SUBSTITUTED HYDANTOIN COMPOUNDS, METHODS FOR PREPARATION THEREOF AND USE THEREOF IN THE TREATMENT AND/OR PREVENTION OF A CORONA VIRUS DISEASE

Described is a compound of Formula II,   wherein R1 is an optionally substituted mono or bicyclic saturated, partly unsaturated or aromatic heterocyclyl having at least one nitrogen atom, and the other variables are as defined herein. The compounds are inhibitors of the corona virus main protease (MPRO) Disclosed are also methods for preparation of the compounds, and uses of the compounds, e.g., in the treatment and/or prevention of corona virus diseases such as COVID-19.

TECHNICAL FIELD

The present disclosure pertains to substituted hydantoin derivatives. More specifically, the present disclosure pertains to substituted 5,7-diazaspiro[3.4]octane-6,8-diones, methods of preparation thereof as well as use thereof as inhibitors of the corona virus main protease (abbreviated Mpro) in the treatment and/or prevention of corona virus diseases e.g. COVID-19.

BACKGROUND

Coronavirus disease 2019, abbreviated COVID-19, is a contagious disease caused by severe acute respiratory syndrome coronavirus 2, abbreviated SARS-CoV-2. The SARS-CoV-2 virus has caused the greatest health crisis of this generation and COVID-19 has already led to >3 million deaths worldwide. Despite promising vaccination efforts, antiviral drugs will likely be crucial to control future outbreaks of coronaviruses. SARS-CoV-2 will continue to circulate and will likely be a major threat to our society as it is the third deadly coronavirus in recent history. Antiviral agents are needed to treat patients that have been infected, as well as be given prophylactically to patients who run a high risk of being infected.

WO 2017/047146 A2 relates to inhibitors of viral replication. Preferred embodiments provide for a compound of the Formula (I), which includes a hydantoin moiety.

Nature, Vol. 258, 11 Jun. 2020, 289 relates to the structure of Mprofrom SARS-CoV-2 and discovery of its inhibitors. It is stated that the crystal structure and docketing data show that the drug leads identified can bind to the substrate-binding pocket of SARS-CoV-2 Mpro, which is highly conserved among all coronaviruses.

ACS Comb. Sci. 2018, 20, 35-43 relates to parallel synthesis of hydantoin libraries by reaction of in situ generated 2,2,2-trifluoroethylcarbamates and α-amino esters. A library of 1158 hydantoins designed according to the lead-likeness criteria (MW 200-350, c Log P 1-3) was prepared.

Among the proteins encoded by the SARS-CoV-2 genome, the chymotrypsin-like main protease (abbreviated Mpro) has emerged as a promising drug target. Inhibition of this enzyme blocks processing of polypeptides produced by translation of the viral RNA, which is essential for viral replication. After the SARS-CoV outbreak in 2002, inhibitors of Mprowere identified and several of these were recently confirmed active against the highly homologous SARS-CoV-2 protease. However, many of these are peptidomimetics with limited druglikeness or covalent modifiers reacting with the active site cysteine that may be promiscuous inhibitors. Therefore, there is a need for novel non-covalent inhibitors of Mprowith favourable physiochemical properties. Accordingly, one objective of the present disclosure is the provision of compounds that are inhibitors of the SARS-CoV-2 main protease (Mpro).

SUMMARY

It is an object of the present disclosure to fulfill the above-mentioned need, and/or to provide advantages and aspects not provided by hitherto known techniques.

The aforementioned object is wholly or at least partly achieved as described in the appended independent claims1,14,15,16,18and20. Embodiments are set forth in the appended dependent claims and in the following description and examples.

DESCRIPTION

The present disclosure provides a compound of Formula II:

The compound of Formula II may be a compound of Formula IIIa, or a pharmaceutically acceptable salt thereof. Thus, there is provided a compound of Formula IIIa:

Further, the compound of Formula II may be a compound of Formula IIIb, or a pharmaceutically acceptable salt thereof. Thus, there is provided a compound of Formula IIIb:

The compound of Formula II may be a compound of Formula I, or a pharmaceutically acceptable salt thereof. Thus, the present disclosure provides a compound of Formula I:

The terms and expressions used herein throughout the present document such as the abstract, specification and claims shall be interpreted as defined herein such as below unless otherwise indicated. The meaning of each term is independent at each occurrence. A term or expression used herein, which is not explicitly defined, shall be interpreted as having its ordinary meaning used in the art in light of the disclosure and the context. The following definitions of terms and expressions shall apply throughout this document.

The term “C1-Cnalkyl” wherein n is an integer ≥1, denotes a straight or branched saturated alkyl chain of one to n carbon atoms. For example, C1-C4alkyl means an alkyl chain having one, two, three or four carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Similarly, the term C1-C3alkyl includes methyl, ethyl, n-propyl and isopropyl

The term “fluoroC1-Cnalkoxy” wherein n is an integer ≥1 as used herein represents fluoroC1-Cnalkoxy as defined above wherein at least one C atom is substituted with one, two or three fluorine atom(s). For example, “fluoroC1-Cnalkoxy” includes, but is not limited to, trifluoromethoxy, difluoromethoxy, fluoromethoxy and trifluoroethoxy.

The term “C1-Cnalkoxy” wherein n is an integer ≥1 denotes a C1-Cnalkyl group as defined above which is linked to an oxygen atom. For example, “C1-C4alkoxy” includes, but is not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy and butoxy.

The term “C3-Cncycloalkyl” wherein n is an integer ≥3 denotes a saturated or unsaturated non-aromatic monocyclic ring composed of three to n carbon atoms. For example “C3-C6cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. “C3-C4cycloalkyl” is understood to include cyclopropyl and cyclobutyl

The term “hydroxyC1-Cnalkyl” wherein n is an integer ≥1 as used herein represents C1-Cnalkyl as defined above wherein at least one C atom is substituted with one hydroxy group. Typical hydroxyC1-Cnalkyl groups are C1-Cnalkyl wherein one C atom is substituted with one hydroxy group. Exemplary hydroxyC1-Cnalkyl includes hydroxyC1-C4alkyl such as hydroxymethyl and hydroxyethyl.

The term “fluoroC1-Cnalkyl” wherein n is an integer ≥1 as used herein represents C1-Cnalkyl as defined above wherein at least one C atom is substituted with one, two or three fluoro atom(s). Typical fluoroC1-Cnalkyl groups are C1-Cnalkyl wherein one C atom is substituted with one, two or three fluoro atoms. Exemplary fluoroC1-Cnalkyl groups includes fluoroC1-C4alkyl such as fluoromethyl, difluoromethyl and trifluoromethyl.

The term ‘C2-Cnalkenyl’ wherein n is an integer ≥2 as used herein as a group or part of a group denotes a straight or branched chain hydrocarbon radical having saturated carbon-carbon bonds and at least one carbon-carbon double bond, and having from 2 to n carbon atoms. Exemplary alkenyl groups include, but are not limited to, 1-propenyl, 2-propenyl (or allyl), isopropenyl, and the like.

The term ‘C2-Cnalkynyl’ wherein n is an integer ≥2 as used herein as a group or part of a group denotes a straight or branched 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.

The term “oxo” denotes a double bonded oxygen, i.e. forming a carbonyl moiety when bound to a carbon atom; and a sulfoxide or sulfone when one or two oxo groups respectively are bound to a sulfur atom. It should be noted that the group “oxo” can be present as substituent only where valence so permits.

The term “bicyclic heterocyclyl” as used herein intends a stable ring system of two rings joined together wherein the two rings share one, two or more atoms, said ring system is composed of 6-14 atoms, preferably 6-10 atoms. The ring system comprises carbon atoms and one or more heteroatom(s) selected from nitrogen, oxygen and sulphur. Examples of bicyclic heterocyclyl include, but is not limited to, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxazolinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazinolyl, benzisothiazinolyl, benzothiazolyl, benzoxadiazolyl, benzo-1,2,3-triazolyl, benzo-1,2,4-triazolyl, benzotetrazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidyl, benzopyridazinyl, benzopyrazolyl, phthalazinyl, etc.

The term “heterocyclyl” is intended to include monocyclic heterocyclyl and bicyclic heterocyclyl as defined above.

The term “substituted” refers to wherein, in a molecule or part of a molecule, at least one hydrogen atom is replaced with a substituent.

The monocyclic heterocyclyl comprising at least one nitrogen of R1described herein may be selected from, but are not limited to, the group consisting of pyrrole, pyrrolidine, imidazole, thiazole, oxazole, triazole, tetrazole, pyridine, piperidine, pyrimidine, pyrazine and morpholine,

orthe bicyclic heterocyclyl comprising at least one nitrogen of R1described herein may be selected from, but are not limited to, the group consisting of indolyl, isoindolyl, benzimidazolyl, quinolinyl and isoquinolinyl, especially isoquinolinyl, phthalazinyl.

orthe bicyclic heterocyclyl comprising at least one nitrogen of R1described herein may be selected from, but are not limited to, the group consisting of indolyl, isoindolyl, benzimidazolyl, quinolinyl and isoquinolinyl, especially isoquinolinyl, phthalazinyl.

Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated. For instance pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl, 3-pentyl and the like.

In one configuration of compounds of Formula II or III, R4is H.

In one configuration of the compounds described herein such as a compound of Formula I, Formula II, Formula IIIa or Formula IIIb, R1is pyrid-3-yl which is substituted with 0, 1, 2 substituents each independently selected from C1-C3alkyl, F, Cl and Br.

In an alternative configuration of the compounds described herein such as a compound of Formula I, Formula II, Formula IIIa or Formula IIIb, R1is isoquinolin-4-yl which is substituted with 0, 1, 2 substituents each independently selected from C1-C3alkyl, F, Cl and Br.

In an alternative configuration of the compounds described herein such as a compound of Formula I, Formula II, Formula IIIa or Formula IIIb, R1is isoquinolin-4-yl which is substituted with 0, 1, 2, 3, or 4 substituents each independently selected from C1-C3alkyl, F, Cl and Br, or ring carbons are replaced with nitrogen atoms.

R2described herein may be selected from the group consisting of H, C1-C4alkyl, C1-C4alkoxy, F, Cl and Br. For instance, R2may be H. Further, R2may be methyl.

In a configuration of the compounds described herein such as a compound of Formula I, Formula II, Formula IIIa or Formula IIIb, R3is phenyl which is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: F, Cl, Br, CN, CF3, OMe, Me.

In one configuration of the compounds described herein such as a compound of Formula II, Formula IIIa or Formula IIIb, R4is C1-C3alkyl and may be substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: F, Cl, OH, CF3, oxo, C1-C4alkoxy, fluoroC1-C4alkoxy.

The present disclosure also provides a compound as described herein, which is one or more of the following:2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 1 or 2 described herein,2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as 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, such as isomer 1 or 2 as described herein,2-(2-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 1 or 2 as described herein,7-(isoquinolin-4-yl)-2-(2-methoxyphenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as 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 as described herein,2-(4-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 as described herein,2-(2,6-dichlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as 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, such as 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, such as 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, such as 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, such as isomer 1 or 2 as described herein,7-(isoquinolin-4-yl)-2-methyl-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, such as 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, such as 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, such as 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, such as 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 as 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, such as 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 as 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 as 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 as described herein,2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 as 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 as 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 as 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 as described herein,2-(2-chlorophenyl)-7-(pyridin-3-yl)-5,7-diazaspiro[3.4]octane-6,8-dione,or a pharmaceutically acceptable salt of any one of the foregoing compounds.

The present disclosure provides a compound of Formula I, which is one or more of the following:(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-oxopyrrolidin]octane-6,8-dione,2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione2-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 pharmaceutically acceptable salt of any one of the foregoing compounds.

The present disclosure provides a compound of Formula I, or a pharmaceutically 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, such as isomer 1 described herein,2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as 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.

Further, the present disclosure provides a compound of Formula I, which is one or more of the following: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 pharmaceutically acceptable salt or composition of any one of the foregoing compounds.

Further, the present disclosure provides a compound of Formula I or Formula II, which is one or more of the following:2-(3-bromothiophen-2-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione such as Isomer 2 as described herein,2-(3-chlorothiophen-2-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 as described herein,2-(2-chlorophenyl)-7-(phthalazin-1-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 as described herein,2-(2-chloro-6-fluorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 as described herein,2-(2-chlorophenyl)-7-(6-fluoroisoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione isomer 27-(isoquinolin-4-yl)-2-methyl-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, such as 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 as described herein,2-(2-chlorothiophen-3-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 as 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 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, 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 as 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 as described herein,2-(2,6-dichlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 as 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 pharmaceutically acceptable salt or composition of any one of the foregoing compounds.

The present disclosure also provides a compound which is one or more of the following: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, such as 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, such as 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, such as isomer 1 or 2 as described herein,7-(isoquinolin-4-yl)-2-methyl-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, such as 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, such as 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 as 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 as described herein,or a pharmaceutically acceptable salt of any one of the foregoing compounds.

The present disclosure also provides a compound which is one or more of the following: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, such as 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, such as 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, such as 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, such as isomer 1 or 2 as described herein,7-(isoquinolin-4-yl)-2-methyl-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, such as 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, such as 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, such as 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 as described herein,or a pharmaceutically acceptable salt of any one of the foregoing compounds.

The present disclosure also provides a compound which is one or more of the following:2-(2-chlorophenyl)-7-(phthalazin-1-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 49 as 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 pharmaceutically acceptable salt of any one of the foregoing compounds.

The present disclosure also provides a compound which is one or more of the following: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 pharmaceutically acceptable salt of any one of the foregoing compounds.

The present disclosure also provides a compound which is one or more of the following: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 pharmaceutically acceptable salt of any one of the foregoing compounds.

The present disclosure also provides a compound which is one or more of the following:2-(2-chlorothiophen-3-yl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as 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, such as 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, such as 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 pharmaceutically acceptable salt of any one of the foregoing compounds.

The present disclosure also provides a compound which is one or more of the following:2-cyclobutyl-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 1 or 2 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 pharmaceutically acceptable salt of any one of the foregoing compounds.

The present disclosure also provides a compound which is one or more of the following:7-(isoquinolin-4-yl)-2-methyl-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, such as 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 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 as described herein,2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-2-methyl-5,7-diazaspiro[3.4]octane-6,8-dione, such as isomer 2 as described herein,or a pharmaceutically acceptable salt of any one of the foregoing compounds.

The present disclosure also provides a compound which is one or more of the following: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 pharmaceutically acceptable salt of any one of the foregoing compounds.

The present disclosure also provides a compound which is one or more of the following: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, such as 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, such as 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, such as 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, such as 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 as 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 as described herein,or a pharmaceutically acceptable salt of any one of the foregoing compounds.

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

The present disclosure also provides a compound which is one or more of the following: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-dion,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 pharmaceutically acceptable salt of any one of the foregoing compounds.

The compounds described herein, such as a compound of Formula I, Formula II or Formula III may or may not comprise one or more of the following compounds, or a pharmaceutically acceptable salt 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 as described herein,7-(isoquinolin-4-yl)-2-methyl-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione, such as 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, such as 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 as 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-dione, such as isomer 2 as 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 as described herein.

Further, 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 pharmaceutically acceptable salt thereof.

The compound of Formula I, Formula II, Formula IIIa or Formula IIIb described herein, or pharmaceutically acceptable salt thereof, may be provided as a mixture of enantiomers, (−)-enantiomer and/or a (+)-enantiomer. For instance, the compound of Formula I, Formula II, Formula IIIa or Formula IIIb described herein, or pharmaceutically acceptable salt thereof, may be provided as a racemic mixture or as a substantially enantiomerically pure (−)-enantiomer or (+)-enantiomer.

There is also provided a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula IIIa or Formula IIIb as described herein, or a pharmaceutically acceptable salt thereof, in a mixture with a pharmaceutically acceptable excipient, carrier and/or diluent.

Further, there is provided a compound as described herein, such as a compound of Formula I, Formula II, Formula IIIa or Formula IIIb as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for use as a medicament such as a medicament in therapy.

There is also provided a compound as described herein of Formula I, Formula II, Formula IIIa or Formula IIIb as described herein, or a pharmaceutically acceptable salt thereof, ora pharmaceutical composition as described herein for use in the treatment and/or prevention of a disease or disorder caused by a corona virus.

It will be appreciated that the corona virus described herein may be SARS-CoV-2. Further, it will be appreciated that the corona virus described herein may cause a disease or disorder such as COVID-19

There is also provided a compound as described herein, such as a compound Formula II, Formula IIIa or Formula IIIb of Formula I as described herein, or a pharmaceutically 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 associated therewith such as COVID-19.

There is also provided a compound of Formula I as described herein, or a pharmaceutically 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 corona virus. Thus, there is provided a use of a compound as described herein, such as a compound of Formula I, Formula II, Formula IIIa or Formula IIIb described herein, or a pharmaceutical composition as described hereinfor the manufacture of a medicament for the treatment and/or prevention of a disease or disorder caused by a corona virus.

There is also provided a compound of Formula I as described herein, or a pharmaceutically 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, there is provided a use of a compound as described herein, such as a compound of Formula I, Formula II, Formula IIIa or Formula IIIb 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.

There is also provided a method for treatment and/or prevention ofa disease or disorder caused by a corona virus which method comprises the step of administering a therapeutically effective amount 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein to a patient such as a human or an animal in need thereof.

There is also provided a method for treatment and/or prevention ofSARS-CoV-2 or a disease or disorder associated therewith such as COVID-19 which method comprises the step of administering a therapeutically effective amount ofa compound as described herein, such as a compound of Formula I, Formula II, Formula IIIa or Formula IIIb as described herein, or a pharmaceutically acceptable salt thereof, ora pharmaceutical composition as described hereinto a patient such as a human or an animal in need thereof.

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.

Pharmaceutically Acceptable Salts

Compounds of the present disclosure may be provided in the form of a pharmaceutically acceptable salt. As used herein “pharmaceutically acceptable salt”, where such salts are possible, includes salt(s) prepared from pharmaceutically acceptable non-toxic acid(s), i.e. pharmaceutically acceptable acid addition salt(s).

Other acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a compound of the present disclosure and its pharmaceutically acceptable acid addition salt.

Certain compounds of the present disclosure may exist as solvates or hydrates. It is to be understood that the present disclosure encompasses all such solvates or hydrates.

In a salt, proton transfer may occur between the active pharmaceutical ingredient and the counter ion of the salt. However, in some cases there is no or only partial proton transfer and the solid is therefore not a true salt. It is accepted that the proton transfer is in fact a continuum, and can change with temperature, and therefore the point at which a salt is better described as a “co-crystal” may be subjective. The term “co-crystal” as used herein refers to multicomponent system in which there exists a host molecule or molecules (active pharmaceutical ingredient) and a guest (or co-former) molecule or molecules. The guest or co-former molecule is defined as existing as a solid at room temperature in order to distinguish the co-crystal from solvates. However, a co-crystal may itself form solvates. In a co-crystal there is generally predominance for interaction through non-ionic forces, such as hydrogen bonding.

Compounds of the present disclosure may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. Thus, it is to be understood that all polymorphs, such as mixtures of different polymorphs, are included within the scope of the claimed compounds.

Isotopically Labelled Compounds

Compounds of the present disclosure may be used in their labelled or unlabeled form. In the context of this present disclosure the labelled compound has one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. The labelling will allow easy quantitative detection of said compound.

Labelled compounds of the present disclosure may contain at least one radio-nuclide as a label. Positron emitting radionuclides are all candidates for usage. In the context of this present disclosure the radionuclide may be selected from isotopes of hydrogen, carbon, nitrogen, fluorine and oxygen, such as2H (deuterium),3H (tritium),11C,13C,14C,18O,17O,19F and18F. It is known that substitution with heavier isotopes, such as substitution of one or more hydrogen atoms with deuterium (2H) might provide pharmacological advantages in some instances, such as increased metabolic stability.

The physical method for detecting a labelled compound 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 X-ray Tomography (CAT), or combinations thereof.

Compounds of the present disclosure may be administered in the form of a prodrug. A prodrug is a compound, which may have little or no pharmacological activity itself, but when such compound is administered into or onto the body of a patient, it is converted into a compound of Formula I. The prodrug may contain a metabolically or chemically labile acyl function such as a carboxylate ester, amide or carbamate, or an acetal/ketal or hemiaminal derivatives.

Combinations

The compounds of the present disclosure may be combined with other pharmaceutical drugs such as other antiviral drugs and/or metabolism blocking drugs.

Methods of Preparation

The compound of Formula I, Formula II, Formula IIIa or Formula IIIb described herein may be prepared using methods described in the art and/or as described herein. For instance, the compound of Formula I may be prepared as depicted in Scheme 1.

It will be appreciated that the substituents R1, R2, R3in Schemes 1 and 2 may be as described herein for the compound of Formula I, Formula II, Formula IIIa or Formula IIIb.

Cyclobutyl amino acids (S2) for use in the preparation of compounds of Formula I, Formula II, Formula IIIa or Formula IIb can be prepared as generally outlined in Scheme 2.

An alternative route to compounds of Formula I, II or III is depicted in Scheme 3. In this route, the starting material is a styrene derivative, i.e. one of R2and R3is phenyl or substituted phenyl.

It will be appreciated that the substituents R1, R2, R3and R4in Scheme 3 may be as described herein for the compound of Formula I, Formula II, Formula IIIa or Formula IIIb.

EXAMPLES

In this document, unless otherwise stated the drawings of the chemical compounds have been made using the Chem Doodle version 7.0.1 or version 7.0.2, ChemDraw Professional 17.0. or Chem Draw Ultra 12.0. Unless otherwise stated, the naming of the chemical compounds has been made 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. If the name and chemical structure are inconsistent the structure shall be considered to be correct. Unless stated otherwise the compounds have been prepared as a mixture of stereoisomers.

Abbreviations

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, whereas THF was purchased from Sigma-Aldrich. Reagents and solvents were used as such without further purification. All reactions involving air, or moisture-sensitive reagents or intermediates, were performed under a nitrogen atmosphere. LC-MS was used for monitoring reactions and assessing purity using an Agilent 1100 series HPLC having a C18 Atlantis T3 column (3.0×50 mm, 5 m). Acetonitrile-water (both containing 0.1% HCOOH, flow rate 0.75 ml/min, and with a gradient of 5-95% acetonitrile over 6 min.) was used as mobile phase. A Waters micromass ZQ(model code: MM1) mass spectrometer with electrospray ionization was used for detection of molecular ions. Silica gel 60 F254TLC plates from Merck were also sometimes used for monitoring reactions and particularly during purification of compounds. Visualization of the developed TLC was done using UV light (254 nm) and staining with ninhydrin or anisaldehyde. After workup, organic phases were dried over Na2SO4/MgSO4and filtered before being concentrated under reduced pressure. Silica gel (Matrex, 60 Å, 35-70 m, Grace Amicon) was used for purification of intermediate compounds with flash column chromatography. Preparative reversed-phase HPLC was performed on a Kromasil C8 column (250×21.2 mm, 5 m) on a Gilson HPLC equipped with Gilson 322 pump, UV/Visible-156 detector and 202 collector using acetonitrile-water gradients as eluents with a flow rate of 15 ml/min and detection at 210 or 254 nm. Unless otherwise stated, all the tested compounds were purified by HPLC.1H and13C NMR spectra for the synthesized compounds were recorded at 298 K on an Agilent Technologies 400 NMR spectrometer at 400 MHz or 100 MHz, or on Bruker Avance Neo spectrometers at 500/600 MHz or 125/150 MHz. Chemical shifts are reported in parts per million (ppm, δ) referenced to the residual1H resonance of the solvent [(CD3)2CO, δ 2.05; CDCl3, δ 7.26; CD3OD 3.31; DMSO-d6δ 2.50]. Splitting patterns are designated as follows: s (singlet), d (doublet), t (triplet) and m (multiplet), br (broad). Coupling constants (J values) are listed in hertz (Hz). The purity of the compounds was ≥95% as determined by high resolution1H NMR spectroscopy (600 MHz) and LCMS.

General Synthetic Description

The compounds were prepared as shown in Schemes 1, 2 and 3. More specifically, the compounds were synthesized as described below.

Triphosgene mediated formation of isocyanates from amine S1, followed by addition of amino acid ester S2 afforded the key urea ester intermediates S3 (see Ref. 1). Hydantoin analogues could be prepared directly by cyclization of urea ester intermediates S3 under basic condition using NaH (see Ref. 1). Alternatively, hydrolysis of esters S3 afforded urea acid intermediates S4 which were cyclized under acidic condition using TFA to afford hydantoin analogues (see Ref. 2).

General Procedure for Synthesis of Urea Ester Intermediates S3, Modified from Ref. 1

Et3N (3 equiv) was added to a mixture of the amine (S1, 0.25 mmol, 1 equiv) in DCM (2 ml) at 0° C. A solution of triphosgene (0.5 equiv) in DCM (0.5 ml) was added dropwise to the mixture. The reaction was stirred at 0° C. for 45 min. Then, amino acid ester hydrochloride (S2, 0.2 mmol) was added to the reaction mixture in one portion. The mixture was stirred overnight at rt, then diluted with DCM (15 ml) and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated to give crude urea ester intermediate S3, which was used as such for the next step without purification.

General Procedure for Cyclization of Urea Ester Intermediates S3 to Form Hydantoin Analogues Using Nah (Ref. 1)

NaH (3-6 equiv) was added to a mixture of urea ester intermediates 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% of CH3CN in H2O to afford the desired product as slightly yellow solid. Repurification by HPLC using 5-100% of CH3CN in H2O (H2O+0.1% TFA) afforded pure compounds as solid TFA salts.

General 2-Step Procedure for Cyclization of Urea Ester Intermediates S3 to Form Hydantoin Analogues Using TFA (Ref. 2)

NaOH (2 equiv) was added to a mixture of urea ester intermediates S3 in MeOH (2 ml) at 0° C. The mixture was stirred at rt for 15 min, after which LCMS showed complete ester hydrolysis to acid intermediate S4 and partial cyclization. The reaction mixture was neutralized with TFA, then concentrated to dryness. The residue was dissolved in TFA (2 ml) and heated overnight at 60° C. Then the solution was cooled and concentrated to dryness. The residue was dissolved in DMSO, filtered and purified by HPLC using 5-100% of CH3CN in H2O to afford the desired product as slightly yellow solid. Repurification by HPLC using 5-100% of CH3CN in H2O (H2O+0.1% TFA) afforded pure compounds as solid TFA salts.

Cyclobutanes (S6) are formed from the corresponding styrene (S5) via a Tf2O mediated cyclisation with DMA (Ref. 3). A microwave promoted Bucherer-Bergs reaction of S6 formed the requisite hydantoin ring (S7) (Ref. 4). Copper mediated N-arylation of S7 could be performed using the Aryl iodide/bromide (Ref. 5) or boronic acid (Ref. 6). N1 alkylated hydantoins (S8) were prepare via alkylation with alkyl iodides and tBuOK.

To a solution of DMA (1.2 equiv.) in DCE (1M) triflic anhydride (1.5 equiv.) was added dropwise under stirring at 0° C. The addition was accompanied by white solid precipitation. The mixture was stirred at the same temperature for 30 min and 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 down to room temperature and treated with water and then refluxed for a further 8 h. After cooling down to room temperature, the water layer was extracted with DCM. Organic layers were combined, dried under Na2SO4, concentrated in vacuo and purified by flash column chromatography.

General Procedure for Conversion of Ketone Intermediates S6 to Form Hydantoins S7 (Ref. 4)

To a microwave vial ketone (1 equiv.) was dissolved in ethanol. The freshly powdered ammonium carbonate (5 equiv.) and potassium cyanide (1.3 equiv.) were dissolved in H2O and the mixture added into the vial and irradiated at microwave oven at 100° C. for 10 min. After completion, the reaction mixture was chilled in an ice bath. Most of the EtOH was removed under reduced pressure and saturated NaHCO3was added to the reaction mixture and the water layer was extracted with EtOAc. Organic layers were combined, dried under Na2SO4, concentrated in vacuo and purified by flash column chromatography.

General Procedure for N-Arylation of S7 with Aryl Bromides or Iodides to Form Hydantoin Analogues (Ref. 5)

A pressure tube was charged with the hydantoin (1 equiv.) and copper oxide (1) (0.2 equiv.) and aryl halide (2 equiv.) (If solid). The tube was fitted with a rubber septum, evacuated under high vacuum, and backfilled with N2before adding the aryl halide (if it is liquid) (2 equiv.) and anhydrous DMF. The rubber septum was then replaced by 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 with column chromatography to obtain the target compound.

General Procedure for N-Arylation of S7 with Aryl Boronic Acids to Form Hydantoin Analogues (Ref. 6)

To a solution of hydantoin (1 equiv.) and copper (II) acetate (0.1 equiv.) in MeOH was added arylboronic acid (2 equiv.) under O2. 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 with column chromatography to obtain the target compound.

General Procedure for N-Alkylation to Form Hydantoin Analogues

To a solution of hydantoin (1 equiv.) in THF, tBuOK (1 equiv.) was added at r.t. 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 vacuo, and the crude product was dissolved in DMSO, filtered and purified by HPLC using 5-100% of CH3CN in H2O to afford the desired product S8.

The synthesized compounds are shown in Table 1A and Table 1B.

The compounds of the present disclosure may also encompass the prophetic compounds listed in Table 2A and Table 2B.

Biology

Enzyme Assay

Expression and purification of SARS-CoV-2 Mproprotease. SARS-CoV-2 Mproprotease was produced adopting a published construct used for the expression of SARS-CoV Mproprotease (Ref. 7), containing nucleotide sequences corresponding to residues S1-Q306 (Chinese isolate, NCBI accession number YP_009725301). Using this construct, the produced Mproprotease is flanked by an N-terminal GST (glutathione S-transferase) tag followed by a SARS-CoV-2 Mprorecognition sequence for auto proteolysis, and a C-terminal 6×His-tag preceded by a HRV 3C protease recognition sequence.

Except for some minor adjustments, the expression and purification of SARS-CoV-2 Mproprotease was performed according to the procedure described in reference 8. The vector (pGEX-6P-1) containing the coding sequence of the SARS-CoV-2 Mproprotease was transformed intoE. coliBL21 (DE3)-T1R competent cells. L-Broth media (Formedium, Norfolk, UK) supplemented with carbenicillin (100 μg/ml) was inoculated with fresh transformants and grown at 37° C. until an OD600of 1.5 was reached. The starter culture was then used to inoculate the main culture in Auto Induction Media (AIM) Terrific Broth base with trace elements (Formedium, Norfolk, UK) supplemented with 1% glycerol and carbenicillin (100 μg/ml). The cultures were grown at 37° C. until an OD600of 2 was reached and the protein expression was continued overnight at 18° C. for 13.5 hours. Cells were thereafter harvested by centrifugation (10 min at 4500×g, 4° C.), re-suspended 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 supernatants were 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 the bound protein was 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, the 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 the protein was treated with HRV 3C protease directly after the IMAC purification step and the buffer was at the same time exchanged by dialysis (dialysis buffer 50 mM Tris, 300 mM NaCl, 0.5 mM TCEP and 0.5 mM DTT, pH 8.0) with a dialysis cassette (Slide-A-Lyzer Dialysis Cassette, 10K MWCO, 3 ml, Thermo Fisher Scientific, Waltham, MA, USA) over night at 4° C. The cleaved SARS-CoV-2 Mproprotease samples were subsequently purified by reverse IMAC purification using a HisTrap 1 ml column (Cytiva, Little Chalfont, UK). The same wash buffer described above was used and the flow through was collected. The reverse IMAC purification was followed by a second SEC step using the same column and buffer as described earlier. Fractions containing the target protein were examined by SDS PAGE, pooled together, and concentrated with Vivaspin® 20 ml centrifugal concentrators (10 kDa MWCO, Sartorius, Goettingen, Germany) at 4,000×g, 4° C. The protein was finally flash frozen in liquid nitrogen and stored at −80° C.

Proteins and compounds. The Mproused for catalytic activity assays was obtained from the Protein Science Facility (PSF, Karolinska Institutet, Stockholm, Sweden) and is described in a prior section. All test compounds were dissolved to 10 mM stocks in 100% DMSO (Merck KGaA, Darmstadt, Germany) and transferred to ECHO LDV source plates (Labcyte, Inc, Ca, USA).

Mproactivity was analysed by detection of hydrolysis of a quenched FRET substrate, essentially as described in NCATS protocol for their SARS-CoV-2 MproProtease Enzyme Assay (Mproassay described at NIH, National Center for Advancing Translational Sciences Data portal)30. It was performed in 20 mM Tris, 50 mM NaCl and 0.1 mM EDTA (Merck KGaA, Darmstadt, Germany), pH 7.5 at room temperature. Compounds were transferred with Echo 550 non-contact dispenser (Labcyte, Inc., USA) to a Corning 3575 non-binding 384 well assay plates. Mpro(75 nM final concentration), was added to the assay plate using a 16-channel pipette (Integra ViaFlo, BergmanLabora AB, Sweden), and shaken for 15 minutes at 1500 rpm in an Eppendorf Mixmate. After a pulse centrifugation, the Mprofluorogenic substrate (stock solution at 5 mM in DMSO) was added to the assay plate to a final concentration of 10 μM, thus contributing with 0.2% DMSO in final assay, with a Labcyte ECHO 550 non-contact dispenser. After 10 minutes incubation and a pulse centrifugation, fluorescence was measured in a PerkinElmer Envision plate reader at ambient temperature using kinetic mode and with excitation at 340 nm and emission at 490 nm. Activity was calculated as percent of control activity in each data point (100*(RFU sample−RFU Blank control)/(RFU DMSO control−RFU Blank control)). Non-linear fit of 11-point dose response curves (log(inhibitor) vs. response−Variable slope (four parameters) and IC50calculations was performed using GraphPad Prism version 9.1.0 for Windows, GraphPad Software, San Diego, California USA, www.graphpad.com.

Compound screening. Compounds were screened at three concentrations, (50, 15 and 5 μM) and hits were re-tested in an 11-point concentration series (1:3 dilutions, starting concentration 50 μM). The dose-response curve was generated using Echo 550 non-contact dispensing from 10 mM compound stocks.

Table 5A, Table 5B, Table 5C, Table 5D and Table 5E show IC50values.

The direct interaction between the inhibitors and Mprowas confirmed and the affinities determined using surface plasmon resonance (SPR) biosensor analysis.

Protein Production

Avi-tagged Mprowas used for SPR biosensor assays. The expression vector and method for production is essentially as described in reference 9 with some minor modifications. The C-terminal Avi-tag replaces the His-tag, giving the final construct GST-3C-MPro-3C-AviTag inserted between BamHI and XhoI in vector pGEX-P-1. The GST-3C part is autocatalytic removed by MProupon expression. The volume of expression cultures was gradually increased in three steps over eight hours from 1 to 100 mL LB, i.e. Luria Broth, supplemented with 100 μg/mL ampicillin (Sigma) and 25 μg/mL chloramphenicol (Sigma). Ten millilitres of the starter culture was used to inoculate one litre of auto induction medium (Formedium, Hunstanton, Norfolk, UK) supplemented with 10 mL of glycerol and 100 μg/mL ampicillin and 25 μg/mL chloramphenicol. The cultures were grown at 37° C., 220 rpm for 5 h then switched to 18° C., 220 rpm for 10-12 h. The 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). The cells were lysed by sonication for 5 min on ice, using 15 s on/15 s off pulses. The lysate was 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 manufacturer 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 by 50 mM Tris pH 8, 300 mM NaCl, and for elution 10 mM and 50 mM biotin in the same buffer was used. 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.

Interaction Analysis

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

After immobilization, compounds were injected over the surface using a 10-point concentration series, at a flow rate 30 μL/min in 50 mM TrisHCl, pH 7.5, 0.05% Tween-20. An association phase was monitored for 60 s and a dissociation phase for 120 s. Sensorgrams were double-referenced by subtracting the signals from a reference surface and the signal from one blank injection. A solvent correction accounting for 2% DMSO was performed. The data was analyzed using Biacore S200 Evaluation Software, v. 3.1 (Cytiva, Uppsala, Sweden). For determination of KDvalues, an equation corresponding to a reversible, one-step, 1:1 interaction model was fitted by nonlinear regression analysis to report points taken at the end of the injection, representing steady-state signals.

Results

The SPR biosensor analysis showed that the interactions between the compounds and Mproare 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 provides the equilibrium dissociation constants (KD) determined from steady-state analysis for a selection of compounds with KD-values below 100 nM.

Inhibition of Human Proteases

Catalytic assays were set up for a panel of common human proteases in order to test if the compounds of the present disclosure can inhibit other proteases. The clinical candidate drug PF-07321332 was also tested in a comparative example. The results are shown in Table 7, Table 8 and Table 9.

TABLE 7Inhibition of cathepsin SCompound Example No.Inhibition of cathepsin S (IC50, μM)1>504>5015>50

TABLE 9Enzyme inhibition of the compound of Example 15for a set of human proteasesHuman proteaseIC50, μMCathepsin K>10Cathepsin D>10Cathepsin B>10Cathepsin L>10Thrombin>10Caspase-2>10Elastase>10Calpain 1>10Trypsin>10

It was observed that the compounds of the present disclosure such as the compounds of examples 1, 4 and 15 had IC50values >10 μM for all of the human proteases tested above. Accordingly, the compounds of the present disclosure appear to selectively inhibit the chymotrypsin-like main protease, Mpro. In contrast, the comparative compound PF-07321332 had a low IC50value (6 μM) indicating that it is not a selective inhibitor of the chymotrypsin-like main protease, Mpro.

CONCLUSIONS

As shown above by the results from the enzyme and surface plasmon resonance biosensor assays, the compounds of Formula I, II or III are inhibitors of the chymotrypsin-like main protease, Mpro. Accordingly, the compounds of Formula I, II or III fulfil the objective of the present disclosure to provide inhibitors of the chymotrypsin-like main protease, Mpro. Further, the compounds of the present disclosure selectively inhibit the chymotrypsin-like main protease, Mpro.

REFERENCES

Items

A compound of Formula I:

The compound of Formula I according to item 1, wherein R1is selected from the group consisting of pyrrole, pyrrolidine, imidazole, thiazole, oxazole, triazole, tetrazole, pyridine, piperidine, pyrimidine, pyrazine and morpholine, orthe bicyclic heterocyclyl comprising at least one nitrogen of R1is selected from the group consisting of indole, isoindole, benzimidazole, quinoline and isoquinoline.

The compound of Formula I according to item 1, wherein R1is pyrid-3-yl which is substituted with 0, 1, 2 substituents each independently selected from C1-C3alkyl, F, Cl and Br.

The compound of Formula I according to item 1, wherein R1is isoquinolin-4-yl which is substituted with 0, 1, 2 substituents each independently selected from C1-C3alkyl, F, Cl and Br.

The compound of Formula I according to anyone of the preceding items, wherein R2is selected from the group consisting of H, C1-C4alkyl, C1-C4alkoxy, F, Cl and Br.

The compound of Formula I according to any one of the preceding items, wherein R2is H.

The compound of Formula I according to any one of the preceding items, whereinR3is C1-C4alkyl substituted with 0, 1, 2 or 3 substituents each independently selected from F, Cl, C3-C6cycloalkyl, phenyl, a monocyclic or bicyclic saturated, partly unsaturated or aromatic heterocyclyl.

The compound of Formula I according to any one of items 1-7, wherein R3is tert-butyl, cyclobutyl or phenyl.

The compound of Formula I according to item 1, which is one or more of the following: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 pharmaceutically acceptable salt or composition of any one of the foregoing compounds.

A pharmaceutical composition comprising:a compound of Formula I as defined in any one of the preceding items, or a pharmaceutically acceptable salt thereof,in admixture with a pharmaceutically acceptable excipient, carrier and/or diluent.

The compound of Formula I according to any one of items 1-10, orthe pharmaceutical composition according to claim11for use as a medicament in therapy.

The compound of Formula I according to any one of items 1-10, orthe pharmaceutical composition according to claim12for use in the treatment and/or prevention of COVID-19.

A compound of Formula IIIb:

The compound of Formula III according to item 14, wherein R1is selected from the group consisting of pyrrole, pyrrolidine, imidazole, thiazole, oxazole, triazole, tetrazole, pyridine, piperidine, pyrimidine, pyrazine and morpholine, orthe bicyclic heterocyclyl comprising at least one nitrogen of R1is selected from the group consisting of indole, isoindole, benzimidazole, quinoline and isoquinoline, or a pharmaceutical composition thereof for use in the treatment and/or prevention of a corona virus disease e.g. COVID-19.

The compound of Formula III according to item 14, wherein R1is selected from the group consisting of 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-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]pyridine-5-yl, 5H,6H,7H,8H,9H-[1,2,4]triazolo[4,3-a]azepine-5-yl, and 4-methylfurazan-3-yl, or a pharmaceutical composition thereof for use in the treatment and/or prevention of a corona virus disease e.g. COVID-19.

The compound of Formula III according to item 14, wherein R1is pyrid-3-yl which is substituted with 0, 1, 2 substituents each independently selected from C1-C3alkyl, F, Cl and Br, or a pharmaceutical composition thereof for use in the treatment and/or prevention of a corona virus disease e.g. COVID-19.

The compound of Formula III according to item 14, wherein R1is isoquinolin-4-yl which is substituted with 0, 1, 2 substituents each independently selected from C1-C3alkyl, F, Cl and Br, or a pharmaceutical composition thereof for use in the treatment and/or prevention of a corona virus disease e.g. COVID-19.

The compound of Formula III according to anyone of items 14-18, wherein R2is selected from the group consisting of H, C1-C4alkyl, C1-C4alkoxy, F, Cl and Br, or a pharmaceutical composition thereof for use in the treatment and/or prevention of a corona virus disease e.g. COVID-19.

The compound of Formula III according to any one items 14-19, wherein R2is H, or a pharmaceutical composition thereof for use in the treatment and/or prevention of a corona virus disease e.g. COVID-19.

The compound of Formula III according to any one items 14-20, wherein R3is C1-C4alkyl substituted with 0, 1, 2 or 3 substituents each independently selected from F, Cl, C3-C6cycloalkyl, phenyl, a monocyclic or bicyclic saturated, partly unsaturated or aromatic heterocyclyl, or a pharmaceutical composition thereof for use in the treatment and/or prevention of a corona virus disease e.g. COVID-19.

The compound of Formula III according to any one of items 14-20, wherein R3is tert-butyl, cyclobutyl or phenyl or a pharmaceutical composition thereof for use in the treatment and/or prevention of a corona virus disease e.g. COVID-19.

The compound of Formula III according to item 14, which is one or more of the following: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 pharmaceutically acceptable salt or composition of any one of the foregoing compounds or a pharmaceutical composition thereof for use in the treatment and/or prevention of a corona virus disease e.g. COVID-19.