Compound

Abstract

The present invention relates to a compound of formula (I): TIFF2023535621000022.tif54161 (In the formula, Y is selected from C or N; X is O; Bond a is a single bond or a double bond; When a is a single bond, x is 1, and when a is a double bond, x is 0; R1 is selected from hydrogen and methyl; R2 (if present) is selected from hydrogen and methyl; R3 is selected from hydrogen, (1-6C)alkyl and (1-6C)alkyl-phenyl; wherein the phenyl is optionally substituted by one or more (e.g., 1 to 3) substituents each independently selected from hydroxy, (1-6C)alkoxy, (1-6C)alkyl, and halo (e.g., chloro and fluoro). or a pharmaceutically acceptable salt or solvate thereof.

Description

[Technical Field]

[0001] The present invention relates to novel compounds and their use in treating conditions mediated by the queuin-tRNA ribosyltransferase pathway (also known as the TGT pathway), including autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, and neurodegenerative conditions such as Parkinson's disease and Alzheimer's disease. The present invention also relates to pharmaceutical compositions comprising the novel compounds. [Background technology]

[0002] The TGT pathway, also known as the queuin-tRNA ribosyltransferase (QTRT) enzyme pathway, was first elucidated in a 2009 publication (Boland et al., J. Biol. Chem. 2009. 3;284(27):18218-27). Cells that proliferate at abnormal rates, such as T cells in autoimmune diseases, have been found to be queuin-deficient (Fergus et al., Nutrients 2015, 7(4):2897-2929).

[0003] The TGT pathway has been utilized to provide treatments for diseases. WO 2016 / 050804 and WO 2016 / 050806 each describe cuein mimetic compounds acting via the TGT pathway that are suitable for use in the treatment of autoimmune diseases, particularly multiple sclerosis (MS), rheumatoid arthritis (RA), irritable bowel disease (IBD), and diabetes.

[0004] The present invention provides new compounds for use in the treatment of diseases mediated by the TGT pathway.

[0005] There is a strong need for new treatment methods for specific autoimmune diseases. Currently, most autoimmune diseases are not incurable, and existing treatment methods focus on improving the symptoms. Autoimmune diseases such as MS, RA, alopecia areata, IBD, and diabetes are debilitating diseases that present various symptoms. Currently, there is no cure for autoimmune diseases, and only treatments for the broad range of symptoms associated with these diseases are available, which are treated with a range of drugs. Many of the drugs currently in use only have moderate effectiveness and may cause side effects that are difficult for patients to tolerate. Therefore, new drug therapies for the treatment of autoimmune diseases are highly desirable.

[0006] For example, MS is an autoimmune disease that causes a wide range of symptoms, including fatigue, blurred vision, cognitive impairment, and spasticity. Many patients develop irreversible motor disabilities, and 50% of patients are unable to walk unaided within 15 years of onset. Currently, there is no known cure for MS, but drugs exist to treat its symptoms. Examples of such medications include fingolimod, teriflunomide, dimethyl fumarate (tesifudela), ocrelizumab, siponimod, cladribine, and random polymer glatiramer acetate. While these drugs act to alter the relapse and remission rates of disease onset and / or severity, they do not reverse disease progression and are associated with numerous adverse side effects. In some subclasses of MS, such as progressive MS, only a small proportion of patients derive any benefit from existing medications.

[0007] RA is another autoimmune disease that causes a wide range of symptoms, including joint pain and stiffness, fatigue, high fever, sweating, and loss of appetite. As with MS, there is currently no known cure for RA, and patients are treated with drugs that alleviate disease symptoms, such as joint inflammation, and minimize damage. Typically, disease-modifying therapies such as methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine are administered.

[0008] Common side effects of methotrexate include feeling ill, loss of appetite, mouth sores, diarrhea, headache, and hair loss. Patients treated with methotrexate also require regular blood tests to check for liver and blood cell damage, and may require x-rays to check for lung damage.

[0009] Biologic treatments such as etanercept and infliximab are newer forms of treatment for RA. These treatments can cause patients to suffer from serious infection-related side effects.

[0010] JAK inhibitors are a new class of RA drugs and include tofacitinib and baricitinib.

[0011] Another area of significant medical need is neurodegeneration, with treatments particularly sought after for indications such as Alzheimer's disease and Parkinson's disease.

[0012] Thus, there is a need to provide effective and well-tolerated treatments for autoimmune and neurodegenerative diseases such as MS and RA. Summary of the Invention

[0013] A further object of the present invention is to provide compounds useful in the treatment of pathologies mediated by the TGT pathway, including, in particular, the treatment of autoimmune diseases such as MS and / or RA.

[0014] The present invention relates to a compound of formula (I): [ka] (In the formula, Y is selected from C or N; X is O; Bond a is a single bond or a double bond; When a is a single bond, x is 1, and when a is a double bond, x is 0; R1 is selected from hydrogen and methyl; R2 (if present) is selected from hydrogen and methyl; R3 is selected from hydrogen, (1-6C)alkyl, and (1-6C)alkyl-phenyl, wherein said phenyl is optionally substituted with one or more (e.g., 1 to 3) substituents each independently selected from hydroxy, (1-6C)alkoxy, (1-6C)alkyl, and halo (e.g., chloro and fluoro). or a pharmaceutically acceptable salt or solvate thereof.

[0015] The present invention also provides a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use as a pharmaceutical.

[0016] The present invention also provides a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a disease or condition mediated by the queuin-tRNA ribosyltransferase pathway.

[0017] The present invention also provides a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of an autoimmune disease.

[0018] The present invention also provides a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a neurodegenerative disease.

[0019] The present invention also provides a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of an inflammatory disease.

[0020] The present invention also provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0021] The present invention also provides a pharmaceutical product comprising a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, and an additional therapeutic agent.

[0022] The invention also provides a pharmaceutical product in a container containing a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, and the pharmaceutical product and instructions for use of the pharmaceutical composition in the treatment of an autoimmune disease, a neurodegenerative disease, or an inflammatory disease. Detailed Description of the Invention

[0023] The present invention provides novel compounds, medicaments, pharmaceutical compositions and uses of said compounds as pharmaceutical products as set out in the accompanying claims. Other features of the invention will become apparent from the dependent claims and the description that follows.

[0024] Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0025] The terms "comprising" or "comprises" mean including a specific component, but not excluding the presence of other components. The terms "substantially consisting of" or "substantially consisting of" mean including a specific component, but not including other components, other than unavoidable materials present as a result of the process used to provide said component, and materials present as impurities, that is, components added for purposes other than achieving the technical effects of the invention. The terms "consisting of" or "consisting of" mean including a specific component, but not including other components.

[0026] Depending on the context, wherever appropriate, use of the terms "comprise" or "comprising" may also be interpreted to mean "consist essentially of" or "consist essentially of" and also to mean "consist of" or "consisting of."

[0027] The optional features described herein may be used individually or in combination with one another, where appropriate, and in the combinations specifically set forth in the appended claims. When described herein, optional features with respect to each aspect or exemplary embodiment of the invention are also applicable, where appropriate, to all other aspects or exemplary embodiments of the invention. That is, those skilled in the art who understand this specification should consider the optional features with respect to each aspect or exemplary embodiment of the invention to be interchangeable and combinable among the various aspects and exemplary embodiments.

[0028] References to "treating" or "treatment" include prevention as well as the alleviation of established symptoms of a disease or condition. Thus, "treating" a disease or condition or "treatment" of a disease or condition includes (1) preventing or delaying the appearance of clinical symptoms of the disease or condition that develop in a human who may be afflicted with or susceptible to said disease or condition, but who has not yet experienced or manifested clinical or subclinical symptoms thereof; (2) suppressing said disease or condition, i.e., arresting, alleviating, or delaying the progression of said disease or condition, or its recurrence (in the case of maintenance treatment) or at least one clinical or subclinical symptom thereof; or (3) alleviating or attenuating said disease, i.e., causing the regression of said disease or condition, or at least one clinical or subclinical symptom thereof.

[0029] A "therapeutically effective amount" means a compound in an amount that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, the method of administration, and the age, weight, etc., of the mammal being treated.

[0030] The term "(1-6C)alkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Similarly, "(1-3C)alkyl" refers to such a group containing 1, 2 or 3 carbon atoms.

[0031] The term "(1-6C)alkoxy" refers to an -O-alkyl group, where alkyl is as defined above. (1-6C)alkoxy includes alkyl groups having 1 to 6 carbon atoms. Non-limiting examples of (1-6C)alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, 2-methyl-1-propoxy, 2-methyl-2-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

[0032] The term "halo" refers to one of the halogens in Group 17 of the periodic table. Specifically, the term refers to fluoro, chloro, bromo, and iodo. Preferably, the term refers to fluoro or chloro.

[0033] When a moiety is substituted, it may be substituted at any point on the moiety that is chemically feasible and consistent with valence requirements. The moiety may be substituted with one or more substituents, for example, 1, 2, or 3 substituents, optionally with one or two substituents per group. When there are two or more substituents, the substituents may be the same or different.

[0034] Substituents are present only where chemically possible, and those skilled in the art can determine (experimentally or theoretically) chemically possible substitutions without undue effort.

[0035] The phrase "compounds of the invention" means those compounds, i.e., compounds of formula (I), both generic and specific, as disclosed herein, and pharmaceutically acceptable salts or solvates thereof.

[0036] compound The present invention relates to a compound of formula (I): [ka] (In the formula, Y is selected from C or N; X is O; Bond a is a single bond or a double bond; When a is a single bond, x is 1, and when a is a double bond, x is 0; R1 is selected from hydrogen and methyl; R2 (if present) is selected from hydrogen and methyl; R3 is selected from hydrogen, (1-6C)alkyl, and (1-6C)alkyl-phenyl, wherein said phenyl is optionally substituted with one or more (e.g., 1 to 3) substituents each independently selected from hydroxy, (1-6C)alkoxy, (1-6C)alkyl, and halo (e.g., chloro and fluoro). or a pharmaceutically acceptable salt or solvate thereof.

[0037] As used herein, when reference is made to a bond a representing a single bond (and x is 1), the resulting structure is of formula (IA) below: [ka] (wherein Y, X, R1, R2, and R3 are as defined herein.) As expressed in the following.

[0038] As used herein, when reference is made to bond a representing a double bond (and x is 0), the resulting structure is of formula (IB) below: [ka] wherein Y, X, R1 and R3 are as defined herein. In compounds of formula IB where a represents a double bond, the compounds can exist as two geometric isomers, namely isomers having E- and Z-configurations due to the presence of the oxime group. The general formula (I) encompasses both a mixture of geometric isomers and the individual separated geometric isomers.

[0039] When the group R3 represents a (1-6C)alkyl-phenyl, the group is attached to the oxygen via the alkyl group to form the group -0-[(1-6C)alkyl]phenyl.

[0040] The compounds of the present invention may contain one or more chiral centers and general formula (I) encompasses both the racemic and resolved individual enantiomeric forms.

[0041] The compounds of the present invention are substrates for the TGT enzyme and are distinguished from other cuein mimetic compounds by their enhanced efficacy as treatments. Typically, the compounds of the present invention are more potent than other cuein mimetic compounds, have a more favorable pharmacokinetic profile, better bioavailability, tolerability, and / or stability, and / or are easier to formulate and / or manufacture than other cuein mimetic compounds.

[0042] Suitably, in formula (I), Y is N.

[0043] Suitably, in formula (I), R1 is hydrogen.

[0044] Suitably, in formula (I), Y is N.

[0045] Suitably, in formula (I), Y is N and R1 is hydrogen.

[0046] Suitably, in formula (I), a is a double bond and x is 0.

[0047] Suitably, in formula (I), a is a single bond and x is 1. Suitably, when x is 1, R2 is hydrogen.

[0048] Suitably, in formula (I), when phenyl is unsubstituted, R3 is selected from hydrogen, (1-6C)alkyl and (1-6C)alkyl-phenyl.

[0049] Suitably, in formula (I), Y is N and R3 is selected from hydrogen, (1-6C)alkyl and (1-6C)alkyl-phenyl, wherein said phenyl is optionally substituted by one or more (e.g., 1 to 3) substituents each independently selected from hydroxy, (1-6C)alkoxy, (1-6C)alkyl and halo (e.g., chloro and fluoro).

[0050] Suitably, in formula (I), Y is N and R3 is selected from hydrogen, (1-6C)alkyl and (1-6C)alkyl-phenyl, wherein said phenyl is unsubstituted.

[0051] Suitably, in formula (I), R3 is selected from hydrogen, (1-3C)alkyl and (1-4C)alkyl-phenyl, wherein said phenyl is optionally substituted by one or more (e.g., 1 to 3) substituents each independently selected from hydroxy, (1-6C)alkoxy, (1-6C)alkyl and halo (e.g., chloro and fluoro).

[0052] Suitably, in formula (I), R3 is selected from hydrogen, (1-3C) alkyl and (1-4C) alkyl-phenyl, wherein said phenyl is unsubstituted.

[0053] Suitably, in formula (I), Y is N and R3 is selected from hydrogen, (1-3C)alkyl and (1-4C)alkyl-phenyl, wherein said phenyl is optionally substituted by one or more (e.g., 1 to 3) substituents each independently selected from hydroxy, (1-6C)alkoxy, (1-6C)alkyl and halo (e.g., chloro and fluoro).

[0054] Suitably, in formula (I), Y is N and R3 is selected from hydrogen, (1-3C) alkyl and (1-4C) alkyl-phenyl, wherein said phenyl is unsubstituted.

[0055] Suitably, in formula (I), R3 is selected from hydrogen, CH3 and (1-2C)alkyl-phenyl, wherein said phenyl is optionally substituted by one or more (e.g., 1 to 3) substituents each independently selected from hydroxy, (1-6C)alkoxy, (1-6C)alkyl and halo (e.g., chloro and fluoro).

[0056] Suitably, in formula (I), R3 is selected from hydrogen, CH3 and (1-2C)alkyl-phenyl, wherein said phenyl is unsubstituted.

[0057] Suitably, in formula (I), Y is N and R3 is selected from hydrogen, CH3 and (1-2C)alkyl-phenyl, wherein said phenyl is optionally substituted by one or more (e.g., 1 to 3) substituents each independently selected from hydroxy, (1-6C)alkoxy, (1-6C)alkyl and halo (e.g., chloro and fluoro).

[0058] Suitably, in formula (I), Y is N and R3 is selected from hydrogen, CH3 and (1-2C)alkyl-phenyl, wherein said phenyl is unsubstituted.

[0059] The present invention also provides the following: 2-Amino-5-((phenethoxyamino)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-methyloxime; 2-amino-5-(((benzyloxy)amino)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; and 2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime, The present invention provides a compound of formula (I) selected from:

[0060] Suitably, these compounds are obtained as the HCl salt.

[0061] Suitable pharmaceutically acceptable salts of compounds of formula (I) are, for example, acid addition salts such as acid addition salts with hydrochloric acid, citric acid, tartaric acid and fumaric acid (especially hydrochloric acid). Acid addition salts may be obtained, for example, by reacting compounds of formula (I) with a suitable acid (e.g., hydrochloric acid, citric acid, tartaric acid and fumaric acid) using conventional methods.

[0062] Alternatively, pharmaceutically acceptable salts may be formed by converting one salt of a compound of the invention into another salt by reaction with a suitable acid or base, or by using a suitable ion exchange column.

[0063] Typically, pharmaceutically acceptable salts are prepared in solution. The resulting salt precipitates and is collected by filtration or can be recovered by evaporation of the solvent.

[0064] The compounds of formula (I) may form salts in situ under physiological conditions, for example when used as pharmaceuticals.

[0065] It is to be understood that the compounds of formula (I) can exist in solvated or unsolvated forms, such as, for example, hydrated forms. The present invention encompasses all pharmaceutically acceptable solvated forms, particularly solvated forms that have an effect on the quein-tRNA ribosyltransferase pathway such that they are useful in treating disease.

[0066] Insofar as certain of the compounds of formula (I) defined herein may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, it should be understood that the invention includes within its definition any such optically active or racemic forms, particularly optically active or racemic forms which have an effect on the cuein-tRNA ribosyltransferase pathway so as to be useful in the treatment of disease.

[0067] It is to be understood that the present invention relates to all tautomeric forms of the compounds of formula (I), particularly those that have an effect on the queuin-tRNA ribosyltransferase pathway so as to be useful in the treatment of disease.

[0068] It is to be understood that the present invention relates to all isomers of the compounds of formula (I), particularly those isomeric forms that exhibit an effect on the queuin-tRNA ribosyltransferase pathway so as to be useful in the treatment of disease.

[0069] It should be understood that the present invention relates to all geometric forms of compounds of formula (I), particularly those that have an effect on the queuin-tRNA ribosyltransferase pathway so as to be useful in the treatment of disease.

[0070] It should be understood that the present invention relates to isotopically labeled (i.e., radiolabeled) compounds of formula (I). In such compounds, one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of radionucleotides that can be included in the compounds of the present invention include: 2 H (also written as "D" for deuterium), 3 H (also written as "T" for tritium),11 C. 13 C. 14 C. 15 O, 17 O, 18 O. 18 F, etc. The particular radionucleotide used will depend on the particular application of the radiolabeled compound.

[0071] Some compounds of the present invention may contain one or more chiral centers and therefore may exist as stereoisomers. Stereoisomers can be separated using conventional techniques, such as chromatography or fractional crystallization. Enantiomers can be separated by separation of racemates, e.g., fractional crystallization, resolution, or HPLC. Diastereomers can be separated by virtue of the different physical properties of diastereomers, e.g., fractional crystallization, HPLC, or flash chromatography. Alternatively, specific stereoisomers can be prepared by chiral synthesis from chiral starting materials under conditions that do not cause racemization or epimerization, by derivatization with chiral reagents, or by asymmetric catalytic synthesis. When a specific stereoisomer is isolated, it is suitably isolated substantially free of other stereoisomers (e.g., containing less than 10%, particularly less than 5%, and less than 20%, by weight, of other stereoisomers).

[0072] It is to be understood that compounds of formula (I) may exhibit polymorphism, and the invention encompasses all such forms, particularly those which exhibit an effect on the queuin-tRNA ribosyltransferase pathway so as to be useful in the treatment of autoimmune diseases.

[0073] Compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, may be prepared by any process known to be applicable to the preparation of chemically related compounds. Such processes, when used to prepare compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, are provided as further features of the invention and are exemplified by the following representative variants, in which, unless otherwise specified, X, Y, R1, R2, R3, a, and x have the above-defined meanings. The necessary starting materials are either commercially available or can be prepared by standard procedures of organic chemistry (e.g., as described in conjunction with the following representative processes and accompanying examples) that are within the skill of an organic chemist.

[0074] For example, compounds of formula (I) can be prepared according to Scheme 1: [ka] It can be prepared by a process according to wherein PG represents a suitable amine protecting group. In Scheme 1, a compound of formula (II) is reacted with a suitable amine protecting group in step (i) to provide a compound of formula (III). In step (ii), a compound of formula (IV) is prepared from a compound of formula (III) by suitable reduction and hydrolysis steps (in either order). When reduction precedes hydrolysis, a suitable reducing agent for use in step (ii) is DiBAL. In step (iii), a compound of formula (V) is prepared by amination of a compound of formula (IV). In step (iv), a compound of formula (I) in which a represents a double bond is prepared by removing the protecting group by a suitable means, or a compound of formula (I) in which a represents a single bond is prepared by reduction of the double bond with a suitable reducing agent (e.g., sodium cyanoborohydride) followed by removal of the protecting group by a suitable means. Suitable protecting groups may be used for other substituents of compounds of formula (II), (III), (IV), and (V) as needed.

[0075] The use and deprotection of protecting groups are well known to organic chemists, and one skilled in the art would readily be able to select an appropriate amine protecting group. One example of a suitable amine protecting group is triphenylmethyl (trityl). One example of a suitable hydroxyl protecting group is tert-butyl (dimethyl) silyl.

[0076] The resulting compounds of the invention formed from the above methods may be isolated and purified using techniques well known in the art.

[0077] The compounds of the present invention may exist in a single crystalline form or a mixture of crystalline forms, or may be in amorphous form. Accordingly, compounds of the present invention intended for pharmaceutical use may be administered in crystalline or amorphous form of the product.

[0078] Medical uses The present invention provides a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use as a pharmaceutical.

[0079] The present invention also provides a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a disease or condition that can be mediated by a substrate of the queuin-tRNA ribosyltransferase pathway.

[0080] The invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a disease or condition that can be mediated by a substrate of the queuin-tRNA ribosyltransferase pathway.

[0081] The present invention also provides a method for treating a disease or condition that can be mediated by a substrate of the quein-tRNA ribosyltransferase pathway in a warm-blooded animal in need of such treatment, which method comprises administering to the warm-blooded animal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.

[0082] The compounds of the present invention are substrates for TGT (tRNA guanine transglycosylase), an enzyme complex consisting of two proteins known as queuine tRNA-ribosyltransferase 1 and its partner protein QTRTD1 (queuine tRNA transglycosylase domain containing 1), also known as QTRT2 or Qv1.

[0083] This enzyme converts the natural product queuin into tRNA in every cell in the body. asp , tRNA asn , tRNA his , and tRNA tyr Quein is known to insert into tRNAs. Cells proliferating at abnormal rates, such as T cells in autoimmune diseases, have been found to be deficient in queuin (Fergus et al., Nutrients 2015, 7(4):2897-2929). tRNA is essential for protein translation. Problems in protein translation are strongly associated with autoimmune, inflammatory, and neurodegenerative diseases. Quein mimetics, which are substrates for the TGT enzyme, insert into tRNAs exclusively and at the same position on tRNAs as queuin. They have been shown to act through both T cell and innate immune mechanisms in the treatment of autoimmune diseases, normalizing cytokine levels with combined effects. Furthermore, queuin deficiency has been shown to be associated with increased glycolysis and impaired mitochondrial function, which are themselves markers associated with inflammation and neurodegenerative disorders (Hayes et al., Nutrients 2020 12(3)).

[0084] Without being bound by theory, it is believed that this effect on protein translation and protein folding (including the unfolding response) may also have an effect on protein aggregation in pathologies such as Alzheimer's disease. Furthermore, it is believed that the effect on cellular metabolism and mitochondrial function may influence pathologies such as Alzheimer's disease.

[0085] The present invention provides a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of an autoimmune disease.

[0086] The present invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of an autoimmune disease.

[0087] The present invention also provides a method for treating an autoimmune disease in a warm-blooded animal in need of such treatment, which method comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.

[0088] The present invention provides a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a neurodegenerative disease.

[0089] The present invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a neurodegenerative disease.

[0090] The present invention also provides a method for treating a neurodegenerative disease in a warm-blooded animal in need of such treatment, which method comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.

[0091] The present invention provides a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of an inflammatory disease.

[0092] The present invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of an inflammatory disease.

[0093] The present invention also provides a method for treating an inflammatory disease in a warm-blooded animal in need of such treatment, which method comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.

[0094] Autoimmune diseases include: Achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Baro's disease, Behçet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman's disease (CD), celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome eosinophilic granulomatosis (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid gestationis (PG)Hidradenitis suppurativa (HS) (inverse acne), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, collagenous conjunctivitis, linear immunoglobulin A disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD) ), Mooren corneal ulcer, Much-Habermann disease, multifocal motor neuropathy (CIDP) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy rheumatic disease, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, type II, type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, related These include rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmune systemic stiffening syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, and Vogt-Koyanagi-Harada disease.

[0095] Specifically, autoimmune diseases are mediated by T cells.

[0096] Preferred examples of autoimmune diseases that can be treated include MS, RA, alopecia areata, optic neuritis, IBD, psoriasis, and diabetes. Also included are use in transplantation and co-administration with biological drugs that are subject to immune rejection. Suitable neurodegenerative diseases include those with a potential autoimmune component, such as dementia, Huntingdon's disease, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as depression and schizophrenia. Suitable inflammatory diseases include conditions caused by cytokine responses, or cytokine storms.

[0097] The present invention also provides a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of MS.

[0098] The present invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of MS.

[0099] The present invention also provides a method for treating MS in a patient in need of such treatment, which method comprises administering to said patient a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.

[0100] Suitable forms of MS include relapsing remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS) and progressive relapsing MS (PPMS).

[0101] The present invention also provides a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of RA.

[0102] The present invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of RA.

[0103] The present invention also provides a method for treating RA in a warm-blooded animal in need of such treatment, which method comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.

[0104] The compounds of the invention, or pharmaceutically acceptable salts or solvates thereof, may be administered as monotherapy or in combination with additional therapeutic agents, which may be administered simultaneously, separately or sequentially with the compounds of formula (I).

[0105] The present invention provides a pharmaceutical product comprising a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, and an additional therapeutic agent.

[0106] Furthermore, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of an autoimmune disease, wherein the compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is administered simultaneously, separately or sequentially with an additional therapeutic agent.

[0107] Furthermore, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a neurodegenerative disease, wherein the compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is administered simultaneously, separately or sequentially with an additional therapeutic agent.

[0108] Furthermore, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of an inflammatory disease, wherein the compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is administered simultaneously, separately or sequentially with an additional therapeutic agent.

[0109] Furthermore, the present invention relates to compounds of the present invention in combination with other suitable agents for use in the treatment of MS.

[0110] Furthermore, the present invention relates to compounds of the present invention in combination with other suitable agents for use in the treatment of RA.

[0111] Patients with MS are commonly co-administered with additional therapeutic agents. For patients suffering from severe attacks, intravenous corticosteroids such as methylprednisolone, or procedures such as plasma exchange therapy, may be administered concurrently with either treatment.

[0112] The effects of nerve cell damage caused by MS result in many different forms of damage to patients. Nerve damage can cause pain, difficulty controlling the bladder, and many other problems. For this reason, additional medications are often prescribed to treat the damaging effects of MS in patients with MS. Suitable co-administered medications include: For bladder problems: Botulinum toxin (Botox) Desmopressin (Desmospray, Desmotabs) Oxybutynin (Ditropan, Lyrinel) Tolterodine (Detrusitol) For depression, Amitriptyline (Triptafen) Fluoxetine (Prozac) Imipramine (Tofranil) Paroxetine (Seroxat) For erectile dysfunction, Alprostadil (Caverject, MUSE, ViridalDuo) Sildenafil citrate (Viagra) Tadalafil (Cialis) Vardenafil (Levitra) For fatigue, Amantadine (Lysovir, Symmetrel) Modafinil (Provigil) For optic neuritis, ·steroid For pain, Amitriptyline (Triptafen) Carbamazepine (Tegretol) Gabapentin (Neurontin) Ibuprofen Imipramine (Tofranil) Lamotrigine (Lamictal) Phenytoin (Epanutim) Pregabalin (Lyrica) For walking problems, Fampridine (Fampyra) Regarding the pseudobulbar effect Nudexta Regarding spasticity and convulsions: Baclofen (Lioresal) Botulinum toxin (Botox) Carbamazepine (Tegretol) Clonazepam (Rivotril) Dantrolene (Dantrium) Diazepam (Valium) Gabapentin (Neurontin) Phenol Tetrahydrocannabinol and cannabidiol (Sativex) Tizanidine (Zanaflex) For tremors, Clonazepam (Rivotril) Thalamotomy For trigeminal neuralgia, Carbamazepine (Tegretol) Gabapentin (Neurontin) Oxcarbazepine (Trileptal) Phenytoin (Epanutim) Pregabalin (Lyrica) Includes:

[0113] Other therapeutic agents are commonly administered to patients with MS, and such other medications are well known to physicians and others skilled in treatment.

[0114] composition The present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0115] The compositions of the present invention may be in a form suitable for oral administration (e.g., as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, aqueous or oily solutions or suspensions), administration by inhalation (e.g., finely divided powders or liquid aerosols), administration in insufflation (e.g., finely divided powders), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, or intramuscular administration or as suppositories for rectal administration).

[0116] Suitably, the pharmaceutical composition is in the form of an oral administration, in particular a tablet.

[0117] The compositions of the present invention may be obtained by conventional procedures using conventional pharmaceutical carriers or excipients known in the art. Thus, oral compositions may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0118] Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation are described, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

[0119] The compounds of the present invention can be administered orally. Oral administration can involve swallowing so that the compound enters the digestive tract, or it can be buccal or sublingual, where the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, microparticles, capsules containing liquid or powder, lozenges (containing liquid fillers), chewable tablets, multiparticulates and nanoparticulates, gels, solid solutions, liposomes, films, ovules, sprays, and liquid formulations.

[0120] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules and typically contain a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying and / or suspending agents. Liquid formulations can also be prepared by reconstituting a solid, for example, from a sachet.

[0121] The compounds of the present invention may also be used in fast-dissolving, fast-disintegrating dosage forms, such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).

[0122] In tablet dosage forms, depending on the dose, the drug may comprise 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. In addition to the drug, tablets usually contain a disintegrant. Examples of disintegrants include sodium saccharified starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant comprises 1% to 25% by weight. In one embodiment of the invention, the disintegrant comprises 5% to 20% by weight of the dosage form. Binders are commonly used to impart cohesive properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate. Tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and lubricants such as silicon dioxide and talc. When present, surfactants may comprise 0.2% to 5% by weight of the tablet, and lubricants may comprise 0.2% to 1% by weight of the tablet. Typically, tablets also contain a lubricant such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. Typically, the lubricant comprises 0.25% to 10% by weight. In one embodiment of the present invention, the lubricant comprises 0.5% to 3% by weight of the tablet. Other possible ingredients include antioxidants, colouring agents, flavouring agents, preservatives and flavouring agents.

[0123] Exemplary tablets contain up to about 80% drug, about 10% to about 90% binder by weight, about 0% to about 85% diluent by weight, about 2% to about 10% disintegrant, and about 0.25% to about 10% lubricant by weight.

[0124] Tablet blends can be compressed directly or by roller to form tablets. Alternatively, tablet blends or portions of blends can be wet-, dry-, or melt-granulated, melt congealed, or extruded prior to tabletting. The final formulation can contain one or more layers and can be coated or uncoated, or can be encapsulated. Tablet formulations are discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

[0125] Consumable oral films for humans or animals are typically flexible, water-soluble or water-swellable thin film dosage forms that can be rapidly dissolving or mucoadhesive, and typically contain a compound of the present invention, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity modifier, and a solvent. Some components of the formulation may serve multiple functions. The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in an amount ranging from 0.01 to 99% by weight, more typically from 30 to 80% by weight. Other ingredients include antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulants, cooling agents, cosolvents (including oils), emollients, bulking agents, antifoaming agents, surfactants, and flavor masking agents. Films according to the present invention are typically prepared by evaporative drying of thin aqueous films coated on a peelable support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze drying or vacuuming.

[0126] Solid dosage forms for oral administration can be formulated for immediate release and / or modified release. Modified release includes delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Modified release formulations suitable for the purposes of the present invention are described in U.S. Pat. No. 6,106,864. Details of other suitable release technologies, such as high-energy dispersion systems and osmotic and coated particles, can be found in Pharmaceutical Technology Online, 25(2), 1-14, by Verma et al. (2001). The use of chewing gum to achieve controlled release is described in WO-A-00 / 35298.

[0127] The compounds of the present invention can also be administered directly into the bloodstream, muscle, or an internal organ. Such parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous administration. Devices suitable for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0128] The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.

[0129] The compounds of the present invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (alone, as a dry mixture with, for example, lactose, or as mixed-component particles mixed with, for example, a phospholipid, such as phosphatidylcholine) from a dry powder inhaler, such as an aerosol spray consisting of a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as a nasal solution. For intranasal use, the powder can include a bioadhesive agent, such as chitosan or cyclodextrin. For intranasal use, the powder can include a bioadhesive agent, such as chitosan or cyclodextrin.

[0130] The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of a compound of the invention, for example, with ethanol, aqueous ethanol, or another suitable agent for dispersing, solubilizing, or prolonging the release of the compound, a propellant as a solvent, and an optional surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0131] Prior to use in a dry powder or suspension formulation, the drug is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any suitable fine comminution method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0132] Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters, and cartridges for use in an inhaler or insufflator can be formulated containing a powder mix of a compound of the invention, a suitable powder base such as lactose or starch, and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose can be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0133] Suitable solution formulations for use in electrohydrodynamic atomizers to generate a fine mist can contain 1 μg to 20 mg of a compound of the present invention per actuation, and the actuation volume can vary from 1 μL to 100 μL. A typical formulation can include a compound of the present invention, propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol.

[0134] Suitable flavors, such as menthol and l-menthol, or suitable sweeteners, such as saccharin and saccharin sodium, may be added to those formulations of the present invention intended for intranasal administration. Formulations for intranasal administration may be formulated to be immediate and / or modified release, for example, using PGLA. Modified release includes delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0135] The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.

[0136] When using any of the above-mentioned administration modes, the compounds of the present invention can be combined with soluble polymeric entities such as cyclodextrin and its suitable derivatives or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste, bioavailability, and / or stability. For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, i.e., as a carrier, diluent, or solubilizer. The most commonly used for these purposes are α-, β-, and γ-cyclodextrins, examples of which can be found in International Patent Publications WO-A-91 / 11172, WO-A-94 / 02518, and WO-A-98 / 55148.

[0137] The amount of active ingredient (i.e., a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof) that can be combined with a carrier or excipient to produce a single dosage form will vary depending upon the patient being treated and the particular route of administration. For example, a composition intended for oral administration to humans will generally contain from 0.5 to 500 mg of active ingredient, admixed with an appropriate and convenient amount of carrier or excipient, which may vary, for example, from about 5 to about 96% by weight of the total composition.

[0138] The size of the therapeutic or prophylactic dose of the compound of the present invention, or its pharmaceutically acceptable salt or solvate, will naturally vary according to principles well known in medicine, depending on the nature and severity of the disease, the age and sex of the patient, and the route of administration. An example of a daily dose may be, for example, 0.5 mg to 50 mg per kg of body weight.

[0139] The compounds of the present invention, or a pharmaceutically acceptable salt or solvate thereof, may be administered in the form of a pro-drug, which means a compound that is broken down in a warm-blooded animal such as man to release a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. [Example]

[0140] The invention will now be illustrated by the following non-limiting examples, unless otherwise stated: (i) Temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, i.e., at temperatures ranging from 18°C to 25°C; (ii) the final product had sufficient proton and carbon nuclear magnetic resonance (NMR) spectral and / or mass spectral data; (iii) yields are given for illustrative purposes only and are not necessarily those obtained by diligent process development; preparations were repeated if more material was required; (iv) Where given, NMR data are in the form of δ values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as the internal standard, measured at 400 MHz using perduteriodimethylsulfoxide (DMSO-d6) as the solvent unless otherwise indicated; the following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad; (v) Chemical symbols have their usual meanings; SI units and symbols are used.

[0141] 2-chloro-3-oxopropanenitrile [ka] In a dry round-bottom flask under positive argon pressure, a suspension of NaOMe (7.14 g, 0.13 mol) in dry THF (9 mL) was cooled to -5 °C. Methyl formate (9 mL, 0.15 mol) was added dropwise via syringe over 1 min, and stirring was continued at -5 °C for 20 min. Chloroacetonitrile (8.33 mL, 0.13 mol) was then added dropwise via addition funnel over 45 min. The mixture changed from white to yellow and was stirred at -5 °C for an additional 2 h, at which point the reaction mixture was orange. The bath was removed, and the reaction was allowed to warm to room temperature. An aliquot of the reaction mixture was treated with one drop of concentrated HCl and analyzed by TLC, which showed the presence of the desired product, Rf = 0.45, eluted with 100% EtOAc. The mixture was cooled to 0 °C, and concentrated HCl (12 mL) was added dropwise, during which the reaction mixture turned cherry red. The resulting suspension was filtered through a pad of Celite, and the Celite was washed with EtOAc until the filtrate was colorless. The collected filtrate was concentrated under reduced pressure with a water bath temperature below 40° C. to give chloro(formyl)acetonitrile as a black oil in quantitative yield, which was used without further purification.

[0142] 2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile [ka] 2,4-Diamino-6-hydroxypyrimidine (3.00 g, 24 mmol) was added to a solution of sodium acetate (6.4 g, 76 mmol) in Millipore water (90 mL) and stirred at 50 °C for 1 h. A solution of crude chloro(formyl)acetonitrile (S2) (3.00 g, 32 mmol) in mQ water (44 mL) was added dropwise via addition funnel while the reaction mixture turned beige. Heating was continued at 50 °C for 18 h, then at 100 °C for 3 h. The reaction mixture was allowed to cool to room temperature and the solid was filtered off. The solid was suspended in EtOH and 5 M aqueous KOH was added until the solid dissolved. Charcoal was added to the solution, and the mixture was stirred for 30 min, after which the solid was filtered off. The pH of the filtrate was adjusted to pH = 6 with concentrated aqueous HCl, during which time a precipitate formed and was collected by filtration. To remove final traces of water from the solid, it was dissolved in a 1 / 1 mixture of toluene and methanol and then concentrated under reduced pressure. The resulting solid was dried over P2O5 to give the desired compound (1.68 g, 9.6 mmol, 40% yield) as a beige solid. mp: >250 °C (decomp). δ H (400 MHz, DMSO-d6): 6.49 (2H, bs, NH2), 7.59 (1 H, s), 10.78 (1 H, bs), 11.90 (1 H, bs) HRMS (m / z-ES): Found: 174.0420 ([MH] - C7H4N5O; theoretical value: 174.0421)

[0143] 4-Oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile [ka] In a dry round-bottom flask under argon, trityl chloride (1.20 g, 4.28 mmol) was added to a solution of 2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (0.50 g, 2.85 mmol) in dry pyridine (29 mL). The reaction mixture was heated at 90 °C for 48 h. The reaction mixture was concentrated under reduced pressure, absorbed onto silica gel, and purified by flash chromatography on silica gel, eluting with a gradient of dichloromethane / MeOH starting at 2% and increasing to 10% MeOH. The desired compound was obtained as a brown solid (0.63 g, 1.5 mmol, 53% yield). mp:196~198℃. δ H (400 MHz, DMSO-d6): 7.13-7.26 (15H, m), 7.37 (1 H, s), 7.57 (1 H, bs), 10.67 (1 H, bs), 11.74(1 H, bs, NH) HRMS (m / z-ES): Found: 418.1665 ([M+H] + C 26 H 26 N 5O O; theoretical value: 418.1662)

[0144] 4-Oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde [ka] Hexamethyldisilazane (HMDS) (6 mmol, 1.3 mL) was added to a mixture of 4,7-dihydro-4-oxo-2-[(triphenylmethyl)amino]-3H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (1.30 g, 3 mmol) and ammonium sulfate (397 mg, 0.3 mmol) in a round-bottom flask containing dry toluene (8 mL). A reflux condenser was attached and the flask was heated at reflux overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. Under a positive pressure of argon, the crude reaction mixture was solubilized in dry dichloromethane (8 mL) and cooled to −78 °C. At this temperature, diisobutylaluminum hydride (DiBAL-H) (4.5 mL, 1 M in dichloromethane, 4.5 mmol) was added dropwise. After 2 hours, analysis by thin layer chromatography (TLC) (ethyl acetate (EtOAc) 100%) indicated that some starting material remained. Therefore, an additional 2 mL of diisobutylaluminum hydride (DiBAL-H) solution was added dropwise. After 1 hour, the reaction was complete, and a mixture of water / acetic acid (9 / 1, 3.5 mL) was added at −78° C., and the reaction mixture was allowed to warm slowly to room temperature. A mixture of ethyl acetate / water (1 / 1, 300 mL) was added to the reaction mixture, and stirring was continued at room temperature for 2 hours. The layers were separated, the organic layer was washed with brine, and the aqueous layer was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude reaction product was filtered through a pad of silica gel eluting with ethyl acetate to give a yellow solid (1.01 g, 2.38 mmol, 76% yield). mp: Over 250℃ (decompressed). δ H (400 MHz, DMSO-d6): 7.15-7.29 (16H, m), 7.54 (1 H, bs, NH), 9.99 (1 H, s), 10.64 (1 H, bs),11.81 (1 H, bs, NH) HRMS (m / z-ES): Found: 443.1478 ([M+Na] + C 26 H 20 N4NaO2; theoretical value: 443.1478)

[0145] 4-Oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-phenethyl oxime: [ka] 4-Oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (300 mg, 0.72 mmol) and O-(2-phenylethyl)hydroxylamine (107 mg, 0.78 mmol) in MeOH (5 cm 3 A solution of 4-oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-phenethyl oxime was prepared. One spatula of NaSO was added, and the resulting suspension was stirred at room temperature for 20 hours. The resulting suspension was then concentrated in vacuo and purified by flash chromatography (7:3 hexane / ethyl acetate) to give 4-oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-phenethyl oxime as a white powder (150 mg, 39% yield), mp: 188-191°C. δ H (400 MHz, DMSO-d6): 2.89 (2H, t, 36.9), 4.16 (2H, t, J 6.9), 6.83 (1H, s), 7.17-7.29 (20H, m), 7.44(1H, s), 8.29 (1H, s), 10.45 (1H, bs), 11.24 (1H, bs) δ C (100 MHz, DMSO-d6): 35.3, 35.4, 70.5, 74.0, 99.1 , 110.4, 115.4, 126.5, 127.0, 128.1 , 128.7, 129.3, 139.1 , 143.7, 145.3, 150.3, 159.0 HRMS (m / z)-APCl): Found: 540.2393 ([M+H] + C3H 30 N5O2; theoretical value: 540.2394) V max (film) / cm -1 :1630, 1676, 2105, 2927, 3398, 3676

[0146] Example 1 2-Amino-5-((phenethoxyamino)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one [ka] 4-Oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-phenethyl oxime (130 mg, 0.25 mmol) in CHCl (5 cm 3 To the solution was added NaCNBH (32 mg, 0.51 mmol). Methanol-soluble HCl (1.25 M) was added dropwise to adjust the pH to approximately 3. The resulting solution was stirred at room temperature for 3 h, taking care to maintain the pH at 3. Further methanol-soluble HCl was added as needed. The reaction mixture was then diluted with HO (15 cm 3 ) and extracted with CH2Cl2 (3 × 10 cm 3 ). The combined organic extracts were dried (MgSO4) and concentrated in vacuo, then taken up in 1 M HCl in dioxane and stirred at room temperature for 1 h. The product precipitate was isolated by vacuum filtration and washed with Et2O to give the HCl salt of 2-amino-5-((phenethoxyamino)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one as a white powder (35 mg, 50% yield). 250 °C (decomp). δ H (400 MHz, DMSO-d6): 2.90 (2H, t, J 6.6), 4.28 (2H, t, J 6.6), 4.43 (2H, s), 6.44 (2H, bs), 6.79 (1 H, d, J 2.2), 7.17-7.27 (5H, m), 10.97 (1H, bs), 11.30 (1H, bs) δ C(100 MHz, DMSO-d6): 35.4, 35.6, 66.8, 98.9, 111.4, 117.2, 125.2, 128.2, 129.2, 129.9, 148.3, 125.7, 160.0 HRMS (m / z-APCI): Found: 300.1462 ([M+H] + C 15 H 18 N5O2; theoretical value: 300.1455) V max (film) / cm -1 :1670, 2531, 3024, 3261

[0147] 4-Oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-methyloxime: [ka] Methoxylamine hydrochloride (94.0 mg, 0.78 mmol) and triethylamine (156 μL, 0.78 cm) were used in place of O-(2-phenylethyl)hydroxylamine. 3 4-Oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-methyloxime was prepared using the same procedure as for 4-oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-phenyloxime, except for the use of (2). The crude reaction product was purified by flash chromatography (7:3 hexane / ethyl acetate) to yield 4-oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-methyloxime (137 mg, 42% yield) as a white powder as a single isomer. mp: 186-190 °C. δ H(400 MHz, DMSO-d6): 3.74 (3H, s), 6.81 (1 H, d, J 2.3), 7.17-7.21 (4H, m), 7.22-7.29 (1 H, m),7.45 (1 H, s), 8.29 (1 H, s), 10.44 (1 H, bs), 11 .26 (1 H, bs) δ C (100 MHz, DMSO-d6): 61.4, 70.5, 99.1, 110.3, 115.3, 127.0, 128.1, 129.1, 143.6, 145.3, 150.3, 150.5, 159.0 V max (film) / cm -1 :1066, 1250, 1552, 1611, 1654, 3663

[0148] Example 2 2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-methyloxime [ka] The compound 4-oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-methyloxime was dissolved in 1 M HCl in dioxane (9 equivalents), and the solution was stirred at room temperature overnight, during which time a precipitate of the product formed. The product was isolated via vacuum filtration and washed with CHCl to yield 2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-methyloxime hydrochloride salt (10 mg, 16%) as a white powder containing an inseparable mixture of E / Z isomers in a 97:3 ratio. mp: >250 °C (decomp). δ H (400 MHz, DMSO-d6): 3.87 (1 H, s), 6.18 (2H, bs), 7.38 (1 H, s), 7.84 (1 H, s), 10.46 (1 H, bs), 11.47 (1 H, bs) δ C (100 MHz, DMSO-d6): 41.0, 97.8, 109.0, 123.0, 139.4, 150.6, 153.4, 159.5 V max (film) / cm -1 :1053, 1593, 1672, 2854, 3132

[0149] 4-Oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-benzyloxime: [ka] 4-Oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-benzyloxime was prepared using the same procedure as above for 4-oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-phenethyloxime, except that O-benzylhydroxylamine was used instead of O-(2-phenylethyl)hydroxylamine. The product was purified by flash chromatography (7:3 hexanes / ethyl acetate) to yield 4-oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-benzyloxime (120 mg, 32%) as a white powder, a 9:1 mixture of E / Z isomers. mp:186~189℃. δ H (400 MHz, DMSO-d6): Abundant isomers - 5.02 (2H, bs), 6.81 (1 H, d, J 1.7), 7.17-7.35 (20H, m), 7.45 (1 H, s), 8.36 (1 H, s), 10.44 (1 H, bs), 11 .27 (1 H, bs) Minor isomers - 5.13 (s), 7.17-7.35 (m), 7.48 (s), 7.84 (s), 10.51 (bs), 11.37 (bs) δ C (100 MHz, DMSO-d6): Major isomers - 70.5, 75.3, 99.1, 110.3, 115.5, 127.0, 127.1, 128.0, 128.1, 128.5, 128.7, 129.1, 138.4, 144.1, 145.3, 150.3, 150.5, 159.0 Minor isomers - 70.6, 75.8, 98.5, 109.0, 127.0, 128.0, 128.7, 128.9, 138.7, 140.0, 145.3, 149.7, 150.8, 159.2 (all peaks not visible due to overlap with aromatic region) HRMS (m / z-APCl): Found: 526.2232 ([M+H] + C 33 H 28 N5O2; theoretical value: 526.2237) V max (film) / cm -1 :1656, 2230, 2902, 297, 3662

[0150] Example 3 2-Amino-5-(((benzyloxy)amino)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one [ka] 4-Oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-benzyloxime (50 mg, 0.18 mmol) in CHCl (5 cm 3 To the solution was added NaCNBH (23 mg, 0.36 mmol). Methanol-soluble HCl (1.25 M) was added dropwise to adjust the pH to approximately 3. The resulting solution was stirred at room temperature for 3 h, taking care to maintain the pH at 3. Further methanol-soluble HCl was added as needed. The reaction mixture was then diluted with HO (15 cm 3 ) and extracted with CH2CI2 (3 × 10 cm3 ). The combined organic extracts were dried (MgSO4) and concentrated in vacuo, then taken up in 1 M methanolic HCl and stirred at room temperature for 1 h. The product precipitate was isolated by vacuum filtration and washed with Et2O to yield the hydrochloride salt of 2-amino-5-(((benzyloxy)amino)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (11 mg, 12% yield) as a white powder. mp: >250 °C (decomp). δ H (400 MHz, DMSO-d6): 4.32 (2H, s), 5.01 (2H, s), 6.34 (2H, bs), 6.79 (1H, s), 7.35-7.36 (5H, m), 10.86 (1 H, bs), 11.24 (1 H, bs) δ C (100 MHz, DMSO-d6): 44.6, 75.1, 99.0, 107.1, 128.4, 129.0, 129.7, 130.3, 134.0, 146.5, 152.6, 159.4 HRMS (m / z-APCl): Found: 286.1299 ([M+H] + C 14 H 16 N5O2; theoretical value: 286.1292) V max (film) / cm -1 :1604, 1672, 2764, 2971

[0151] Example 4 2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime: [ka] 2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime was prepared from 4-oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde by the same procedure as for 2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-phenethyloxime above, except that hydroxylamine hydrochloride and triethylamine were used instead of O-(2-phenylethyl)hydroxylamine. Using the same general procedure as described in Example 1 above, except using 1 M HCl in dioxane, the compound 4-oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime was deprotected to yield the hydrochloride salt of 2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime as a white powder (34 mg, 39%) containing an inseparable mixture of 92:8 E / Z isomers. mp: >250° C. (decomp). δ H (400 MHz, DMSO-d6): Major isomer - 7.54 (1 H, d, J 2.4), 7.84 (1 H, s), 11.00 (1 H, bs), 11.67 (1 H, bs) Minor isomers - 7.16 (d, J 2.2), 8.37 (s), 11.81 (bs) δ C (100 MHz, DMSO-d6): Major isomers - 102.7, 114.6, 129.2, 142.9, 143.0, 156.9, 162.7 Minor isomers - 102.5, 115.9, 127.9, 146.2, 146.3, 157.6, 163.5 HRMS (m / z-APCl): Found: 192.0525 ([MH] - C7H6N5O2; theoretical value: 192.0527) Vmax (film) / cm -1 :1578, 1671, 2625, 2971, 3088, 3676

[0152] Alternatively, 2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime was prepared by treating 4-oxo-2-(tritylamino)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (150 mg) with O-(tert-butyldimethylsilyl)hydroxylamine (60 mg) and a trace of anhydrous sodium sulfate in methanol (3 mL). After stirring for 95 minutes, the volatiles were removed, and the crude reaction mixture was dissolved in ethyl acetate and then washed with 10% aqueous sodium bicarbonate. The combined organic fractions were dried over anhydrous magnesium sulfate, followed by removal of the volatiles under reduced pressure. Purification was carried out by column chromatography on silica gel eluting with 30% ethyl acetate / hexane to give the expected oxime (120 mg). Deprotection was achieved by treating a cooled (0 °C) solution of the protected oxime (100 mg) in 1,4-dioxane (1.5 mL) and methanol (0.5 mL) with 4 M HCl in dioxane (0.5 mL). After 5 min, the cooling bath was removed, and the reaction mixture was stirred for an additional 90 min. The resulting precipitate was filtered off and washed three times with ether to yield 2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime hydrochloride (35 mg) as a white powder containing an inseparable mixture of E / Z isomers in a 99:1 ratio favoring the major isomer. δ H (400 MHz, DMSO-d6): Major isomer - 7.54 (1 H, d, J 2.4), 7.84 (1 H, s), 11.00 (1 H, bs), 11.67 (1 H, bs)

[0153] The compounds of the examples were tested in the following biological assays: The compounds of the examples were tested to confirm that they are substrates for the queuin-tRNA ribosyltransferase enzyme complex. Compounds capable of acting as substrates for the queuin-tRNA ribosyltransferase enzyme complex can be identified through the use of the displacement assay described below.

[0154] [8- 14 C]guanine-labeled tRNA (tRNA * ) generation The components were added in the order listed in Table 1. The reaction was 14 Before adding the [8-C]guanine solution 14 The solution was neutralized with an equal volume (vol / vol) of 0.01 M NaOH to provide [C]guanine in 0.01 M aqueous HCl. In vitro synthesized human tyrosyl-tRNA was prepared by T7 transcription in ultrapure nuclease-free water as previously described (Alqasem et al., 2020). Recombinant human QTRT1 enzyme containing an N-terminal polyhistidine tag and human QTRT2 containing a C-terminal TEV-Strep-Tag™ II tag were transfected with BL21(DE3)tgt::Km ligase as previously described (Alqasem et al., 2020). r Produced in cells. [Table 1]

[0155] The reaction mixture was incubated at 37°C for 1 hour. The reaction mixture was extracted by adding an equal volume (500 μL) of acid phenol:chloroform (5:1; pH 4.5) and centrifuged at 16,000 × g for 5 minutes. The upper aqueous phase was transferred to a new 1.5 mL tube. The third position of the anticodon loop was replaced with [8- 14 The tRNA radiolabeled with [C]guanine was precipitated by adding 0.1 volumes (50 μL) of 3 M sodium acetate (aqueous) and 2 volumes (1 mL) of ethanol and incubated overnight at -20°C. The next morning, the tRNA *The tRNA was pelleted by centrifugation at 16,000 x g for 20 minutes at 4°C. The pellet was washed with 1 mL of ice-cold 70% ethanol without disturbing the pellet. * Resuspend the pellet in 30 µL of nuclease-free water and adjust its concentration to A 260 was measured spectrophotometrically.

[0156] Displacement assay Each reaction consisted of triplicates and was incubated for 30 minutes at 37°C. Reaction components were added in the order shown in Table 2, with tRNA added last. * The reaction was initiated by the addition of "Compound" refers to the compound of the invention under investigation.

[0157] [Table 2] After 30 minutes, the reaction was quenched by mixing with 2.5 mL of ice-cold 10% trichloroacetic acid (TCA) and placed on ice for 1 hour to precipitate the tRNA. The RNA precipitate was collected using vacuum filtration onto GF / C 2.4 cm glass fiber filter discs (mounted on a Millipore polymeric vacuum filter manifold). Each disc was washed with 40 mL of ice-cold 5% TCA. The filters were then vacuum-dried by washing with 5 mL of freshly prepared ice-cold 95% ethanol. The vacuum manifold was removed, and the filters were collected and again dried at room temperature before being placed in scintillation vials containing 10 mL of EcoscintA, and the radioactivity levels were determined by scintillation counting.

[0158] In this assay, the maximal substitution rate by 50 μM of cuine base, the natural substrate of the cuine-tRNA ribosyltransferase enzyme complex, was [ 14 The substitution rate is greater than 98% for [C]guanine. The background substitution rate is less than 2%. Therefore, substitutions of 5% or more are considered positive substrates for TGT.

[0159] All compounds of the present invention were shown to have a substitution rate of 5% or more and were therefore shown to be substrates for the TGT enzyme complex.

[0160] To demonstrate the effectiveness of the compounds of the invention in treating disease, the compounds are assayed in various disease models and tested on samples from human patients.

[0161] Synovial fibroblast assay To evaluate the compounds in human rheumatoid arthritis samples, the following protocol was employed: Isolation of primary fibroblasts: RA synovial biopsies were digested with 1 mg / mL collagenase type 1 (Worthington Biochemical, Freehold, NJ, USA) in RPMI-1640 (Gibco-BRL, Paisley, UK) for 4 hours at 37°C in a humidified atmosphere with 5% CO2. Isolated cells were grown to confluence in 10 mL of RPMI-1640, 10% FCS (Gibco-BRL), 1 mmol / L HEPES (Gibco-BRL), penicillin (100 units / mL; Bioscience), streptomycin (100 units / mL; Bioscience), and fungizone (0.25 μg / mL; Bioscience) before passage. Cells were used for passages 3–8. Compounds (200 PM) were tested in n=3 RASFCs

[0162] RASFCs were grown in 48-well plates to 80% confluence. RASFCs were treated with TNF (10 ng / mL) in the presence of 200 μM of each compound. After 24 hours, the medium was changed and fresh medium and compounds were added. Cell supernatants were collected at 72 hours. DMSO-treated cells served as a vehicle control (red dotted line represents the DMSO control).

[0163] IL-6 ELISA: Levels of the pro-inflammatory cytokine IL6 were measured in the supernatants of cultured RASFCs by a specific ELISA according to the manufacturer's requirements (R&D systems, UK).

[0164] This assay measures IL6 production as an indicator of immune system activation; the lower this value, the better in terms of alleviating RA symptoms. All compounds of the present invention demonstrated efficacy compared to DMSO vehicle, which represents no treatment. Furthermore, compounds of the present invention demonstrated activity equivalent to or greater than that of the JAK-STAT inhibitor tofacitinib (Xeljanz, Pfizer). Results for specific example compounds are shown below. [Table 3]

[0165] Experimental autoimmune encephalomyelitis (EAE) To demonstrate the efficacy of these compounds in multiple sclerosis, the molecules were tested in the gold standard "EAE" model of MS. To evaluate the potential of these compounds in vivo, chronic monophasic EAE disease was induced in mice prior to treatment with novel chemical entities (NCEs). EAE disease was induced by injecting 100 μg of MOG in 50% complete Freund's adjuvant (CFA; 50% CFA containing 4 mg / mL heat-inactivated Mycobacterium tuberculosis and 50% incomplete Freund's adjuvant (Chondrex)). 33-55 Eight- to ten-week-old female mice (C57BL / 6) were induced with 200 μL of emulsion containing the peptide (Genscript) by subcutaneous injection. On the same day, the mice received 200 ng of pertussis toxin (Kemo-Sero-Therapeutic Research Institute, Japan) intraperitoneally (ip), and again 2 days later.

[0166] Disease severity was recorded every 24 hours and a score was assigned as follows: 0 - normal; 1 - flaccid tail; 2 - impaired / unsteady gait; 3 - complete hindlimb weakness; 4 - hindlimb and forelimb paralysis; 5 - moribund / death. The protocol, including the scoring method, was based on Nature Protocols for active induction of experimental allergic encephalomyelitis: Stromnes IM, Goverman JM (2006) Active induction of experimental allergic encephalomyelitis. Nat Protoc. 1(4):1810-9.

[0167] Once a clinical score of between 1.5 and 2 was reached, the animals were administered 200 μL of PBS as a control or the example cuein mimetic compound at a concentration of 4 mM in a volume of 200 μL intraperitoneally (ip) daily for a total of 7 days.

[0168] As expected, control animals showed a consistent worsening of disease throughout the experimental period. In contrast, diseased animals treated with example compounds showed a brief increase in disease severity followed by a gradual recovery.

[0169] Attention is drawn to all papers and documents related to this application that are filed contemporaneously or previously hereto and that are open to public inspection herewith, and the contents of all such papers and documents are incorporated herein by reference.

[0170] All features disclosed in this specification (including any accompanying claims and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive.

[0171] Each feature disclosed in this specification (including any accompanying claims and drawings), unless expressly stated otherwise, may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

[0172] The invention is not limited to the details of the foregoing embodiments, and extends to any novel single or novel combination of features disclosed herein (including any accompanying claims and drawings), or any novel single or novel combination of any method or process so disclosed.

Claims

1. Formula (I): 【Chemistry 17】 (In the formula, Y is selected from C or N; X is O; Bond a is a single bond or a double bond; When a is a single bond, x is 1, and when a is a double bond, x is 0; R １ is selected from hydrogen and methyl; R ２ (when present) is selected from hydrogen and methyl; R ３ is selected from hydrogen, (1-6C)alkyl, and (1-6C)alkyl-phenyl, wherein said phenyl is optionally substituted with one or more (e.g., 1 to 3) substituents each independently selected from hydroxy, (1-6C)alkoxy, (1-6C)alkyl, and halo (e.g., chloro and fluoro). or a pharmaceutically acceptable salt or solvate thereof.

2. 2. A compound of formula (I) according to claim 1, wherein Y is N, or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of formula (I) according to claim 1 or 2 (wherein R １ is hydrogen), or a pharmaceutically acceptable salt or solvate thereof.

4. 4. A compound of formula (I) according to any one of claims 1 to 3, wherein a is a double bond and x is 0, or a pharmaceutically acceptable salt or solvate thereof.

5. 4. A compound of formula (I) according to any one of claims 1 to 3, wherein a is a single bond and x is 1, or a pharmaceutically acceptable salt or solvate thereof.

6. The compound of formula (I) according to claim 5 (wherein R ２ is hydrogen), or a pharmaceutically acceptable salt or solvate thereof.

7. 7. The compound of formula (I) according to any one of claims 1 to 6, wherein R ３ is selected from hydrogen, (1-3C)alkyl, and (1-4C)alkyl-phenyl, wherein said phenyl is optionally substituted by one or more (e.g., 1 to 3) substituents each independently selected from hydroxy, (1-6C)alkoxy, (1-6C)alkyl, and halo (e.g., chloro and fluoro), or a pharmaceutically acceptable salt or solvate thereof.

8. 7. The compound of formula (I) according to any one of claims 1 to 6, wherein R ３ is selected from hydrogen, methyl and (1-2C)alkyl-phenyl, wherein said phenyl is optionally substituted by one or more (e.g., 1 to 3) substituents each independently selected from hydroxy, (1-6C)alkoxy, (1-6C)alkyl and halo (e.g., chloro and fluoro), or a pharmaceutically acceptable salt or solvate thereof.

9. 9. The composition according to any one of claims 1 to 8, comprising: 2-amino-5-((phenethoxyamino)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde O-methyloxime; 2-amino-5-(((benzyloxy)amino)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; and 2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime or a pharmaceutically acceptable salt or solvate thereof.

10. 10. A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, for use as a pharmaceutical.

11. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 9, for use in the treatment of a disease or condition that can be mediated by a substrate of the cuein-tRNA ribosyltransferase pathway.

12. 10. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 9 for use in the treatment of an autoimmune disease.

13. 10. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 9 for use in the treatment of multiple sclerosis or rheumatoid arthritis.

14. 10. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 9 for use in the treatment of a neurodegenerative or inflammatory disease or condition.

15. 10. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

16. 10. A pharmaceutical product comprising a compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, and an additional therapeutic agent.

17. 17. The pharmaceutical product of claim 16, wherein the additional therapeutic agent comprises a medication for the treatment of an autoimmune disease.

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