Deuterated analogs of sirtuin 6 modulator IMU-856

Abstract

The present disclosure relates to novel deuterated analogs of the sirtuin 6 (SIRT6) modulator IMU-856, pharmaceutical formulations comprising them, a process for their preparation and their use as medicament, alone or in combination with one or more additional agents, for preventing and / or treating of various diseases, wherein the modulation of SIRT6 is desirable, e.g. in celiac disease.

Description

[0001]I75236WO BOEHMERT & BOEHMERT DEUTERATED ANALOGS OF SIRTUIN 6 MODULATOR IMU-856 SUMMARY OF THE INVENTION The present disclosure relates to novel deuterated analogs of the sirtuin 6 (SIRT6) modulator IMU-856, pharmaceutical formulations comprising them, a process for their preparation and their use as medicament, alone or in combination with one or more additional agents, for preventing and / or treating of various diseases, wherein the modulation of SIRT6 is desirable, e.g. in celiac disease. BACKGROUND, INTRODUCTION AND PRIOR ART Sirtuins are a family of proteins related to the founding member of the family - the silent information regulator 2 protein (Sir2p) of Saccharomyces cerevisiae, a nicotinamide adenine dinucleotide (NAD+)- dependent histone deacetylase (HDAC) regulating chromatin silencing. Mammals contain at least seven sirtuin homologues numbered SIRT1 to SIRT7, characterized by significant sequence homology, particularly within their conserved NAD+-binding domains (Biochem. Biophys. Res. Commun. 2000;273:793). Sirtuins usually possess NAD+-dependent deacetylase activity which removes acetyl groups from Ac-Lys of histones or non-histone protein substrates, while producing nicotinamide and acetyl ester metabolites 2'-O- and 3'-O-acetyl-ADP ribose (AADPR). AADPR may themselves function as second messengers in cells. Other sirtuins, e.g., SIRT4 and SIRT6, may lack significant deacetylase activity but display a robust NAD+-dependent ADP-ribosyl transferase activity (J. Biol. Chem. 2005;280:21313). Previous reports suggested that some members of the sirtuin family could negatively regulate inflammatory responses. WO2008 / 138943 describes the prophylactic and therapeutic use of sirtuin modulators, and specifically modulators targeting SIRT6, for the treatment of tumor necrosis factor alpha (TNFα)-mediated pathologies, such as various inflammatory and autoimmune disorders (e.g. celiac disease (CelD)). IMU-856 is a small molecule, orally available and selective modulator of the deacetylase activity of the sirtuin 6 enzyme (SIRT6) covered in WO2019 / 054427 with chemical formula , chemical name 6-(trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-4H- 1,2,4-triazol-3-yl)cyclohexyl)-1H-pyrazol-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane and with CAS-number 2303528-97-2. As an orally available and systemically acting small molecule modulator, IMU-856 targets SIRT6, which serves as a transcriptional regulator of intestinal barrier function and regeneration of bowel epithelium. Based on preclinical data, the compound represents a unique treatment approach, as the mechanism of action targets the restoration of the intestinal barrier function and bowel wall architecture in patients suffering from gastrointestinal diseases such as celiac disease, atypical wheat allergy, gluten intolerance (e.g., non-celiac gluten sensitivity (NCGS), gluten ataxia, dermatitis herpetiformis (DH) and wheat allergy), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis or IBD- associated diarrhea), irritable bowel syndrome (IBS), (especially irritable bowel syndrome with diarrhea (IBS-D)), microscopic colitis (e.g., collagenous colitis and lymphocytic colitis) and eosinophilic esophagitis (EoE). Targeting SIRT6 with IMU-856 prevents the deacetylation of one of its ligands, acetylated lysine (K) 56 of histone H3 (H3K56), in an in vitro cell free and cellular system and significantly accelerates the recovery of transepithelial electrical resistance (TEER) across a monolayer of colorectal adenocarcinoma-2 (Caco-2) cells following inflammation with tumor necrosis factor (TNF-α) or interleukin (IL)-6. In one TEER model, tight junction (TJ)-related proteins were investigated, and a normalization of TJ proteins (claudin (Cldn)-1 and claudin-2) was observed. TJ-proteins play a key role in the pathogenesis of CelD. Furthermore, IMU-856 demonstrated efficacy in different settings of the dextran sodium sulphate (DSS)-induced colitis model in mice by reducing disease severity, improving diarrhea symptoms, increasing colon length, and improving colon mucosal histology. IMU-856 mediated inhibition is highly selective for SIRT6 over other members of the human SIRT protein family and does not inhibit enzymatic activity of other histone deacetylases (HDACs). There is a need to develop novel SIRT6 modulators. In particular, there is a need to develop SIRT6 modulators with improved pharmacokinetic properties. Deuterated compounds have not yet been described in WO2019 / 054427, especially no compounds with with the defined deuteration pattern according to Formula (I). From metabolite profiling experiments with IMU-856 in human hepatocytes and human microsomes we identified its metabolic soft spots, which is located in the spirocyclic moiety of IMU-856. Metabolites identified were formed by oxygenation, bis-oxygenation as well as oxygenation / hydrogenation and their presence has been confirmed in clinical phase 1. By replacing the relevant hydrogen atoms to deuterium, we were surprisingly able to improve the metabolic stability of IMU-856. BRIEF SUMMARY OF THE INVENTION The present invention relates to compounds according to Formula (I) or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof, wherein R1, R2and R3are independently selected from hydrogen or deuterium; provided, that at least one hydrogen in Formula (I) is replaced by deuterium; and provided, that the level of deuterium incorporation at each substituent designated as deuterium is at least 50.1%. The compounds of the present invention exhibit an advantageous stability or pharmacokinetic profile compared to IMU-856 when used as medicament due to the replacement of hydrogen to deuterium. Thus, the present invention further relates to a pharmaceutical composition comprising a compound according to Formula (I) and at least one pharmaceutically acceptable carrier or excipient. The present invention is further directed to compounds according to Formula (I) for use in the prophylaxis and / or treatment of diseases mediated by SIRT6 modulation. Accordingly, the present invention relates to the prophylaxis and / or treatment of the disease, disorder, therapeutic indication or medical condition which is selected from the group comprising celiac disease, atypical wheat allergy, gluten intolerance (e.g., non-celiac gluten sensitivity, gluten ataxia, dermatitis herpetiformis and wheat allergy), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis or inflammatory bowel disease-associated diarrhea), irritable bowel syndrome (especially irritable bowel syndrome with diarrhea), microscopic colitis (e.g., collagenous colitis and lymphocytic colitis) and eosinophilic esophagitis. The present invention is further directed to use of compounds according to Formula (I) for the manufacturing a medicament for prophylaxis and / or treatment of the diseases, disorders, therapeutic indications or medical conditions as defined above as well as to the method of prophylaxis and / or treatment of these diseases.DETAILED DESCRIPTION OF THE INVENTIONSurprisingly, we found that by selectively deuterating certain positions, the metabolic stability of IMU- 856 can be dramatically improved. Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulae. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. Rather, the invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the present invention as defined by the claims. The present invention is not limited to the methods and materials described herein but include any methods and materials similar or equivalent to those described herein that could be used in the practice of the present invention. In the event that one or more of the incorporated literature references, patents or similar materials differ from or contradict this application, including but not limited to defined terms, term usage, described techniques or the like, this application controls. In certain embodiments the present invention relates to a compound of Formula (I) as described in the following items: 1. A compound according to Formula (I): or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof, wherein R1, R2and R3are independently selected from hydrogen or deuterium; provided, that at least one hydrogen in Formula (I) is replaced by deuterium; and provided, that the level of deuterium incorporation at each substituent designated as deuterium is at least 50.1%. 2. A compound according to item 1, wherein R1, R2and R3are independently selected from hydrogen or deuterium; provided, that at least one hydrogen in R1, R2or R3of Formula (I) is replaced by deuterium; and provided, that the level of deuterium incorporation at each substituent designated as deuterium is at least 50.1%. 3. A compound according to item 1 or 2, wherein Formula (I) is or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof. 4. A compound according to any of items 1 to 3, wherein Formula (I) is 5. The compound according to any of items 1 to 4 or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof for use as a medicament. 6. The compound according to any of items 1 to 4 or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof for use in the prophylaxis and / or treatment of a disease or medical condition in which sirtuin 6 modulation is beneficial. 7. The compound or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof for use according to item 6 wherein the disease or medical condition is selected from the group consisting of celiac disease, atypical wheat allergy, gluten intolerance (e.g., non-celiac gluten sensitivity, gluten ataxia, dermatitis herpetiformis and wheat allergy), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis or inflammatory bowel disease-associated diarrhea), irritable bowel syndrome (especially irritable bowel syndrome with diarrhea), microscopic colitis (e.g., collagenous colitis and lymphocytic colitis) and eosinophilic esophagitis. 8. Use of a compound of Formula (I) as defined in any item 1 to 4, or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof in the manufacture of a medicament for the prophylaxis and / or treatment of a disease or medical condition in which sirtuin 6 modulation is beneficial. 9. The use of item 6 wherein the disease or medical condition is selected from the group consisting of celiac disease, atypical wheat allergy, gluten intolerance (e.g., non-celiac gluten sensitivity, gluten ataxia, dermatitis herpetiformis and wheat allergy), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis or inflammatory bowel disease-associated diarrhea), irritable bowel syndrome (especially irritable bowel syndrome with diarrhea), microscopic colitis (e.g., collagenous colitis and lymphocytic colitis) and eosinophilic esophagitis. 10. Method of preventing and / or treating a disease or medical condition in which sirtuin 6 modulation is beneficial comprising administering a compound of Formula (I) as defined in any items 1 to 4, or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof to a subject in the need thereof. 11. Method of preventing and / or treating a disease or medical condition according to item 10, wherein the disease or medical condition is selected from the group consisting of celiac disease, atypical wheat allergy, gluten intolerance (e.g., non-celiac gluten sensitivity, gluten ataxia, dermatitis herpetiformis and wheat allergy), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis or inflammatory bowel disease-associated diarrhea), irritable bowel syndrome (especially irritable bowel syndrome with diarrhea), microscopic colitis (e.g., collagenous colitis and lymphocytic colitis) and eosinophilic esophagitis. 12. A pharmaceutical composition comprising a compound of Formula (I) according to any one of items 1 to 4 or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof and a pharmaceutically acceptable carrier or excipient. DEFINITIONS AND PARTICULAR EMBODIMENTS In particular embodiments, as used herein, wherein when any one of the substituent is deuterium, the level of deuterium incorporation at each of substituent designated as deuterium is at least 50.1%, at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%. In particular embodiments, the level of deuterium incorporation at each substituent designated as deuterium is at least 50.1%. In particular embodiments, the level of deuterium incorporation at each substituent designated as deuterium is at least 52.5%.More particularly, the level of deuterium incorporation at each substituent designated as deuterium is atleast 90%. Even more particularly, the level of deuterium incorporation at each substituent designated as deuterium is at least 95%. Most particularly, the level of deuterium incorporation at each substituent designated as deuterium is at least 98%. Quantitative analysis of specifically deuterated compounds can be achieved by a number of conventional methods, such as mass spectroscopy (peak area) or by quantifying the remaining residual1H-NMR signals of the specific deuteration site compared to signals from internal standards or other, non- deuterated1H signals in the compound. It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of a not-specifically deuterated compound will inherently contain small amounts of deuterated isotopologues. The concentration of naturally abundant stable hydrogen and carbon isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this invention. See, for instance, Comp. Biochem. Physiol.1998;119A:725. The term “isotopic enrichment factor” at a particular position normally occupied by hydrogen refers to the ratio between the abundance of deuterium at the position and the natural abundance of deuterium at that position. By way of example, an isotopic enrichment factor of 3500 means that the amount of deuterium at the particular position is 3500-fold the natural abundance of deuterium, or that 52.5% of the compounds have deuterium at the particular position (i.e., 52.5% deuterium incorporation at the given position). The abundance of deuterium in the oceans of Earth is approximately one atom in 6500 hydrogen atoms (about 154 parts per million (ppm)). Deuterium thus accounts for approximately 0.015 percent (on a weight basis, 0.030 percent) of all naturally occurring hydrogen atoms in the oceans on Earth; the abundance changes slightly from one kind of natural water to another. When a particular position in a compound of the invention (e.g., a compound represented by Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof) is designated by name or structure as containing hydrogen or deuterium, it is to be understood that the position can contain hydrogen at its natural abundance or can be enriched in deuterium with an isotopic enrichment factor of, for example, at least 835 (12.5% deuterium incorporation), at least 1670 (25% deuterium incorporation, at least 3340 (50.1% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). When a particular position in a compound of the invention (e.g., a compound represented by Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof) is designated specifically by name or structure as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. When a particular position in a compound of the invention (e.g., a compound represented by Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof) is designated specifically by name or structure as “D” or “deuterium”, the position is understood to have deuterium at an abundance that is at least 3340 times of the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium), at least 3500 times of the natural abundance of deuterium (52.5% deuterium incorporation), at least 4500 times of the natural abundance of deuterium (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 times of the natural abundance of deuterium (82.5% deuterium incorporation), at least 6000 times of the natural abundance of deuterium (90% deuterium incorporation), at least 6333.3 times of the natural abundance of deuterium (95% deuterium incorporation), at least 6466.7 times of the natural abundance of deuterium (97% deuterium incorporation), at least 6600 times of the natural abundance of deuterium (99% deuterium incorporation), or at least 6633.3 times of the natural abundance of deuterium (99.5% deuterium incorporation). The percentage of deuterium incorporation can be obtained by quantitative analysis using a number of conventional methods, such as mass spectroscopy (peak area) or by quantifying the remaining residual1H-NMR signals of the specific deuteration site compared to signals from internal standards or other, non-deuterated1H signals in the compound. When a chemical name or structure is silent as to whether a particular position in a compound normally occupied by hydrogen is isotopically enriched, it is intended that the particular position is occupied by hydrogen at its natural abundance. By way of example, the structural element “cyclohexyl” or without any further designation as to isotopic enrichment indicates that all hydrogen atoms are present at natural abundance. The term “compound,” when referring to any compound of this disclosure, including a compound represented by Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent hydrogen atoms of the molecules. The relative amount of isotopic variation in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound. “D” and “d” both refer to deuterium. “H” refers to hydrogen. “Substituted with deuterium” refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms. Any formula or structure given herein, is also intended to represent deuterated compounds comprising in addition further isotopically labelled atoms. Examples of additional isotopes that can be incorporated into compounds of the disclosure include further isotopes of hydrogen (i.e. tritium or3H), as well as isotopes of carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to11C,13C,14C,15N,18F,31P,32P,35S,36Cl and125I. The disclosure further comprises various isotopically labelled compounds into which radioactive isotopes such as3H,13C and14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or radioactive treatment of patients. In one embodiment, in the compound of Formula (I) R1and R2each is hydrogen and at least one of R3is deuterium. In one embodiment, in the compound of Formula (I) R1and R3each is hydrogen and at least one of R2is deuterium. In one embodiment, in the compound of Formula (I) R2and R3each is hydrogen and at least one of R3is deuterium. In one embodiment, in the compound of Formula (I) R1and R2each is hydrogen and R3is deuterium. In one embodiment, in the compound of Formula (I) R1and R3each is hydrogen and R2is deuterium. In one embodiment, in the compound of Formula (I) R2and R3each is hydrogen and R3is deuterium. In one embodiment, in the compound of Formula (I) R1and R2each is deuterium and R3is hydrogen. In one embodiment, in the compound of Formula (I) R1and R3each is deuterium and R2is hydrogen. In one embodiment, in the compound of Formula (I) R2and R3each is deuterium and R3is hydrogen. In particular embodiments of the present invention, the compound of Formula (I) is deuterated within (a) the spirocyclic moiety; and / or (b) in alpha position(s) of the substituents to the triazole moiety (e.g. and / or (c) in alpha position(s) to other nitrogen atoms (e.g. combinations thereof). In particular embodiments of the present invention, the compound of Formula (I) is selected from or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof. In particular embodiments of the present invention, the compound of Formula (I) is , or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof. In a particular embodiment of the present invention, the compound of Formula (I) is . The invention also provides the compound of the present invention for the use as a medicament. Also provided is the compound of the present invention for use in the prophylaxis and / or treatment of a disease or medical condition is selected from celiac disease, atypical wheat allergy, gluten intolerance (e.g., non-celiac gluten sensitivity, gluten ataxia, dermatitis herpetiformis and wheat allergy), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis or inflammatory bowel disease- associated diarrhea), irritable bowel syndrome (especially irritable bowel syndrome with diarrhea), microscopic colitis (e.g., collagenous colitis and lymphocytic colitis) and eosinophilic esophagitis. In one embodiment the compound of the present invention for use in the prophylaxis and / or treatment of a disease or medical condition is for celiac disease. Also provided is the use of compound of the present invention in the manufacture of a medicament for the prophylaxis and / or treatment of a disease or medical condition in which inverse agonism modulation of sirtuin 6 is beneficial. Also provided is the use of the compound of the present invention in the manufacture of a medicament for the prophylaxis and / or treatment of a disease or medical condition is selected from celiac disease, atypical wheat allergy, gluten intolerance (e.g., non-celiac gluten sensitivity, gluten ataxia, dermatitis herpetiformis and wheat allergy), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis or inflammatory bowel disease-associated diarrhea), irritable bowel syndrome (especially irritable bowel syndrome with diarrhea), microscopic colitis (e.g., collagenous colitis and lymphocytic colitis) and eosinophilic esophagitis. Also provided is a method of preventing and / or treating a disease or medical condition in which sirtuin 6 modulation is beneficial comprising administering a compound of the present invention to a subject in the need thereof. Also provided is a method of preventing and / or treating a disease or medical condition comprising administering a compound of the present invention to a subject in the need thereof, wherein the disease or medical condition is selected from the group consisting of celiac disease, atypical wheat allergy, gluten intolerance (e.g., non-celiac gluten sensitivity, gluten ataxia, dermatitis herpetiformis and wheat allergy), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis or inflammatory bowel disease-associated diarrhea), irritable bowel syndrome (especially irritable bowel syndrome with diarrhea), microscopic colitis (e.g., collagenous colitis and lymphocytic colitis) and eosinophilic esophagitis. Also provided is a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier or excipient. The pharmaceutical compositions as described herein comprise one or more of the compounds according to this invention and a pharmaceutically acceptable carrier or excipient, further comprising one or more additional therapeutic agents selected from anti-inflammatory agents, immunosuppressive and / or immunomodulatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics and suitable mixtures thereof. Additionally, the invention relates to an article of manufacture, which comprises packaging material and a pharmaceutical agent contained within said packaging material, wherein the pharmaceutical agent is therapeutically effective against the medical conditions as described herein, and wherein the packaging material comprises a label or package insert which indicates that the pharmaceutical agent is useful for preventing and / or treating said medical conditions, and wherein said pharmaceutical agent comprises one or more compounds of Formula (I) according to the invention. The packaging material, label and package insert otherwise parallel or resemble what is generally regarded as standard packaging material, labels and package inserts for pharmaceuticals having related utilities. The pharmaceutical compositions according to this invention are prepared by processes which are known per se and familiar to the person skilled in the art. As pharmaceutical compositions, the compounds of the invention (= active compounds) are either employed as such, or particularly in combination with suitable pharmaceutical auxiliaries and / or excipients, e.g. in the form of tablets, coated tablets, capsules, caplets, suppositories, patches (e.g. as TTS), emulsions, suspensions, gels or solutions, the active compound content advantageously being between 0.1 and 95% and where, by the appropriate choice of the auxiliaries and / or excipients, a pharmaceutical administration form (e.g. a delayed release form or an enteric form) exactly suited to the active compound and / or to the desired onset of action can be achieved. The person skilled in the art is familiar with auxiliaries, vehicles, excipients, diluents, carriers or adjuvants which are suitable for the desired pharmaceutical formulations, preparations or compositions on account of his / her expert knowledge. In addition to solvents, gel formers, ointment bases and other active compound excipients, for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers, colorants, complexing agents or permeation promoters, can be used. Depending upon the particular disease, to be treated or prevented, additional therapeutic active agents, which are normally administered to treat or prevent that disease, may optionally be co-administered with the compounds according to the present invention. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease are known as appropriate for the disease being treated. In a further aspect of the present invention, the compounds according to this invention or the salts or solvates of said compounds of Formula (I) may be combined with standard therapeutic agents which are commonly used for the prophylaxis and / or treatment of the medical conditions as described herein. The person skilled in the art is aware on the base of his / her expert knowledge of the total daily dosage(s) and administration form(s) of the additional therapeutic agent(s) co-administered. Said total daily dosage(s) can vary within a wide range. In practicing the present invention and depending on the details, characteristics or purposes of their uses mentioned above, the compounds according to the present invention may be administered in combination therapy separately, sequentially, simultaneously or chronologically staggered (e.g. as combined unit dosage forms, as separate unit dosage forms or a adjacent discrete unit dosage forms, as fixed or nonfixed combinations, as kit-of-parts or as admixtures) with one or more standard therapeutics, in particular art-known chemotherapeutic or target specific anti- cancer agents, such as those mentioned above. Thus, a further aspect of the present invention is a combination or pharmaceutical composition comprising a first active ingredient, which is a compound according to this invention or a pharmaceutically acceptable salt or solvate thereof, a second active ingredient, which is an art-known standard therapeutic for the medical conditions as described herein, and optionally a pharmacologically acceptable carrier, diluent and / or excipient for sequential, separate, simultaneous or chronologically staggered use in therapy in any order, e.g. to treat, prevent or ameliorate in a patient the medical conditions as described herein. In this context, the present invention further relates to a combination comprising a first active ingredient, which is at least one compound according to this invention, and a second active ingredient, which is at least one art-known standard therapeutic for the medical conditions as described herein, for separate, sequential, simultaneous or chronologically staggered use in therapy, such as e.g. in therapy of those diseases mentioned herein. The term "combination" according to this invention may be present as a fixed combination, a non-fixed combination or a kit-of-parts. A "fixed combination" is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity. One example of a "fixed combination" is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture. A "kit-of-parts" is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit. One example of a "kit-of- parts" is a combination wherein the said first active ingredient and the said second active ingredient are present separately. The components of the kit-of-parts may be administered separately, sequentially, simultaneously or chronologically staggered. The first and second active ingredient of a combination or kit-of-parts according to this invention may be provided as separate formulations (i.e. independently of one another), which are subsequently brought together for simultaneous, sequential, separate or chronologically staggered use in combination therapy; or packaged and presented together as separate components of a combination pack for simultaneous, sequential, separate or chronologically staggered use in combination therapy. The type of pharmaceutical formulation of the first and second active ingredient of a combination or kit-of-parts according to this invention can be similar, i.e. both ingredients are formulated in separate tablets or capsules, or can be different, i.e. suited for different administration forms, such as e.g. one active ingredient is formulated as tablet or capsule and the other is formulated for e.g. intravenous administration. The amounts of the first and second active ingredients of the combinations, compositions or kits according to this invention may together comprise a therapeutically effective amount for the treatment, prophylaxis or amelioration of a medical condition as described herein. A further aspect of the present invention is a method for preventing and / or treating co-therapeutically the medical conditions as described herein, in a patient in need of such treatment comprising administering separately, sequentially, simultaneously, fixed or non-fixed a therapeutically effective and tolerable amount of one or more of the compounds according to the present invention and a therapeutically effective and tolerable amount of one or more art-known therapeutic agents for the medical conditions as described herein, to said patient. References and claims to the use of a compound of the Formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the prophylaxis and / or treatment of a disease or medical condition in their general and specific forms likewise refer to the corresponding methods of preventing and / or treating said disease or medical condition, said method comprising administering a therapeutically effective and tolerable amount of a compound of the Formula (I) or a pharmaceutically acceptable salt or solvate thereof to a subject in need thereof, compositions comprising a compound of the Formula (I) or a pharmaceutically acceptable salt or solvate thereof for the prophylaxis and / or treatment of said disease or medical condition, a compound of the Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the prophylaxis and / or treatment of said disease or medical condition, and vice versa. For the production of the pharmaceutical compositions, the compounds of the invention (= active compounds) are particularly mixed with suitable pharmaceutical auxiliaries and further processed to give suitable pharmaceutical formulations. Suitable pharmaceutical formulations are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions. The pharmaceutical compositions according to the invention are prepared by processes known per se. The dosage of the active compounds is carried out in the customary order of magnitude. Topical application forms (such as ointments) thus contain the active compounds in a concentration of, for example, 0.1 to 99% by weigth. The customary dose in the case of systemic therapy (p.o.) is usually between 0.3 and 30 mg / kg per day, (i.v.) is usually between 0.3 and 30 mg kg / h. The choice of the optimal dosage regime and duration of medication, particularly the optimal dose and manner of administration of the active compounds necessary in each case can be determined by a person skilled in the art on the basis of his / her expert knowledge. The compounds of the invention may, depending on their structure, exist in tautomeric or stereoisomeric forms (enantiomers, diastereomers). The invention therefore also encompasses the tautomers, enantiomers or diastereomers and respective mixtures thereof. The stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. The respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic base in a solvent or dispersant, or by cation exchange with other salts. The present disclosure also includes all salts of the compounds of the present disclosure which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. The term "solvate" refers to a crystalline form of a molecule that further comprises molecules of a solvent or solvents incorporated into the crystalline lattice structure. Thus, the compounds of the present disclosure may be present in the form of solvates, such as those which include as solvate water, or pharmaceutically acceptable solvates, such as alcohols, in particular ethanol. A stoichiometric or non- stoichiometric amount of solvent is bound by non-covalent intermolecular forces. When the solvent is water, the "solvate" is a "hydrate." It is understood, that a "pharmaceutically acceptable salts" can in addition optionally contain a "solvate". The term "polymorph" as used herein refers to a crystalline form of a compound or a salt, hydrate, or solvate thereof, in a particular crystal packing arrangement. All polymorphs have the same elemental composition. The term "crystalline" as used herein, refers to a solid state form which consists of orderly arrangement of structural units. Different crystalline forms of the same compound, or a salt, hydrate, or solvate thereof, arise from different packing of the molecules in the solid state, which results in different crystal symmetries and / or unit cell parameter. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. The term "effective amount" is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of a disorder, disease, or condition being treated. The term "effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician. As used herein, the term “subject” refers to any member of the animal kingdom including humans. In some embodiments, “subject” refers to humans, at any stage of development. In some embodiments, “subject” refers to a human patient. In some embodiments, “subject” refers to non-human animals. In some embodiments, the non-human animal is a mammal (e.g. a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate or a pig). In some embodiments, subjects include, but are not limited to, mammals, birds, reptiles, amphibians, fish or worms. In some embodiments, a subject may be a transgenic animal, genetically-engineered animal or a clone. As used herein, the terms “preventing” and “prophylaxis” in relation to a disease or a medical condition mean, for example, administration of a medicament containing the compound of the present invention to patients who are expected to have a high risk of the onset due to some factor relating to the disease but have not developed the disease or patients who have developed the disease but do not have a subjective symptom, or administration of a medicament containing the compound of the present invention to patients who are feared to show recurrence of the disease after treatment of the disease. The terms “preventing” and “prophylaxis” are used interchangeably throughout the application. The treatment or prevention of a disease, a medical condition, a disorder or a therapeutic indication may be partial or complete. It has unexpectedly been found that deuterated compounds as detailed herein show higher microsomal stability. The following example section shows further details. EXPERIMENTAL PART The undeuterated matched pair of the present invention can be prepared as outlined in WO2019 / 054427. The present invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results. Experimental Section Example 1: Step 1: Oxetane-2,2-diylbis(methan-d2-ol) (1a) To a solution of diethyl oxetane-2,2-dicarboxylate (1 eq.) in dry tetrahydrofuran was added at 0°C lithium aluminum deuteride (3 eq.) in portions. The mixture was stirred for 2 h at this temperature. The mixture was quenched by water (0.25 mL). Then 10% NaOH (0.5 mL) and water (0.75 mL) were added. The mixture was filtered and concentrated to afford compound 1a as a colorless oil, which was used for the next step without purification. Step 2: 6-((trans)-4-(4-((trans)-4-(4-methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-4H- 1,2,4-triazol-3-yl)cyclohexyl)-1H-pyrazol-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane-5,5,7,7-d4 Compound 1a was reacted with (trans)-4-(4-((trans)-4-(4-methyl-5-(((4-(trifluoromethyl)pyridin-2- yl)oxy)methyl)-4H-1,2,4-triazol-3-yl)cyclohexyl)-1H-pyrazol-1-yl)cyclohexan-1-amine using trifluoromethanesulfonic anhydride and diisopropylethylamine in dichloromethane at –78°C for 15 min and then allowing to reach room temperature as outlined in WO2019 / 054427 for the non-deuterated matched pair to obtain compound 1 as an off-white solid. The1H-NMR (CDCl3) is consistent with structure and shows a degree of deuteration of ≥99%. Example 1 / 1: Step 1: Diethyl 2-(2-bromoethoxy-1,1,2,2-d4)malonate (1 / 1a) If one were to treat diethyl 2-diazomalonate with bromoethanol-d4 as described in Angew. Chem. Int. Ed. 2014;53:14230 for the non-deuterated matched pair one would obtain compound 1 / 1a. Step 2: Diethyl oxetane-2,2-dicarboxylate-d4(1 / 1b) If one were to treat compound 1 / 1a with sodium hydride as described in Angew. Chem. Int. Ed. 2014;53:14230 for the non-deuterated matched pair one would obtain compound 1 / 1b. 3: (Oxetane-2,2-diyl-3,3,4,4-d4)bis(methan-d2-ol) (1 / 1c) If one were to treat compound 1 / 1b as described in Example 1, Step 1, one would obtain compound 1 / 1c. Step 4: 6-((trans)-4-(4-((trans)-4-(4-methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-4H- 1,2,4-triazol-3-yl)cyclohexyl)-1H-pyrazol-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane- 2,2,3,3,5,5,7,7-d8(1 / 1) If one were to treat compound 1 / 1c as described in Example 1, Step 2, one would obtain compound 1 / 1. Example 1 / 2: 6-((trans)-4-(4-((trans)-4-(4-methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)- 4H-1,2,4-triazol-3-yl)cyclohexyl)-1H-pyrazol-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane- 2,2,5,5,7,7-d6 (1 / 2) If one were to use 2-bromoethan-1,1-d2-1-ol (synthesized as described in J. Label. Compd. Radiopharm. 1987;24:369 instead of bromoethanol-d4 in Example 1 / 1 on would obtain compound 1 / 2. Example 1 / 3: 6-((trans)-4-(4-((trans)-4-(4-methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)- 4H-1,2,4-triazol-3-yl)cyclohexyl)-1H-pyrazol-1-yl)cyclohexyl)-1-oxa-6-azaspiro[3.3]heptane- 3,3,5,5,7,7-d6 (1 / 3) If one were to use 2-bromoethan-2,2-d2-1-ol (synthesized as described in J. Label. Compd. Radiopharm. 1989;27:199) instead of bromoethanol-d4 in Example 1 / 1 on would obtain compound 1 / 3. Example 2: Microsomal stability Example 1 and the non-deuterated matched pair from WO2019 / 054427 (Comparative Example C1) were incubated using three different batches of pooled human liver microsomes for a period of 60 min at a final solvent content of 0.5% dimethyl sulfoxide. The metabolization was monitored by HPLC-MS / MS. Verapamil served as positive control. The intrinsic clearance was calculated from the measured remaining compound values (in duplicate) at 60 minutes. The data points are as follows: human liver microsomes batch Catalog No. 452117 Catalog No. 452183 Catalog No. 452172 Clint(Lot. No. 38291) (Lot. No. 5061002) (Lot. No. 6029001) (µl / min / mg mixed gender female male protein) 150-donor-pool 20-donor-pool (Corning) 19-donor-pool (Corning) (Corning) Example 1 0.0 0.0 0.0 Verapamil 64.2 46.7 50.3 Conclusion: As exemplified with Example 1, by deuteration of the adjacent position of the basic amino moiety the intrinsic clearance in compounds of the present invention can be surprisingly blocked (not only reduced) in human microsomes compared to the non-deuterated matched pair in a way that no degradation can be detected at all. A reduced or blocked intrinsic clearance is beneficial since it prolongs the residence time of the drug in the body. In addition, there is no difference between the sexes, which can simplify and standardize the dosage to patients.

Claims

I75236WO BOEHMERT & BOEHMERT CLAIMS:

1. A compound according to Formula (I):or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof, wherein R1, R2and R3are independently selected from hydrogen or deuterium; provided, that at least one hydrogen in Formula (I) is replaced by deuterium; and provided, that the level of deuterium incorporation at each substituent designated as deuterium is at least 50.1%.

2. A compound according to claim 1, wherein R1, R2and R3are independently selected from hydrogen or deuterium; provided, that at least one hydrogen in R1, R2or R3of Formula (I) is replaced by deuterium; and provided, that the level of deuterium incorporation at each substituent designated as deuterium is at least 50.1%.

3. A compound according to claim 1 or 2, wherein Formula (I) isor a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof.

4. A compound according to any of claims 1 to 3, wherein Formula (I) is.

5. The compound according to any of claims 1 to 4 or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof for use as a medicament.

6. The compound according to any of claims 1 to 4 or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof for use in the prophylaxis and / or treatment of a disease or medical condition in which sirtuin 6 modulation is beneficial.

7. The compound or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof for use according to claim 6 wherein the disease or medical condition is selected from the group consisting of celiac disease, atypical wheat allergy, gluten intolerance (e.g., non- celiac gluten sensitivity, gluten ataxia, dermatitis herpetiformis and wheat allergy), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis or inflammatory bowel disease-associated diarrhea), irritable bowel syndrome (especially irritable bowel syndrome with diarrhea), microscopic colitis (e.g., collagenous colitis and lymphocytic colitis) and eosinophilic esophagitis.

8. A pharmaceutical composition comprising a compound of Formula (I) according to any one of claim 1 to 4 or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof and a pharmaceutically acceptable carrier or excipient.

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