phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc;C1-C4 alkyl selected from C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle; c) C1-C4 alkoxy substituted with 0, 1, 2, or 3 substituents, each of which is independently F, OH, C3-C6 cycloalkyl, phenyl, monocyclic or bicyclic saturated, partially unsaturated, or aromatic heterocyclyl, wherein the phenyl and heterocyclyl are substituted with 0, 1, 2, 3, or 4 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, NRaRb, where Ra is selected from H, C1-C3 alkyl, and cyclopropyl, and Rb is H, C1-C3 alkyl, a Rc is H, C1-C3 alkyl, phenyl, or heterocyclyl, and the phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, and each of which is independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, and S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, phenyl, or heterocyclyl, and the phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, and where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, and S(=O)2NRaRc, Rc is selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Rb and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, or Rb and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is selected from H, C1-C3 alkyl, phenyl, or heterocyclyl, and phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc,C1-C4 alkoxy selected from C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle; d) C3-C6 cycloalkyl substituted with 0, 1, 2 or 3 F, Cl, Br, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; e) phenyl substituted with 0, 1, 2, 3, or 4 substituents, each independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, NRaRb, where Ra is selected from H, C1-C3 alkyl, and cyclopropyl; Rb is selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, R a and R b are each independently selected from H, C1-C3 alkyl, aryl, C(=O)R c, C(=O)OR c, C(=O)NRaR c, C(=S)NRaR c, C(=S)OR c, C(=O)SR c, S(=O)R c, S(=O)R c, S(=O)NRaR c, and R b are each independently selected from H, C1-C3 alkyl, aryl, C(=O)R c, C(=O)OR c, C(=O)NRaR c, C(=S)OR c, C(=O)SR c, S(=O)R c, S(=O)NRaR c, and or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocyclic ring, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocyclic ring, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is selected from H, C1-C3 alkyl, phenyl, or heterocyclyl, and phenyl and heterocyclyl are preferred. cryl is substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb arephenyl, wherein they are bonded together with the nitrogen atom to which they are bonded to form a 4- to 6-membered heterocycle, or Ra and Rb are bonded together with the nitrogen atom to which they are bonded to form a 4- to 6-membered heterocycle; f) C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, phenyl, heterocyclyl, and the phenyl and heterocyclyl may be substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra is selected from H, C1-C3 alkyl, and cyclopropyl, and Rb is selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, phenyl, or hexafluorophenyl. and tetracyclyl, wherein the phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2R C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)Rc, S(=O)Rc, S(=O)NRaRc, wherein Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle; g) monocyclic or bicycyclic saturated, partially unsaturated, or aromatic heterocyclyl, which is substituted with 0, 1, 2, 3, or 4 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra is selected from H, C1-C3 alkyl, and cyclopropyl, and Rb is H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C Rc is selected from H, C1-C3 alkyl, phenyl, or heterocyclyl, and phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, and each of which is independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=O ... wherein Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle; and C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc , S(=O)2NRaRc, where Rc is selected from H, C1-C3 alkyl, phenyl, or heterocyclyl, and the phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc;S(═O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic ring; and R4 is H, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl and is substituted with 0, 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, OH, CF3, oxo, C1-C4 alkoxy, fluoroC1-C4 alkoxy, phenyl, and monocyclic or bicyclic heterocyclyl, where the phenyl and heterocyclyl are substituted with 0, 1, 2, 3, or 4 substituents and the substituents are each independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra is H, C1-C3 alkyl; and cyclopropyl; Rb is selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, phenyl, or heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, the substituents are each independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb. wherein Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocyclic ring, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocyclic ring. and forming C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is selected from H, C1-C3 alkyl, phenyl, or heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, the substituents being each independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl,aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4-6 membered heterocycle; NRaRb, where Ra is selected from H, C1-C3 alkyl, and cyclopropyl; Rb is selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc, where Rc is H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)ORc, C(=O)SRc, S(=O)2Rc, S(=O)Rc, S(=O)2NRaRc; phenyl, or heterocyclyl, wherein the phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF3, C1-C4 alkyl, and NRaRb, and Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C( ═S)ORc, C(═O)SRc, S(═O)Rc, S(═O)Rc, S(═O)NRaRc, where Rc is H, C1-C3 alkyl, phenyl, or heterocyclyl, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclic ring, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclic ring; The compound of formula II is 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or Stereoisomers of 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or A salt of 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or 2-Cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or A stereoisomer of 2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or It is not a salt of 2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione.

[0011] The compound of formula II may be a compound of formula IIIa, or a pharma- ceutically acceptable salt thereof. Thus, there is provided a compound of formula IIIa, or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, R1 is a monocyclic or bicyclic heterocyclyl containing at least one nitrogen atom, and the monocyclic or bicyclic heterocyclyl is substituted with 0, 1, 2, or 3 substituents selected from the group consisting of: a) C1-C4 alkyl substituted with 0, 1, 2 or 3 F; b) C1-C4 alkoxy substituted with 0, 1, 2 or 3 F; c) CN; d) OH, e) F, Cl or Br, f) oxo or NO2, g) NRaRb, where Ra and Rb are each independently selected from H and C1-C3 alkyl; h) 5-6 membered monocyclic saturated, partially unsaturated or aromatic heterocyclyl substituted with 0, 1 or 2 substituents, each of which is independently selected from F, Cl, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H and C1-C3 alkyl; R2 is selected from the group consisting of: a)H b) F, Cl or Br; c) C1-C4 alkyl substituted with 0, 1, 2, or 3 substituents, each independently selected from F, OH, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; C1-C4 alkyl, where cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, and hydroxyC1-C4 alkyl; d) C1-C4 alkoxy substituted with 0, 1, 2, or 3 substituents, each independently selected from F, OH, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, and hydroxyC1-C4 alkyl; e) C3-C6 cycloalkyl substituted with 0, 1, 2 or 3 F, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; f) phenyl substituted with 0, 1, 2, or 3 substituents, each independently selected from F, Br, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; and g) monocyclic or bicycyclic saturated, partially unsaturated or aromatic heterocyclyl, wherein the monocyclic or bicycyclic heterocyclyl is substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl; R3 is selected from the group consisting of: a) F, Br or Cl, b) C1-C4 alkyl substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; C1-C4 alkyl, where cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, and hydroxyC1-C4 alkyl; c) C1-C4 alkoxy substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, and hydroxyC1-C4 alkyl; d) C3-C6 cycloalkyl substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; e) phenyl substituted with 0, 1, 2, or 3 substituents, each independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; and f) monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, said monocyclic or bicyclic heterocyclyl being substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloalkyl; R4 is H or C1-C3 alkyl; The compound of formula IIIa 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or Stereoisomers of 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or A salt of 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or 2-Cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or A stereoisomer of 2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or It is not a salt of 2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione.

[0012] Additionally, the compound of formula II may be a compound of formula IIIb, or a pharma- ceutically acceptable salt thereof. Thus, there is provided a compound of formula IIIb, or a pharma- ceutically acceptable salt thereof, or a composition: [ka] During the ceremony, R1 is a monocyclic or bicyclic heterocyclyl containing at least one nitrogen atom, and the monocyclic or bicyclic heterocyclyl is substituted with 0, 1, 2, or 3 substituents selected from the group consisting of: a) C1-C4 alkyl substituted with 0, 1, 2 or 3 F; b) C1-C4 alkoxy substituted with 0, 1, 2 or 3 F; c) CN; d) OH, e) F, Cl, Br g) NRaRb, where Ra and Rb are each independently selected from H and C1-C3 alkyl; h) 5-6 membered monocyclic saturated, partially unsaturated or aromatic heterocyclyl substituted with 0, 1 or 2 substituents, each of which is independently selected from F, Cl, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H and C1-C3 alkyl; R2 is selected from the group consisting of: a) H, b) F, Cl, c) C1-C4 alkyl substituted with 0, 1, 2, or 3 substituents, each independently selected from F, OH, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; C1-C4 alkyl, where cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, and hydroxyC1-C4 alkyl; d) C1-C4 alkoxy substituted with 0, 1, 2, or 3 substituents, each independently selected from F, OH, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, and hydroxyC1-C4 alkyl; e) C3-C6 cycloalkyl substituted with 0, 1, 2 or 3 F, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; f) phenyl substituted with 0, 1, 2, or 3 substituents, each independently selected from F, Br, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl, and g) monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, said monocyclic or bicyclic heterocyclyl being substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl; R3 is selected from the group consisting of: a) F or Cl, b) C1-C4 alkyl substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; C1-C4 alkyl, where cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, and hydroxyC1-C4 alkyl; c) C1-C4 alkoxy substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, and hydroxyC1-C4 alkyl; d) C3-C6 cycloalkyl substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; e) phenyl substituted with 0, 1, 2, or 3 substituents, each independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; and f) monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, said monocyclic or bicyclic heterocyclyl being substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloalkyl; R4 is H or C1-C3 alkyl; The compound of formula III is 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or Stereoisomers of 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or A salt of 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or 2-Cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or A stereoisomer of 2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or It is not a salt of 2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione.

[0013] The compound of formula II may be a compound of formula I, or a pharma- ceutically acceptable salt thereof. Embodiments of the present disclosure provide a compound of formula I, or a pharma- ceutically acceptable salt or composition thereof: [ka] During the ceremony, R1 is a monocyclic or bicyclic heterocyclyl containing at least one nitrogen atom, and the monocyclic or bicyclic heterocyclyl is substituted with 0, 1, 2, or 3 substituents selected from the group consisting of: a) C1-C4 alkyl substituted with 0, 1, 2 or 3 F; b) C1-C4 alkoxy substituted with 0, 1, 2 or 3 F; c) CN; d) OH, e) oxo, f) NO2, g) NRaRb, where Ra and Rb are each independently selected from H and C1-C3 alkyl; h) 5-6 membered monocyclic saturated, partially unsaturated or aromatic heterocyclyl substituted with 0, 1 or 2 substituents, each of which is independently selected from F, Cl, OH, CF3, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H and C1-C3 alkyl; and R2 is selected from the group consisting of: a) H, b) F, Cl or Br; c) C1-C4 alkyl substituted with 0, 1, 2, or 3 substituents, each independently selected from F, OH, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; C1-C4 alkyl, where cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, and hydroxyC1-C4 alkyl; d) C1-C4 alkoxy substituted with 0, 1, 2, or 3 substituents, each independently selected from F, OH, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, and hydroxyC1-C4 alkyl; e) C3-C6 cycloalkyl substituted with 0, 1, 2 or 3 F, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; f) phenyl substituted with 0, 1, 2, or 3 substituents, each independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; and g) monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, said monocyclic or bicyclic heterocyclyl being substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl; R3 is selected from the group consisting of: a) In the case of Br, b) C1-C4 alkyl substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; C1-C4 alkyl, where cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, and hydroxyC1-C4 alkyl; c) C1-C4 alkoxy substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, and hydroxyC1-C4 alkyl; d) C3-C6 cycloalkyl substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; e) phenyl substituted with 0, 1, 2, or 3 substituents, each independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; and f) monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, said monocyclic or bicyclic heterocyclyl being substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloalkyl; The compound of formula I is 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or Stereoisomers of 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or A salt of 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or 2-Cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or A stereoisomer of 2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or Provided is a compound, or a pharma- ceutically acceptable salt or composition thereof, that is not a salt of 2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione.

[0014] The terms and expressions used throughout this document, including the abstract, specification, and claims, shall be interpreted as defined herein as follows, unless otherwise indicated. The meaning of each term is independent at each occurrence. Any term or expression used herein that is not expressly defined shall be interpreted as having its ordinary meaning as used in the art in light of this disclosure and context. The following definitions of terms and expressions shall apply throughout this document.

[0015] "C1-C n The term "alkyl" (where n is an integer equal to or greater than 1) refers to a straight or branched saturated alkyl chain of 1 to n carbon atoms. For example, C1-C4 alkyl means an alkyl chain having 1, 2, 3, or 4 carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, the term C1-C3 alkyl includes methyl, ethyl, n-propyl, and isopropyl.

[0016] "Fluoro C1-C n The term "alkoxy" (where n is an integer equal to or greater than 1) as used herein refers to fluoroC-C as defined above, in which at least one C atom is substituted with one, two or three fluorine atoms. n For example, "fluoro C1-C n "Alkoxy" includes, but is not limited to, trifluoromethoxy, difluoromethoxy, fluoromethoxy, and trifluoroethoxy.

[0017] "C1-C n The term "alkoxy" (where n is an integer equal to or greater than 1) refers to a C-C alkyl group, as defined above, attached to an oxygen atom. n Refers to an alkyl group. For example, "C1-C4 alkoxy" includes, but is not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, and butoxy.

[0018] "C3-C n The term "cycloalkyl" (where n is an integer equal to or greater than 3) refers to a saturated or unsaturated non-aromatic monocyclic ring composed of 3 to n carbon atoms. For example, "C3-C6 cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "C3-C4 cycloalkyl" is understood to include cyclopropyl and cyclobutyl.

[0019] As used herein, "hydroxy C1-C n The term "alkyl" (where n is an integer equal to or greater than 1) refers to a C-C alkyl group as defined above, in which at least one C atom is substituted with a hydroxy group. n Represents an alkyl group. Typical hydroxy groups are C1-C n An alkyl group is a C1-C alkyl group in which one C atom is substituted with one hydroxyl group. n Exemplary hydroxy C1-C n Alkyl includes hydroxy C1-C4 alkyl, such as hydroxymethyl and hydroxyethyl.

[0020] "Fluoro C1-C n The term "alkyl" (wherein n is an integer equal to or greater than 1) as used herein refers to any C-C alkyl group as defined above. n alkyl, in which at least one C atom is substituted with 1, 2 or 3 fluoro atoms. n Alkyl groups are C1-C n alkyl, where one C atom is substituted with one, two or three fluoro atoms. Exemplary fluoro C1-C nAlkyl groups include fluoroC1-C4 alkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl.

[0021] "C2-C n The term "alkenyl" (where n is an integer equal to or greater than 1), as used herein as a group or part of a group, refers to a straight or branched chain hydrocarbon radical having a saturated carbon-carbon bond and at least one carbon-carbon double bond, and having 2 to n carbon atoms. Exemplary alkenyl groups include, but are not limited to, 1-propenyl, 2-propenyl (or allyl), isopropenyl, and the like.

[0022] "C2-C n The term "alkynyl" (where n is an integer equal to or greater than 1) as used herein as a group or part of a group refers to a straight or branched chain hydrocarbon radical having saturated carbon-carbon bonds and at least one carbon-carbon triple bond, and having from 2 to n carbon atoms. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.

[0023] The term "oxo" refers to a doubly bonded oxygen, i.e., to a carbon atom which forms a carbonyl moiety when attached to the carbon atom, and to a sulfoxide or sulfone when one or two oxo groups, respectively, are attached to a sulfur atom. It should be noted that the "oxo" group can only be present as a substituent where the valence allows.

[0024] The term "monocyclic heterocyclyl" intends a 3-, 4-, 5-, or 6-membered saturated or unsaturated heterocycle. For example, the monocyclic heterocyclyl can be aziridine, azetidine, pyrrolidine, pyrrole, imidazoline, pyrazolidine, isoxazolidine, thiazolidine, isothiazolidine, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, piperidine, pyridine, piperazine, morpholine, thiomorpholine, thiophene, furan, oxadiazole, thiodiazole, tetrahydrofuran, dihydrofuran, and the like.

[0025] As used herein, the term "bicyclic heterocyclyl" contemplates a stable ring system of two rings linked together, where the two rings share one, two or more atoms, and the ring system is composed of 6 to 14 atoms, preferably 6 to 10 atoms. The ring system includes carbon atoms and one or more heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of bicyclic heterocyclyls include, but are not limited to, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxazolinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazinolyl, benzisothiazinolyl, benzoxadiazolyl, benzo-1,2,3-triazolyl, benzo-1,2,4-triazolyl, benzotetrazolyl, benzofuranyl, benzothienyl, benzopyrimidyl, benzopyridazinyl, benzopyridazinyl, benzopyrazolyl, phthalazinyl, and the like.

[0026] The term "heterocyclyl" is intended to include monocyclic and bicyclic heterocyclyls as defined above.

[0027] The term "substituted" refers to a molecule or portion of a molecule in which at least one hydrogen atom has been replaced with a substituent.

[0028] The monocyclic heterocyclyl containing at least one nitrogen of R1 described herein may be selected from the group consisting of, but is not limited to, pyrrole, pyrrolidine, imidazole, thiazole, oxazole, triazole, tetrazole, pyridine, piperidine, pyrimidine, pyrazine, and morpholine, or the bicyclic heterocyclyl containing at least one nitrogen of R1 described herein may be selected from the group consisting of, but is not limited to, indolyl, isoindolyl, benzimidazolyl, quinolinyl, and isoquinolinyl, particularly isoquinolinyl, phthalazinyl.

[0029] For example, R1 described herein can be 5-bromo-4-methylpyrid-3-yl, 4-methylpyrid-3-yl, 5-fluoropyrid-3-yl, 5-bromopyrid-3-yl, 4-trifluoromethylpyrid-3-yl, 3-trifluoromethylpyrid-2-yl, N-methyl-2-oxopyrrolidin-3-yl, N-(2,2,2-trifluoroethyl)-2-oxopyrrolidin-3-yl, N-(2,2,2-trifluoroethyl)-imidazol-2-yl, 1,2,4-triazol-3-yl, 4-methyl-1,2,4-triazol-3-yl, 1 ...

[0043] R1 may be selected from the group consisting of, but is not limited to, indolyl, isoindolyl, benzimidazolyl, quinolinyl, and isoquinolinyl, particularly isoquinolinyl, phthalazinyl, or the bicyclic heterocyclyl containing at least one nitrogen atom as described herein may be selected from the group consisting of, but is not limited to, indolyl, isoindolyl, benzimidazolyl, quinolinyl, and isoquinolinyl, particularly isoquinolinyl, phthalazinyl.

[0030] Further, R1 described herein can be 5-fluoroisoquinolin-4-yl, 6-fluoroisoquinolin-4-yl, 7-fluoroisoquinolin-4-yl, 6,7,8-trifluoroisoquinolin-4-yl, 6-(dimethylamino)-7,8-difluoroisoquinolin-4-yl, 6-methoxyisoquinolin-4-yl, 6-methylisoquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-4-yl, phthalizin-1-yl, 1,6-naphthyridin-8-yl, 2,7 ... lysin-4-yl, pyrido[3,4-b]pyrazin-8-yl, 4-methylpyridin-3-yl, 4-isopropylidin-3-yl, 5-bromo-4-methylpyridin-3-yl, 5-bromopyridin-3-yl, 5-fluoropyridin-3-yl, 2-fluoropyridin-3-yl, 5-(dimethylamino)pyridin-3-yl, (1H-1,2,3-triazol-1-yl)pyridin-3-yl, 3-methylpyridin-2-yl, and pyrimidin-5-yl.

[0031] Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated, for example, pyridyl includes 2-pyridyl, 3-pyridyl, and 4-pyridyl, pentyl includes 1-pentyl, 2-pentyl, 3-pentyl, etc.

[0032] In one embodiment of the compound of formula II or III, R4 is H.

[0033] In one embodiment of the compounds described herein, such as compounds of Formula I, Formula II, Formula IIIa, or Formula IIIb, R1 is pyrid-3-yl substituted with 0, 1, or 2 substituents, each of which is independently selected from C1-C3 alkyl, F, Cl, and Br.

[0034] In an alternative configuration of the compounds described herein, such as compounds of Formula I, Formula II, Formula IIIa, or Formula IIIb, R1 is isoquinol-4-yl substituted with 0, 1, or 2 substituents, each of which is independently selected from C1-C3 alkyl, F, Cl, and Br.

[0035] In an alternative configuration of the compounds described herein, such as compounds of Formula I, Formula II, Formula IIIa, or Formula IIIb, R1 is isoquinolin-4-yl substituted with 0, 1, 2, 3, or 4 substituents, each of which is independently selected from C1-C3 alkyl, F, Cl, and Br, or a ring carbon is replaced with a nitrogen atom.

[0036] R2 described herein can be selected from the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy, F, Cl, and Br. For example, R2 can be H. Additionally, R2 can be methyl.

[0037] R3 as described herein can be C1-C4 alkyl substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, C3-C6 cycloalkyl, phenyl, monocyclic or bicyclic saturated, partially unsaturated, or aromatic heterocyclyl. For example, R3 can be tert-butyl, cyclobutyl, or phenyl.

[0038] In the compositions of the compounds described herein, such as compounds of Formula I, Formula II, Formula IIIa, or Formula IIIb, R3 is phenyl substituted with 0, 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, CN, CF3, OMe, and Me.

[0039] Furthermore, R3 may be selected from the group consisting of cyclobutyl, tert-butyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-6-fluorophenyl, 2-bromophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-methoxyphenyl, 2-(trifluoromethyl)phenyl, o-cyanophenyl, o-tolyl, 3-chlorothiophen-2-yl, 3-bromothiophen-2-yl, 2-chlorothiophen-3-yl, 1H-pyrazol-1-yl, 1-benzyl-1H-1,2,3-triazol-4-yl, and benzyloxy.

[0040] In one configuration of the compounds described herein, such as compounds of Formula II, Formula IIIa, or Formula IIIb, R4 is C1-C3 alkyl and can be substituted with 0, 1, 2, or 3 substituents selected from the group consisting of F, Cl, OH, CF3, oxo, C1-C4 alkoxy, and fluoroC1-C4 alkoxy.

[0041] Furthermore, R4 may be selected from the group consisting of hydrogen, methyl, ethyl, allyl, cyanomethyl, 2,6-dichloropyridin-4-yl, pyridin-2-ylmethyl, 1H-imidazol-2-yl, 1H-pyrazol-5-yl, 2-oxo-pyrrolidin-1-yl, acetyl, 2-oxo-2-amino-phenyl, and 2-oxo-2-(pyridin-2-yl)ethyl.

[0042] The present disclosure also provides a compound as described herein, 2-Cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-Cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, e.g. isomer 2, 7-(isoquinolin-4-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-tert-butyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-cyclobutyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(5-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(5-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromopyridin-3-yl)-2-cyclobutyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2-bromophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(2-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example isomer 1 or 2 as described herein; 7-(isoquinolin-4-yl)-2-(2-methoxyphenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 7-(isoquinolin-4-yl)-2-(2-(trifluoromethyl)phenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(isoquinolin-4-yl)-2-(o-tolyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(7-(isoquinolin-4-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-2-yl)benzonitrile, 2-(3-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(4-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(4-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2,6-dichlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(2-chloro-3-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example isomer 1 or 2 as described herein; 2-(2-chloro-4-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example isomer 1 or 2 as described herein; 2-(2-chloro-5-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example isomer 1 or 2 as described herein; 2-(2-chloro-6-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example isomer 1 or 2 as described herein; 7-(isoquinolin-4-yl)-2-methyl-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(2-chlorothiophen-3-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(3-chlorothiophen-2-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(3-bromothiophen-2-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 7-(isoquinolin-4-yl)-2-(1H-pyrazol-1-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 1 as described herein; 2-(benzyloxy)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(phthalazin-1-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 49 described herein; 2-(2-chlorophenyl)-7-(1,6-naphthyridin-8-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2,7-naphthyridin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(pyrido[3,4-b]pyrazin-8-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(5-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(6-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(7-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(5,6,7,8-tetrahydroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(6-methoxyisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(6-methylisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(6,7,8-trifluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example isomer 1 or 2 as described herein; 2-(2-chlorophenyl)-7-(6-(dimethylamino)-7,8-difluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 1 as described herein; 2-(2-chlorophenyl)-7-(2-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-isopropylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(4-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)-2-(2-chlorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(5-(dimethylamino)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(pyrimidin-5-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-bromophenyl)-7-(isoquinolin-4-yl)-5-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-5-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(isoquinolin-4-yl)-5-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-cyclobutyl-7-(isoquinolin-4-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)acetamide, 2-cyclobutyl-5-((2,6-dichloropyridin-4-yl)methyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-cyclobutyl-7-(isoquinolin-4-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)acetonitrile, 5-allyl-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-5-ethyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(isoquinolin-4-yl)-5-(pyridin-2-ylmethyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 5-((1H-imidazol-2-yl)methyl)-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(isoquinolin-4-yl)-5-((2-oxopyrrolidin-1-yl)methyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 5-acetyl-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 5-((1H-pyrazol-5-yl)methyl)-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(pyridazin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-phenoxypyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chloro-4-fluorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 1 as described herein; 2-(2-chloro-4-fluorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 7-(5-bromo-2-fluoropyridin-3-yl)-2-(2-chlorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(3-chloroisoquinolin-4-yl)-2-(2-chlorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chloro-4,5-difluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2-chlorophenyl)-7-(5-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(1,6-naphthyridin-8-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2-fluoro-4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-(trifluoromethyl)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-(dimethylamino)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(cinnolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7 diazaspiro[3.4]octane-6,8-dione, such as isomer 1 described herein; 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2-chlorophenyl)-7-(1H-imidazo[4,5-c]pyridin-7-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2-chlorophenyl)-7-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-7-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2-chlorophenyl)-7-(imidazo[1,2-a]pyrazin-5-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2-chlorophenyl)-7-(pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or a pharma- ceutically acceptable salt of any one of the above compounds.

[0043] The present disclosure provides a compound of formula I, (2s,4s)-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, (2r,4r)-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(isoquinolin-4-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-tert-butyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-cyclobutyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-[(3-methylpyridin-2-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(3-methylpyridin-2-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(5-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(5-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromopyridin-3-yl)-2-cyclobutyl-5,7-diazaspiro[3.4-2-oxopyrrolidine]octane-6,8-dione, 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione 2-cyclobutyl-7-[4-(trifluoromethyl)pyridin-3-yl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(1-methyl-2-oxopyrrolidin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(1-methyl-2-oxopyrrolidin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[(1-methyl-2-oxopyrrolidin-3-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 7-[2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-{[1-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[(1-methyl-1H-1,2,4-triazol-5-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[1-(4-methyl-4H-1,2,4-triazol-3-yl)ethyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-{[1-(2,2,2-trifluoroethyl)-1H-1,2,3,4-tetrazol-5-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-{[6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-{[6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-({5H,6H,7H,8H,9H-[1,2,4]triazolo[4,3-a]azepin-3-yl}methyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, or a pharma- ceutically acceptable salt of any one of the above compounds.

[0044] The disclosure provides compounds of formula I, or a pharma- ceutically acceptable salt thereof, which is one or more of the following: 2-Cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 as described herein; 2-Cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 2 as described herein; 7-(isoquinolin-4-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-tert-butyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-cyclobutyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(5-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(5-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromopyridin-3-yl)-2-cyclobutyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-Chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione.

[0045] Further, the present disclosure provides a compound of formula I, 2-(2-chlorophenyl)-7-(4-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(pyridazin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-phenoxypyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chloro-4-fluorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, isomer 1, 2-(2-chloro-4-fluorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, isomer 2, 7-(5-bromo-2-fluoropyridin-3-yl)-2-(2-chlorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(3-chloroisoquinolin-4-yl)-2-(2-chlorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chloro-4,5-difluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(5-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(1,6-naphthyridin-8-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2-fluoro-4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2-fluoro-4-methoxypyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-(trifluoromethyl)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-(dimethylamino)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(cinnolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7-diazaspiro[3.4]octane-6,8-dione isomer 1, 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7-diazaspiro[3.4]octane-6,8-dione isomer 2, 2-(2-chlorophenyl)-7-(1H-imidazo[4,5-c]pyridin-7-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-7-yl)-5,7-iazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(imidazo[1,2-a]pyrazin-5-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or a pharma- ceutically acceptable salt or composition of any one of the above compounds.

[0046] Further, the present disclosure provides a compound of formula I or formula II, 2-(3-bromothiophen-2-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(3-chlorothiophen-2-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2-chlorophenyl)-7-(phthalazin-1-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2-chloro-6-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2-chlorophenyl)-7-(6-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione 2-(2-Chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione isomer 2 7-(isoquinolin-4-yl)-2-methyl-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 as described herein; 2-(2-bromophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2-chlorothiophen-3-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(3-bromothiophen-2-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 1 as described herein; 2-(2-chloro-5-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(7-(isoquinolin-4-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-2-yl)benzonitrile, 2-(2-chloro-4-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 1 as described herein; 2-(2-chloro-4-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2-bromophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 1 as described herein; 2-(2-bromophenyl)-7-(isoquinolin-4-yl)-5-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chloro-3-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2,6-dichlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(3-chlorothiophen-2-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 1 as described herein; 2-(2-chlorophenyl)-7-(7-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(isoquinolin-4-yl)-2-(2-(trifluoromethyl)phenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(1,6-naphthyridin-8-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2,7-naphthyridin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(5,6,7,8-tetrahydroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(5-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(4-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)-2-(2-chlorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-isopropylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or a pharma- ceutically acceptable salt or composition of any one of the above compounds.

[0047] The present disclosure also provides a compound comprising: 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2-bromophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(7-(isoquinolin-4-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-2-yl)benzonitrile, 2-(2-chloro-5-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example isomer 1 or 2 as described herein; 2-(2-chloro-6-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example isomer 1 or 2 as described herein; 7-(isoquinolin-4-yl)-2-methyl-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(3-bromothiophen-2-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(2-chlorophenyl)-7-(phthalazin-1-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 49 described herein; 2-(2-chlorophenyl)-7-(6-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7 diazaspiro[3.4]octane-6,8-dione, such as isomer 1 described herein; or a pharma- ceutically acceptable salt of any one of the above compounds.

[0048] The present disclosure also provides a compound comprising: 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2-bromophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(7-(isoquinolin-4-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-2-yl)benzonitrile, 2-(2-chloro-4-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example isomer 1 or 2 as described herein; 2-(2-chloro-5-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example isomer 1 or 2 as described herein; 2-(2-chloro-6-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example isomer 1 or 2 as described herein; 7-(isoquinolin-4-yl)-2-methyl-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(3-chlorothiophen-2-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(3-bromothiophen-2-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7 diazaspiro[3.4]octane-6,8-dione, such as isomer 1 described herein; or a pharma- ceutically acceptable salt of any one of the above compounds.

[0049] The present disclosure also provides a compound comprising: 2-(2-chlorophenyl)-7-(phthalazin-1-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 49 described herein; 2-(2-chlorophenyl)-7-(1,6-naphthyridin-8-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2,7-naphthyridin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(pyrido[3,4-b]pyrazin-8-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(1,6-naphthyridin-8-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or a pharma- ceutically acceptable salt of any one of the above compounds.

[0050] The present disclosure also provides a compound comprising: 2-(2-chlorophenyl)-7-(5-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(6-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(7-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(6-methoxyisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(6-methylisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(5-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or a pharma- ceutically acceptable salt of any one of the above compounds.

[0051] The present disclosure also provides a compound comprising: 2-(2-chlorophenyl)-7-(5,6,7,8-tetrahydroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-isopropylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(4-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)-2-(2-chlorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2-fluoro-4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-(trifluoromethyl)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-(dimethylamino)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or a pharma- ceutically acceptable salt of any one of the above compounds.

[0052] The present disclosure also provides a compound comprising: 2-(2-chlorothiophen-3-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(3-chlorothiophen-2-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(3-bromothiophen-2-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(2-chlorophenyl)-7-(pyridazin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or a pharma- ceutically acceptable salt of any one of the above compounds.

[0053] The present disclosure also provides a compound comprising: 2-Cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-cyclobutyl-7-(6-methoxyisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(6-methylisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(isoquinolin-4-yl)-5-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, or a pharma- ceutically acceptable salt of any one of the above compounds.

[0054] The present disclosure also provides a compound comprising: 7-(isoquinolin-4-yl)-2-methyl-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(2-chloro-4-fluorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 1 as described herein; 2-(2-chloro-4-fluorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7 diazaspiro[3.4]octane-6,8-dione, such as isomer 1 described herein; 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; or a pharma- ceutically acceptable salt of any one of the above compounds.

[0055] The present disclosure also provides a compound comprising: 2-(2-bromophenyl)-7-(isoquinolin-4-yl)-5-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-5-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(isoquinolin-4-yl)-5-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-cyclobutyl-7-(isoquinolin-4-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)acetamide, or a pharma- ceutically acceptable salt of any one of the above compounds.

[0056] The present disclosure also provides a compound comprising: 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 2-(2-bromophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(7-(isoquinolin-4-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-2-yl)benzonitrile, 2-(2-chloro-4-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example isomer 1 or 2 as described herein; 2-(2-chloro-5-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example isomer 1 or 2 as described herein; 2-(2-chloro-6-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example isomer 1 or 2 as described herein; 2-(2-chlorophenyl)-7-(phthalazin-1-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 49 described herein; 2-(2-chlorophenyl)-7-(1,6-naphthyridin-8-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(6-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7 diazaspiro[3.4]octane-6,8-dione, such as isomer 1 described herein; or a pharma- ceutically acceptable salt of any one of the above compounds.

[0057] The present disclosure also provides 2-(2-bromophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein, or a pharma- ceutically acceptable salt thereof.

[0058] The present disclosure also provides a compound comprising: 7-(isoquinolin-4-yl)-2-(pyridin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(isoquinolin-4-yl)-2-(3-methylphenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(3-chloro-1H-pyrazol-1-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(1H-indol-7-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(isoquinolin-4-yl)-2-phenyl-2-[2-(1H-pyrazol-1-yl)ethyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-fluoro-7-(isoquinolin-4-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-{3H-imidazo[4,5-c]pyridin-7-yl}-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-{[1,2,4]triazolo[4,3-a]pyridin-3-yl}-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(1H-1,3-benzodiazol-1-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(1H-1,2,3-benzotriazol-1-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(1,2-benzoxazol-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(1H-indazol-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-methyl-1,2-benzoxazol-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(4-fluoro-1,2-benzoxazol-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(3-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2-fluoro-4-(1H-imidazol-1-yl)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-2-fluoro-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(3-chloropyridin-2-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-5-(methoxymethyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-8-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(4-(tert-butyl)-2-fluoropyridin-3-yl)-2-(2-chlorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(1-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-2-(trifluoromethyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[4-(trifluoromethyl)pyridin-3-yl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(1-methyl-2-oxopyrrolidin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(1-methyl-2-oxopyrrolidin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[(1-methyl-2-oxopyrrolidin-3-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 7-[2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-{[1-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[(1-methyl-1H-1,2,4-triazol-5-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[1-(4-methyl-4H-1,2,4-triazol-3-yl)ethyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-{[1-(2,2,2-trifluoroethyl)-1H-1,2,3,4-tetrazol-5-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-{[6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-{[6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-({5H,6H,7H,8H,9H-[1,2,4]triazolo[4,3-a]azepin-3-yl}methyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or a pharma- ceutically acceptable salt of any one of the above compounds.

[0059] The compounds described herein, such as those of Formula I, Formula II, or Formula III, may or may not include one or more of the following compounds, or pharma- ceutically acceptable salts thereof: 2-tert-butyl-7-[(3-methylpyridin-2-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(isoquinolin-4-yl)-2-(o-tolyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(3-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(4-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 7-(isoquinolin-4-yl)-2-methyl-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 or 2 as described herein; 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 1 as described herein; 2-(benzyloxy)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(6,7,8-trifluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example isomer 1 or 2 as described herein; 2-cyclobutyl-7-(isoquinolin-4-yl)-5-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-cyclobutyl-7-(isoquinolin-4-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)acetamide, 2-cyclobutyl-5-((2,6-dichloropyridin-4-yl)methyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-cyclobutyl-7-(isoquinolin-4-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)acetonitrile, 5-allyl-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-5-ethyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(isoquinolin-4-yl)-5-(pyridin-2-ylmethyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 5-((1H-imidazol-2-yl)methyl)-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(isoquinolin-4-yl)-5-((2-oxopyrrolidin-1-yl)methyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 5-acetyl-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 5-((1H-pyrazol-5-yl)methyl)-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-phenoxypyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chloro-4-fluorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 described herein; 7-(3-chloroisoquinolin-4-yl)-2-(2-chlorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2-fluoro-4-methoxypyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(cinnolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, Diazaspiro[3.4]octane-6,8-diones, such as isomer 2 described herein; 2-(2-chlorophenyl)-7-(imidazo[1,2-a]pyrazin-5-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, Isomer 2 as described herein.

[0060] Additionally, the present disclosure provides the compound 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as Isomer 2 described herein, or a pharma- ceutically acceptable salt thereof.

[0061] The compounds of formula I, II, IIIa, or IIIb described herein, or pharma- ceutically acceptable salts thereof, may be provided as mixtures of enantiomers, (-)-enantiomers, and / or (+)-enantiomers. For example, the compounds of formula I, II, IIIa, or IIIb described herein, or pharma- ceutically acceptable salts thereof, may be provided as racemic mixtures or as substantially enantiomerically pure (-) or (+) enantiomers.

[0062] Also provided are pharmaceutical compositions comprising a compound of Formula I, Formula II, Formula IIIa, or Formula IIIb described herein, or a pharma- ceutically acceptable salt thereof, in admixture with a pharma- ceutically acceptable excipient, carrier, and / or diluent.

[0063] Further provided is a pharmaceutical composition for use as a compound described herein, e.g., a compound of Formula I, Formula II, Formula IIIa, or Formula IIIb described herein, or a pharma- ceutically acceptable salt thereof, or an agent described herein, e.g., an agent in therapy.

[0064] Also provided is a compound as described herein of Formula I, Formula II, Formula IIIa, or Formula IIIb as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment and / or prophylaxis of a disease or disorder caused by a coronavirus.

[0065] It will be understood that the coronavirus described herein can be SARS-CoV-2. It will be further understood that the coronavirus described herein can cause a disease or disorder, such as COVID-19.

[0066] Also provided is a compound as described herein, e.g., a compound of Formula II, Formula IIIa, or Formula IIIb of Formula I as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment and / or prevention of SARS-CoV-2 or a disease or disorder related thereto, such as COVID-19.

[0067] Also provided is a compound of formula I as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the manufacture of a medicament for the treatment and / or prevention of a disease or disorder caused by a coronavirus. Thus, provided is the use of a compound as described herein, such as a compound of formula I, formula II, formula IIIa, or formula IIIb as described herein, or a pharmaceutical composition as described herein, for the manufacture of a medicament for the treatment and / or prevention of a disease or disorder caused by a coronavirus.

[0068] Also provided is a compound of formula I as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the manufacture of a medicament for the treatment and / or prevention of SARS-CoV-2 or a disease or disorder associated therewith, such as COVID-19. Thus, provided is the use of a compound as described herein, for example a compound of formula I, formula II, formula IIIa, or formula IIIb as described herein, for the manufacture of a medicament for the treatment and / or prevention of SARS-CoV-2 or a disease or disorder associated therewith, such as COVID-19.

[0069] Also provided is a method for the treatment and / or prevention of a disease or disorder caused by a coronavirus, the method comprising the step of administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I, Formula II, Formula IIIa, or Formula IIIb described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein, to a patient, such as a human or animal, in need of treatment and / or prevention.

[0070] Also provided is a method for the treatment and / or prevention of SARS-CoV-2 or a disease or disorder related thereto (such as COVID-19), the method comprising the step of administering a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, Formula II, Formula IIIa, or Formula IIIb described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein, to a patient, such as a human or animal, in need of treatment and / or prevention.

[0071] stereoisomer The compounds of the present disclosure may be provided as a mixture of stereoisomers or as a single stereoisomer. For example, the compounds of the present disclosure may be provided as a single stereoisomer defined as stereoisomer 1 or 2, or as a mixture thereof.

[0072] Pharmaceutically acceptable salts The compounds of the present disclosure may be provided in the form of pharma- ceutically acceptable salts. As used herein, "pharma- ceutically acceptable salts" includes salts prepared from pharma- ceutically acceptable non-toxic acids, i.e., pharma- ceutically acceptable acid addition salts, if such salts are possible.

[0073] Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic inorganic and organic acid addition salts, such as hydrochloride, hydrobromide, borate, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, propionate, salicylate, sorbate, stearate, succinate, tartrate, toluene-sulfonate, etc. Hemisalts of acids, such as hemisulfates, can also be formed. Such salts can be formed by procedures well known and described in the art. In a further example, pharmaceutically acceptable salts do not include hydrochloride salts, i.e., do not include salts of hydrochloric acid.

[0074] Other acids, such as oxalic acid, which may not be considered pharma- ceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the present disclosure and their pharma- ceutically acceptable acid addition salts.

[0075] solvate, hydrate Certain compounds of the present disclosure may exist as solvates or hydrates, and it is to be understood that the present disclosure encompasses all such isomers.

[0076] Cocrystals In salts, proton transfer may occur between the active pharmaceutical ingredient and the counterion of the salt. However, in some cases, there is no proton transfer or only partial proton transfer, and therefore the solid is not a true salt. It is recognized that proton transfer is in fact continuous and may vary with temperature, and therefore it may be subjective to say that a salt is better described as a "cocrystal". As used herein, the term "cocrystal" refers to a multi-component system in which there are one or more host molecules (active pharmaceutical ingredients) and one or more guest (or coformer) molecules. The guest or coformer molecules are defined as existing as solids at room temperature in order to distinguish cocrystals from solvates. However, the cocrystal itself may form a solvate. In cocrystals, interactions via non-ionic forces, such as hydrogen bonding, generally predominate.

[0077] polymorph The compounds of the present disclosure may exist in a continuum of solid states ranging from fully amorphous to fully crystalline, and therefore, all polymorphs, including mixtures of different polymorphs, are understood to be included within the scope of the claimed compounds.

[0078] isotope labeled compounds The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0079] The compounds of the present disclosure can be used in their labeled or unlabeled form.In the context of the present disclosure, a labeled compound has one or more atoms replaced by an atom with different atomic mass or mass number from the atomic mass or mass number that is usually found in nature.The label allows the compound to be easily quantitatively detected.

[0080] The labeled compounds of the present disclosure may contain at least one radionuclide as a label. Positron-emitting radionuclides are all candidates for use. In the context of the present disclosure, a radionuclide is: 2 H (deuterium), 3 H (tritium), 11 C. 13 C. 14 C. 18 O. 17 O. 19 F, and 18 The isotopes may be selected from isotopes of hydrogen, carbon, nitrogen, fluorine, and oxygen, such as F. Deuterium ( 2 It is known that substitution of one or more hydrogen atoms with heavier isotopes, such as replacement of one or more hydrogen atoms with H, can in some instances provide pharmacological advantages, such as increased metabolic stability.

[0081] The physical method for detecting the labeled compounds of the present disclosure may be selected from position emission tomography (PET), single photon imaging computed tomography (SPECT), magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), and computed axial tomography (CAT), or a combination thereof.

[0082] Prodrug The compounds of the present disclosure may be administered in the form of prodrugs. Prodrugs are compounds that have little or no pharmacological activity themselves, but are converted to compounds of formula I when such compounds are administered to or into the patient's body. Prodrugs may contain metabolically or chemically labile acyl functions, such as carboxylate esters, amides or carbamates, or acetals / ketals or hemiaminal derivatives.

[0083] combination The compounds of the present disclosure may be combined with other pharmaceutical agents, such as other antiviral agents and / or metabolic blockers.

[0084] Preparation method The compounds of formula I, II, IIIa, or IIIb described herein can be prepared using methods described in the art and / or methods described herein. For example, compounds of formula I can be prepared as shown in Scheme 1. [ka]

[0085] It is to be understood that the substituents R1, R2, R3 in Schemes 1 and 2 can be as described herein for compounds of Formula I, Formula II, Formula IIIa, or Formula IIIb.

[0086] Cyclobutyl amino acids (S2) for use in the preparation of compounds of Formula I, Formula II, Formula IIIa, or Formula IIIb can be prepared as outlined in Scheme 2. [ka]

[0087] An alternative route to compounds of formula I, II, or III is shown in Scheme 3. In this route, the starting material is a styrene derivative, i.e., one of R2 and R3 is phenyl or substituted phenyl. [ka]

[0088] It is understood that the substituents R1, R2, R3, and R4 in Scheme 3 can be as described herein for compounds of Formula I, Formula II, Formula IIIa, or Formula IIIb. EXAMPLES

[0089] In this document, unless otherwise stated, compound drawings have been created using Chem Doodle version 7.0.1 or version 7.0.2, ChemDraw Professional 17.0, or Chem Draw Ultra 12.0. Unless otherwise stated, compound naming has been done using IUPAC nomenclature and ChemAxon Marvin Suite version 18.10.0, displayVersion 18.10, internalVersion 18.10.0-8214, buildTimestamp 2018-04-10 20:25:49 UTC. In case of discrepancy between name and chemical structure, the structure shall be presumed correct. Unless otherwise stated, compounds have been prepared as mixtures of stereoisomers.

[0090] Abbreviation DCE Dichloroethane DCM Dichloromethane Dias. Diastereoisomers: DABCYL 4-[[4-(Dimethylamino)phenyl]diazenyl]benzoic acid DMA Dimethylacetamide DMF Dimethylformamide DMSO Dimethyl sulfoxide DTT Dithiothreitol EDANS 5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid FRET Fluorescence Resonance Energy Transfer equiv. g grams h time HPLC High Performance Liquid Chromatography IMAC Immobilized Metal Affinity Chromatography LB Luria Broth LC-MS Liquid Chromatography-Mass Spectrometry LCMS(ESI) Liquid Chromatography Mass Spectrometry (Electrospray Ionization) M mole mM millimolar nM nanomolar min. ml milliliter μm micrometer MWCO Molecular Weight Cutoff NCATS National Center for Advancing Translational Sciences NIH National Institutes of Health NMR nuclear magnetic resonance nm nanometer MHz Megahertz OD optical density O.D. 600 Optical density at 600 nm on all night rpm Revolutions per minute rt room temperature SDS PAGE Sodium dodecyl sulfate-polyacrylamide gel electrophoresis SEC Size Exclusion Chromatography TCEP Tris(2-carboxyethyl)phosphine TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer Chromatography Tris Tris(hydroxymethyl)aminomethane Tween Polysorbate UV ultraviolet light

[0091] chemistry general All reagents were purchased from Fluorochem, Sigma-Aldrich, Enamine and Chemtronica. DCM, methanol, DMF and acetonitrile (99.9%) were purchased from VWR International AB, while THF was purchased from Sigma-Aldrich. Reagents and solvents were used as received without further purification. All reactions involving air or moisture sensitive reagents or intermediates were carried out under nitrogen atmosphere. Reaction monitoring and purity assessment were performed using an Agilent 1100 series HPLC with a C18 Atlantis T3 column (3.0×50 mm, 5 μm) and LC-MS. Acetonitrile-water (both with 0.1% HCOOH, flow rate 0.75 ml / min and gradient of 5-95% acetonitrile over 6 min) was used as mobile phase. Molecular ions were detected using a Waters micromass ZQ (model code: MM1) mass spectrometer equipped with electrospray ionization. Silica gel 60 F from Merck was used. 254 TLC plates were also sometimes used for monitoring reactions, especially during purification of compounds. Visualization of developed TLC was performed using UV light (254 nm) and staining with ninhydrin or anisaldehyde. After workup, the organic phase was dried over Na2SO4 / MgSO4, filtered and then concentrated under reduced pressure. Silica gel (Matrex, 60 Å, 35-70 μm, Grace Amicon) was used for purification of intermediate compounds by flash column chromatography. Preparative reversed phase HPLC was performed using a Kromasil C8 column (250×21.2 mm, 5 μm) on a Gilson HPLC equipped with a Gilson 322 pump, UV / Visible-156 detector, and 202 collector, using an acetonitrile-water gradient with a flow rate of 15 ml / min as eluent, detection at 210 or 254 nm, flow rate of 15 ml / min. All test compounds were purified by HPLC unless otherwise stated. 1 H and 13C NMR spectra were recorded on an Agilent Technologies 400 NMR spectrometer at 400 MHz or 100 MHz, or on a Bruker Avance Neo spectrometer at 500 / 600 MHz or 125 / 150 MHz at 298 K. Chemical shifts were determined by the residual solvent. 1 Reported in parts per million (ppm, δ) referenced to the H resonances [(CD3)2CO, δ 2.05; CDCl3, δ 7.26; CD3OD δ 3.31; DMSO-d6 δ 2.50]. Splitting patterns are expressed as s (singlet), d (doublet), t (triplet) and m (multiplet), br (broad). Coupling constants (J values) are given in Hertz (Hz). Purity of compounds was confirmed by high resolution chromatography. 1 It was greater than 95% as determined by 1 H NMR spectroscopy (600 MHz) and LCMS.

[0092] General synthesis description The compounds were prepared as shown in Schemes 1, 2, and 3. More specifically, the compounds were synthesized as described below.

[0093] Triphosgene-mediated formation of the isocyanate from amine S1, followed by addition of amino acid ester S2, afforded the key urea ester intermediate S3 (see Reference 1). Hydantoin analogues could be prepared directly by cyclization of the urea ester intermediate S3 under basic conditions using NaH (see Reference 1). Alternatively, hydrolysis of ester S3 afforded the urea acid intermediate S4, which was cyclized under acidic conditions using TFA to afford the hydantoin analogues (see Reference 2).

[0094] General procedure for the synthesis of urea ester intermediate S3, adapted from ref. 1. Et3N (3 eq.) was added to a mixture of amine (S1, 0.25 mmol, 1 eq.) in DCM (2 ml) at 0° C. A solution of triphosgene (0.5 eq.) in DCM (0.5 ml) was added dropwise to the mixture. The reaction was stirred at 0° C. for 45 min. Amino acid ester hydrochloride (S2, 0.2 mmol) was then added in one portion to the reaction mixture. The mixture was stirred at room temperature overnight, then diluted with DCM (15 ml) and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated to give the crude urea ester intermediate S3, which was used directly in the next step without purification.

[0095] General procedure for the cyclization of urea ester intermediate S3 to form hydantoin analogues using NAH (Reference 1) NaH (3-6 equiv.) was added to a mixture of urea ester intermediate S3 in THF (2 ml) at 0° C. The mixture was stirred at 0° C. for 15 min and then neutralized with TFA. The solvent was removed and the residue was dissolved in DMSO, filtered and purified by HPLC using 5-100% CH3CN in H2O to give the desired product as a pale yellow solid. Repurification by HPLC using 5-100% CH3CN in H2O (H2O+0.1% TFA) gave the pure compound as a solid TFA salt.

[0096] A general two-step procedure for the cyclization of urea ester intermediate S3 to form hydantoin analogues using TFA (Reference 2) NaOH (2 eq.) was added to a mixture of urea ester intermediate S3 in MeOH (2 ml) at 0° C. The mixture was stirred at room temperature for 15 min after which LCMS showed complete ester hydrolysis and partial cyclization to acid intermediate S4. The reaction mixture was neutralized with TFA and then concentrated to dryness. The residue was dissolved in TFA (2 ml) and heated at 60° C. overnight. The solution was then cooled and concentrated to dryness. The residue was dissolved in DMSO, filtered and purified by HPLC using 5-100% CH3CN in H2O to give the desired product as a pale yellow solid. Repurification by HPLC using 5-100% CH3CN in H2O (H2O+0.1% TFA) gave the pure compound as a solid TFA salt.

[0097] Cyclobutanes (S6) are formed from the corresponding styrenes (S5) via TfO-mediated cyclization with DMA (Ref. 3). Microwave-assisted Bucherer-Bergs reaction of S6 afforded the requisite hydantoin ring (S7) (Ref. 4). Copper-mediated N-arylation of S7 can be accomplished using aryl iodides / bromides (Ref. 5) or boronic acids (Ref. 6). N-alkylated hydantoins (S8) were prepared by alkylation with alkyl iodides and tBuOK.

[0098] General procedure for the formation of cyclobutane S6 (Reference 3) To a solution of DMA (1.2 equiv.) in DCE (1M) was added trifluoromethanesulfonic anhydride (1.5 equiv.) dropwise under stirring at 0° C. The addition was accompanied by a white solid precipitate. The mixture was stirred at the same temperature for 30 min, then a mixture of styrene (1 equiv.) and 2,4,6-trimethylpyridine (1.5 equiv.) in DCE (0.25M) was added dropwise. The reaction mixture was refluxed for 14 h. The reaction mixture was cooled to room temperature, treated with water, and then refluxed for another 8 h. After cooling to room temperature, the aqueous layer was extracted with DCM. The organic layers were combined, dried under Na2SO4, concentrated in vacuo, and purified by flash column chromatography.

[0099] General procedure for the conversion of ketone intermediate S6 to the formation of hydantoin S7 (Reference 4) The ketone (1 eq.) in a microwave vial was dissolved in ethanol. Freshly powdered ammonium carbonate (5 eq.) and potassium cyanide (1.3 eq.) were dissolved in H2O and the mixture was added to the vial and irradiated in a microwave oven at 100°C for 10 min. Upon completion, the reaction mixture was cooled in an ice bath. Most of the EtOH was removed under reduced pressure, saturated NaHCO3 was added to the reaction mixture, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried under Na2SO4, concentrated in vacuo, and purified by flash column chromatography.

[0100] General procedure for N-allylation of S7 with aryl bromides or iodides to form hydantoin analogues (Reference 5) A pressure tube was charged with hydantoin (1 eq.) and copper(I) oxide (0.2 eq.) and aryl halide (2 eq.) (if solid). The tube was fitted with a rubber septum, evacuated under high vacuum, and backfilled with N2 before adding aryl halide (if liquid) (2 eq.) and anhydrous DMF. The rubber septum was then replaced with a Teflon-coated screw cap before heating the heterogeneous reaction mixture at 165° C. for 12 h. The suspension was cooled to room temperature and filtered through a pad of Celite (washed with EtOAc), and the filtrate was concentrated in vacuo. The crude reaction mixture was then purified by column chromatography to give the target compound.

[0101] General procedure for N-allylation of S7 with arylboronic acids to form hydantoin analogues (Reference 6) To a solution of hydantoin (1 eq.) and copper(II) acetate (0.1 eq.) in MeOH under O2 was added arylboronic acid (2 eq.). The mixture was heated at 70° C. for 12 h. The solvent was filtered through a pad of Celite (washed with MeOH) and the filtrate was concentrated in vacuo. The crude reaction mixture was then purified by column chromatography to give the target compound.

[0102] General Procedure for N-Alkylation to Form Hydantoin Analogues To a solution of hydantoin (1 equiv.) in THF was added tBuOK (1 equiv.) at room temperature. After 3 min, alkyl iodide (1 equiv.) was added and the mixture was stirred for 5 min. HCl (1N) was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated in vacuum and the crude product was dissolved in DMSO, filtered and purified by HPLC using 5-100% CH3CN in H2O to give the desired product S8.

[0103] The compounds synthesized are shown in Tables 1A and 1B. [Table 1A] TIFF2024517740000010.tif193170TIFF2024517740000011.tif199170TIFF20245177400 00012.tif193170TIFF2024517740000013.tif230170TIFF2024517740000014.tif245170 [Table 1B] TIFF2024517740000016.tif253170TIFF2024517740000017.tif246170TIFF2024517740000018.tif245170TIFF2024517 740000019.tif254170TIFF2024517740000020.tif248170TIFF2024517740000021.tif250170TIFF2024517740000022.t if236170TIFF2024517740000023.tif237170TIFF2024517740000024.tif231170TIFF2024517740000025.tif236170TIF F2024517740000026.tif220170TIFF2024517740000027.tif225170TIFF2024517740000028.tif250170TIFF20245177400 00029.tif229170TIFF2024517740000030.tif244170TIFF2024517740000031.tif254170TIFF2024517740000032.tif22 3170TIFF2024517740000033.tif239170TIFF2024517740000034.tif228170TIFF2024517740000035.tif234170TIFF202 4517740000036.tif212170TIFF2024517740000037.tif232170TIFF2024517740000038.tif254170TIFF20245177400000 39.tif234170TIFF2024517740000040.tif254170TIFF2024517740000041.tif210170TIFF2024517740000042.tif166170

[0104] Compounds of the present disclosure can also include the prophetic compounds listed in Tables 2A and 2B. [Table 2A] TIFF2024517740000044.tif239170TIFF2024517740000045.tif254170 [Table 2B] TIFF2024517740000047.tif254170TIFF2024517740000048.tif238170TIFF2024517740000049.tif237170

[0105] biology Enzyme assays SARS-CoV-2 M pro Expression and purification of the protease. SARS-CoV M, containing the nucleotide sequence corresponding to residues S1-Q306 (Chinese isolate, NCBI accession number YP_009725301), pro We adapted published constructs used for expression of proteases (reference 7) to express SARS-CoV-2 M pro This construct was used to generate the protease. pro The protease is coupled to an N-terminal GST (glutathione S-transferase) tag followed by SARS-CoV-2 M for autoproteolysis. pro The recognition sequence and a C-terminal 6xHis tag are followed by an HRV3C protease recognition sequence.

[0106] With some minor adjustments, SARS-CoV-2 M pro The expression and purification of the protease was performed according to the procedure described in reference 8. pro The vector (pGEX-6P-1) containing the coding sequence of the protease was transformed into E. coli BL21(DE3)-T1R competent cells. Fresh transformants were inoculated into L-Broth medium (Formedium, Norfolk, UK) supplemented with carbenicillin (100 μg / ml) and incubated at OD 600The starter culture was then used to inoculate a main culture in Auto-Induction Medium (AIM) Terrific Broth base with trace elements (Formedium, Norfolk, UK) supplemented with 1% glycerol and carbenicillin (100 μg / ml). Cultures were grown at OD 600Growth was continued at 37°C until a NA of 2 was reached, and protein expression was continued overnight at 18°C ​​for 13.5 h. Cells were then harvested by centrifugation (4500×g, 10 min at 4°C), resuspended in IMAC lysis buffer (50 mM Tris, 300 mM NaCl, pH 8.0) supplemented with benzonase nuclease (10 μl / 1.5 liter culture, 250 U / μl, E1014, Merck, Darmstadt, Germany) and disrupted by sonication (4 s / 4 s 3 min, 80% amplitude, Sonics Vibracell-VCX750, Sonics & Materials Inc., Newtown, CT, USA). Lysates were centrifuged at 49,000×g for 20 min at 4°C. The supernatant was filtered (Corning bottle-top vacuum filter, 0.45 μm, Corning, NY, USA) and imidazole was added to a final concentration of 10 mM before loading onto an IMAC HisTrap HP 5 ml column (Cytiva, Little Chalfont, UK) mounted on an AKTA Xpress FPLC system (Cytiva, Little Chalfont, UK). The column was washed with wash buffer (50 mM Tris, 300 mM NaCl, 25 mM imidazole, pH 8.0) and bound proteins were eluted with elution buffer (50 mM Tris, 300 mM NaCl, 500 mM imidazole, pH 8.0). For crystallization experiments, the protein was further purified by size-exclusion chromatography (SEC) using a HiLoad 16 / 60 Superdex 200 preparative grade column (Cytiva, Little Chalfont, UK) pre-equilibrated with gel filtration buffer (50 mM Tris, 300 mM NaCl, pH 8.0). To remove the His-tag, protein-containing fractions were pooled and treated with HRV 3C protease (1 μg / 500 μg target protein, SAE0045, Merck, Darmstadt, Germany) overnight at 4 °C in gel filtration buffer supplemented with 0.5 mM TCEP and 0.5 mM DTT.For the FRET assay, proteins were treated with HRV 3C protease immediately after the IMAC purification step and buffer exchanged simultaneously by dialysis (dialysis buffer 50 mM Tris, 300 mM NaCl, 0.5 mM TCEP, and 0.5 mM DTT, pH 8.0) in a dialysis cassette (Slide-A-Lyzer dialysis cassette, 10K MWCO, 3 ml, Thermo Fisher Scientific, Waltham, MA, USA) overnight at 4 °C. Subsequently, cleaved SARS-CoV-2 M was purified. pro The protease samples were purified by IMAC reverse purification using HisTrap 1 ml columns (Cytiva, Little Chalfont, UK). The same wash buffers as above were used and the flow-through was collected. After IMAC reverse purification, a second SEC step was performed using the same columns and buffers as above. Fractions containing the target protein were checked by SDS PAGE, pooled together and concentrated in Vivaspin® 20 ml centrifugal concentrators (10 kDa MWCO, Sartorius, Goettingen, Germany) at 4,000×g and 4° C. Finally, the protein was flash frozen in liquid nitrogen and stored at −80° C.

[0107] Enzyme activity assay. pro The quenched fluorogenic substrate for (DABCYL-Lys-HCoV-SARS replicase polyprotein 1ab(3235-3246)-Glu-EDANS trifluoroacetate, 95% ultrapure) was custom synthesized and obtained from Bachem AG (Switzerland).

[0108] Proteins and compounds used in catalytic activity assays prowas obtained from the Protein Science Facility (PSF, Karolinska Institutet, Stockholm, Sweden) and described in the previous section. All test compounds were dissolved in 10 mM stocks in 100% DMSO (Merck KGaA, Darmstadt, Germany) and transferred to an ECHO LDV source plate (Labcyte, Inc, Ca, USA).

[0109] M pro The activity is essentially that of SARS-CoV-2M pro Protease enzyme assays (NIH, National Center for Advancing Translational Sciences data portal) pro Assay) was analyzed by detection of hydrolysis of the quenched FRET substrate as described in the NCATS protocol for 30. This was performed at room temperature in 20 mM Tris, 50 mM NaCl, and 0.1 mM EDTA (Merck KGaA, Darmstadt, Germany), pH 7.5. Compounds were transferred to Corning 3575 non-binding 384-well assay plates using an Echo 550 non-contact dispenser (Labcyte, Inc., USA). pro (75 nM final concentration) was added to the assay plate using a 16-channel pipette (Integra ViaFlo, BergmanLabora AB, Sweden) and shaken at 1500 rpm for 15 min in Eppendorf Mixmate. After pulse centrifugation, M proFluorescent substrate (5 mM stock solution in DMSO) was added to the assay plate to a final concentration of 10 μM, thus contributing 0.2% DMSO in the final assay using a Labcyte ECHO 550 non-contact dispenser. After 10 min incubation and pulse centrifugation, fluorescence was measured on a PerkinElmer Envision plate reader at ambient temperature using kinetic mode with excitation at 340 nm and emission at 490 nm. Activity was calculated as a percentage of control activity at each data point (100*(RFU sample-RFU blank control) / (RFU DMSO control-RFU blank control)). Nonlinear fitting of 11-point dose-response curves (log(inhibitor) vs. response-variable slope (four parameters) and IC50 calculations were performed using GraphPad Prism version 9.1.0 for Windows, GraphPad Software, San Diego, California USA, www.graphpad.com.

[0110] Compound screening. Compounds were screened at three concentrations (50, 15, and 5 μM) and hits were retested in an 11-point concentration series (1:3 dilution, starting concentration 50 μM). Dose-response curves were generated using an Echo 550 non-contact dispense from 10 mM compound stocks.

[0111] Tables 5A, 5B, 5C, 5D, and 5E show the IC50 values. [Table 5A] [Table 5B-C] [Table 5D] [Table 5E]

[0112] Surface plasmon resonance (SPR) biosensor assay. Inhibitors and M pro The direct interaction between was confirmed and the affinity was determined using surface plasmon resonance (SPR) biosensor analysis.

[0113] Protein production AviTaggedM pro was used for SPR biosensor assays. The expression vector and production method were essentially as described in reference 9 with some minor modifications. The C-terminal Avi tag replaced the His tag and the final construct GST-3C-M was inserted between BamHI and XhoI in the vector pGEX-P-1. pro The GST-3C portion gives the M proThe expression culture volume was gradually increased in three steps over 8 h from 1 to 100 mL of LB, i.e., Luria broth supplemented with 100 μg / mL ampicillin (Sigma) and 25 μg / mL chloramphenicol (Sigma). Ten milliliters of starter culture was used to inoculate 1 liter of autoinduction medium (Formedium, Hunstanton, Norfolk, UK) supplemented with 10 mL of glycerol, 100 μg / mL ampicillin, and 25 μg / mL chloramphenicol. Cultures were grown at 37 °C and 220 rpm for 5 h and then switched to 18 °C and 220 rpm for 10 to 12 h. Cells were harvested by centrifugation and stored at -80 °C. Cells were resuspended in 50 mM Tris pH 8, 300 mM NaCl, 0.03 μg / mL benzonase (Merck). Cells were lysed by sonication for 5 min on ice using a 15 sec on / 15 sec off pulse. Lysates were clarified by centrifugation at 50,000×g. The supernatant was then poured into a 50 mL tube and streptavidin mutein matrix (Roche Diagnostics) prepared according to the manufacturer's protocol was added. Binding was allowed for 1 h at +4° C. The mixture was then transferred to a disposable column for washing and elution using gravity flow. Washing was with 50 mM Tris (pH 8), 300 mM NaCl and elution was with 10 mM and 50 mM biotin in the same buffer. Relevant fractions were pooled and concentrated using a 10 kDa MWCO centrifugal filter device. Excess biotin was removed either by PD10-chromatography (GEHC / Cytiva, Uppsala, Sweden) and / or dialysis.

[0114] interaction analysis SPR experiments were performed at 25°C using a Biacore S200 instrument and a CM5 biosensor chip (Cytiva, Uppsala, Sweden). Streptavidin (Sigma) was immobilized by amine coupling. The CM5 chip surface was activated by injecting a 1:1 mixture of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) (Cytiva, Uppsala, Sweden) for 7 min at a flow rate of 10 μL / min. Streptavidin (Sigma) was diluted to 250 μg / mL in sodium acetate buffer (pH 5.0) and injected over the activated surface for 10 min at a flow rate of 2 μL / min. The surface was then inactivated by injecting 1 M ethanolamine (Cytiva, Uppsala, Sweden) for 7 min. The biosensor chip was then conditioned with four pulse injections of 1 M NaCl / 50 mM NaOH solution. pro was diluted to 100 μg / mL in 1.02× running buffer (50 mM TrisHCl, pH 7.5, 0.05% Tween-20) and injected at a flow rate of 2 μL / min, achieving typical immobilization levels of 8000-9000 RU.

[0115] After immobilization, compounds were injected over the surface at a flow rate of 30 μL / min in 50 mM TrisHCl, pH 7.5, 0.05% Tween-20 using a 10-point concentration series. The association phase was monitored for 60 s and the dissociation phase was monitored for 120 s. Sensorgrams were double-referenced by subtracting the signal from the reference phase and from one blank injection. Solvent correction was performed accounting for 2% DMSO. Data were analyzed using Biacore S200 evaluation software, v.3.1 (Cytiva, Uppsala, Sweden). K D For the determination of values, an equation corresponding to a reversible one-step 1:1 interaction model was fitted by nonlinear regression analysis and the point obtained at the end of the infusion, representing the steady-state signal, was reported.

[0116] result SPR biosensor analysis is performed to determine the concentration of compounds and pro We have shown that the interaction between β-lactamase and β-lactamase is well described by a reversible, one-step, 1:1 interaction, in accordance with their mode of action as reversible active site binding competitive inhibitors. Table 6 shows that β-lactamase and β-lactamase have a K of less than 100 nM. D Equilibrium dissociation constants (K D ) is provided. [Table 6]

[0117] Inhibition of human proteases To test whether the compounds of the present disclosure can inhibit other proteases, catalytic assays were set up for a panel of common human proteases.Clinical candidate drug PF-07321332 was also tested in the comparative example.These results are shown in Tables 7, 8, and 9. [Table 7] [Table 8] [Table 9]

[0118] Compounds of the present disclosure, such as the compounds of Examples 1, 4, and 15, have IC of greater than 10 μM for all of the human proteases tested above. 50 It was observed that the compounds of the present disclosure had the following inhibitory effects on the chymotrypsin-like main protease, M pro In contrast, the comparative compound PF-07321332 appears to selectively inhibit the chymotrypsin-like main protease, M pro Low IC indicating that it is not a selective inhibitor of 50 value (6 μM).

[0119] conclusion As shown above by the results of the enzymatic and surface plasmon resonance biosensor assays, the compounds of formula I, II, or III inhibit the chymotrypsin-like main protease, M pro Thus, the compounds of formula I, II, or III achieve the objectives of the present disclosure and are inhibitors of the chymotrypsin-like main protease, M pro Additionally, the compounds disclosed herein inhibit the chymotrypsin-like main protease, M pro Selectively inhibits.

[0120] References

[0121] Reference 1: Chen, Y., et al.Enantioselective synthesis of 3,5-disubstituted thiohydantoins and hydantoins.Tetrahedron 71,9234-9239(2015). Reference 2: Hamuro, Y., et al.Resin-to-resin acyl-and aminoacyl-transfer reactions using oxime supports.Journal of the American Chemical Society 121, 1636(1999). Reference 3: Chernykh, A., et al.Synthesis and Physicochemical Properties of 3-Fluorocyclobutylamines.European Journal of Organic Chemistry,6466(2015). Reference 4: Safari, J., et al.Microwave-Promoted Facile and Rapid Synthesis Procedure for the Efficient Synthesis of 5,5-Disubstituted Hydantoins.Synthetic Communications 43,3115(2013). Reference 5: Thilmany, P., et al. Copper-Mediated N-Arylations of Hydantoins. Journal of Organic Chemistry 84, 392 (2019). Reference 6: Wang, C., et al. Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978). Journal of Medicinal Chemistry 59, 10705 (2016). Reference 7: Xue, X., et al. Production of Authentic SARS-CoV M pro with Enhanced Activity:Application as a Novel Tag-cleavage Endopeptidase for Protein Overproduction.Journal of Molecular Biology 366,965(2007). Reference 8: Akaberi, D., et al. Mitigation of the replication of SARS-CoV-2 by nitric oxide in vitro. Redox Biology 37, 101734 (2020). Reference 9: Douangamath, A., et al. Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease. Nature Communications 11, 5047 (2020). Reference 10: WO2017 / 047146 A2. Reference 11: Nature, Vol. 258, 11 June 2020, 289. Reference 12: ACS Comb. Sci. 2018, 20, 35-43. Reference 13: J. Am. Chem. Soc. 2022, 144, 2905-2929.

[0122] item Item 1 A compound of formula I, or a pharma- ceutically acceptable salt or composition thereof, [ka] During the ceremony, R1 is a monocyclic or bicyclic heterocyclyl containing at least one nitrogen atom, said monocyclic or bicyclic heterocyclyl being substituted with 0, 1, 2, or 3 substituents selected from the group consisting of: a) C1-C4 alkyl substituted with 0, 1, 2 or 3 F; b) C1-C4 alkoxy substituted with 0, 1, 2 or 3 F; c) CN; d) OH, e) oxo, f) NO2, g) NRaRb, where Ra and Rb are each independently selected from H and C1-C3 alkyl; h) 5-6 membered monocyclic heterocyclyl, substituted with 0, 1 or 2 substituents, each of which is independently selected from F, Cl, OH, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H and C1-C3 alkyl; R2 is selected from the group consisting of: a)H b) F, Cl or Br; c) C1-C4 alkyl substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; C1-C4 alkyl, where cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, and hydroxyC1-C4 alkyl; d) C1-C4 alkoxy substituted with 0, 1, 2, or 3 substituents, each independently selected from F, OH, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, and hydroxyC1-C4 alkyl; e) C3-C6 cycloalkyl substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; f) phenyl substituted with 0, 1, 2, or 3 substituents, each independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloalkyl; and g) monocyclic or bicycyclic saturated, partially unsaturated or aromatic heterocyclyl, wherein the monocyclic or bicycyclic heterocyclyl is substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; R3 is selected from the group consisting of: a) F, Cl or Br, b) C1-C4 alkyl substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, OH, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; C1-C4 alkyl, cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, haloC1-C4 alkyl, and hydroxyC1-C4 alkyl; c) C1-C4 alkoxy substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, OH, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, haloC1-C4 alkyl, hydroxyC1-C4 alkyl; d) C3-C6 cycloalkyl substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; e) phenyl substituted with 0, 1, 2, or 3 substituents, each independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; and f) monocyclic or bicycyclic saturated, partially unsaturated or aromatic heterocyclyl, wherein the monocyclic or bicycyclic heterocyclyl is substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; The compound of formula I is 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or A compound, or a pharma- ceutically acceptable salt or composition thereof, which is not a stereoisomer of 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or a salt of 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione.

[0123] Item 2 R1 is selected from the group consisting of pyrrole, pyrrolidine, imidazole, thiazole, oxazole, triazole, tetrazole, pyridine, piperidine, pyrimidine, pyrazine, and morpholine; or The compound of formula I according to item 1, wherein the bicyclic heterocyclyl containing at least one nitrogen of R1 is selected from the group consisting of indole, isoindole, benzimidazole, quinoline, and isoquinoline.

[0124] Item 3 R1 is isoquinolinyl, 5-bromo-4-methylpyrid-3-yl, 4-methylpyrid-3-yl, 5-fluoropyrid-3-yl, 5-bromopyrid-3-yl, 4-trifluoromethylpyrid-3-yl, 3-trifluoromethylpyrid-2-yl, N-methyl-2-oxopyrrolidin-3-yl, N-(2,2,2-trifluoroethyl)-2-oxopyrrolidin-3-yl, N-(2,2,2-trifluoroethyl)-imidazol-2-yl, 1, The compound of formula I according to item 1, selected from the group consisting of 2,4-triazol-3-yl, 4-methyl-1,2,4-triazol-3-yl, 1-(2,2,2-trifluoroethyl)-1,2,4-tetrazol-5-yl, 6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl, 5H,6H,7H,8H,9H-[1,2,4]triazolo[4,3-a]azepin-5-yl, and 4-methylfurazan-3-yl.

[0125] Item 4 The compound of formula I according to item 1, wherein R1 is pyrid-3-yl substituted with 0, 1 or 2 substituents, each of said substituents being independently selected from C1-C3 alkyl, F, Cl and Br.

[0126] Item 5 The compound of formula I according to item 1, wherein R1 is isoquinolin-4-yl substituted with 0, 1 or 2 substituents, each of which is independently selected from C1-C3 alkyl, F, Cl and Br.

[0127] Item 6 The compound of formula I according to any one of the preceding items, wherein R2 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy, F, Cl, and Br.

[0128] Item 7 The compound of formula I according to any one of the preceding items, wherein R2 is H.

[0129] Item 8 A compound of formula I according to any one of the preceding items, wherein R3 is C1-C4 alkyl substituted with 0, 1, 2 or 3 substituents, each of which is independently selected from F, Cl, C3-C6 cycloalkyl, phenyl, monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl.

[0130] Item 9 The compound of formula I according to any one of items 1 to 7, wherein R3 is tert-butyl, cyclobutyl, or phenyl.

[0131] Item 10 2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, (2s,4s)-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, (2r,4r)-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(isoquinolin-4-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-tert-butyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-cyclobutyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-[(3-methylpyridin-2-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(5-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(5-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromopyridin-3-yl)-2-cyclobutyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[4-(trifluoromethyl)pyridin-3-yl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(1-methyl-2-oxopyrrolidin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(1-methyl-2-oxopyrrolidin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[(1-methyl-2-oxopyrrolidin-3-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 7-[2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-{[1-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[(1-methyl-1H-1,2,4-triazol-5-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[1-(4-methyl-4H-1,2,4-triazol-3-yl)ethyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-{[1-(2,2,2-trifluoroethyl)-1H-1,2,3,4-tetrazol-5-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-{[6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-{[6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-({5H,6H,7H,8H,9H-[1,2,4]triazolo[4,3-a]azepin-3-yl}methyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, or a pharma- ceutically acceptable salt or composition of any one of the above compounds.

[0132] Item 11 A pharmaceutical composition comprising a compound of formula I, or a pharma- ceutically acceptable salt thereof, as described in any one of the preceding paragraphs, in admixture with a pharma- ceutically acceptable excipient, carrier, and / or diluent.

[0133] Item 12 A compound of formula I according to any one of items 1 to 10, or a pharmaceutical composition according to item 11, for use as a medicament in therapy.

[0134] Item 13 A compound of formula I according to any one of items 1 to 10, or a pharmaceutical composition according to item 12, for use in the treatment and / or prevention of COVID-19.

[0135] Item 14 A compound of formula IIIb, or a pharma- ceutically acceptable salt or composition thereof, [ka] During the ceremony, R4 is H or C1-C3 alkyl; R1 is a monocyclic or bicyclic heterocyclyl containing at least one nitrogen atom, said monocyclic or bicyclic heterocyclyl being substituted with 0, 1, 2, or 3 substituents selected from the group consisting of: a) C1-C4 alkyl substituted with 0, 1, 2 or 3 F; b) C1-C4 alkoxy substituted with 0, 1, 2 or 3 F; c) CN; d) OH, e) oxo, f) NO2, g) NRaRb, where Ra and Rb are each independently selected from H and C1-C3 alkyl; h) 5-6 membered monocyclic heterocyclyl, substituted with 0, 1 or 2 substituents, each of which is independently selected from F, Cl, OH, C1-C4 alkyl, and NRaRb, where Ra and Rb are each independently selected from H and C1-C3 alkyl; R2 is selected from the group consisting of: a)H b) F, Cl or Br; c) C1-C4 alkyl substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; C1-C4 alkyl, where cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, and hydroxyC1-C4 alkyl; d) C1-C4 alkoxy substituted with 0, 1, 2, or 3 substituents, each independently selected from F, OH, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, and hydroxyC1-C4 alkyl; e) C3-C6 cycloalkyl substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; f) phenyl substituted with 0, 1, 2, or 3 substituents, each independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C6 cycloalkyl; and g) monocyclic or bicycyclic saturated, partially unsaturated or aromatic heterocyclyl, which is substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; R3 is selected from the group consisting of: a) F, Cl or Br, b) C1-C4 alkyl substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, OH, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; C1-C4 alkyl, cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, haloC1-C4 alkyl, and hydroxyC1-C4 alkyl; c) C1-C4 alkoxy substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, OH, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, haloC1-C4 alkyl, hydroxyC1-C4 alkyl; d) C3-C6 cycloalkyl substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; e) phenyl substituted with 0, 1, 2, or 3 substituents, each independently selected from F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; and f) monocyclic or bicycyclic saturated, partially unsaturated or aromatic heterocyclyl, wherein the monocyclic or bicycyclic heterocyclyl is substituted with 0, 1, 2 or 3 F, Cl, OH, CN, NO, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, fluoroC1-C4 alkyl, hydroxyC1-C4 alkyl; The compound of formula II is 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or not a stereoisomer of 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione or a salt of 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione; A compound, or a pharma- ceutically acceptable salt or composition thereof, for use in the treatment and / or prevention of a coronavirus disease, such as COVID-19.

[0136] Item 15 R1 is selected from the group consisting of pyrrole, pyrrolidine, imidazole, thiazole, oxazole, triazole, tetrazole, pyridine, piperidine, pyrimidine, pyrazine, and morpholine; or 15. The compound of formula III according to item 14, or a pharmaceutical composition thereof, for use in the treatment and / or prevention of a coronavirus disease, such as COVID-19, wherein the at least one nitrogen-containing bicyclic heterocyclyl of R1 is selected from the group consisting of indole, isoindole, benzimidazole, quinoline, and isoquinoline.

[0137] Item 16 R1 is isoquinolinyl, 5-bromo-4-methylpyrid-3-yl, 4-methylpyrid-3-yl, 5-fluoropyrid-3-yl, 5-bromopyrid-3-yl, 4-trifluoromethylpyrid-3-yl, 3-trifluoromethylpyrid-2-yl, N-methyl-2-oxopyrrolidin-3-yl, N-(2,2,2-trifluoroethyl)-2-oxopyrrolidin-3-yl, N-(2,2,2-trifluoroethyl)-imidazol-2-yl, 1,2,4-triazol-3-yl, 4-methyl- 15. Compounds of formula III according to item 14 selected from the group consisting of 1,2,4-triazol-3-yl, 1-(2,2,2-trifluoroethyl)-1,2,4-tetrazol-5-yl, 6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl, 5H,6H,7H,8H,9H-[1,2,4]triazolo[4,3-a]azepin-5-yl and 4-methylfurazan-3-yl for use in the treatment and / or prevention of coronavirus diseases, such as COVID-19, Or a pharmaceutical composition thereof.

[0138] Item 17 15. The compound of formula III according to item 14, or a pharmaceutical composition thereof, for use in the treatment and / or prevention of a coronavirus disease, such as COVID-19, wherein R1 is pyrid-3-yl substituted with 0, 1 or 2 substituents, each of said substituents being independently selected from C1-C3 alkyl, F, Cl and Br.

[0139] Item 18 15. The compound of formula III according to item 14, or a pharmaceutical composition thereof, for use in the treatment and / or prevention of a coronavirus disease, such as COVID-19, wherein R1 is isoquinolin-4-yl substituted with 0, 1 or 2 substituents, each of said substituents being independently selected from C1-C3 alkyl, F, Cl and Br.

[0140] Item 19 19. The compound of formula III according to any one of items 14 to 18, or a pharmaceutical composition thereof, for use in the treatment and / or prevention of a coronavirus disease, such as COVID-19, wherein R2 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, F, Cl, and Br.

[0141] Item 20a 20. The compound of formula III according to any one of items 14 to 19, or a pharmaceutical composition thereof, for use in the treatment and / or prevention of a coronavirus disease, such as COVID-19, wherein R2 is H.

[0142] Item 20b 21. The compound of formula III according to any one of items 14 to 20, or a pharmaceutical composition thereof, for use in the treatment and / or prevention of a coronavirus disease, such as COVID-19, wherein R3 is C1-C4 alkyl substituted with 0, 1, 2 or 3 substituents, said substituents being each independently selected from F, Cl, C3-C6 cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl.

[0143] Item 21 21. The compound of formula III according to any one of items 14 to 20, or a pharmaceutical composition thereof, for use in the treatment and / or prevention of a coronavirus disease, such as COVID-19, wherein R3 is tert-butyl, cyclobutyl, or phenyl.

[0144] Item 22 2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, (2s,4s)-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, (2r,4r)-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(isoquinolin-4-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-tert-butyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-cyclobutyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-[(3-methylpyridin-2-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(5-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(5-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromopyridin-3-yl)-2-cyclobutyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[4-(trifluoromethyl)pyridin-3-yl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(1-methyl-2-oxopyrrolidin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(1-methyl-2-oxopyrrolidin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[(1-methyl-2-oxopyrrolidin-3-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 7-[2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-{[1-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[(1-methyl-1H-1,2,4-triazol-5-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[1-(4-methyl-4H-1,2,4-triazol-3-yl)ethyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-{[1-(2,2,2-trifluoroethyl)-1H-1,2,3,4-tetrazol-5-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-{[6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-{[6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-({5H,6H,7H,8H,9H-[1,2,4]triazolo[4,3-a]azepin-3-yl}methyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, or a pharma- ceutically acceptable salt or composition of any one of the aforementioned compounds, or a pharmaceutical composition thereof, for use in the treatment and / or prophylaxis of a coronavirus disease, such as COVID-19, wherein the compound of formula III according to item 14 is one or more of the following:

Claims

1. A compound of formula II, or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, R １ is a monocyclic or bicyclic heterocyclyl containing at least one nitrogen atom, said monocyclic or bicyclic heterocyclyl being substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of: a) C substituted with 0, 1, 2 or 3 F １ -C ４ Alkyl, b) C substituted with 0, 1, 2 or 3 F １ -C ４ Alkoxy, c) C.N.; d) OH, e) oxo, f)NO ２ 、 g) NRaRb, where Ra is H, C １ -C ３ alkyl, and cyclopropyl; Rb is selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ NRaRb, which is alkyl, aryl, heterocyclyl, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocycle, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocycle; h) 5-6 membered monocyclic saturated, partially unsaturated, or aromatic heterocyclyl substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra is selected from H, C1-C3 alkyl, and cyclopropyl; Rb is H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C1-C3 alkyl, phenyl, or heterocyclyl, and the phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or a 5-6 membered monocyclic saturated, partially unsaturated, or aromatic heterocyclyl, in which Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocyclic ring, or Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocyclic ring; i) F, Cl, Br, I, j) C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, heterocyclyl, where phenyl and heterocyclyl may be substituted with 0, 1, or 2 substituents, each independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra is H, C １ -C ３ alkyl, and cyclopropyl; Rb is selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) is alkyl, aryl, heterocyclyl, or Ra and Rb are bonded together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocycle, or Ra and Rb are bonded together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocycle; ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, k) phenyl substituted with 0, 1, 2, 3, or 4 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, NRaRb, where Ra is H, C １ -C ３ alkyl, and cyclopropyl; Rb is selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, wherein phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring; phenyl; and R ２ is selected from the group consisting of: a) H, b) F, Cl, or Br; c) C substituted with 0, 1, 2 or 3 substituents １ -C ４ alkyl, wherein the substituents are each independently selected from F, OH, C ３ -C ６ Cycloalkyl, phenyl, monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, 2, 3 or 4 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, NRaRb, where Ra is H, C １ -C ３ alkyl, and cyclopropyl; Rb is selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, and C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, wherein phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring; １ -C ４ Alkyl, d) C substituted with 0, 1, 2 or 3 substituents １ -C ４ Alkoxy, wherein the substituents are each independently selected from F, OH, C ３ -C ６ Cycloalkyl, phenyl, monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, 2, 3 or 4 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, NRaRb, where Ra is H, C １ -C ３ alkyl, and cyclopropyl; Rb is selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, wherein phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring; １ -C ４ Alkoxy, e) 0, 1, 2 or 3 of F, Cl, Br, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ Alkyl-substituted C ３ -C ６ Cycloalkyl, f) phenyl substituted with 0, 1, 2, 3, or 4 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, NRaRb, where Ra is H, C １ -C ３ alkyl, and cyclopropyl; Rb is selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, wherein phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring; phenyl; g) C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, heterocyclyl, where phenyl and heterocyclyl may be substituted with 0, 1, or 2 substituents, each independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra is H, C １ -C ３ alkyl, and cyclopropyl; Rb is selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb are bonded together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocycle, or Ra and Rb are bonded together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocycle, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, h) monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, which is substituted with 0, 1, 2, 3, or 4 substituents, each of which is independently selected from F, Cl, OH, CF ３ , C １ -C ４ alkyl, NRaRb, where Ra is H, C １ -C ３ alkyl, and cyclopropyl; Rb is selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, wherein phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring; R ３ is selected from the group consisting of: a) F, Cl, or Br, b) C substituted with 0, 1, 2 or 3 substituents １ -C ４ alkyl, wherein the substituents are each independently selected from F, OH, C ３ -C ６ Cycloalkyl, phenyl, monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, 2, 3 or 4 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, NRaRb, where Ra is H, C １ -C ３ alkyl, and cyclopropyl; Rb is selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, and C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, wherein phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring; １ -C ４ Alkyl, c) C substituted with 0, 1, 2 or 3 substituents １ -C ４ Alkoxy, wherein the substituents are each independently selected from F, OH, C ３ -C ６ Cycloalkyl, phenyl, monocyclic or bicyclic saturated, partially unsaturated, or aromatic heterocyclyl, where the phenyl and heterocyclyl are substituted with 0, 1, 2, 3, or 4 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, NRaRb, where Ra is H, C １ -C ３ alkyl, and cyclopropyl; Rb is selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, wherein phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring; １ -C ４ Alkoxy, d) 0, 1, 2 or 3 of F, Cl, Br, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ Alkyl-substituted C ３ -C ６ Cycloalkyl, e) phenyl substituted with 0, 1, 2, 3, or 4 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, NRaRb, where Ra is H, C １ -C ３ alkyl, and cyclopropyl; Rb is selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, wherein phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C1-C3 alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring; phenyl; f) C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, heterocyclyl, where phenyl and heterocyclyl may be substituted with 0, 1, or 2 substituents, each independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra is H, C １ -C ３ alkyl, and cyclopropyl; Rb is selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) is alkyl, aryl, heterocyclyl, or Ra and Rb are bonded together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocycle, or Ra and Rb are bonded together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocycle; ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, g) monocyclic or bicyclic saturated, partially unsaturated, or aromatic heterocyclyl, which is substituted with 0, 1, 2, 3, or 4 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, NRaRb, where Ra is H, C １ -C ３ alkyl, and cyclopropyl; Rb is selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, where phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, wherein phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C1-C3 alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic ring; and R ４ But, H, C １ -C ３ Alkyl, C ２ -C ３ Alkenyl, or C ２ -C ３ Alkynyl, F, Cl, Br, OH, CF ３ , Oxo, C １ -C ４ Alkoxy, Fluoro C １ -C ４ alkoxy, phenyl, monocyclic or bicyclic heterocyclyl, wherein the phenyl and heterocyclyl are substituted with 0, 1, 2, 3, or 4 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, NRaRb, where Ra is H, C １ -C ３ alkyl, and cyclopropyl; Rb is selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, wherein the phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, and C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, wherein phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, aryl, heterocyclyl, or NRaRb, where Ra and Rb are joined together with the nitrogen atom to which they are attached to form a 4-6 membered heterocycle, where Ra is H, C １ -C ３ alkyl, and cyclopropyl; Rb is selected from H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl, wherein the phenyl and heterocyclyl are substituted with 0, 1, or 2 substituents, each of which is independently selected from F, Cl, Br, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently H, C １ -C ３ Alkyl, aryl, C(=O)Rc, C(=O)ORc, C(=O)NRaRc, C(=S)NRaRc, C(=S)ORc, C(=O)SRc, S(=O) ２ Rc, S(=O) Rc, S(=O) ２ NRaRc, where Rc is H, C １ -C ３ alkyl, phenyl, or heterocyclyl; or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring; or Ra and Rb taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring; The compound of formula (II) 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or A stereoisomer of 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or A salt of 2-tert-butyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or 2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or A stereoisomer of 2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or A compound, or a pharma- ceutically acceptable salt thereof, which is not a salt of 2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione.

2. R １ is a monocyclic or bicyclic heterocyclyl containing at least one nitrogen atom, said monocyclic or bicyclic heterocyclyl being substituted with 0, 1, 2, or 3 substituents selected from the group consisting of: a) C substituted with 0, 1, 2 or 3 F １ -C ４ Alkyl, b) C substituted with 0, 1, 2 or 3 F １ -C ４ Alkoxy, c) C.N.; d) OH, e) F, Cl, or Br; f) oxo or NO ２ , g) NRaRb, where Ra and Rb are each independently H and C １ -C ３ alkyl), h) 5-6 membered monocyclic saturated, partially unsaturated or aromatic heterocyclyl substituted with 0, 1 or 2 substituents, each of which is independently selected from F, Cl, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H and C １ -C ３ a 5-6 membered monocyclic saturated, partially unsaturated or aromatic heterocyclyl selected from alkyl, R ２ is selected from the group consisting of: a) H b) F, Cl, or Br; c) C substituted with 0, 1, 2 or 3 substituents １ -C ４ alkyl, wherein the substituents are each independently selected from F, OH, C ３ -C ６ cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; During the ceremony, Cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, Fluoro C １ -C ４ Alkyl and hydroxy C １ -C ４ alkyl, C １ -C ４ Alkyl, d) C substituted with 0, 1, 2 or 3 substituents １ -C ４ Alkoxy, wherein the substituents are each independently selected from F, OH, C ３ -C ６ cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; During the ceremony, Cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ alkyl, C １ -C ４ Alkoxy, e) 0, 1, 2 or 3 of F, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ Alkyl-substituted C ３ -C ６ Cycloalkyl, f) phenyl substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Br, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C ３ -C ４ Cycloalkyl, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ alkyl, g) monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, said monocyclic or bicyclic heterocyclyl containing 0, 1, 2 or 3 of F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C ３ -C ４ Cycloalkyl, haloC １ -C ４ Alkyl, Hydroxy C １ -C ４ heterocyclyl substituted with alkyl; R ３ is selected from the group consisting of: a) F, Br, or Cl, b) C substituted with 0, 1, 2 or 3 substituents １ -C ４ alkyl, wherein the substituents are each independently F, Cl, C ３ -C ６ cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; During the ceremony, Cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ alkyl, C １ -C ４ Alkyl, c) C substituted with 0, 1, 2 or 3 substituents １ -C ４ Alkoxy, wherein the substituents are each independently selected from F, C ３ -C ６ cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; During the ceremony, Cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ alkyl, C １ -C ４ Alkoxy, d) 0, 1, 2 or 3 of F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ Alkyl-substituted C ３ -C ６ Cycloalkyl, e) phenyl substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C ３ -C ４ Cycloalkyl, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ alkyl, phenyl, and f) monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, said monocyclic or bicyclic heterocyclyl being 0, 1, 2 or 3 of F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C ３ -C ４ Cycloalkyl, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ heterocyclyl substituted with alkyl; or R ２ and R ３ together with the nitrogen atom to which they are attached, ３ -C ６ Forming a cycloalkyl, and R ４ is H or C １ -C ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

3. R １ is a monocyclic or bicyclic heterocyclyl containing at least one nitrogen atom, said monocyclic or bicyclic heterocyclyl being substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: a) C substituted with 0, 1, 2 or 3 F １ -C ４ Alkyl, b) C substituted with 0, 1, 2 or 3 F １ -C ４ Alkoxy, c) C.N.; d) OH, e) oxo, f)NO ２ 、 g) NRaRb, where Ra and Rb are each independently H and C １ -C ３ alkyl), h) 5-6 membered monocyclic saturated, partially unsaturated or aromatic heterocyclyl substituted with 0, 1 or 2 substituents, each of which is independently selected from F, Cl, OH, CF ３ , C １ -C ４ alkyl, and NRaRb, where Ra and Rb are each independently selected from H and C1-C3 alkyl, R ２ is selected from the group consisting of: a) H b) F, Cl, or Br; c) C substituted with 0, 1, 2 or 3 substituents １ -C ４ alkyl, wherein the substituents are each independently selected from F, OH, C ３ -C ６ cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; During the ceremony, Cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, Fluoro C １ -C ４ Alkyl and hydroxy C １ -C ４ alkyl, C １ -C ４ Alkyl, d) C substituted with 0, 1, 2 or 3 substituents １ -C ４ Alkoxy, wherein the substituents are each independently selected from F, OH, C ３ -C ６ cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; During the ceremony, Cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ alkyl, C １ -C ４ Alkoxy, e) 0, 1, 2 or 3 of F, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ Alkyl-substituted C ３ -C ６ Cycloalkyl, f) phenyl substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C ３ -C ４ Cycloalkyl, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ alkyl, phenyl, and g) monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, said monocyclic or bicyclic heterocyclyl containing 0, 1, 2 or 3 of F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C ３ -C ４ Cycloalkyl, haloC １ -C ４ Alkyl, Hydroxy C １ -C ４ heterocyclyl substituted with alkyl; R ３ is selected from the group consisting of: a) F or Br, b) C substituted with 0, 1, 2 or 3 substituents １ -C ４ alkyl, wherein the substituents are each independently F, Cl, C ３ -C ６ cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; During the ceremony, Cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ alkyl, C １ -C ４ Alkyl, c) C substituted with 0, 1, 2 or 3 substituents １ -C ４ Alkoxy, wherein the substituents are each independently selected from F, C ３ -C ６ cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl; During the ceremony, Cycloalkyl, phenyl, and heterocyclyl are substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ alkyl, C １ -C ４ Alkoxy, d) 0, 1, 2 or 3 of F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ Alkyl-substituted C ３ -C ６ Cycloalkyl, e) phenyl substituted with 0, 1, 2, or 3 substituents, each of which is independently selected from F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C ３ -C ４ Cycloalkyl, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ alkyl, phenyl, and f) monocyclic or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, said monocyclic or bicyclic heterocyclyl being 0, 1, 2 or 3 of F, Cl, OH, CN, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C ３ -C ４ Cycloalkyl, Fluoro C １ -C ４ Alkyl, Hydroxy C １ -C ４ heterocyclyl substituted with alkyl; or R ２ and R ３ together with the nitrogen atom to which they are attached, ３ -C ６ Forming a cycloalkyl, R ４ is H, Thereby, formula I: 【Chemistry 2】 3. The compound of claim 2, wherein the compound is:

4. R １ is selected from the group consisting of pyrrole, pyrrolidine, imidazole, thiazole, oxazole, triazole, tetrazole, pyridine, piperidine, pyrimidine, pyrazine, and morpholine; or R １ The compound according to any one of claims 1 to 3, wherein the bicyclic heterocyclyl containing at least one nitrogen is selected from the group consisting of indole, isoindole, benzimidazole, quinoline, and isoquinoline, or a pharma- ceutically acceptable salt thereof.

5. R １ isoquinolinyl, 5-bromo-4-methylpyrid-3-yl, 4-methylpyrid-3-yl, 5-fluoropyrid-3-yl, 5-bromopyrid-3-yl, 4-trifluoromethylpyrid-3-yl, 3-trifluoromethylpyrid-2-yl, N-methyl-2-oxopyrrolidin-3-yl, N-(2,2,2-trifluoroethyl)-2-oxopyrrolidin-3-yl, N-(2,2,2-trifluoroethyl)-imidazol-2-yl, 1,2,4-triazole-3-yl, 4. The compound according to claim 1, wherein the compound is selected from the group consisting of 4-methyl-1,2,4-triazol-3-yl, 1-(2,2,2-trifluoroethyl)-1,2,4-tetrazol-5-yl, 6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl, 5H,6H,7H,8H,9H-[1,2,4]triazolo[4,3-a]azepin-5-yl, and 4-methylfurazan-3-yl, or a pharma- ceutically acceptable salt thereof.

6. R １ is pyrid-3-yl substituted with 0, 1 or 2 substituents, each of which is independently selected from the group consisting of C １ -C ３ The compound of any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein R is selected from alkyl, F, Cl, and Br.

7. R １ is isoquinolin-4-yl substituted with 0, 1 or 2 substituents, each of which is independently selected from the group consisting of C １ -C ３ The compound of any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein R is selected from alkyl, F, Cl, and Br.

8. R ２ But, H, C １ -C ４ Alkyl, C １ -C ４ The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkoxy, F, Cl, and Br.

9. R ２ The compound according to any one of claims 1 to 3, wherein is H, or a pharma- ceutically acceptable salt thereof.

10. R ３ but, C substituted with 0, 1, 2 or 3 substituents １ -C ４ alkyl, each of the substituents being independently selected from F, Cl, C ３ -C ６ selected from cycloalkyl, phenyl, mono- or bicyclic saturated, partially unsaturated or aromatic heterocyclyl, or 4. The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein said aryl group is selected from tert-butyl, cyclobutyl, or phenyl.

11. The compound according to any one of claims 1 to 3, which is not 2-(2-chlorophenyl)-7-(2-fluoro-4-methoxypyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or a pharma- ceutically acceptable salt thereof.

12. 2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(isoquinolin-4-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-tert-butyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-cyclobutyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(5-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(5-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromopyridin-3-yl)-2-cyclobutyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-bromophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(isoquinolin-4-yl)-2-(2-methoxyphenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(isoquinolin-4-yl)-2-(2-(trifluoromethyl)phenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(isoquinolin-4-yl)-2-(o-tolyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(7-(isoquinolin-4-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-2-yl)benzonitrile, 2-(3-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(4-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(4-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2,6-dichlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chloro-3-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chloro-4-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chloro-6-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(benzyloxy)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(phthalazin-1-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(1,6-naphthyridin-8-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2,7-naphthyridin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(pyrido[3,4-b]pyrazin-8-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(5-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(6-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(7-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(5,6,7,8-tetrahydroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(6-methoxyisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(6-methylisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(6,7,8-trifluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(6-(dimethylamino)-7,8-difluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, for example, isomer 1 as described herein; 2-(2-chlorophenyl)-7-(2-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-isopropylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(4-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)-2-(2-chlorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(5-(dimethylamino)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(pyrimidin-5-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-bromophenyl)-7-(isoquinolin-4-yl)-5-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-5-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(isoquinolin-4-yl)-5-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-cyclobutyl-7-(isoquinolin-4-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)acetamide, 2-cyclobutyl-5-((2,6-dichloropyridin-4-yl)methyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-cyclobutyl-7-(isoquinolin-4-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)acetonitrile, 5-allyl-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-5-ethyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(isoquinolin-4-yl)-5-(pyridin-2-ylmethyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 5-((1H-imidazol-2-yl)methyl)-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(isoquinolin-4-yl)-5-((2-oxopyrrolidin-1-yl)methyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 5-acetyl-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 5-((1H-pyrazol-5-yl)methyl)-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(pyridazin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-phenoxypyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chloro-4-fluorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chloro-4-fluorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-2-fluoropyridin-3-yl)-2-(2-chlorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(3-chloroisoquinolin-4-yl)-2-(2-chlorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chloro-4,5-difluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(5-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(1,6-naphthyridin-8-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2-fluoro-4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-(trifluoromethyl)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(4-(dimethylamino)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(cinnolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7 diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(1H-imidazo[4,5-c]pyridin-7-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-7-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(imidazo[1,2-a]pyrazin-5-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-(2-chlorophenyl)-7-(pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, or a pharma- ceutically acceptable salt of any one of the above compounds.

13. (2S,4S)-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, (2R,4R)-2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(isoquinolin-4-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-tert-butyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-cyclobutyl-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromo-4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(4-methylpyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(5-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(5-fluoropyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 7-(5-bromopyridin-3-yl)-2-cyclobutyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[4-(trifluoromethyl)pyridin-3-yl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-(1-methyl-2-oxopyrrolidin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-(1-methyl-2-oxopyrrolidin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[(1-methyl-2-oxopyrrolidin-3-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 7-[2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-{[1-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[(1-methyl-1H-1,2,4-triazol-5-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[1-(4-methyl-4H-1,2,4-triazol-3-yl)ethyl]-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-{[1-(2,2,2-trifluoroethyl)-1H-1,2,3,4-tetrazol-5-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-tert-butyl-7-{[6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-{[6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}-5,7-diazaspiro[3.4]octane-6,8-dione, 2-phenyl-7-({5H,6H,7H,8H,9H-[1,2,4]triazolo[4,3-a]azepin-3-yl}methyl)-5,7-diazaspiro[3.4]octane-6,8-dione, 2-cyclobutyl-7-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-5,7-diazaspiro[3.4]octane-6,8-dione, or a pharma- ceutically acceptable salt of any one of the above compounds.

14. Comprising a compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, in admixture with a pharma- ceutically acceptable excipient, carrier and / or diluent. Pharmaceutical compositions.

15. 15. A pharmaceutical composition according to claim 14 for use as a medicament in therapy.

16. 15. A pharmaceutical composition as claimed in claim 14 for use in the treatment and / or prevention of a disease or disorder caused by a coronavirus.

17. 17. The pharmaceutical composition for use according to claim 16, wherein the disease or disorder is COVID-19.

18. 15. Use of the pharmaceutical composition according to claim 14 for the manufacture of a medicament for the treatment and / or prevention of a disease or disorder caused by a coronavirus.

19. The use according to claim 18, wherein the disease or disorder is COVID-19.

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