Tropane compounds for the treatment of diabetes

Abstract

Disclosed herein are compounds of Formula (I). Pharmaceutical compositions comprising the same, methods of treating diseases using the same, and methods of making the compounds of Formula (I) are also disclosed.

Description

[0001] Docket No. 135304-00620 TROPANE COMPOUNDS FOR THE TREATMENT OF DIABETES CROSS-REFERENCE TO RELATED APPLICATIONS The instant application claims the benefit of priority to U.S. Provisional Application No. 63 / 681,614, filed on August 9, 2024, the entire contents of which are incorporated herein by reference. FIELD OF THE INVENTION Provided herein are tropanes, pharmaceutical compositions thereof, and methods of their use for treating one or more symptoms of diabetes. BACKGROUND OF THE INVENTION Diabetes mellitus, commonly referred to as diabetes is a disorder in which the body does not produce enough or respond normally to insulin, causing glucose levels to be abnormally high. Diabetes is commonly described as two distinct types: type 1 or insulin dependent diabetes and type 2 or insulin independent diabetes. Diabetes has been estimated to affect over 500 million adults worldwide with approximately 400 million of these cases being type 2 diabetes. The number of those affected is expected to continue to rapidly rise over the next decade. Diabetes commonly results in hyperglycemia or high blood sugar which is a condition in which an excessive amount of glucose circulates in the blood plasma. If not treated, hyperglycemia can lead to serious health problems and potentially develop into life- threatening conditions such as ketoacidosis. Moreover, chronic hyperglycemia can cause injury to the heart, and is strongly associated with heart attacks and death in subjects with no coronary heart disease or history of heart failure. Type 1 diabetes is an autoimmune disorder that leads to the destruction of insulin- producing pancreatic cells. Insulin is a hormone the body which enables the flow of glucose into the cell to produce energy. There is presently no cure for type 1 diabetes, but the symptoms are commonly managed with insulin replacement therapies. However, if left untreated, glucose can build up in the blood plasma leading to the serious side effects of hyperglycemia outlined above. Type 2 diabetes is characterized by insulin resistance in peripheral tissues, specifically skeletal muscle and adipose tissues and / or pancreatic β-cell dysfunction. With disease progression, pancreatic β-cell dysfunction is gradually exacerbated, leading to pancreatic β- Docket No. 135304-00620 cell destruction, increased severity of diabetic symptoms, and the need for insulin replacements therapies in this patient population. There is presently no cure for type 2 diabetes and most treatments are focused on attenuating dysfunctional insulin signaling or inhibiting glucose output from the liver, but many of those treatments have several drawbacks and side effects. Thus, there is significant interest in identifying novel insulin-independent ways to treat type 2 diabetes and specifically preventing the destruction of pancreatic β-cell function to inhibit the progression of type 2 diabetes. SUMMARY OF THE INVENTION Disclosed herein are a series of compounds useful for treating one or more symptoms of diabetes. Provided herein are experiments showing that the disclosed compounds protect pancreatic β-cells from ER stress-induced cell death in a cellular model of diabetes (see Exemplification). One embodiment of the invention is a compound represented by Formula (I): or a pharmaceutically acceptable salt thereof, wherein: X and X’ are independently selected from the group consisting of O, S, and NR2; R1is hydrogen or C1-6alkyl (e.g., methyl); R2is hydrogen or C1-6alkyl (e.g., methyl); Ar is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein said aryl or heteroaryl are optionally substituted with one or more RArAr’ is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein said aryl or heteroaryl are optionally substituted with one or more RAr’; RArand RAr’are independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, –CN, –OH, –NO2, –NR3aR3b, –C(O)R4, –C(S)R4, – C(O)OR4, –OC(O)R4, –C(O)NR3aR3b, –SR4, –S(O)R4, –S(O)2R4, and –SO2NR3aR3b; R3aand R3bare each independently hydrogen or C1-6alkyl (e.g., methyl), wherein said C1-6alkyl is optionally substituted with hydroxyl or C1-3alkoxy; or R3aand R3btogether with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; and Docket No. 135304-00620 R4is selected from the group consisting of H or C1-6alkyl, wherein said C1-6alkyl is optionally substituted with –OH or C1-3alkoxy; each R5is independently hydrogen or C1-6alkyl; or an R5group taken together with their intervening atoms form a 5- or 6-membered heterocyclyl; each R6is independently hydrogen or C1-6alkyl; or together with their intervening atoms form a 5- or 6-membered heterocyclyl. Another embodiment of the invention is a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Another embodiment of the invention is a method of treating diabetes in a subject. The method comprises administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof. In exemplary embodiments, the diabetes may be type 1 or type 2. DETAILED DESCRIPTION 1. Compounds of the Invention Disclosed herein are a series of compounds that demonstrate the ability to protect cells for endoplasmic reticulum stress-induced cell death. Compounds of the invention are described herein below. A first embodiment of the invention is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula (I). A second embodiment of the invention is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein each R5and each R6are independently Docket No. 135304-00620 hydrogen or C1-6alkyl; and the remainder of the variables are as described in the first embodiment. A third embodiment of the invention is a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5and each R6are independently selected from hydrogen or methyl; and the remainder of the variables are as described in the first embodiment. A fourth embodiment of the invention is a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5and each R6are hydrogen; and the remainder of the variaables are as described in the first embodiment. A fifth embodiment of the invention is a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein X and X’ are O; and the remainder of the variables are as described in the first, second, third, or fourth embodiments. A sixth embodiment of the invention is a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen; and the remainder of the variables are as described in the first, second, third, fourth, or fifth embodiments. A seventh embodiment of the invention is a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl or a 6-membered heteroaryl optionally substituted with 1 or 2 RArand Ar’ is phenyl or a 6-membered heteroaryl optionally substituted with 1 or 2 RAr’; and the remainder of the variables are as described in the first, second, third, fourth, fifth, or sixth embodiments. An eighth embodiment of the invention is a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl optionally substituted with 1 and Ar’ phenyl optionally substituted with 1 or 2 RAr’; and the remainder of the variables are as described in the first, second, third, fourth, fifth, or sixth embodiments. A ninth embodiment of the invention is a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein each RArand RAr’ is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, –CN, –NO2, and – NR3aR3b; and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiments. A tenth embodiment of the invention is a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein each RArand RAr’ is independently selected from halogen, C1-6alkyl; and C1-6haloalkyl; and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiments. Docket No. 135304-00620 An eleventh embodiment of the invention is a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein each RArand RAr’ is independently selected from –F, –Cl, –CHF2, and –CF3; and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiments. A twelfth embodiment of the invention is a compound, or a pharmaceutically acceptable salt thereof, having the structure as shown in Table 1. Docket No. 135304-00620 2. Definitions To facilitate understand of the disclosure set forth herein, a number of terms are defined as follows. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. “Alkyl” means a saturated aliphatic straight-chain or branched monovalent aliphatic radical. Unless otherwise specified, an alkyl group typically has 1 to 6 carbon atoms (C1-6alkyl), alternatively, 1 to 3 carbon atoms (C1-3alkyl) (i.e., 1, 2 or 3). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n- propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms). Docket No. 135304-00620 “Halo” or “halogen” refers to fluorine, chlorine, bromine, or iodine. “Haloalkyl” means an alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo and includes alkyl moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkyl). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6haloalkyl”). “Alkoxy” refers to an –O-alkyl radical, e.g., with between 1 and 6 carbon atoms. “Heterocyclyl” refers to a radical of a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“4- to 6-membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Examples include, but are not limited to azetidinyl, pyrrolidinyl, dihydropyrrolyl, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, dihydropyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, and triazinanyl. “Aryl” refers to a radical of a monocylic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having 6-10 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-10aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). “Heteroaryl” refers to a monocyclic or polycyclic (e.g., bicyclic) radical of a 5- to 10- membered 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In some embodiments, a heteroaryl group is a “6- membered heteroaryl” refers to a 6-membered monocyclic and unfused 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Exemplary monocyclic 6- membered heteroaryl groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl.. “Subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject. In one embodiment, the subject is a human. Docket No. 135304-00620 “Effective amount” is meant to include the amount of a compound that, when administered, is sufficient to alleviate, at least to some extent, one or more symptoms of the disease of the disease being treated. “An effective amount” of the disclosed compounds or pharmaceutically acceptable salts thereof, is determined by the physician on the basis of the patient-specific parameters, such as age, weight, sex, severity of the disease, etc. The dosage is preferably between 0.0001 mg to 1000 mg / kg body weight. Compounds of the present disclosure are generally administered as part of a pharmaceutical compositions, which comprises the compound and a pharmaceutically acceptable carrier or excipient. The term “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 7th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2012; Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; and Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009. Exemplary routes of administration and suitable carriers and excipients are disclosed in U.S. Patent no. 11,730,729, the teachings of which are incorporated herein by reference. When a compound provided herein contains an acidic or basic moiety, it may also be provided as a pharmaceutically acceptable salt (See, Berge et al., J. Pharm. Sci. 1977, 66, 1- 19; and “Handbook of Pharmaceutical Salts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA, Zurich, 2002). Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)- camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, Docket No. 135304-00620 cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino- salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid. Suitable bases for use in the preparation of pharmaceutically acceptable salts, include, but are not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including, but not limited to, L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)- pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl)-1,3-propanediol, and tromethamine. 3. Methods of Treatment “Treat,” “treating,” and “treatment” includes therapeutically treating, therapeutic treatment, prophylactically treating, and prophylactic treatment. “Therapeutically treating” and “therapeutic treatment” are meant to include alleviating or attenuating a disorder, disease, or condition, or one or more symptoms of the disorder, disease, or condition. “Prophylactically treating” and “prophylactic treatment” are meant to include reducing the likelihood of developing or delaying the onset of the disorder, disease, or condition in a subject. In instances where prophylactic treatment is used, the subject belongs to an at-risk population. Docket No. 135304-00620 An “at-risk population” is meant to include subject that possess characteristics that result in the subjects being likely to develop the disorder, disease, or condition. For example, an at-risk population for diabetes may include subjects who are obese, hyperglycemic, insulin deficient, insulin resistant, or suffer from metabolic syndrome. In another embodiment, providing herein is a method of treating diabetes in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the diabetes is type 1 diabetes. In other embodiments, the diabetes is type 2 diabetes. The following examples are only representative and do not exclude other related procedures. EXEMPLIFICATION 1. Definitions The disclosure will be further understood by the following non-limiting examples. As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); mL (microliters); M (molar); mM (millimolar); mM (micromolar); mol (moles); mmol (millimoles); h (hour or hours); and min (minutes). For all of the following examples, standard procedures and methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in ºC (degrees Centigrade). All procedures are conducted at room temperature unless otherwise noted. 2. Biological Assays Protection of Pancreatic β-cells from ER Stress-Induced Cell Death Rat insulinoma-derived insulin−producing INS-1 β-cells were plated in 96-well plates at about 12,000 cells per well. After 1 day, the cell culture media was changed to complete media and compounds 1-7 were added to achieve a final concentration of 10 μM along with Docket No. 135304-00620 vehicle containing no compound. The INS-1 cells and compounds were incubated at 10% CO2at 37 ºC in a humidified environment of the incubator with compound for 1 hour prior to addition of the GlcNAc phosphotransferase inhibitor tunicamycin (TM), a potent inducer of ER stress, to achieve a final TM concentration of 100 nM. The cells were incubated with compounds and TM for 48 hours prior to the addition of CCK-8 reagent. Cells were incubated for an additional 3-4 hours, and viability was read at 450 nm absorbance in a standard plate reader. Controls included blank (no cells), ± vehicle, and ± TM. Vehicle- treated control cells showed similar viability as that of untreated cells. The percentage of viability increase with compound versus TM alone without compound was calculated and the results are summarized in Table 2. Table 2, A represents a cell viability percentage increase compared to TM alone of 101%-125%, B represents an increase between 76%-100%, C represents an increase between 51%-75%, and D represents a cell viability increase of 25%- 50%. TABLE 2 3. Synthesis of Compounds Procedure for preparation of Compound 1: Docket No. 135304-00620 To a solution of 1b (0.20 g, 975 μmol, 152 μL, 1.00 eq) in DCM (4.00 mL) was added 1a (87.40 mg, 438 μmol, 0.45 eq, 2HCl) and TEA (394 mg, 3.90 mmol, 543 μL, 4.00 eq). The mixture reaction was stirred at 25 °C for 2 hrs. LCMS (product: Rt = 0.458 mins) showed 1a was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep - HPLC (column: CD01 - Phenomenex luna C18150 * 25 * 10um; mobile phase: [water (FA) - ACN]; gradient: 40%-70% B over 10 min) to give Compound 1 (0.112 g, 234 μmol, 24.0% yield, 97% purity) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ ppm 7.83 (br d, J = 5.38 Hz, 1 H), 7.27 - 7.39 (m, 4 H), 6.90 - 7.01 (m, 4 H), 4.65 - 4.83 (m, 2 H), 4.54 (s, 2 H), 4.42 (br s, 1 H), 4.26 (br s, 1 H), 3.88 (br d, J = 5.38 Hz, 1 H), 2.04 - 2.15 (m, 1 H), 1.68 - 2.00 (m, 7 H).

[0002] Docket No. 135304-00620 Procedure for preparation of Compound 2: Step 1: To a solution of 2a (1.00 g, 4.89 mmol, 1.00 eq) in DCM (20 mL) was added (COCl)2(3.10 g, 24.4 mmol, 2.14 mL, 5.00 eq) and DMF (0.016 mL) at 0 C. The mixture was stirred at 25 °C for 2 h. TLC (Petroleum ether: Ethyl acetate=0:1, ref=0.46) indicated 2a was consumed completely and one new spot formed. The mixture was concentrated under reduced pressure to give 2b (1.09 g, crude) as a colorless oil. Step 2: To a solution of compound 2c (364 mg, 2.24 mmol, 1.00 eq, HCl) in DCM (5 mL) was added TEA (907 mg, 8.97 mmol, 1.25 mL, 4.00 eq) and 2b (500 mg, 2.24 mmol, 1.00 eq). The mixture was stirred at 25 C for 2 hrs. LC-MS showed 2b was consumed completely and the desired mass was detected. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD01-Phenomenex luna C18 150*25*10um; mobile phase: [water (FA)-ACN]; gradient: 44%-74% B over 11 min) to give compound 2 (253 mg, 508 μmol, 11.3% yield) as an off-white solid.1H NMR: (400 MHz, DMSO) δ ppm 7.87 (br d, J=5.25 Hz, 1 H), 7.48 (dt, J=14.01, 8.88 Hz, 2 H), 7.07 (dt, J=11.41, 2.74 Hz, 2 H), 6.79 - 6.87 (m, 2 H), 4.71 - 4.86 (m, 2 H), 4.59 (s, 2 H), 4.43 (br s, 1 H), 4.26 (br s, 1 H), 3.87 (br d, J=5.25 Hz, 1 H), 2.12 (dt, J=13.91, 5.36 Hz, 1 H), 1.89 - 2.02 (m, 4 H), 1.77 (br t, J=12.82 Hz, 3 H). Procedure for preparation of compound 3: Step 1: To a solution of 3a (1.30 g, 5.91 mmol, 1.00 eq) in DCM (15.0 mL) was added (COCl)2(2.12 g, 16.7 mmol, 1.47 mL, 2.83 eq) and DMF (43.1 mg, 590 μmol, 45.4 μL, 0.10 eq). The reaction was stirred at 25 °C for 2 h. TLC (Petroleum ether: Ethyl acetate = 2: 1 Rf = 0.57) indicated 3a was consumed completely and one new spot was formed. The Docket No. 135304-00620 reaction mixture was concentrated under reduced pressure to give 3b (1.40 g, crude) as a yellow oil. Step 2: To a solution of 3b (0.30 g, 1.26 mmol, 1.10 eq) in DCM (6.00 mL) was added TEA (462 mg, 4.57 mmol, 636 μL, 4.00 eq) and 3c (144 mg, 1.14 mmol, 1 eq). The mixture was stirred at 25 °C for 2 h. LCMS (product: Rt = 0.478 mins) showed 3c was consumed completely and one main peak with the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep - HPLC (column: CD01 - Phenomenex luna C18150 * 25 * 10um; mobile phase: [water (FA) - ACN]; gradient: 40% - 70% B over 11 min) to give compound 3 (0.189 g, 352 μmol, 30.8% yield, 99% purity) as a white solid.1H NMR: (400 MHz, DMSO- d6) δ ppm 7.91 (br d, J = 5.00 Hz, 1 H), 7.66 (br dd, J = 12.94, 8.69 Hz, 4 H), 7.11 (br dd, J = 14.38, 8.63 Hz, 4 H), 4.77 - 4.98 (m, 2 H), 4.65 (s, 2 H), 4.42 (br s, 1 H), 4.24 - 4.32 (m, 1 H), 3.89 (br d, J = 5.00 Hz, 1 H), 2.10 - 2.19 (m, 1 H), 1.67 - 2.04 (m, 7 H). Procedure for preparation of compound 4: Step 1: To a solution of 4a (1.00 g, 4.89 mmol, 1.00 eq) in DCM (20 mL) was added (COCl)2(3.10 g, 24.4 mmol, 2.14 mL, 5.00 eq) and DMF (0.016 mL) at 0°C. The mixture was stirred at 25 °C for 2 h. TLC (Petroleum ether: Ethyl acetate=0:1, ref=0.46) indicated 4a was consumed completely and one new spot was formed. The mixture was concentrated under reduced pressure to give 4b (1.09 g, crude) as colorless oil. Step 2: To a solution of 4c (456 mg, 2.02 mmol, 0.90 eq) in DCM (5 mL) was added TEA (907 mg, 8.97 mmol, 1.25 mL, 4.00 eq) and 4b (500 mg, 2.24 mmol, 1.00 eq). The mixture was stirred at 25 °C for 2 h. LC-MS showed 4b was consumed completely and the desired mass was detected. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 1 to 0 / 1) to give 4d (720 mg, 1.74 mmol, 77.7% yield) as a white solid. Step 3: A solution of 4d (0.40 g, Docket No. 135304-00620 968 μmol, 1.00 eq) in HCl / dioxane (10 mL) was stirred at 25 °C for 12 h. LC-MS showed 4d was consumed completely and the desired mass was detected. Concentration under reduced pressure gave 4e (0.4 g, crude, HCl) as a white solid. Step 4: To a solution of 4e (253 mg, 724 μmol, 1.00 eq, HCl) in DCM (3 mL) was added TEA (293 mg, 2.90 mmol, 403 μL, 4.00 eq) and 4f (178 mg, 869 μmol, 135 μL, 1.20 eq). The mixture was stirred at 25oC for 2 h. LC-MS showed 4e was consumed completely and the desired mass was detected. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD01-Phenomenex luna C18150*25*10um; mobile phase: [water (FA)-ACN]; gradient: 36%-66% B over 11 min) to give compound 4 (70.0 mg, 138 μmol, 19.0% yield, 95.3% purity) as a white solid.1H NMR: (400 MHz, DMSO) δ ppm 7.87 (d, J=5.25 Hz, 1 H), 7.50 (t, J=8.88 Hz, 1 H), 7.30 - 7.35 (m, 2 H), 7.08 (dd, J=11.38, 2.75 Hz, 1 H), 6.92 - 6.97 (m, 2 H), 6.85 (dd, J=8.94, 2.19 Hz, 1 H), 4.67 - 4.82 (m, 2 H), 4.59 (s, 2 H), 4.42 (br s, 1 H), 4.27 (br s, 1 H), 3.87 (br d, J=5.50 Hz, 1 H), 2.08 - 2.16 (m, 1 H), 1.87 - 1.99 (m, 4 H), 1.76 (br t, J=13.20 Hz, 3 H). Procedure for preparation of compound 5: Step 1: To a solution of 5a (993 mg, 4.39 mmol, 0.90 eq) in DMF (10.0 mL) was added TEA (1.97 g, 19.5 mmol, 2.72 mL, 4.00 eq) and 5b (1.00 g, 4.88 mmol, 761 μL, 1.00 eq). The mixture was stirred at 25 °C for 1 hr. LCMS (product: Rt = 0.468 mins) showed 5a was consumed completely and one main peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 3 / 1) to give Compound 5c (1.40 g, 3.51 mmol, 71.9% yield, 99% purity) as a brown solid. Step 2: A solution of Compound 5c (0.7 g, 1.77 mmol, 1 eq) in HCl / dioxane (7.00 mL) was stirred at 25 °C for 16 hrs. LCMS (EC22437-4-P1Y1, product: Rt = 0.260 min) showed Compound 5c Docket No. 135304-00620 was consumed completely and one main peak with desired mass was detected. The reaction mixture concentrated under reduced pressure to give compound 5d (0.50 g, 1.51 mmol, 85.1% yield, HCl) as a brown solid. Step 3: To a solution of Compound 5d (0.20 g, 603 μmol, 1.00 eq, HCl) in DCM (4.00 mL) was added TEA (244 mg, 2.42 mmol, 336 μL, 4.00 eq) and Compound 5e (148 mg, 664 μmol, 1.10 eq). The mixture was stirred at 25 °C for 2 hrs. LCMS (EC22437-9-P1Z1, product: Rt = 0.463 mins) showed Compound 5d was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD01 - Phenomenex luna C18150 * 25 * 10um; mobile phase: [water (FA) - ACN]; gradient: 40% - 70% B over 11 min) to give Compound 5 (0.114 g, 229 μmol, 38.0% yield, 97% purity) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ ppm 7.83 (br d, J = 5.25 Hz, 1 H), 7.42 - 7.51 (m, 1 H), 7.30 - 7.39 (m, 2 H), 7.07 (dd, J = 11.51, 2.75 Hz, 1 H), 6.97 (d, J = 8.88 Hz, 2 H), 6.82 (dd, J = 8.82, 1.94 Hz, 1 H), 4.69 - 4.88 (m, 2 H), 4.54 (s, 2 H), 4.42 (br s, 1 H), 4.25 (br s, 1 H), 3.88 (br d, J = 5.63 Hz, 1 H), 2.06 - 2.17 (m, 1 H), 1.66 - 2.03 (m, 7 H). Procedure for preparation of compound 6: Step 1: To a solution of 6a (993 mg, 4.39 mmol, 0.90 eq) in DMF (10.0 mL) was added TEA (1.97 g, 19.5 mmol, 2.72 mL, 4.00 eq) and 6b (1.00 g, 4.88 mmol, 761 μL, 1.00 eq). The mixture was stirred at 25 °C for 1 h. LCMS (product: Rt = 0.468 mins) showed 6a was consumed completely and one main peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 3 / 1) to give 6c (1.40 g, 3.51 mmol, 71.9% yield, 99% purity) as a brown solid. Step 2: A solution of 6c (0.7 g, 1.77 mmol, 1 eq) in HCl / dioxane (7.00 mL) was stirred at 25 °C for 16 h. LCMS Docket No. 135304-00620 (product: Rt = 0.260 mins) showed 6c was consumed completely and one main peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give 6d (0.50 g, 1.51 mmol, 85.1% yield, HCl) as a brown solid. Step 3: To a solution of 6d (0.300 g, 905 μmol, 1.00 eq, HCl) in DCM (4.00 mL) was added TEA (366 mg, 3.62 mmol, 504 μL, 4.00 eq) and 6e (237 mg, 996 μmol, 1.10 eq). The mixture was stirred at 25 °C for 2 h. LCMS (product: Rt = 0.467 mins) showed 6d was consumed completely and one main peak with the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep - HPLC (column: CD01 - Phenomenex luna C18150 * 25 * 10um; mobile phase: [water (FA) - ACN]; gradient: 40% - 70% B over 11 min) to give compound 6 (0.167 g, 329 μmol, 36.3% yield, 98% purity) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ ppm 7.84 (br d, J = 5.38 Hz, 1 H), 7.65 (br d, J = 8.63 Hz, 2 H), 7.31 - 7.38 (m, 2 H), 7.09 (br d, J =8.50 Hz, 2 H), 6.93 - 7.01 (m, 2 H), 4.75 - 4.96 (m, 2 H), 4.54 (s, 2 H), 4.42 (br s, 1 H), 4.27 (br s, 1 H), 3.89 (br d, J =5.38 Hz, 1 H), 2.08 - 2.19 (m, 1 H), 1.67 - 2.02 (m, 7 H). Procedure for preparation of compound 7: Step 1: To a solution of 7a (0.500 g, 2.10 mmol, 1.00 eq) in DCM (2.00 mL) was added TEA (848 mg, 8.38 mmol, 1.17 mL, 4.00 eq) and 7b (474 mg, 2.10 mmol, 1 eq). The mixture was stirred at 25 °C for 2 h. LCMS (product: Rt = 0.474 mins) showed 7a was consumed completely and one main peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 3 / 1) to give 7c (0.700 g, 1.63 mmol, 77.9% yield, 100% purity) as a white solid. Step 2: A solution of 7c (0.350 g, 816 μmol, 1.00 eq) in HCl / dioxane (5.00 mL) was stirred at 25 °C for 16 h. LCMS (product: Rt = 0.279 mins) showed 7c was consumed completely and one main peak with the Docket No. 135304-00620 desired mass was detected. The reaction mixture concentrated under reduced pressure to give 7d (0.298 g, crude, HCl) was obtained as a white solid. Step 3: To a solution of 7d (0.298 g, 907 μmol, 1.00 eq) in DCM (5.00 mL) was added TEA (367 mg, 3.63 mmol, 505 μL, 4.00 eq) and 7e (204 mg, 998 μmol, 155 μL, 1.10 eq). The mixture was stirred at 25 °C for 2 h. LCMS (product: Rt = 0.469 mins) showed 7d was consumed completely and one main peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep - HPLC (column: CD01 - Phenomenex luna C18150 * 25 * 10um; mobile phase: [water (FA) - ACN]; gradient: 40% - 70% B over 11 min) to give Compound 7 (0.196 g, 386 μmol, 42.5% yield, 98% purity) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ ppm 7.90 (br d, J = 5.25 Hz, 1 H), 7.63 - 7.72 (m, 2 H), 7.28 - 7.35 (m, 2 H), 7.12 (br d, J =8.51 Hz, 2 H), 6.89 - 6.98 (m, 2 H), 4.62 - 4.82 (m, 4 H), 4.42 (br s, 1 H), 4.27 (br s, 1 H), 3.82 - 3.93 (m, 1 H), 2.07 - 2.17 (m, 1 H), 1.68 - 2.01 (m, 7 H).

Claims

Docket No. 135304-00620 CLAIMS What is claimed is:

1. A compound represented by Formula (I):or a pharmaceutically acceptable salt thereof, wherein: X and X’ are independently selected from the group consisting of O, S, and NR2; R1is hydrogen or C1-6alkyl (e.g., methyl); R2is hydrogen or C1-6alkyl (e.g., methyl); Ar is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein said aryl or heteroaryl are optionally substituted with one or more RArAr’ is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein said aryl or heteroaryl are optionally substituted with one or more RAr’; RArand RAr’are independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, –CN, –OH, –NO2, –NR3aR3b, –C(O)R4, –C(S)R4, – C(O)OR4, –OC(O)R4, –C(O)NR3aR3b, –SR4, –S(O)R4, –S(O)2R4, and –SO2NR3aR3b; R3aand R3bare each independently hydrogen or C1-6alkyl (e.g., methyl), wherein said C1-6alkyl is optionally substituted with hydroxyl or C1-3alkoxy; or R3aand R3btogether with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; and R4is selected from the group consisting of H or C1-6alkyl, wherein said C1-6alkyl is optionally substituted with –OH or C1-3alkoxy; each R5is independently hydrogen or C1-6alkyl; or an R5group and an RArgrouptaken together with their intervening atoms form a 5- or 6-membered heterocyclyl; each R6is independently hydrogen or C1-6alkyl; orDocket No. 135304-00620 an R6group and an RAr’grouptogether with their intervening atoms form a 5- or 6-membered heterocyclyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R5and each R6are independently hydrogen or C1-6alkyl.

3. The compound of claim 1 or claim 2, or pharmaceutically acceptable salt thereof, wherein each R5and each R6are independently selected from hydrogen or methyl.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein each R5and each R6are hydrogen.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein X and X’ are O.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl or a 6-membered heteroaryl optionally substituted with 1 or 2 RArand Ar’ is phenyl or a 6-membered heteroaryl optionally substituted with 1 or 2 RAr’.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl optionally substituted with 1 or 2 RArand Ar’ phenyl optionally substituted with 1 or 2 RAr’.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein each RArand RAr’is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, –CN, –NO2, and –NR3aR3b.Docket No. 135304-00620 10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each RArand RAr’is independently selected from halogen, C1-6alkyl; and C1-6haloalkyl.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein each RArand RAr’is independently selected from –F, –Cl, –CHF2, and –CF3.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by a compound in Table 1, or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

14. A method of treating diabetes in a subject comprising administering to a subject an effective amount of a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 13.

15. The method of claim 14, wherein the diabetes is type 1.

16. The method of claim 14, wherein the diabetes is type 2.

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