Compounds for treating diabetes and related conditions

Abstract

Compounds useful for treating or preventing diabetes and related conditions, and for preventing, inhibiting or reversing amylin-amyloid fibril formation, preventing islets of Langerhans (Beta)-cell death, preventing or reversing the transition from soluble human amylin to insoluble human amylin, preventing and inhibiting or reversing cytotoxic amylin fibril formation. The invention relates to compounds of Formula (I): (I)

Description

[0001] COMPOUNDS FOR TREATING DIABETES AND RELATED CONDITIONS FIELD OF THE INVENTION The present invention relates to compounds useful for treating or preventing diabetes and related conditions, and for preventing, inhibiting or reversing amylin-amyloid fibril formation, preventing islets of Langerhans (Beta)-cell death, preventing or reversing the transition from soluble human amylin to insoluble human amylin, preventing and inhibiting or reversing cytotoxic amylin fibril formation. The present invention also relates to pharmaceutical compositions comprising compounds of the invention, uses of the compounds for the above-mentioned purposes, and their use in the manufacture of medicaments for the above-mentioned purposes. BACKGROUND OF THE INVENTION Misfolded protein aggregates known as amyloids have been reported to play a key role in the pathology of a number of diseases, such as rheumatoid arthritis, atherosclerosis, Alzheimer's disease, Parkinson's disease, Huntington’s disease, and diabetes. Misfolded human amylin (hA) is the main component of islet amylin amyloid in diabetic patients and is thought to be at least partly responsible for the development and progression of type II diabetes mellitus (type II diabetes). Human amylin therefore represents a potential target for developing medicines that can prevent or slow the progression of type II diabetes. Some molecules capable of altering hA-misfolding and aggregation are already known in the art, and include the broad-spectrum antibiotic, tetracycline. However, many of these molecules suffer from disadvantages, for example side-effect profiles or off-target activities, which make them unsuitable for long-term use. There remains a need for compounds capable of preventing, inhibiting and or reversing amylin-amyloid fibril formation, and / or of preventing islets of Langerhans Beta-cell death, and / or of preventing and / or reversing the transition from soluble human amylin to insoluble human amylin, and / or of preventing and inhibiting and / or reversing cytotoxic amylin fibril formation. It is an object of the present invention to provide compounds which overcome or at least partially ameliorate some of the abovementioned disadvantages and / or which at least provide the public with a useful choice. Other objects of the invention may become apparent from the following description which is given by way of example only. In this specification, where reference has been made to external sources of information, including patent specifications and other documents, this is generally for the purpose of providing a context for discussing the features of the present invention. Unless stated otherwise, reference to such sources of information is not to be construed, in any jurisdiction, as an admission that such sources of information are prior art or form part of the common general knowledge in the art. SUMMARY OF THE INVENTION In one aspect the invention provides a compound of Formula (I): wherein: X is C1-C5alkyl, cyclopropyl, or C2-C4dialkyl ether; A is absent or is C1-C6alkyl optionally substituted with halide, C1-C3alkoxy, or C1- C3haloalkoxy, or A is phenyl; B is absent or is C1-C6alkyl; each R1is independently selected from OH, halide, C1-C3alkoxy, C1-C3deuteroalkoxy, C1-C3haloalkoxy, C1-C3deuterohaloalkoxy, CO2R3, OCO2R4, and O-glycosyl; R3is H or C1-C3alkyl; R4is C1-C3alkyl; and u is 1, 2 or 3; each R2is independently selected from OH, halide, C1-C3alkoxy, C1-C3deuteroalkoxy, C1-C3haloalkoxy, and C1-C3deuterohaloalkoxy; and v is 1, 2 or 3; or a pharmaceutically acceptable salt thereof. In certain embodiments of the invention X is CH2. In other embodiments, X is (CH2)2, (CH2)3, or (CH2)4. In other embodiments, X is CH2-O-CH2. In further embodiments, X is cyclopropyl. In certain embodiments of the invention A is C1-C5alkyl substituted with OCH3, OCD3, OCH2F, or F. In certain embodiments of the invention R1is OH, F, CO2H, OCH3, OCD3, OCF2H, OCOEt, OCO2Pr or O-glucosyl. In certain embodiments of the invention R2is OH, F, OCH3or OCD3. In certain embodiments of the invention u is 2 and each R1is OH, O-glucosyl or OCO2Pr. In certain embodiments of the invention u is 2 and one R1is OH and the other R1is CO2H. In certain embodiments of the invention u is 2 and one R1is OH and the other R1is OCF2H. In certain embodiments of the invention u is 2 and one R1is OH and the other R1is F. In certain embodiments of the invention v is 1 and R2is OCH3or OCD3. In certain embodiments of the invention v is 2 and one R2is OCH3or OCD3and the other R2is F. Compounds of the invention include, but are not limited to, the following:

[0002] In another aspect the invention relates to a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable diluent, carrier or excipient. In a further aspect the invention relates to a method of treating or preventing diabetes, an amylin amyloid-associated disease, or islet of Langerhans beta-cell death comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In a further aspect the invention relates to a method of inhibiting, preventing, or reversing an amylin amyloidosis or the formation of amylin-amyloid fibrils or amylin amyloid plaques in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In a further aspect the invention relates to a method of inhibiting, preventing, or reversing an amylin amyloidosis, or the formation of one or more amylin-amyloid fibrils or amylin amyloid plaques, the method comprising contacting the amylin amyloidosis or one or more amylin-amyloid fibrils or amylin amyloid plaques with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the method is a method of inhibiting, preventing, or reversing the formation of islet amylin-amyloid fibrils. In another aspect the invention relates to a method of treating or preventing diabetes in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In another aspect the invention relates to a method of treating or preventing islet of Langerhans beta-cell death in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In a further aspect the invention relates to a method of treating or preventing islet of Langerhans beta-cell death, the method comprising contacting one or more islet of Langerhans beta-cells with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, the invention provides a pharmaceutical composition comprising one or more compounds of Formula (I), optionally together with a pharmaceutically acceptable carrier or excipient. The invention further relates to a compound of Formula (I) for use in one or more of treating or preventing an amylin amyloid-associated disease, inhibiting, preventing, or reversing an amylin amyloidosis or the formation of amylin-amyloid fibrils or amylin amyloid plaques, inhibiting, preventing, or reversing the formation of islet amylin-amyloid fibrils, treating or preventing diabetes, or treating or preventing islet of Langerhans beta-cell death, for example in a subject in need thereof. The invention additionally relates to the use of a compound of Formula (I) in the preparation of a medicament for one or more of treating or preventing an amylin amyloid- associated disease, inhibiting, preventing, or reversing an amylin amyloidosis or the formation of amylin-amyloid fibrils or amylin amyloid plaques, inhibiting, preventing, or reversing the formation of islet amylin-amyloid fibrils, treating or preventing diabetes, or treating or preventing islet of Langerhans beta-cell death, for example in a subject in need thereof. The embodiments set out herein may relate to any of the above aspects. Other aspects of the invention, which are not limited to or by the information in this Summary of the Invention, may become apparent from the following description which is given by way of example only and with reference to the accompanying figures. This invention may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, and any or all combinations of any two or more of said parts, elements or features, and where specific integers are mentioned herein which have known equivalents in the art to which this invention relates, such known equivalents are deemed to be incorporated herein as if individually set forth. ▲RIEF DESCRIPTION OF THE FIGURES Figure 1 is a graph showing thioflavin-T fluorescence following incubation of hA (25 μM) and thioflavin-T (10 μM) in the absence (■) or presence of 25 μM of either ZBBP92 (●) or HC8768 . Results are means + / − S.E.M. (n = 3). Figure 2 is a graph showing thioflavin-T fluorescence following incubation of hA (25 μM) and thioflavin-T (10 μM) in the absence (■) or presence of 25 μM of either ZBBP92 (●), HC87610 , HC8762 or HC8768 ( ). Results are means + / − S.E.M. (n = 3). Figure 3 is a graph showing thioflavin-T fluorescence following incubation of hA (25 μM) and thioflavin-T (10 μM) in the absence (■) or presence of 25 μM of either ZBBP92 (●), HC8764 , HC8765 or HC8766 . Results are means + / − S.E.M. (n = 3). Figure 4 is a graph showing thioflavin-T fluorescence following incubation of hA (25 μM) and thioflavin-T (10 μM) in the absence (■) or presence of 25 μM of either ZBBP92 (●), HC87610 ) or HC8769 ). Results are means + / − S.E.M. (n = 3). Figure 5 is a graph showing thioflavin-T fluorescence following incubation of hA (25 μM) and thioflavin-T (10 μM) in the absence (■) or presence of 25 μM of either ZBBP92 (●) or HC8761 ). Results are means + / − S.E.M. (n = 3). Figure 6 is a graph showing thioflavin-T fluorescence following incubation of hA (25 μM) and thioflavin-T (10 μM) in the absence (■) or presence of 25 μM of either ZBBP92 (●) or HC9534 . Results are means + / − S.E.M. (n = 3). Figure 7 is a graph showing thioflavin-T fluorescence following incubation of hA (25 μM) and thioflavin-T (10 μM) in the absence (■) or presence of 2.5 μM of either ZBBP92 (●) or HC9534 ). Results are means + / − S.E.M. (n = 3). Figure 8 is a graph showing thioflavin-T fluorescence following incubation of hA (25 μM) and thioflavin-T (10 μM) in the absence (■) or presence of 25 μM of ZBBP92 (●), HC9534 , HC9532 ( ^) or HC9533 . Results are means + / − S.E.M. (n = 3). Figure 9 is a graph showing thioflavin-T fluorescence following incubation of hA (25 μM) and thioflavin-T (10 μM) in the absence (■) or presence of 25 μM of ZBBP92 (●), HC9534 or HC87682 . Results are means + / − S.E.M. (n = 3). Figure 10 shows the results of cell death assays for CN cells. Values are mean ± SE of four independent experiments, each performed in duplicate. ***P<0.001 versus control;#P<0.05;##P<0.01;###P<0.001 versus hA-treated cells. Figure 11 shows the results of cell death assays for RINm5F cells. Values are mean ± SE of four independent experiments, each performed in duplicate. ***P<0.001 versus control;#P<0.05;##P<0.01;###P<0.001 versus hA-treated cells. DETAILED DESCRIPTION Definitions The terms "amyloid", "amyloid fibril" and "amyloid plaque" refer to protein aggregates resulting from the misfolding of proteins into forms that facilitate and / or promote aggregation, and / or that may lead to cytotoxicity. The term "amyloidosis" refers to the deposition of amyloid in the body. The terms "amylin amyloid", "amylin-amyloid fibril", "amylin aggregate" or "amylin amyloid plaque" refer to amylin amyloids comprising human amylin as the protein component in an insoluble state. The terms "islet amylin amyloids", "islet amylin-amyloid fibrils", "islet aggregates" or "islet amylin amyloid plaques" refer to amylin amyloids comprising human amylin as the protein component in an insoluble state and typically found in the islets of Langerhans. The term "disruption" as used herein refers to both priori disruption and posteriori disruption of amylin amyloidosis. The term "amylin monomer" refers to 37-residue peptide hormone produced in and secreted by the Beta-cells of the islets of Langerhans. The amino acid sequence for human preprotein, also referred to as islet amyloid polypeptide preprotein, is present at RefSeq NP_000406.1, and at UniProtKB / SwissProt A0A024RAU1. The term "oligomer" refers to a molecule with two or more monomer units. Amylin oligomers may comprise from about 2, 3, 4, 5, 6, 7, 8, 10, 15, 16, 20 or 25 monomer units to about 100 monomer units, or from about 100 to about 1000, 2000, 3000, or more monomer units. The term "amylin oligomer" refers to oligomers in which the monomer units are human amylin. The term "interfere" and "interference" in the context of protein aggregation refers to the disruption of the process of aggregation by a compound described herein, such that aggregation is slowed or prevented. The terms "aggregation" or "aggregate" refer to the accumulation of protein, such as human amylin or its precursor proIAPP, particularly in insoluble forms. The term "amylin amyloid-associated disease" refers to diseases including but not limited to diabetes, including type II diabetes (T2D), metabolic syndrome, syndrome X, dysregulation of blood glucose, insulin resistance, and the like. The term "prevent" refers to the halting of a process, for example amylin-amyloid fibril formation, islet of Langerhans beta- cell death, the transition from soluble human amylin to insoluble human amylin, and cytotoxic oligomer formation that has not yet begun. The term "inhibit" is used in a similar manner to "prevent" but refers to the halting of a process, for example amylin-amyloid fibril formation, islet of Langerhans Beta- cell death, the transition from soluble human amylin to insoluble human amylin and cytotoxic oligomer formation, that has already begun. The term "treat" refers to inhibiting or arresting the development of an amylin amyloid-associated disease and / or causing the reduction, remission or regression of an amylin amyloid-associated disease or one or more side effects thereof. The term "treat" refers to inhibiting or arresting the development of an amylin amyloid-associated disease and / or causing the reduction, remission or regression of an amylin amyloid-associated disease or one or more side effects thereof. The term "reverse" refers to the return of an amylin amyloid-associated disease to a former or less developed state. The terms "remission" and "regression" are to be interpreted in a similar manner. The term "reverse" refers to the return of an amylin amyloid-associated disease to a former or less developed state. The terms "remission" and "regression" are to be interpreted in a similar manner. The term "administering" refers to providing a therapeutically effective amount of a compound to a subject using one or more methods of administering compounds known in the art. These methods comprise administering compounds using oral, sublingual, intravenous, subcutaneous, transcutaneous, intramuscular, intracutaneous, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, and the like administration. The term "therapeutically effective amount" refers to a dose of a compound sufficient to provide a concentration high enough to affect the desired result. For example, in certain embodiments a therapeutically effect amount is a dose of a compound described herein sufficient to result in one or more of the following; the prevention, inhibition or reversal of amylin-amyloid fibril formation, islet of Langerhans beta- cell death, the transition from soluble human amylin to insoluble human amylin, and cytotoxic oligomer formation. The term "pharmaceutically acceptable salt" refers to the salt of a given compound, wherein the salt is suitable for administration as a pharmaceutical. For example, such salts may be formed by the reaction of an acid or a base with an amine or a carboxylic acid group respectively. Acid / base addition salts tend to be more soluble in aqueous solvents than the corresponding free acid / base forms. The term "pro-drug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art and include, for example, compounds where a free hydroxy group is converted into an ester derivative or a ring nitrogen atom is converted to an N-oxide. Examples of ester derivatives include alkyl esters (for example acetates, lactates and glutamines), phosphate esters and those formed from amino acids (for example valine). The term "solvate" is a complex of variable stoichiometry formed by a solute (in this invention, a compound of the invention) and a solvent. The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier, to give a capsule in which the active ingredient (with or without other carrier) is surrounded by carriers. The terms "including" and "comprising" are used herein in their open, non-limiting sense. The terms "(C1-C6)" and so forth refer to moieties having 1 to 6 carbon atoms and so forth, respectively. Within composed terms like "hydroxy-(C0-C4)-alkyl" the option "(C0)- alkyl refers to a bond (i.e. in this case a directly bound hydroxy group), or in case of an unsubstituted "(C0)-alkyl" it refers to a hydrogen. The term "alkyl" refers to saturated, monovalent hydrocarbon radicals. The term "alkenyl" refers to monovalent hydrocarbon radicals, which contain at least one carbon-carbon double bond, wherein each double bond can have E- or Z-configuration. The term "alkynyl" refers to monovalent hydrocarbon radicals, which contain at least one carbon-carbon triple bond. The alkyl, alkenyl and alkynyl groups can be linear, i.e. straight-chain, or branched. This also applies when they are part of other groups, for example alkyloxy groups (=alkoxy groups, O-alkyl groups), alkyloxycarbonyl groups or alkyl-substituted amino groups, or when they are substituted. Depending on the respective definition, the number of carbon atoms in an alkyl group can be 1-22, such as 1 to 12, such as 1, 2, 3, 4, 5 or 6, or 1, 2, 3, or 4. Examples of alkyl are methyl, ethyl, propyl including n-propyl and isopropyl, butyl including n-butyl, sec-butyl, isobutyl and tert-butyl, pentyl including n-pentyl, 1- methylbutyl, isopentyl, neopentyl and tert-pentyl, hexyl including n-hexyl, 3,3- dimethylbutyl and isohexyl. Double bonds and triple bonds in alkenyl groups and alkynyl groups respectively can be present in any positions. Examples of alkenyl and alkynyl are ethenyl, prop-1-enyl, prop-2-enyl (=allyl), but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2- enyl, hex-3-enyl, hex-4-enyl, prop-2-ynyl (=propargyl), but-2-ynyl, but-3-ynyl, hex-4-ynyl or hex-5-ynyl. Substituted alkyl groups, alkenyl groups and alkynyl groups can be substituted in any positions, provided that the respective compound is sufficiently stable and is suitable for the desired purpose such as use as a therapeutic substance. The prerequisite that a specific group and a compound of formula (I) is sufficiently stable and suitable for the desired purpose such as use as a therapeutic substance, applies in general with respect to the definitions of all groups in the compounds of formula (I). The term "alkyloxy" (also referred to as “alkoxy”), unless otherwise indicated, refers to a radical -ORa where Ra is an alkyl as defined above, e.g., methoxy, ethoxy, propoxy, butoxy and the like. The term “deuteroalkoxy”, unless otherwise indicated, refers to an alkoxy group where one or more of the hydrogen atoms have been replaced with a deuterium atom. Examples include mono-, di-, and tri-deuteroalkoxy groups, such as OCDH2, OCD2H and OCD3. The term "halo", unless otherwise indicated, refers to fluoro, chloro, bromo, or iodo, preferably fluoro and chloro. In some embodiments halo is F. It will be understood that in certain circumstances a fluorine atom may function as an isostere for hydrogen, and accordingly the skilled person may in certain embodiments substitute one or more hydrogen atoms in an alkyl, alkenyl, aryl and / or cycloalkyl group, for example, for fluorine atoms. The term "haloalkyl", unless otherwise indicated, refers to alkyl substituted with one or more, preferably one, two or three, same or different halo atoms, e.g., -CH2Cl, -CF3, - CH2CF3, -CH2CCl3, and the like. The term "haloalkoxy", unless otherwise indicated, refers to a radical -ORbwhere Rbis a haloalkyl as defined above, e.g., trifluoromethoxy, trichloroethoxy, 2,2-dichloropropoxy, and the like. The term “deuterohaloalkoxy”, unless otherwise indicated, refers to a haloalkoxy group where one or more of the hydrogen atoms have been replaced with a deuterium atom. Examples include mono-, di-, and tri-deuterohaloalkoxy groups, such as OCDF2, OCD2F and OCD3. The term "and / or" means "and" or "or", or both. It is intended that reference to a range of numbers disclosed herein (for example, 1 to 10) also incorporates reference to all rational numbers within that range (for example, 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9 and 10) and also any range of rational numbers within that range (for example, 2 to 8, 1.5 to 5.5 and 3.1 to 4.7) and, therefore, all sub-ranges of all ranges expressly disclosed herein are hereby expressly disclosed. These are only examples of what is specifically intended and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application in a similar manner. The term "comprising" as used in this specification means "consisting at least in part of". When interpreting statements in this specification which include that term, the features, prefaced by that term in each statement or claim, all need to be present but other features can also be present. Related terms such as "comprise" and "comprised" are to be interpreted in the same manner. Compounds of the invention The invention provides various compounds suitable for use in the treatment of amylin amyloidoses, including, for example, diabetes. The compounds have advantageous physicochemical and / or therapeutic properties rendering them particularly suitable for use in the treatment of amylin amyloid-associated diseases, such as diabetes. The invention provides compounds of Formula (I): wherein: X is C1-C5alkyl, cyclopropyl, or C2-C4dialkyl ether; A is absent or is C1-C6alkyl optionally substituted with halide, C1-C3alkoxy, or C1- C3haloalkoxy, or A is phenyl; B is absent or is C1-C6alkyl; each R1is independently selected from OH, halide, C1-C3alkoxy, C1-C3deuteroalkoxy, C1-C3haloalkoxy, C1-C3deuterohaloalkoxy, CO2R3, OCO2R4, and O-glycosyl; R3is H or C1-C3alkyl; R4is C1-C3alkyl; and u is 1, 2 or 3; each R2is independently selected from OH, halide, C1-C3alkoxy, C1-C3deuteroalkoxy, C1-C3haloalkoxy, and C1-C3deuterohaloalkoxy; and v is 1, 2 or 3; or a pharmaceutically acceptable salt thereof. In certain embodiments of the invention, the compound incorporates one or more deuterium atoms in place of hydrogen atoms. Depending on the compound's route of metabolism and the location of the deuterium, deuteration can be metabolically silent thereby enabling utility as a PK tracer, or it can alter the compound's metabolism thereby acting as a mechanistic probe. The incorporation of deuterium into pharmacologically active agents offers potential benefits, such as improved exposure profiles and the decreased production of toxic metabolites that could yield improvements in efficacy, tolerability, or safety. Deuterated drugs can show a differentiated PK profile compared to their “hydrogen- only” equivalent compounds. The compounds of the invention may be in crystalline form or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention. Solvents should not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol or acetic acid. Methods of solvation are generally known within the art. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric centre. Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Thus, this invention encompasses each diastereomer or enantiomer substantially free of other isomers (>90%, and preferably >95%, free from other stereoisomers on a molar basis) as well as a mixture of such isomers. Particular optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereomeric salts, by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulphonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another method involves synthesis of covalent diastereomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesised diastereomers can be separated by conventional means such as chromatography, distillation, crystallisation or sublimation, and then hydrolysed to deliver the enantiomerically pure compound. Optically active compounds of the invention can be obtained by using active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt. Where the compounds of the invention require purification, chromatographic techniques such as high-performance liquid chromatography (HPLC) and reversed-phase HPLC may be used. The compounds may be characterised by mass spectrometry and / or other appropriate methods. Where the compound comprises one or more functional groups that may be protonated or deprotonated (for example at physiological pH) the compound may be prepared and / or isolated as a pharmaceutically acceptable salt. It will be appreciated that the compound may be zwitterionic at a given pH. In some embodiments, pharmaceutically acceptable salts of one or more compounds described herein are administered in a therapeutically effective amount to a subject. Such salts may be prepared by methods known in the art that involve reacting the compound with a suitable organic or inorganic acid or base. Representative organic salts include methanesulphonate, acetate, oxalate, adipate, alginate, aspartate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, toluenesulphonate (tosylate), citrate, malate, maleate, fumarate, succinate, tartrate, napsylate, methanesulphonate, 2- naphthalenesulphonate, nicotinate, benzenesulphonate, butyrate, camphorate, camphorsulphonate, cyclopentanepropionate, digluconate, dodecylsulphate, glucoheptanoate, glycerophosphate, heptanoate, hexanoate, undecanoate, 2- hydroxyethanesulphonate, ethanesulphonate, and the like. Representative inorganic salts can be formed from inorganic acids such as sulphate, bisulphate, hemisulphate, hydrochloride, chlorate, perchlorate, hydrobromide, hydroiodide, and the like. Examples of a base salt include ammonium salts; alkali metal salts such as sodium salts, potassium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, phenylethylamine, and the like; and salts with amino acids such as arginine, lysine, and the like. Such salts can readily be prepared employing methods well known in the art. In some embodiments one or more compounds described herein is administered to a subject as a pro-drug. Pro-drugs are well known in the art and are compounds which are administered in a form that is then metabolised into a pharmacologically active drug. Any compound that is a prodrug of a compound of the invention is within the scope and spirit of the invention. Conventional procedures for the preparation of suitable prodrugs according to the invention are described in text books, such as "Design of Prodrugs" Ed. H. Bundgaard, Elsevier, 1985 - the entire contents of which is incorporated herein by reference. Compound synthesis Certain compounds of the invention were synthesised according to the following reaction schemes, which are provided by way of example only. The aniline intermediates were synthesised from 4-nitrobenzene-1,2-diol (2-1), applying an alkylation reaction to protect the phenol group followed by the reduction of the nitro group. The two fragments were then coupled using HATU followed by deprotection of the benzyl group to provide the target compounds. Biaryl compounds were synthesised from the pyridin-2-amine (1-5), which underwent amide coupling reactions to provide carboxylic acid intermediate (5-2). Further coupling with bromoaniline leads to intermediate (5-3), which were then reacted with substituted phenylboronic acid via the Suzuki coupling reaction to yield intermediate (5-4). Subsequent deprotection of the methyl group provided the target compounds. Compounds of the invention are referred to herein by an identifier code “HC” followed by a 4- or 5-digit number. The compound identified as ZBBP-92 is a reference compound and has the following chemical structure: . Synthesis of N-(3,4-dihydroxyphenyl)-N-(6-(methoxy-d3)pyridin-2- yl)cyclopropane-1,1-dicarboxamide

[0003] Synthesis of 4-hydroxy-2'-(3-((6-(methoxy-d3)pyridin-2-yl)amino)-3- oxopropanamido)-[1,1'-biphenyl]-3-carboxylic acid Discussion of thioflavin-T assay A comparison of the structures of HC8766 and HC8768, and their activities in the thioflavin-T assay (see Figures 1-3), indicates that there are two (possibly three) differences between the two structures that could impact on their ability to significantly increase inhibition of amylin fibril formation: 1) The spacing (length) between the two NH groups in the central chain with shorter spacing being more favourable (but not too short). 2) The orientation of these two NH groups (and C=O groups) (cis or trans) with trans NH groups being more favourable for inhibition of fibril formation. 3) The difference in position of the OH groups (relative to the NH group) on the left benzene ring may impact on the Structure Activity Relationship of the two compounds. The importance of the spacing between the NH groups is highlighted with the results from HC8761 (Figure 5), which showed similar inhibition of fibril formation as ZBBP92 at 1:1 molar ratios of hA:compound, but inhibition was not as great as HC8768 at the same molar ratios. HC8761 has the NH and C=O groups positioned in the same orientation as HC8768, but there is an additional two methyl groups (or ethyl groups) in the backbone chain which enables further spacing between the NH groups. HC87610 is structurally very similar to HC8761, but with the addition of an oxygen moiety in the central methyl group of the backbone. While HC87610 does show inhibition of fibril formation (see Figure 4), it inhibits to a lesser degree than both ZBBP92 and HC8761, possibly indicating a change in conformational flexibility around the central oxygen moiety which reduces its ability to bind and inhibit fibril formation. HC8762, HC8765 and HC8769 each contain a carboxylic acid moiety on the left benzene ring in the meta position relative to the attached NH group. None of these compounds show good inhibition of fibril formation in the thioflavin-T assay. HC9532, HC9533 and HC9534 are isomers, with the biphenyl hydroxy carboxylic acid moiety of each compound attached to the NH group at a different position. This positioning affects inhibition of hA fibril formation which may be due to steric hindrance. The HC87682 structure is different to HC8768 in that the hydroxyl groups are replaced by ester groups on the left benzene ring. This reduced solubility (in 70% aqueous conditions) which may have affected observed activity. In addition, the presence of two longer groups on the benzene chain may have affected binding capacity to hA. Cytotoxicity Example 17 shows that compound HC87682 is cytotoxic while it was cultured alone with RINm5F and CM cells. Compounds HC956, HC9532, HC9533 and HC9534 alone were not cytotoxic and were subjected to analysis for anti-hA-mediated beta cell death. The cell death prevention assays that HC956 has no cell death prevention activity. However, HC9532, HC9533 and HC9534 show significant prevention activity against hA- mediated beta-cell death, with HC9534 demonstrating the highest prevention activity amount of the compounds tested. Human amylin and amylin amyloidosis The invention relates in certain embodiments to compounds capable of preventing or reversing human amylin (hA) misfolding, aggregation and / or amylin plaque amyloid formation. In certain embodiments, the invention relates to compounds capable of preventing and / or reversing the transition from soluble human amylin to insoluble human amylin, and / or of preventing and inhibiting and / or reversing cytotoxic amylin fibril formation. Human amylin, also known as islet amylin amyloid polypeptide (IAPP), is a 37-residue peptide hormone produced in and secreted by the beta-cells of the islets of Langerhans in the human pancreas. The production of hA in the body involves the conversion of an 89- residue coding sequence into a 67 amino acid residue proamylin sequence (proIAPP). This proamylin sequence then undergoes post-translational modification to produce hA. Human amylin is produced under normal conditions in the body and, together with insulin, plays a role in glycaemic control. It will be apparent to a person skilled in the art that there is usually a relationship between the identity of the protein and where in the body an amyloidosis manifests. Consequently, several types of amyloids exist, each of which is classified depending on the protein it comprises, and specific types of amyloidoses are classified based on the site of amyloid accumulation. The deposition of amyloids in the body often involves the accumulation of insoluble amyloid fibrils that comprise misfolded proteins. Human amylin is one protein that may misfold leading to the conversion of soluble amylin monomers and soluble amylin oligomers into insoluble amylin-amyloid fibrils. When present in the islets, these insoluble aggregates may lead to beta-cell death and other cytotoxic effects, the mechanisms of which are poorly understood. Without wishing to be bound by theory the inventors believe that aggregation of islet amylin amyloids into islet amylin-amyloid fibrils and / or hA misfolding is at least partly responsible for the toxicity that is observed in, and that is thought to play a role in the pathology of amylin amyloid- associated diseases, for example, type II diabetes. Disruption of amylin amyloids The inventors have found that the compounds described herein are capable of disrupting amylin amyloid formation, for example islet amylin amyloid formation. Amylin amyloidosis disruption maybe priori disruption or posteriori disruption of amylin amyloidosis. Priori disruption refers to the interference of the compounds described herein with any part of the process involving the conversion of soluble monomers and oligomers, such as amylin monomers and oligomers, into insoluble amylin amyloids. Posteriori disruption refers to the disaggregation of insoluble amylin amyloids that are already formed, for example islet amylin amyloids, which may include the re-solubilisation of the constituent protein. Disruption of insoluble amylin amyloids may occur directly or indirectly. Direct disruption involves one or more compounds described herein or a metabolite thereof binding to a part of the protein monomers or oligomers, such as human amylin monomers or oligomers, or part of a pre-formed aggregate, and physically preventing further aggregation and / or reversing aggregation, for example by weakening interactions between the monomers and / or oligomers in the aggregate. Indirect disruption, in contrast, involves preventing fibril or aggregate formation via mechanisms that do not require direct contact between the compound and the protein, for example, by altering local conditions to favour a soluble form of the protein over an insoluble form, or by favouring a non-aggregating conformation of the monomers or oligomers. In some embodiments of the invention direct disruption of aggregates, such as islet aggregates, by the compounds described herein involves binding via covalent interactions, and in other embodiments involves binding via non-covalent interactions. In various embodiments the compounds described herein interact with the monomers or with oligomers of the proteins making up the amylin amyloids or to the amylin amyloids themselves, by a combination of one or more covalent interactions and / or one or more non- covalent interactions, for example van der Waals interactions. For example, without wishing to be bound by theory the inventors believe that in various embodiments the compounds described herein bind covalently to the monomeric forms of proteins, for example hA. This is believed, again without wishing to be bound by any theory, to stabilise the conformation of monomeric forms and / or soluble oligomers, non-toxic forms, inhibit amylin amyloid formation directly. Disruption of amylin amyloids may also occur indirectly, for example if the compounds do not bind directly to monomers or oligomers of proteins making up the amylin amyloids, or to amylin amyloids themselves, but affect another part of the amylin amyloidosis process that prevents or inhibits the formation of further aggregates or leads to the disaggregation of pre-formed aggregates. Without wishing to be bound by theory the inventors believe that one mechanism for the formation of insoluble islet amylin amyloids begins with the aggregation of proamylin, which then serves as an initiation site for the deposition of insoluble islet amylin-amyloid fibrils. In some embodiments, disruption of islet amylin amyloids thus occurs by directly or indirectly disrupting the aggregation of or on proamylin. In the case of islet amylin amyloids, experiments report that under normal conditions hA may be reasonably unstructured and made up mostly of random coil structures. Under certain conditions often associated with pathogenesis, hA is expected to misfold to produce beta-sheets that stack to form highly structured aggregates comprising layers of beta- sheets. In some embodiments disruption of islet amylin amyloids comprises the prevention or reversal of hA misfolding. Misfolding of the protein components of amylin amyloids is also thought to play a role in other diseases associated with amylin amyloidosis. In various embodiments the compounds described herein disrupt amylin amyloid aggregates by one or more mechanisms selected from the group consisting of preventing, inhibiting and / or reversing amylin-amyloid fibril formation, preventing and / or reversing the transition from soluble human amylin to insoluble human amylin, and preventing, inhibiting and / or reversing cytotoxic amylin fibril formation. In some embodiments the compounds described herein disrupt amylin-amyloid fibril formation by preventing, inhibiting and / or reversing protein misfolding. For example, the compounds described herein disrupt islet amylin-amyloid fibril formation by preventing, reversing and / or reversing hA misfolding. In various embodiments the compounds described herein prevent, inhibit and / or reverse protein misfolding and / or prevent, inhibit and / or reverse protein aggregation. Without wishing to be bound by theory, the inventors believe that the aggregation potential of hA is promoted by the misfolding of amylin into structured Beta-sheets. Effect on disease states Amylin amyloids are thought to play a role in the pathogenesis of a number of diseases. Amylin amyloid-associated diseases occur in a number of animals, including mammals, for example human beings. The inventors have found that the compounds described herein are able to prevent, inhibit and / or reverse, for example, amylin-amyloid fibril formation, islet of Langerhans Beta-cell death, the transition from soluble human amylin to insoluble human amylin and cytotoxic oligomer formation. Without wishing to be bound by theory, the inventors believe that these processes are associated with the development and / or progression of one or more amylin amyloid-associated diseases, such as, for example, type II diabetes. The term "prevent" refers to the halting of a process, for example amylin-amyloid fibril formation, islet of Langerhans beta- cell death, the transition from soluble human amylin to insoluble human amylin, and cytotoxic oligomer formation that has not yet begun. In certain embodiments, such prevention is for a certain period of time – for example, for so long as the concentration of the compound or compounds as described herein, such as the concentration local to the hA, is maintained above a certain threshold. It will be appreciated that in such embodiments the term “prevent” does not contemplate prevention in perpetuity. The term "inhibit" as used herein is used in a similar manner to "prevent" but refers to the halting of a process, for example amylin-amyloid fibril formation, islet of Langerhans beta-cell death, the transition from soluble human amylin to insoluble human amylin and cytotoxic oligomer formation, that has already begun. The prevention, inhibition or reversal of processes associated with the development of one or more amylin amyloid-associated diseases may manifest in a number of ways. For example, in some embodiments the prevention, inhibition or reversal of processes such as for example amylin-amyloid fibril formation, islet of Langerhans beta-cell death, the transition from soluble human amylin to insoluble human amylin and cytotoxic oligomer formation, leads to slowing of disease progression and improved quality of life in subjects with the disease. In various embodiments the prevention, inhibition or reversal of processes associated with the development of one or more amylin amyloid-associated diseases manifests as an increased rate of survival. For example, prevention, inhibition or reversal of a process associated with hA amylin amyloid formation will in certain embodiments manifest as an increased rate of survival of islet beta-cells, for example. The term "treat" refers to inhibiting or arresting the development of an amylin amyloid-associated disease and / or causing the reduction, remission or regression of an amylin amyloid-associated disease or one or more side effects thereof. Methods of assessing treatment, including methods of assessing inhibition, arrest, reduction, remission and / or regression of disease states are known and will be apparent to a person skilled in the art. The term "reverse" refers to the return of an amylin amyloid-associated disease to a former or less developed state. The terms "remission" and "regression" are to be interpreted in a similar manner. Administration and formulation The term "administering" refers to providing a therapeutically effective amount of a compound to a subject using one or more methods of administering compounds known in the art. These methods comprise administering compounds using oral, sublingual, intravenous, subcutaneous, transcutaneous, intramuscular, intracutaneous, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, and the like administration. In exemplary embodiments one or more active agents may be administered orally. It will be apparent to a person skilled in the art that the formulation of the compounds described herein will depend on the method of administration. For example, the compounds described herein are in certain embodiments formulated as creams, lotions, tablets, capsules, pellets, dispersible powders, granules, suppositories, syrups, elixirs, lozenges, injectable solutions, sterile aqueous or non-aqueous solutions, suspension or emulsions, patches and the like. For example, in various embodiments the compounds described herein are formulated as tablets, capsules, pellets, dispersible powders, granules, syrups, suspensions or emulsions. In exemplary embodiments the compounds described herein formulated as a solid dosage form, such as tablets, capsules or pellets. The formulations that are suitable for a particular method of administration will be apparent to those skilled in the art. As will be readily appreciated by those skilled in the art, the route of administration and the nature of the pharmaceutically acceptable carrier will depend on the nature of the condition and the mammal to be treated. It is believed that the choice of a particular carrier or delivery system, and route of administration could be readily determined by a person skilled in the art. In the preparation of any formulation containing the compound actives care should be taken to ensure that the activity of the compound is not destroyed in the process and that the compound is able to reach its site of action without being destroyed. In some circumstances it may be necessary to protect the compound by means known in the art, such as, for example, microencapsulation. Similarly, the route of administration chosen should be such that the compound reaches its site of action. Those skilled in the art may readily determine appropriate formulations for the compounds of the present invention using conventional approaches. Identification of preferred pH ranges and suitable excipients, for example antioxidants, is routine in the art. Buffer systems are routinely used to provide pH values of a desired range and include carboxylic acid buffers for example acetate, citrate, lactate and succinate. A variety of antioxidants are available for such formulations including phenolic compounds such as BHT or vitamin E, reducing agents such as methionine or sulphite, and metal chelators such as EDTA. The compounds of the invention, or pharmaceutically acceptable salts thereof, may be prepared in parenteral dosage forms, including those suitable for intravenous, intrathecal, and intracerebral or epidural delivery. The pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions. They should be stable under the conditions of manufacture and storage and may be preserved against reduction or oxidation and the contaminating action of microorganisms such as bacteria or fungi. The solvent or dispersion medium for the injectable solution or dispersion may contain any of the conventional solvent or carrier systems for compound actives, and may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about where necessary by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include agents to adjust osmolality, for example, sugars or sodium chloride. In various embodiments, the formulation for injection will be isotonic with blood. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin. Pharmaceutical forms suitable for injectable use may be delivered by any appropriate route including intravenous, intramuscular, intracerebral, intrathecal, epidural injection or infusion. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients such as those enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilised active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying or freeze-drying of a previously sterile-filtered solution of the active ingredient plus any additional desired ingredients. Other pharmaceutical forms include oral and enteral formulations of the present invention, in which the active compound may be formulated with an inert diluent or with an assimilable edible carrier, or it may be enclosed in a hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal or sublingual tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. The tablets, troches, pills, capsules and the like may also contain the components as listed hereafter: a binder such as gum, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such a sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and formulations, including those that allow specific delivery of the active compound to specific regions of the gut. Liquid formulations may also be administered enterally via a stomach or oesophageal tube. Enteral formulations may be prepared in the form of suppositories by mixing with appropriate bases, such as emulsifying bases or water-soluble bases. It is also possible, but not necessary, for the compounds of the invention to be administered topically, intranasally, intravaginally, intraocularly and the like. The invention also extends to any other forms suitable for administration, for example topical application such as creams, lotions and gels, or compositions suitable for inhalation or intranasal delivery, for example solutions, dry powders, suspensions or emulsions. The compounds of the invention may be administered by inhalation in the form of an aerosol spray from a pressurised dispenser or container, which contains a propellant such as carbon dioxide gas, dichlorodifluoromethane, nitrogen, propane or other suitable gas or combination of gases. The compounds may also be administered using a nebuliser. Pharmaceutically acceptable vehicles and / or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. It is especially advantageous to formulate the compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutically acceptable vehicle. The specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding active materials for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail. The principal active ingredient may be compounded for convenient and effective administration in therapeutically effective amounts with a suitable pharmaceutically acceptable vehicle in dosage unit form. A unit dosage form can, for example, contain the principal active compound in amounts ranging from 0.25 μg to about 2000 mg. Expressed in proportions, the active compound may be present in from about 0.25 μg to about 2000 mg / mL of carrier. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients. In certain embodiments of the invention, a therapeutically effect amount is a dose of a compound sufficient to result in one or more of the following; the prevention, inhibition or reversal of amylin-amyloid fibril formation, islet of Langerhans beta-cell death, the transition from soluble human amylin to insoluble human amylin, and cytotoxic oligomer formation. The therapeutically effective amount of a compound will in certain embodiments be affected by a number of factors, and can be adjusted based on these factors. For example, the therapeutically effective dose may be affected by the bodyweight of the subject, metabolic capacity and synergy between combinations of actives administered. The dose that can be administered to a subject may also be affected by other factors such as interactions with other medicines that the subject is taking and severity of / ability to tolerate any side effects of the compounds administered. In some embodiments, the desired result to be achieved by the therapeutically effective amount comprises the slowing of disease progression, an improvement in the quality of life of the subject and / or an increased rate of survival. In various embodiments, the desired result to be achieved by the therapeutically effective amount is the amelioration of one or more symptoms associated with an amylin amyloid-associated disease, for example reduction in loss of kidney function, heart failure, obstructive sleep apnoea, difficulty swallowing or synovitis. In various embodiments, the desired result to be achieved by the therapeutically effective amount is the amelioration of one or more symptoms associated with type II diabetes, for example weight loss, polyuria, polydipsia, polyphagia, blurry vision, headache, fatigue or diabetic dermadromes, and signs such as lowering of blood glucose levels and HbA1C. The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or diluent. The compounds described herein are in certain embodiments administered individually, and in other embodiments are administered in combination, either with other compounds described herein, or with other therapeutic agents or both. The combination may allow for separate, sequential or simultaneous administration of a compound with another active ingredient. The combination may be provided in the form of a pharmaceutical composition. For example, in some embodiments two or more compounds are administered to a subject together. When administering combinations of compounds to a subject, the dose of each individual compound may be less than the therapeutically effective amount such that the combined dose of the two or more compounds is equal to or greater than the therapeutically effective amount. Furthermore, in some embodiments one or more compounds is administered to a subject together with one or more additional agents. The additional agents may be, for example, agents that treat, inhibit and / or reverse amylin-amyloid fibril formation, islet of Langerhans beta-cell death, the transition from soluble human amylin to insoluble human amylin and cytotoxic oligomer formation. In some embodiments the one or more additional agents may be compounds that prevent or treat amylin amyloid-associated diseases, such as type II diabetes. For example, the one or more additional agents will in certain embodiments be selected from the group comprising blood glucose modulating agents, such as an insulin, an insulin analogue or derivative, Symlin, GLP- agonists, metformin, sulphonylureas, thiazolidinediones, SGLT2 inhibitors, and selective dipeptidyl peptidase (DPP-IV) inhibitors. In various examples, the GLP-1 agonist is exenatide, liraglutide, lixisenatide, albiglutide, or dulaglutide, or any combination of two or more thereof. In various examples, the selective dipeptidyl peptidase (DPP-IV) inhibitor is selected from the group comprising Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Anagliptin, Teneligliptin, Alogliptin, Trelagliptin, Gemigliptin, Dutogliptin, and Omarigliptin. In one example, the selective dipeptidyl peptidase (DPP-IV) inhibitor is selected from the group comprising alogliptin, linagliptin, saxagliptin, sitagliptin, Nesina, Tradjenta, Onglyza, and Januvia. In some embodiments the one or more additional agents may for example be agents that reduce side effects associated with the compounds described herein. In various embodiments one or more compounds may be administered to a subject with one or more additional agents selected from the group comprising quinacrine, tetracycline and doxycycline. In various embodiments employed in vitro, one or more compounds may be administered to or contacted with a sample in vitro with one or more additional agents selected from the group comprising anthracene, phenanthrene, quinacrine, neutral red, chlorpromazine, acridine, acridine orange, methylene blue, phenodiazine, phenothiazine, tetracycline, doxycycline, Congo red, pyrene, chrysene, benz[a]anthracene, benz[m]anthracene, benzo[c]phenanthrene and tetracene. When one or more compounds are administered in combination with one or more additional agents, the dose of each compound administered may be less than the dose that would be administered if the compounds were administered separately. In some embodiments when one or more compounds are administered in combination with one or more additional agents, the dose of each compound administered may be greater than the dose that would be administered if the compounds were administered separately. For example, this may be the case if the one or more additional agents leads to reduced side effects, allowing a greater dose to be tolerated. EXAMPLES Example 1: Synthesis of N-(3,4-dihydroxyphenyl)-N-(6-(methoxy-d3)pyridin-2- yl)cyclopropane-1,1-dicarboxamide (HC863O) Step 1. Synthesis of (((4-nitro-1,2-phenylene)bis(oxy))bis(methylene))dibenzene (2-2) To the solution of 4-nitrobenzene-1,2-diol (5.0 g, 32.2 mmol) in DMF was added sodium hydroxide (3.87 g, 96.7 mmol) and benzyl bromide (16.54 g, 96.7 mmol). The resulting solution was stirred for 8 h at 80 °C. Upon completion, the reaction mixture was allowed to cool to room temperature. Then, the mixture was quenched by slow addition of 200 mL of water. The resulting solid was filtered, washed with water, and dried under reduced pressure to yield the title compound as white solids (7.6 g, 70%).1H NMR (500 MHz, DMSO) δ 7.88 (d, J = 9.4 Hz, 1H), 7.86 – 7.84 (m, 1H), 7.45 (d, J = 7.6 Hz, 4H), 7.37 (d, J = 8.2 Hz, 4H), 7.33 (t, J = 6.0 Hz, 2H), 7.27 (d, J = 9.0 Hz, 1H), 5.29 (s, 2H), 5.25 (s, 2H). Step 2. Synthesis of 3,4-bis(benzyloxy)aniline (2-3) To a solution of (((4-nitro-1,2-phenylene)bis(oxy))bis(methylene))dibenzene (3.0 g, 9 mmol) in 10 mL ethanol and 10 mL water was added iron powder (2.0 g, 36 mmol) and ammonium chloride (1.9 g, 36 mmol). The resulting solution was heated to 90 °C and stirred for additional 2 h. Upon completion, the mixture was allowed to cool to room temperature and filtered through a celite pad. The resulting filtrate was extracted with ethyl acetate. The organic layer was separated and dried over sodium sulfate. Volatile components were removed under reduced pressure, and the residue was purified on a silica gel column with petroleum ether / ethyl acetate = 3:1 as eluents. Pure fractions were evaporated to dryness to yield the title compound as a yellow solid (2.30 g, 84%).1H NMR (500 MHz, DMSO-d6)) δ 7.42 – 7.33 (m, 10H), 6.71 (d, J = 8.5 Hz, 1H), 6.37 (s, 1H), 6.07 (d, J = 8.5 Hz, 1H), 5.10 (s, 2H), 5.01 (s, 2H), 4.90 (s, 2H). Step 3. Synthesis of methyl 1-((6-(methyl-d3)pyridin-2-yl)carbamoyl)cyclopropane- 1-carboxylate (2-4) To a solution of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid (0.97 g, 6.8 mmol) in 5 mL DCM was added HOBT (0.91 g, 6.8 mmol) and EDCI (1.29 g, 6.8 mmol) at room temperature. The resulting solution was stirred for 10 min. Then, 6-(methoxy- d3)pyridin-2-amine (1-5, 0.5 g, 4.5 mmol) was added in one portion. The reaction mixture was stirred for additional 4 h. Upon completion, the reaction was dilute with water and extracted by DCM. The organic layer was separated and dried over sodium sulfate. Volatile components were removed under reduced pressure, and the residue was purified on a silica gel column with petroleum ether / dichloromethane = 1:1 as eluents. Pure fractions were evaporated to dryness to yield the title compound as a brown solid (0.77 g, 72%).1H NMR (400 MHz, DMSO-d6)) δ 10.88 (s, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 7.1 Hz, 1H), 6.54 (d, J = 7.8 Hz, 1H), 3.68 (s, 3H), 1.52 (s, 4H). Step 4. Synthesis of 1-((6-(methyl-d3)pyridin-2-yl)carbamoyl)cyclopropane-1- carboxylic acid (2-5) To a solution of methyl 1-((6-(methyl-d3)pyridin-2-yl)carbamoyl)cyclopropane-1- carboxylate (2-4, 0.77 g, 6.8 mmol) in 5 mL THF and 5 mL water was added sodium hydroxide (0.39 g, 9.7 mmol) at room temperature. The resulting solution was stirred for 1 h. Upon completion, the reaction was dilute with water, acidified with hydrochloric acid, and extracted with DCM. The organic layer was separated and dried over sodium sulfate. Volatile components were removed to yield the title compound as yellow solids. (0.68 g, 94%).1H NMR (500 MHz, DMSO-d6) δ 11.20 (s, 1H), 7.66 (td, J = 7.9, 2.5 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 6.51 (dd, J = 7.9, 2.5 Hz, 1H), 1.52 (s, 2H), 1.51 (s, 2H). Step 5. Synthesis of N-(3,4-bis(benzyloxy)phenyl)-N-(6-(methoxy-d3)pyridin-2- yl)cyclopropane-1,1-dicarboxamide (2-6) To a solution of 1-((6-(methyl-d3)pyridin-2-yl)carbamoyl)cyclopropane-1-carboxylic acid (2-5, 0.37 g, 1.6 mmol) in 5 mL DMF was added HATU (0.93 g, 2.5 mmol) and triethylamine (0.33 g, 3.3 mmol). The resulting solution was stirred for 10 min. Then, 3,4- bis(benzyloxy)aniline (2-3, 0.5 g, 1.6 mmol) was added in one portion. The reaction mixture was stirred for additional 4 h. Upon completion, the reaction was dilute with water and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over sodium sulfate. Volatile components were removed to yield a yellow solid, which was directly used in the next step without further purification. Step 6. Synthesis of N-(3,4-dihydroxyphenyl)-N-(6-(methoxy-d3)pyridin-2- yl)cyclopropane-1,1-dicarboxamide (HC863O) To a solution of N-(3,4-bis(benzyloxy)phenyl)-N-(6-(methoxy-d3)pyridin-2- yl)cyclopropane-1,1-dicarboxamide (0.68 g, 1 mmol) in 3 mL dichloromethane and 3 mL methanol was added palladium 10% on carbon (wetted with ca. 55% water, 0.1 g). The resulting mixture was stirred at room temperature for 3 h. Upon completion, the mixture was filter through a celite pad. The filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column with dichloromethane / methanol = 10:1 as eluents. Pure fractions were evaporated to dryness to yield the title compound as a white solid. (0.35 g, 61% for two steps).1H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 9.75 (s, 1H), 9.01 (d, J = 10.1 Hz, 1H), 8.66 (s, 1H), 7.67 (dt, J = 15.2, 7.6 Hz, 2H), 7.10 (s, 1H), 6.78 (d, J = 8.7 Hz, 1H), 6.64 (d, J = 8.7 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 3.79 (t, J = 6.4 Hz, 1H), 3.64 (t, J = 6.5 Hz, 2H), 2.30 (q, J = 6.8 Hz, 2H). m / z (ES-) [M - H]- = 345.2. Example 2: Synthesis of 2-hydroxy-5-(1-((6-(methoxy-d3)pyridin-2- yl)carbamoyl)cyclopropane-1-carboxamido)benzoic acid (HC863C) Synthesised by a similar procedure to Example 1 from 2-hydroxy-5-nitrobenzoic acid instead of 4-nitrobenzene-1,2-diol in step 1.1H NMR (400 MHz, DMSO) δ 13.68 (s, 1H), 11.40 (s, 1H), 10.59 (s, 1H), 9.87 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 7.3 Hz, 1H), 7.36 (s, 1H), 7.16 (d, J = 8.7 Hz, 1H), 6.53 (d, J = 7.9 Hz, 1H), 1.58 (s, 2H), 1.52 (d, J = 7.3 Hz, 2H). m / z (ES-) [M - H]- = 373.2 Example 3: Synthesis of N1-(3,4-dihydroxyphenyl)-N5-(6-(methoxy-d3)pyridin-2- yl)glutaramide (HC8761) Synthesised by a similar procedure to Example 1 from 5-methoxy-5-oxopentanoic acid instead of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid in step 3.1H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 9.52 (s, 1H), 8.89 (s, 1H), 8.62 – 8.46 (m, 1H), 7.78 – 7.57 (m, 2H), 7.14 (s, 1H), 6.78 (d, J = 8.6 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 6.49 (d, J = 5.9 Hz, 1H), 2.43 (s, 2H), 2.27 (t, J = 6.7 Hz, 2H), 1.90 – 1.81 (m, 2H). m / z (ES+) [M + H]+= 348.8 Example 4: Synthesis of 2-hydroxy-5-(5-((6-(methoxy-d3)pyridin-2-yl)amino)-5- oxopentanamido)benzoic acid (HC8762) Synthesised by a similar procedure to Example 1 from 5-methoxy-5-oxopentanoic acid instead of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid in step 3, and 2- hydroxy-5-nitrobenzoic acid instead of 4-nitrobenzene-1,2-diol in step 1.1H NMR (400 MHz, DMSO) δ 11.57 – 11.15 (m, 1H), 10.23 (s, 1H), 10.16 (s, 1H), 7.78 – 7.57 (m, 3H), 7.37 (d, J = 1.8 Hz, 1H), 7.06 (dd, J = 8.7, 1.9 Hz, 1H), 6.54 – 6.42 (m, 1H), 2.46 (t, J = 7.3 Hz, 2H), 2.40 (t, J = 7.4 Hz, 3H), 1.89 (p, J = 7.3 Hz, 2H). m / z (ES+) [M + H]+= 376.8 Example 5: Synthesis of N1-(3,4-dihydroxyphenyl)-N6-(6-(methoxy-d3)pyridin-2- Synthesised by a similar procedure to Example 1 from 6-methoxy-6-oxohexanoic acid instead of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid in step 3.1H NMR (400 MHz, DMSO) δ 10.19 (s, 1H), 9.50 (s, 1H), 8.89 (s, 1H), 8.54 (s, 1H), 7.65 (d, J = 6.9 Hz, 2H), 7.13 (d, J = 2.4 Hz, 1H), 6.76 (dd, J = 8.6, 2.4 Hz, 1H), 6.60 (d, J = 8.5 Hz, 1H), 6.53 – 6.43 (m, 1H), 2.40 (d, J = 6.7 Hz, 2H), 2.25 (q, J = 6.7, 5.3 Hz, 2H), 1.59 (p, J = 3.6 Hz, 4H). m / z (ES+) [M + H]+= 362.8 Example 6: Synthesis of 2-hydroxy-5-(6-((6-(methoxy-d3)pyridin-2-yl)amino)-6- oxohexanamido)benzoic acid (HC8765) Synthesised by a similar procedure to Example 1 from 6-methoxy-6-oxohexanoic acid instead of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid in step 3, and 2-hydroxy-5- nitrobenzoic acid instead of 4-nitrobenzene-1,2-diol in step 1.1H NMR (400 MHz, DMSO) δ 11.37 (s, 2H), 10.19 (s, 1H), 10.16 (s, 1H), 7.80 – 7.52 (m, 3H), 7.36 (d, J = 2.0 Hz, 1H), 7.05 (dd, J = 8.7, 2.0 Hz, 1H), 6.54 – 6.38 (m, 1H), 2.43 (d, J = 6.2 Hz, 2H), 2.35 (d, J = 6.5 Hz, 2H), 1.61 (h, J = 3.5 Hz, 4H). m / z (ES+) [M + H]+= 412.8 Example 7: Synthesis of N1-(3,4-dihydroxyphenyl)-N4-(6-(methoxy-d3)pyridin-2- yl)succinamide (HC8766) Synthesised by a similar procedure to Example 1 from 4-methoxy-4-oxobutanoic acid instead of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid in step 3.1H NMR (400 MHz, DMSO) δ 10.27 (s, 1H), 9.60 (s, 1H), 8.88 (s, 1H), 8.53 (s, 1H), 7.64 (d, J = 5.4 Hz, 2H), 7.13 (d, J = 2.4 Hz, 1H), 6.78 (dd, J = 8.5, 2.5 Hz, 1H), 6.61 (d, J = 8.5 Hz, 1H), 6.55 – 6.40 (m, 1H), 2.70 (t, J = 7.0 Hz, 2H), 2.56 (t, J = 7.0 Hz, 2H). m / z (ES+) [M + H]+= 334.8 Example 8: Synthesis of N1-(3,4-dihydroxyphenyl)-N3-(6-(methoxy-d3)pyridin-2- yl)malonamide (HC8768) Synthesised by a similar procedure to Example 1 from 3-methoxy-3-oxopropanoic acid instead of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid in step 3.1H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 9.80 (s, 1H), 8.98 (s, 1H), 8.62 (s, 1H), 7.83 – 7.58 (m, 2H), 7.14 (d, J = 2.6 Hz, 1H), 6.79 (dd, J = 8.5, 2.5 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 6.57 – 6.49 (m, 1H), 3.50 (d, J = 5.2 Hz, 2H). m / z (ES+) [M + H]+= 320.8 Example 9: Synthesis of 2-hydroxy-5-(3-((6-(methoxy-d3)pyridin-2-yl)amino)-3- oxopropanamido)benzoic acid (HC8769) Synthesised by a similar procedure to Example 1 from 3-methoxy-3-oxopropanoic acid instead of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid in step 3, and 2- hydroxy-5-nitrobenzoic acid instead of 4-nitrobenzene-1,2-diol in step 1.1H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 10.41 (s, 1H), 7.74 – 7.62 (m, 3H), 7.32 (d, J = 2.1 Hz, 1H), 7.04 (dd, J = 8.7, 2.1 Hz, 1H), 6.59 – 6.50 (m, 1H), 3.61 (s, 2H). m / z (ES+) [M + H]+= 348.9. Example 10: Synthesis of N-(3,4-dihydroxyphenyl)-2-(2-((6-(methoxy-d3)pyridin- 2-yl)amino)-2-oxoethoxy)acetamide (HC87610) Synthesised by a similar procedure to Example 1 from 2-(2-methoxy-2- oxoethoxy)acetic acid instead of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid in step 3.1H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 9.74 (s, 1H), 8.98 (s, 1H), 8.65 (s, 1H), 7.71 (q, J = 11.3, 9.6 Hz, 2H), 7.19 (d, J = 2.4 Hz, 1H), 6.85 (dd, J = 8.5, 2.5 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 4.30 (s, 2H), 4.19 (s, 2H). m / z (ES+) [M + H]+= 350.8. Example 11: Synthesis of 4-(3-((6-(methoxy-d3)pyridin-2-yl)amino)-3- oxopropanamido)-1,2-phenylene dipropionate (HC87682) To a solution of N1-(3,4-dihydroxyphenyl)-N3-(6-(methoxy-d3)pyridin-2- yl)malonamide (0.1 g, 0.3 mmol) in 1 mL THF was added triethylamine (0.09 g, 0.9 mmol) and propionyl chloride (0.09 g, 0.9 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified on a silica gel column with dichloromethane / methanol = 50:1 as eluents. Pure fractions were evaporated to dryness to yield the title compound as a white solid (0.082 g, 61%).1H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 10.41 (s, 1H), 7.75 – 7.62 (m, 3H), 7.39 (dd, J = 8.8, 2.5 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.58 – 6.49 (m, 1H), 3.58 (s, 2H), 2.58 (p, J = 7.5 Hz, 4H), 1.11 (t, J = 7.5 Hz, 6H). m / z (ES+) [M + H]+= 433.1803. Example 12: Synthesis of 4-hydroxy-2'-(3-((6-(methoxy-d3)pyridin-2-yl)amino)-3- oxopropanamido)-[1,1'-biphenyl]-3-carboxylic acid (HC9532) Step 1. Synthesis of 3-((6-(methoxy-d3)pyridin-2-yl)amino)-3-oxopropanoic acid (5- 2) To a solution of 6-(methoxy-d3)pyridin-2-amine (0.50 g, 3.9 mmol) in 5 mL DCM was added triethylamine (0.80 g, 7.9 mmol) at room temperature. Afterwards, the resulting solution was cooled to 0 °C and methyl 3-chloro-3-oxopropanoate (5-1, 0.81 g, 5.9 mmol) was added to the reaction mixture dropwise. Then, the reaction was allowed to warm to room temperature and stirred for additional 1 h. Upon completion, the mixture was quenched by water and extracted by dichloromethane. The organic phase was dry under sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in 5 mL of tetrahydrofuran and 2 mL of water. To this mixture was added sodium hydroxide (0.47 g, 11.8 mmol). The resulting mixture was stirred at room temperature for 2 h. Upon completion, the reaction was quench by 10 mL of 1N hydrochloride acid and extracted by ethyl acetate. The organic layer was washed by brine, dried under sodium sulfate, and concentrated under reduced pressure to yield the title compound as a pale- yellow solid (0.79 g, 94%).1H NMR (500 MHz, DMSO) δ 12.62 (s, 1H), 10.31 (s, 1H), 7.55 – 7.52 (m, 1H), 7.51 – 7.39 (m, 2H), 3.34 (s, 2H). m / z (ES+) [M + H]+= 214.1. Step 2. Synthesis of N1-(2-bromophenyl)-N3-(6-(methoxy-d3)pyridin-2- yl)malonamide (5-3) Synthesized by a similar procedure to Example 7 from 5-2 instead of 2-5 and 2- bromoaniline instead of 3,4-bis(benzyloxy)aniline in step 5.1H NMR (500 MHz, dmso) δ 10.48 (s, 1H), 9.85 (s, 1H), 7.78 (dd, J = 8.2, 1.6 Hz, 1H), 7.72 – 7.58 (m, 3H), 7.37 (td, J = 7.7, 1.5 Hz, 1H), 7.11 (td, J = 7.7, 1.6 Hz, 1H), 6.56 – 6.47 (m, 1H), 3.67 (s, 2H). m / z (ES+) [M + H]+= 367.1. Step 3. Synthesis of 4-methoxy-2'-(3-((6-(methoxy-d3)pyridin-2-yl)amino)-3- oxopropanamido)-[1,1'-biphenyl]-3-carboxylic acid (5-4) To a solution of N1-(2-bromophenyl)-N3-(6-(methoxy-d3)pyridin-2-yl)malonamide (5-3, 0.3 g, 0.8 mmol), 5-borono-2-methoxybenzoic acid (0.24 g, 1.2 mmol) and sodium carbonate (0.26 g, 0.25 mmol) in 5 mL dioxane and 3 mL water was added Tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmol) under nitrogen atmosphere. The reaction mixture was heated to 100 °C and stirred for 3 h under nitrogen atmosphere. Upon completion, the reaction mixture was cooled to room temperature and filtered through a celite pad. The filtrate was then portion between ethyl acetate and water. The organic layer was washed by brine, dried under sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column with dichloromethane / methanol = 15:1 as eluents. Pure fractions were evaporated to dryness to yield the title compound as a white solid (0.27 g, 75%) .1H NMR (500 MHz, DMSO) δ 12.57 (s, 1H), 10.34 (s, 1H), 9.56 (s, 1H), 7.70 – 7.58 (m, 4H), 7.53 (dd, J = 8.6, 2.4 Hz, 1H), 7.36 – 7.28 (m, 2H), 7.28 – 7.23 (m, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.51 (d, J = 7.9 Hz, 1H), 3.79 (s, 3H), 3.44 (s, 2H). m / z (ES+) [M + H]+= 439.3. Step 4. Synthesis of 4-hydroxy-2'-(3-((6-(methoxy-d3)pyridin-2-yl)amino)-3- oxopropanamido)-[1,1'-biphenyl]-3-carboxylic acid (HC9532) To a solution of 4-methoxy-2'-(3-((6-(methoxy-d3)pyridin-2-yl)amino)-3- oxopropanamido)-[1,1'-biphenyl]-3-carboxylic acid (5-4, 0.27 g, 0.6 mmol) in 2 mL DCM was added tribromoborane (1 mol / L solution in DCM, 1.85 mL, 1.85 mmol) under nitrogen atmosphere at -78 °C. The reaction mixture was then allowed to warm to room temperature and stirred for additional 2 h. Upon completion, the reaction mixture was quench with water. The resulting participate was then filtered, washed with methanol and dried under reduced pressure to yield the title compound as white solid (0.15 g, 57%).1H NMR (400 MHz, DMSO) δ 14.02 (s, 1H), 11.30 (s, 1H), 10.34 (s, 1H), 9.59 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.3 Hz, 2H), 7.55 (dd, J = 8.6, 2.4 Hz, 1H), 7.40 – 7.34 (m, 1H), 7.34 – 7.25 (m, 2H), 6.97 (d, J = 8.5 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 3.46 (s, 2H). m / z (ES+) [M + H]+= 425.1536. Example 13: Synthesis of 4-hydroxy-3'-(3-((6-(methoxy-d3)pyridin-2-yl)amino)-3- oxopropanamido)-[1,1'-biphenyl]-3-carboxylic acid (HC9533) Synthesised by a similar procedure to Example 12 from 3-bromoaniline instead of 2- bromoaniline in step 2.1H NMR (400 MHz, DMSO) δ 11.26 (s, 1H), 10.47 (s, 1H), 10.29 (s, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.91 – 7.85 (m, 1H), 7.81 (dd, J = 8.6, 2.5 Hz, 1H), 7.73 – 7.63 (m, 2H), 7.64 – 7.46 (m, 2H), 7.40 (t, J = 7.8 Hz, 1H), 7.37 – 7.30 (m, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.65 – 6.51 (m, 1H), 3.60 (s, 2H). m / z (ES+) [M + H]+= 425.1537. Example 14: Synthesis of 4-hydroxy-4'-(3-((6-(methoxy-d3)pyridin-2-yl)amino)-3- oxopropanamido)-[1,1'-biphenyl]-3-carboxylic acid (HC9534) Synthesized by a similar procedure to Example 12 from 4-bromoaniline instead of 2- bromoaniline in step 2.1H NMR (400 MHz, DMSO) δ 11.23 (s, 1H), 10.48 (s, 1H), 10.27 (s, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.83 (dd, J = 8.6, 2.4 Hz, 1H), 7.72 – 7.65 (m, 4H), 7.64 – 7.57 (m, 2H), 7.05 (d, J = 8.6 Hz, 1H), 6.58 – 6.50 (m, 1H), 3.60 (s, 2H). m / z (ES+) [M + H]+= 425.1539. Example 15: Synthesis of N1-(3,4-bis(difluoromethoxy)phenyl)-N3-(6-(methoxy- d3)pyridin-2-yl)malonamide (HC956) To a solution of N1-(3,4-dihydroxyphenyl)-N3-(6-(methoxy-d3)pyridin-2- yl)malonamide (HC8768, Example 8, 0.05 g, 0.15 mmol) in 1 mL DCM was added an aqueous KOH solution (20 wt%, 0.26 mL, 0.9 mmol) with vigorous stirring. Then a solution of TMSCF2Br (0.16 g, 0.8 mmol) in DCM (0.5 mL) was added at 0 °C and the reaction mixture was then allowed to warm to room temperature and stirred for additional 30 min. Upon completion, the reaction mixture was portioned between ethyl acetate and water. The organic layer was washed by brine, dried under sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column with dichloromethane / methanol = 15:1 as eluents. Pure fractions were evaporated to dryness to yield the title compound as a white solid. (0.053 g, 81%).1H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 10.46 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.72 – 7.67 (m, 1H), 7.46 – 7.40 (m, 1H), 7.33 – 7.30 (m, 1H), 7.20 – 7.11 (m, 1H), 7.03 – 6.91 (m, 1H), 6.54 (d, J = 7.6 Hz, 1H), 6.01 – 5.82 (m, 1H), 3.58 (s, 2H). m / z (ES+) [M + H]+= 421.1216. Example 16: Inhibition of amylin fibril formation This example describes the analysis of representative compounds of Formula (I) using the thioflavin-T assay to assess compound-mediated inhibition of amylin fibril formation. All compounds were solubilised in aqueous solution with NaOH to a pH >10, then brought down to a pH of 7-8 with HCl. All compounds were 100% soluble and stable in solution under these conditions for at least 24 hours, with the exception of HC8768 which began to precipitate after 30 min at pH>10. The ability of the compounds to inhibit human amylin (hA) fibril formation was assessed using the thioflavin-T assay, as described in J.F. Aitken et al., Suppression by polycyclic compounds of the conversion of human amylin into insoluble amylin amyloid., Biochem J., 374 (2003), 779-784. Interactions were measured using thioflavin-T fluorescence. When bound to hA fibrils, thioflavin-T shows a marked increase in fluorescence that can be quantified. If a compound is added to a solution of human amylin and interacts with amylin to inhibit or prevent amylin fibril formation, then there will be a quantifiable decrease in thioflavin-T fluorescence. Compounds were thus tested using the thioflavin-T assay for their ability to inhibit human amylin fibril formation. Effects of the compounds on human amylin fibril formation were measured by fluorescence spectroscopy, using a Spectra-MAX Gemini XS fluorescence spectrophotometer (Molecular Devices Corporation, Sunnyvale, CA, U.S.A.). Excitation and emission maxima were set to 450 nm and 510 nm respectively using a cut-off filter at 495 nm. The rate of human amylin fibril formation was determined in 10 mM Tris, pH 7.4, by monitoring thioflavin-T fluorescence in the presence or absence of each of the compounds. Each experiment was performed in triplicate and was repeated independently at least twice. Inhibition was assessed at two hA:compound ratios (1:1, 1:0.1) for each compound. The results for the hA:compound ratio 1:1 are shown in Figures 1-9. Figure 1 shows that HC8768 significantly increased the inhibition of fibril formation over that of ZBBP92 (●) and both compounds showed inhibition of fibril formation compared to human amylin alone. Figure 2 shows that HC87610 ( ) inhibits fibril formation, but to a lesser degree than ZBBP92 (●). HC8762 showed no inhibition of fibril formation. HC8768 showed significantly increased inhibition of fibril formation over that of ZBBP92 (●). Figure 3 shows that HC8765 shows little inhibition of fibril formation. HC8764 showed similar fibril inhibition to ZBBP92 (●). HC8766 was less effective than ZBBP92 or HC8764. Figure 4 shows that HC8769 ( ) did not inhibit fibril formation. HC87610 ( ) showed inhibition of fibril formation, but to a lesser degree than ZBBP92 (●). Figure 5 shows that HC8761 inhibits amylin fibril formation in a similar degree to ZBBP92 (●). Figure 6 shows that HC9534 has inhibition of fibril formation activity comparable to ZBBP92 (●). Figure 7 shows that HC9534 has a greater inhibitory effect on fibril formation activity than ZBBP92 (●) at 2.5 µM compared to activity levels at 25 µM (see Figure 6). Figure 8 shows that HC9532 shows some, but little inhibition, and HC9533 has a greater inhibitory effect on hA fibril formation, although not as strongly as HC9534 or ZBBP92 (●). Figure 9 shows that HC87682 has a greater inhibitory effect on hA fibril formation, although not as strongly as HC9534 or ZBBP92 (●). Example 17: Effect on prevention of human amylin-evoked beta-cell death CM and RINm5F cells were plated in a 48-well plate and cultured o / n in RPMI medium (5%FBS and 10% FBS, respectively). Human amylin (hA) stock solutions (500 ^M) were prepared freshly in water and diluted in medium to a final concentration of 10 ^M. Stock solutions of each compound (40 µM) were prepared in DMSO. Aliquots of hA-medium (200ul each) were then pre-mixed with various compounds at 1:10 molar ratio and incubated for 2 hrs at RT. The mixtures were then added to cells and incubation o / n for 16- 18 hours. Untreated control cells were treated similarly with water. Apoptotic cell death was measured as described (Zhang et al, Diabetes 57, 348-356, 2008; Zhang et al, J. Biol. Chem. 278, 52810-52819, 2003) using Cell Death Detection Elisa kit (Roche). The results shown in Figures 10 and 11 represent levels of enrichment of nucleosomes in the sample (cell lysate) and are expressed as relative to controls (Co) which were set at one. Values are mean ± SE of four independent experiments, each performed in duplicate. ***P<0.001 versus control;#P<0.05;##P<0.01;###P<0.001 versus hA- treated cells.

Claims

CLAIMS 1. A compound of Formula (I):wherein: X is C1-C5alkyl, cyclopropyl, or C2-C4dialkyl ether; A is absent or is C1-C6alkyl optionally substituted with halide, C1-C3alkoxy, or C1- C3haloalkoxy, or A is phenyl; B is absent or is C1-C6alkyl; each R1is independently selected from OH, halide, C1-C3alkoxy, C1-C3deuteroalkoxy, C1-C3haloalkoxy, C1-C3deuterohaloalkoxy, CO2R3, OCO2R4, and O-glycosyl; R3is H or C1-C3alkyl; R4is C1-C3alkyl; and u is 1, 2 or 3; each R2is independently selected from OH, halide, C1-C3alkoxy, C1-C3deuteroalkoxy, C1-C3haloalkoxy, and C1-C3deuteroalkoxy; and v is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1, wherein X is CH2.

3. A compound as claimed in claim 1, wherein X is (CH2)2, (CH2)3, or (CH2)4.

4. A compound as claimed in claim 1, wherein X is CH2-O-CH2.

5. A compound as claimed in claim 1, wherein X is cyclopropyl.

6. A compound as claimed in any one of claims 1 to 5, wherein A is C1-C5alkyl substituted with OCH3, OCD3, OCH2F, or F.

7. A compound as claimed in any one of claims 1 to 6, wherein R1is OH, F, CO2H, OCH3, OCD3, OCF2H, OCOEt, OCO2Pr or O-glucosyl.

8. A compound as claimed in any one of claims 1 to 7, wherein R2is OH, F, OCH3or OCD3.

9. A compound as claimed in any one of claims 1 to 8, wherein u is 2 and each R1is OH.

10. A compound as claimed in any one of claims 1 to 8, wherein u is 2 and each R1is O- glucosyl.

11. A compound as claimed in any one of claims 1 to 8, wherein u is 2 and each R1is OCO2Pr.

12. A compound as claimed in any one of claims 1 to 8, wherein u is 2 and one R1is OH and the other R1is CO2H.

13. A compound as claimed in any one of claims 1 to 8, wherein u is 2 and one R1is OH and the other R1is OCF2H.

14. A compound as claimed in any one of claims 1 to 8, wherein u is 2 and one R1is OH and the other R1is F.

15. A compound as claimed in any one of claims 1 to 14, wherein v is 1 and R2is OCH3or OCD3.

16. A compound as claimed in any one of claims 1 to 14, wherein v is 2 and one R2is OCH3or OCD3and the other R2is F.

17. A compound as claimed in claim 1 selected from the group comprising:

18. A pharmaceutical composition comprising a compound of any one of claims 1 to 17 and a pharmaceutically acceptable diluent, carrier or excipient.

19. A method of treating or preventing diabetes, an amylin amyloid-associated disease, or islet of Langerhans beta-cell death comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 17.

20. A method of inhibiting, preventing, or reversing an amylin amyloidosis, or the formation of one or more amylin-amyloid fibrils or amylin amyloid plaques, comprising contacting the amylin amyloidosis or one or more amylin-amyloid fibrils or amylin amyloid plaques with an effective amount of a compound of any one of claims 1 to 17.

21. The use of a compound of any one of claims 1 to 17 in the manufacture of a medicament for treating or preventing diabetes, an amylin amyloid-associated disease, or islet of Langerhans beta-cell death.

22. A composition for treating or preventing diabetes, an amylin amyloid-associated disease, or islet of Langerhans beta-cell death comprising a compound of any one of claims 1 to 17.

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