Quinoline compounds for the treatment of diabetes

Abstract

Disclosed herein are compounds of Formula (I): Pharmaceutical compositions comprising the same, methods of treating diseases mediated by sarcoplasmic / endoplasmic reticulum Ca2+ ATPase (SERCA) using the same, and methods of making the compounds of Formula (I) are also disclosed.

Description

[0001] QUINOLINE COMPOUNDS FOR THE TREATMENT OF DIABETES

[0002] RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 672,389, filed on July 17, 2024, the entire teachings of which are incorporated herein by reference.

[0004] FIELD OF THE INVENTION

[0005] Provided herein are quinolones, pharmaceutical compositions thereof, and methods of their use for treating one or more symptoms of diabetes. Also, provided herein are methods of their use for modulating the activity of a sarcoplasmic / endoplasmic reticulum Ca2+ATPase (SERCA).

[0006] BACKGROUND OF THE INVENTION

[0007] The endoplasmic reticulum (ER) is an organelle, which plays an essential role in multiple cellular processes that are central for cell survival and normal cellular functions. Those vital cellular processes include intracellular calcium homeostasis, protein secretion, and lipid biosynthesis. Anelli et al., EMBO J. 2008, 27, 315-327; Pizzo et al., Trends Cell Biol. 2007, 17, 511-517; Ma et al., J. Chem. Neuroanat. 2004, 28, 51-65.

[0008] Perturbation of ER homeostasis leads to accumulation of unfolded protein in the ER, triggering an evolutionarily conserved response known as the unfolded protein response (UPR). Ron et al., Nat. Rev. Mol. Cell Biol. 2007, 8, 519-529; Malhotra et al., Semin. Cell Dev. Biol. 2007, 18, 716-731. Disturbances that lead to ER stress include, for example, disturbances in cellular redox regulation, glucose deprivation, aberration of calcium regulation in the ER, viral infection, high-fat diet, protein-inclusion-body diseases (e.g., chronic neurodegenerative diseases), and inclusion-body myositis. Kim et al., Nat. Rev. Drug Dis. 2008, 7, 1013-1030; Ma et al., J. Chem. Neuroanat. 2004, 28, 51-65; Ozcan et al., Science 2004, 306, 457-461; Frand et al., Trends Cell Biol. 2000, 10, 203-310. ER stress has been linked to a wide range of diseases, including neurodegeneration (e.g.. Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, poly glutamine disease, and prion disease), stroke, bipolar disorder, heart disease, atherosclerosis, cancer, diabetes (types 1 and 2), muscle degeneration, inflammatory diseases, and autoimmune disease. Kim et al., Nat. Rev. Drug Dis. 2008, 7, 1013-1030; Oyadomari et al., Cell Death Differ. 2004, 11, 381-389. Sarcoplasmic / endoplasmic reticulum Ca2+ATPase (SERCA), is a major regulator of ER stress and glucose homeostasis in obesity. Park et al., Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 19320-19325. Obesity disrupts intracellular Ca2+homeostasis and induces ER stress. Fu et al., Nature 2011, 473, 528-531. Chronic activation of ER stress has been implicated in the development of insulin resistance and diabetes in obesity. Hotamisligil, Cell 2010, 140, 900-917; Kim et al. Nat. Rev. Drug Discov. 2008, 7, 1013-1030. Therefore, there is a need for therapeutic agents capable of reducing ER stress or restoring ER homeostasis for treating ER stress-caused diseases.

[0009] Diabetes mellitus, commonly referred to as diabetes is a disorder associated with ER stress. It 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.

[0010] 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 lifethreatening 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.

[0011] Type 1 diabetes is an autoimmune disorder that leads to the destruction of insulinproducing 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.

[0012] Type 2 diabetes is characterized by insulin resistance in peripheral tissues, specifically skeletal muscle and adipose tissues and / or pancreatic P-cell dysfunction. With disease progression, pancreatic P-cell dysfunction is gradually exacerbated, leading to pancreatic P- 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 P-cell function to inhibit the progression of type 2 diabetes.

[0013] SUMMARY OF THE INVENTION

[0014] Disclosed herein are a series of compounds useful for treating one or more symptoms of a disease or disorder mediated by sarcoplasmic / endoplasmic reticulum Ca2+ATPase (SERCA), for example, diabetes. Provided herein are experiments showing that the disclosed compounds protect pancreatic P-cells from ER stress-induced cell death in a cellular model of diabetes (see Exemplification).

[0015] One embodiment of the invention is a compound represented by Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0016] X is O, NR3, or S

[0017] Y1, Y2, Y3, and Y4are independently selected from CR2, and N, wherein at least two of Y1, Y2, Y3, and Y4are CR2;

[0018] R1is selected from the group consisting of H, halogen, Ci-ealkyl, Ci-ehaloalkyl, and Ci-6alkoxy; each R2is independently selected from the group consisting of H, halogen, C i -ealkyl, Ci-6haloalkyl, Ci-6alkoxy, -CN, -OH, -NO2, -NR2aR2b, -OR4, -C(O)R4, -C(S)R4, -C(O)OR4, -OC(O)R4, -C(O)NR2aR2b, -C(S)NR2aR2b, -OC(O)NR2aR2b, -SR4, -S(O)R4, -S(O)2R4, -SO2NR2aR2b, -NR4C(O)R4, -NR4C(O)OR4, -NR4C(O)NR2aR2b, -NR4SO2NR2aR2b, and -NR4SO2R4; R2aand R2bare each independently hydrogen, Chalky I or Ci -ealky 1 substituted with - OH or Ci -3 alkoxy; or

[0019] R2aand R2btogether with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl;

[0020] R3is H or Ci-6alkyl; each R4is independently selected from the group consisting of H and Ci-ealkyl, wherein said Ci-ealkyl is optionally substituted with -OH or Ci-aalkoxy; and m is 1 or 2.

[0021] 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.

[0022] Another embodiment of the invention is a method of treating a disease or disorder mediated by sarcoplasmic / endoplasmic reticulum Ca2+ATPase (SERCA) in a subject in need thereof. In one example, the disease or disorder is diabetes. In another example, the disease or disorder is Alzheimer’s disease. In yet another example, the disease or disorder is Parkinson’s disease. The method comprises administering 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.

[0023] DETAILED DESCRIPTION

[0024] 1. Compounds of the Invention

[0025] 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.

[0026] 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).

[0027] A second embodiment of the invention is a compound represented by Formula (la): or a pharmaceutically acceptable salt thereof, wherein the variables are as described in the first embodiment.

[0028] A third embodiment of the invention is a compound represented by Formula (lb): or a pharmaceutically acceptable salt thereof, wherein the variables are as described in the first embodiment.

[0029] A fourth embodiment of the invention is a compound represented by Formula (I), (la), or (lb), or a pharmaceutically acceptable salt thereof, wherein X is O; and the remainder of the variables are as described in the first embodiment.

[0030] A fifth embodiment of the invention is a compound represented by Formula (I), (la), or (lb), or a pharmaceutically acceptable salt thereof, wherein R1is Ci -ealkyl; and the remainder of the variables are as described in the first or fourth embodiments.

[0031] A sixth embodiment of the invention is a compound represented by Formula (I), (la), or (lb), or a pharmaceutically acceptable salt thereof, wherein R1is methyl; and the remainder of the variables are as described in the first, fourth or fifth embodiments.

[0032] A seventh embodiment of the invention is a compound represented by Formula (I), (la), or (lb), or a pharmaceutically acceptable salt thereof, wherein Y1, Y2, Y3, and Y4is CR2; and the remainder of the variables are as described in the first, fourth, fifth, or sixth embodiments. An eighth embodiments of the invention is a compound represented by Formula (I), (la), or (lb), or a pharmaceutically acceptable salt thereof, wherein each R2is independently selected from the group consisting of H, halogen, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, NR2aR2b, CN, and NO2; and the remainder of the variables are as described in the first, fourth, fifth, sixth or seventh embodiments.

[0033] A ninth embodiment of the invention is a compound represented by Formula (I), (la), or (lb), or a pharmaceutically acceptable salt thereof, wherein each R2is independently selected from the group consisting of H, halogen, C 1 -ealky 1, Ci-ealkoxy, and NR2aR2b; and the remainder of the variables are as described in the first, fourth, fifth, sixth, seventh, or eighth embodiments.

[0034] A tenth embodiment of the invention is a compound represented by Formula (I), (la), or (lb), or a pharmaceutically acceptable salt thereof, wherein each R2is independently selected from the group consisting of H, Cl, methyl, -OCH3, -OCH(CH3)2, and N(CH3)2; and the remainder of the variables are as described in the first, fourth, fifth, sixth, seventh, eighth or ninth embodiments.

[0035] An eleventh embodiment of the invention is a compound, or a pharmaceutically acceptable salt thereof, having the structure as shown in Table 1.

[0036]

[0037] 2. Definitions

[0038] To facilitate understand of the disclosure set forth herein, a number of terms are defined as follows.

[0039] 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.

[0040] “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 (Ci-6 alkyl), alternatively, 1 to 3 carbon atoms (C1-3 alkyl) (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, .scc-butyl, / -butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms).

[0041] “Halo” or “halogen” refers to fluorine, chlorine, bromine, or iodine.

[0042] “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., perfluoro alkyl). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“Ci-6 haloalkyl”).

[0043] “Alkoxy” refers to an -O-alkyl radical, e.g., with between 1 and 6 carbon atoms.

[0044] “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.

[0045] “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.

[0046] “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.

[0047] 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.

[0048] 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).

[0049] 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, (+)-(lS)- camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, 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, a-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, l-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.

[0050] 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, IH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(2-hydroxyethyl)- pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl)-l,3-propanediol, and tromethamine.

[0051] 3. Methods of Treatment

[0052] “Treat,” “treating,” and “treatment” include 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.

[0053] “Prophylactically treating” and “prophylactic treatment” are meant to include reducing the likelihood of developing or delaying the onset the disorder, disease, or condition in a subject. In instances where prophylactic treatment is used, the subject belongs to an at-risk population.

[0054] An “at-risk population” is meant to include subjects 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.

[0055] In one embodiment, provided herein is a method for treating a disorder, disease, or condition mediated by a SERCA in a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0056] The term “SERCA” or “sarco(endo)plasmic reticulum Ca2+ ATPase” refers to a sarcoplasmic / endoplasmic reticulum Ca2+ ATPase or a variant thereof.

[0057] The terms “SERCA-mediated disorder, disease, or condition” and “a disorder, disease, or condition mediated by SERCA” refer to a disorder, disease, or condition in which modulation of a SERCA activity results in some effect on the underlying disorder, disease, or condition, e.g., a SERCA agonist results in some improvement in at least some of patients being treated.

[0058] In certain embodiments, the disorder, disease, or condition mediated by a SERCA is a disorder, disease, or condition mediated by a SERCA2a. In certain embodiments, the disorder, disease, or condition mediated by a SERCA is a disorder, disease, or condition mediated by a SERCA2b.

[0059] The term “endoplasmic reticulum stress” or “ER stress” refers to perturbation of endoplasmic reticulum homeostasis, e.g., perturbation of the protein folding functionality of the endoplasmic reticulum.

[0060] In some embodiments, the disorders, diseases, and conditions mediated by a SERCA is a cardiovascular disease, cancer, diabetes, an inflammatory disease, a metabolic disease, or a neurological disease. In certain embodiments, the disorders, diseases, and conditions mediated by a SERCA is a heart disease, stroke, stenosis, restenosis, a disease associated with vascular smooth muscle cell proliferation, a disease associated with neointima formation, a disease associated with calcineurin PP2B, a disease associated with NF AT, arteriovenous fistula failure, a cardiac disease, a disease associated with a cardiac disease, urinary incontinence, cancer, asthma, pulmonary hypertension, chronic obstructive pulmonary disease, diabetes, a neurodegenerative disease, bipolar disorder, atherosclerosis, muscle degeneration, or an autoimmune disease.

[0061] The disorders, diseases, or conditions treatable with a compound provided herein, include, but are not limited to, (1) inflammatory or allergic diseases, including systemic anaphylaxis and hypersensitivity disorders, atopic dermatitis, urticaria, drug allergies, insect sting allergies, food allergies (including celiac disease and the like), and mastocytosis; (2) inflammatory bowel diseases, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (3) vasculitis, and Behcet's syndrome; (4) psoriasis and inflammatory dermatoses, including dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, viral cutaneous pathologies including those derived from human papillomavirus, HIV or RLV infection, bacterial, flugal, and other parasital cutaneous pathologies, and cutaneous lupus erythematosus; (5) asthma and respiratory allergic diseases, including allergic asthma, exercise induced asthma, allergic rhinitis, otitis media, allergic conjunctivitis, hypersensitivity lung diseases, and chronic obstructive pulmonary disease; (6) autoimmune diseases, including arthritis (including rheumatoid and psoriatic), systemic lupus erythematosus, type I diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, and glomerulonephritis; (7) graft rejection (including allograft rejection and graft-v-host disease), e.g., skin graft rejection, solid organ transplant rejection, bone marrow transplant rejection; (8) fever; (9) cardiovascular disorders, including acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary artery disease, restenosis, and vascular stenosis; (10) cerebrovascular disorders, including traumatic brain injury, stroke, ischemic reperfusion injury and aneurysm; (11) cancers of the breast, skin, prostate, cervix, uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colon and gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain, thyroid, blood, and lymphatic system; (12) fibrosis, connective tissue disease, and sarcoidosis, (13) genital and reproductive conditions, including erectile dysfunction; (14) gastrointestinal disorders, including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15) neurologic disorders, including Alzheimer's disease; (16) sleep disorders, including insomnia, narcolepsy, sleep apnea syndrome, and Pickwick Syndrome; (17) pain; (18) renal disorders; (19) ocular disorders, including glaucoma; and (20) infectious diseases, including HIV.

[0062] In certain embodiments, provided herein is a method for treating diabetes in a subject comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula I, a pharmaceutically acceptable thereof.

[0063] 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.

[0064] In certain embodiments, the diabetes is type 1 diabetes. In other embodiments, the diabetes is type 2 diabetes.

[0065] The compounds provided herein can be prepared, isolated, or obtained by any methods known to one of skill in the art, and the following examples are only representative and do not exclude other related procedures.

[0066] EXEMPLIFICATION 1. Definitions

[0067] The disclosure will be further understood by the following non-limiting examples.

[0068] 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); hr or hrs (hour or hours); and min (minutes).

[0069] 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 °C (degrees Centigrade). All procedures are conducted at room temperature unless otherwise noted.

[0070] 2. Biological Assays

[0071] Protection of Pancreatic P-cells from ER Stress-Induced Cell Death

[0072] Rat insulinoma-derived insulin-producing INS-1 P-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 1-9 were added to achieve a final concentration of 3.13 pM along with vehicle containing no compound. The INS-1 cells and compounds were incubated at 10% CO2 at 37 °C 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 1. Table 1, A represents a cell viability percentage increase compared to TM alone of 51%-75% and B represents an increase between 26%-50%. TABLE 1

[0073] 3. Synthesis of Compounds

[0074] Procedure for preparation of Compound 1

[0075] Step 1: To a solution of compound la (2.00 g, 13.4 mmol, 1.00 eq) in DMF (20 mL) was added K2CO3 (5.56 g, 40.2 mmol, 3.00 eq), and the mixture was stirred at 25 °C for 1 hr. Compound lb (6.84 g, 40.2 mmol, 4.02 mL, 3.00 eq) was added to the mixture and stirred at 80 °C for 12 hrs. LC-MS showed compound la was consumed completely and the desired mass was detected. The reaction mixture was quenched by addition of H2O (10 mL) and extracted with ethyl acetate (10 mL x3). The combined organic layers were washed with NaCl (10 mL x2), dried over Na2SO4, filtered, concentrated under reduced pressure, and triturated with ethyl acetate (10 mL) at 25 °C for 30 min to give the product. Compound 1c (2.20 g, 11.5 mmol, 85.7% yield) was obtained as a yellow solid. Step 2: A mixture of compound 1c (1.00 g, 5.23 mmol, 1.00 eq), compound Id (1.16 g, 5.23 mmol, 1.00 eq), Pd2(dba)3 (239 mg, 261 pmol, 0.05 eq), Xantphos (605 mg, 1.05 mmol, 0.20 eq), and CS2CO3 (3.41 g, 10.4 mmol, 2.00 eq) in dioxane (20 mL) was degassed and purged with N2 3 times and stirred at 100 °C for 12 hrs under an N2 atmosphere. LC-MS showed compound 1c was consumed completely and the desired mass was detected. The reaction mixture was filtered and then the reaction mixture was quenched by addition H2O (50 mL) and extracted with ethyl acetate (50 mL x3). The combined organic layers were washed with NaCl (20 mL x2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD05-Phenomenex luna C18 150*40*10 um; mobile phase: [water (FA)-ACN]; gradient: 26%-56% B over 10 min). Compound 1 (454 mg, 1.32 mmol, 25.1% yield, 96.4% purity) was obtained as a yellow solid. ’ H NMR: (400 MHz, DMSO) d ppm 8.35 (d, 7=8.38 Hz, 1 H), 7.94 (dd, 7=8.07, 1.06 Hz, 1 H), 7.82 (dd, 7=7.38, 1.13 Hz, 1 H), 7.71 (d, 7=8.50 Hz, 1 H), 7.61 (t, 7=7.75 Hz, 1 H), 7.49 (d, 7=8.38 Hz, 1 H), 7.23 (s, 1 H), 7.07 (dd, 7=8.44, 2.06 Hz, 1 H), 5.20 (s, 2 H), 4.78 (m, 1 H), 2.62 (s, 3 H), 1.33 (d, 7=6.00 Hz, 6 H)

[0076] Procedure for preparation of Compound 2

[0077] 100 °C, 12 h

[0078] Step 1: The first reaction step was run by flow chemistry. A solution of compound 2a (3.80 g, 25.1 mmol, 1.00 eq) in [dimethylamine (11.3 g, 25 mmol, 12.7 mL, 10.0 eq) and THF (2 mL)] was pumped (0.8 mL / min) to a flow reactor [SS, coils reactor, 3.175 (1 / 8”) mm, 120.75 mL, 240 °C]. The residence time was 150 min. The back pressure regulator was adjusted to 3 MPa. The mixture was collected with a bottle after running 150 min. TLC (petroleum ether: ethyl acetate=0:l) showed about 50% of 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: CD07-Daisogel SP-100-8-ODS-PK 150*25* lOum; mobile phase: [water (NH4HCO3)-ACN]; gradient: 2%-32% B over 10 min). Compound 2b (1.70 g, 9.36 mmol, 37.2% yield, 97% purity) was obtained as a yellow solid. Step 2: A mixture of compound 2b (1.00 g, 5.67 mmol, 1.00 eq), compound 2c (1.26 g, 5.67 mmol, 1.00 eq), Pd2(dba)3 (779 mg, 851 pmol, 0.15 eq), XantPhos (985 mg, 1.70 mmol, 0.30 eq), and CS2CO3 (3.70 g, 11.3 mmol, 2.00 eq) in dioxane (20 mL) was degassed and purged with N23 times and stirred at 110 °C for 12 h under an N2 atmosphere. LCMS showed compound 2b was consumed completely and the desired mass was detected. The reaction mixture was filtered and extracted with ethyl acetate (50 mL x3). The combined organic layers were washed with saturated NaCl solution (20 mL x2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD06-Waters Xbidge C18 150*40*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 35%-65% B over 10 min). Compound 2 (1.35 g, 4.21 mmol, 74.1% yield, 98.9% purity) was obtained as off-white solid.!H NMR: (400 MHz, DMSO) 3 ppm 8.33 (d, 7=8.38 Hz, 1 H), 7.90 (d, 7=7.50 Hz, 1 H), 7.80 (d, 7=7.38 Hz, 1 H), 7.54 - 7.64 (m, 2 H), 7.47 (d, 7=8.38 Hz, 1 H), 6.82 - 6.91 (m, 2 H), 5.17 (s, 2 H), 3.04 (s, 6 H), 2.62 (s, 3 H)

[0079] Procedure for preparation of Compound 3 L, 1.50 eq) were added to a solution of compound 3a (20.0 g, 106 mmol, 1.00 eq) in ACN (200 mL). After 30 minutes of stirring at 20 °C, (CHO)n (22.4 g, 748 mmol, 20.6 mL, 7.00 eq) was added and the reaction mixture was heated at 80 °C for 2 hours. The residue was dissolved in HC1 (100 mL) and stirred at 20 °C for 30 minutes. TLC (Dichloromethane :Methanol=5:l) indicated compound 3a was consumed completely and one new spot was formed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. Compound 3b (10.0 g, crude) was obtained as a yellow oil. Step 2: To a solution of compound 3b (10.0 g, 46.5 mmol, 1.00 eq) in DME (100 mL) were added K2CO3 (12.8 g, 93.0 mmol, 2.00 eq) and Mel (6.60 g, 46.5 mmol, 2.89 mL, 1.00 eq). The reaction mixture was stirred at 20 °C for 1 h. TLC (Dichloromethane:Methanol=l:l) indicated compound 3b was consumed completely and one new spot was formed. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. Compound 3c (9.00 g, crude) was obtained as a yellow oil. Step 3: To a solution of compound 3c (9.00 g, 39.2 mmol, 1.00 eq) in THF (100 mL), H2O (50 mL) and t-BuOH (20 mL) were added NaFhPCL (18.8 g, 157 mmol, 4.00 eq) and NaCICh (14.2 g, 157. mmol, 4.00 eq). The reaction mixture was stirred at 15 °C for 15 min. Then 2-methylbut- 2-ene (19.2 g, 275 mmol, 29.1 mL, 7.00 eq) was added and the mixture was stirred at 15 °C for another 45 min. TLC (Dichloromethane :Methanol=l : 1) indicated compound 3c was consumed completely and one new spot was formed. The reaction mixture was poured into water (100 mL) and adjust to pH=9~10 with 1 M sodium hydroxide. The aqueous phase was extracted with ethyl acetate (3x100 mL). The aqueous phase was adjusted to pH= 5~6 with IM hydrochloric acid. The aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 3d (7.00 g, crude) was obtained as a yellow oil. Step 4: To a solution of compound 3d (7.00 g, 28.5 mmol, 1.00 eq) in DMF (100 mL) were added K2CO3 (7.90 g, 57.1 mmol, 2.00 eq) and Mel (4.05 g, 28.5 mmol, 1.78 mL, 1.00 eq). The reaction mixture was stirred at 20 °C for 1 h. TLC (Dichloromethane:Methanol=l:l) indicated compound 3d was consumed completely and one new spot was formed. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (3 x 15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. Compound 3e (5.00 g, crude) was obtained as a yellow oil. Step 5: To a solution of compound 3e (2.00 g, 7.72 mmol, 1.00 eq) in CHCh (30 mL) was added NBS (1.51 g, 8.49 mmol, 1.10 eq) and AIBN (253 mg, 1.54 mmol, 0.20 eq). The mixture was stirred at 80 °C for 8 hrs. TLC (Petroleum ether:Ethyl acetate=20:l) indicated compound 3e was consumed completely and one new spot was formed. The reaction mixture was quenched by addition H2O 50 mL and extracted with DCM (50 mLx3). The combined organic layers were washed with NaCl (20 mLx2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / O to 20 / 1). Compound 3f (1.80 g, 5.33 mmol, 68.9% yield) was obtained as a yellow oil. Step 6: To a solution of compound 3f (1.80 g, 5.33 mmol, 1.00 eq) in AcOH (20 mL) was added compound 3g (842 mg, 5.33 mmol, 1.00 eq). The mixture was stirred at 100 °C for 12 hrs. LC-MS (EC23824-27-P1A1) showed compound 3f was consumed completely and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by recrystallization from Ethyl acetate (20 mL) at 20 °C. Compound 3h (1.80 g, 4.70 mmol, 88.1% yield) was obtained as a yellow solid. Step 7: To a solution of compound 3h (1.20 g, 3.13 mmol, 1.00 eq) in H2O (6 mL) and dioxane (30 mL) was added potassium;trifluoro(methyl)boranuide (1.53 g, 12.5 mmol, 4.00 eq), K2CO3 (1.30 g, 9.39 mmol, 3.00 eq), and Pd(dppf)Ch (229 mg, 313 pmol, 0.10 eq) under nitrogen. The mixture was stirred at 110 °C for 12 hrs. LC-MS showed compound 3h was consumed completely and desired mass was detected. The reaction mixture was filtered and extracted with Ethyl acetate (50 mLx3). The combined organic layers were washed with NaCl (20 mLx2), dried overNa2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Daisogel C18 250*70mm*10um; mobile phase: [water (NH3H2O)- ACN]; gradient: 40%-70% B over 5 min). Compound 3 (254 mg, 781. pmol, 24.9% yield, 97.6% purity) was obtained as a gray solid.!H NMR: (400 MHz, DMSO) d ppm 8.35 (d, 7=8.50 Hz, 1 H), 7.96 (dd, 7=8.07, 1.19 Hz, 1 H), 7.83 (dd, 7=7.38, 1.25 Hz, 1 H), 7.62 (t, 7=7.75 Hz, 1 H), 7.50 (m, 2 H), 7.29 (d, 7=7.63 Hz, 1 H), 5.14 (s, 2 H), 3.96 (s, 3 H), 2.61 (s, 3 H), 2.31 (s, 3 H)

[0080] Procedure for preparation of Compound 4

[0081] Step 1: To a solution of compound 4a (10.0 g, 37.9 mmol, 1.00 eq) in CCI4 (100 mL) was added BPO (459 mg, 1.90 mmol, 0.05 eq) and NBS (6.75 g, 37.9 mmol, 1.00 eq). The mixture was stirred at 85 °C for 12 hrs. LCMS showed compound 4a was consumed completely and the desired mass was detected. The reaction mixture was quenched by addition H2O (20 mL), and extracted with DCM (20 mL x3). The combined organic layers were washed with aq NaCl (120 mL x2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate=l / O to 20 / 1). Step 2: To a solution of Compound 4b (3.00 g, 8.76 mmol, 1.00 eq) in AcOH (30 mL) was added compound 4c (1.39 g, 8.76 mmol, 1.00 eq). The mixture was stirred at 100 °C for 4 hrs. LCMS showed compound 4b was consumed completely and the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue that was triturated with Ethyl acetate (30 mL) at 25 °C for 30 min. Compound 4d (2.80 g, 7.22 mmol, 82.4% yield) was obtained as a blue solid. Step 3: To a solution of compound 4d (2.80 g, 6.25 mmol, 1.00 eq, HO AC) in H2O (6 mL) and dioxane (30 mL) was added potassium;trifluoro(methyl)boranuide (3.05 g, 25.0 mmol, 4.00 eq), K2CO3 (2.59 g, 18.7 mmol, 3.00 eq), and Pd(dppf)Ch (457 mg, 625 pmol, 0.10 eq) under nitrogen. The mixture was stirred at 110 °C for 2 hrs. LCMS showed compound 4d was consumed completely and the desired mass was detected. The reaction mixture was filtered and extracted with Ethyl acetate (50 mLx3). The combined organic layers were washed with NaCl (20mLx2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: XPT C18 250*70*7um; mobile phase: [water (NH4HCO3)- ACN]; gradient: 35%-75% B over 28 minn). Compound 4 (700 mg, 2.07 mmol, 33.0% yield, 95.2% purity) was obtained as a yellow solid. ’ H NMR: (400 MHz, DMSO) d ppm 8.36 (d, 7=8.25 Hz, 1 H), 7.97 (d, 7=8.00 Hz, 1 H), 7.83 (d, 7=7.00 Hz, 1 H), 7.63 (t, 7=7.57 Hz, 1 H), 7.39 - 7.54 (m, 3 H), 5.17 (s, 2 H), 2.61 (s, 3 H), 2.46 (s, 3 H)

[0082] Procedure for preparation of Compound 5

[0083] Step 1: To a solution of compound 5a (2.00 g, 12.2 mmol, 1.00 eq) in DMF (20 mL) was added K2CO3 (5.08 g, 36.7 mmol, 3.00 eq) and the mixture was stirred at 25 °C for 1 h. 2-iodopropane (6.25 g, 36.77 mmol, 3.67 mL, 3.00 eq) was added and the mixture was stirred at 80°C for an additional 12 h. LC-MS showed compound 5a was consumed completely and the desired mass was detected. The reaction mixture was quenched by addition H2O (10 mL) and extracted with ethyl acetate (10 mL x3). The combined organic layers were washed with NaCl (10 mL x2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was triturated with ethyl acetate (10 mL) at 25 °C for 30 min. Compound 5b (1.4 g, 6.82 mmol, 55.6% yield) was obtained as a yellow solid. Step 2: A mixture of compound 5b (1.40 g, 6.82 mmol, 1.00 eq), compound 5c (1.51 g, 6.82 mmol, 1.00 eq) , Pd2(dba)3 (624 mg, 682 pmol, 0.10 eq), Xantphos (789 mg, 1.36 mmol, 0.20 eq), and CS2CO3 (4.44 g, 13.6 mmol, 2.00 eq) in dioxane (20 mL) was degassed and purged with N2 3 times and stirred at 115 °C for 12 hrs under an N2 atmosphere. TLC showed compound 5b was consumed completely and a major spot was detected. The reaction mixture was filtered and quenched by addition H2O (50 mL) and extracted with Ethyl acetate (50 mLx3). The combined organic layers were washed with saturated NaCl (20 mLx2) solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD06-Waters Xbidge C18 150*40*10um; mobile phase: [water (NFUHCChj-ACN]; gradient: 42%-72% B over 10 min). Compound 5 (366 mg, 1.01 mmol, 14.81% yield, 98% purity) was obtained as a yellow solid.!H NMR: (400 MHz, DMSO) d ppm 8.33 (d, 7=8.50 Hz, 1 H), 7.93 (d, 7=8.13 Hz, 1 H), 7.83 (d, 7=8.0 Hz, 1 H), 7.69 (d, 7=1.25 Hz, 1 H), 7.54 - 7.62 (m, 1 H), 7.47 (d, 7=8.38 Hz, 1 H), 6.90 - 6.95 (m, 2 H), 4.76 (m, 1 H), 4.04-3.73(brs, 2 H), 3.25(s, 1 H), 2.61 (s, 3 H), 1.31 (d, 7=6.00 Hz, 6 H)

[0084] Procedure for preparation of Compound 6

[0085] Step 1: The first reaction step was run by flow chemistry. Compound 6a (5.00 g, 30.2 mmol, 1.00 eq) in dimethylamine (13.6 g, 302 mmol, 15.3 mL, 10.0 eq) and THF (2 mL) was pumped to a flow reactor (SS, Coils reactor, 3.175(1 / 8”) mm, 120.75 mL, 240 °C). The residence time was 150 min. The pressure was set at 3 MPa and flow rate was 0.805 mL / min. After 150 min, the mixture was collected with a bottle. TLC (Petroleum ether: ethyl acetate=0: 1) showed about 50% of the desired mass was detected. The reaction mixture was filtered and extracted with ethyl acetate (50 mL x3). The combined organic layers were washed with saturated NaCl solution (20 mL x2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate=3 / l to 0 / 1). Compound 6b (0.60 g, 3.07 mmol, 10.1% yield, 97.2% purity) was obtained as a brown solid. Step 2: A mixture of compound 6b (0.60 g, 3.15 mmol, 1.00 eq), compound 6c (700 mg, 3.15 mmol, 1.00 eq), Pd2(dba)3 (433 mg, 473 pmol, 0.15 eq), XantPhos (364 mg, 630 pmol, 0.20 eq), and CS2CO3 (2.06 g, 6.31 mmol, 2.00 eq) in dioxane (5 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 110 °C for 12 hr under an N2 atmosphere. LC-MS showed compound 6b was consumed completely and the desired mass was detected. The reaction mixture was filtered and extracted with H2O (50 mL) and ethyl acetate (50 mL x3). The combined organic layers were washed with saturated NaCl solution (20 mL x2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD06-Waters Xbidge C18 150*40*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 40%-70% B over 10 min). Compound 6 (0.205 g, 609.97 pmol, 69.71% yield, 98.61% purity) was obtained as a yellow solid.JH NMR: (400 MHz, DMSO) 3 ppm 8.30 (d, 7=8.50 Hz, 1 H), 7.86 - 7.94 (m, 1 H), 7.63 - 7.76 (m, 2 H), 7.52 - 7.59 (m, 1 H), 7.45 (d, 7=8.50 Hz, 1 H), 6.69 (d, 7=8.76, 1 H), 6.61 (d, 7=2.00 Hz, 1 H), 3.62 - 4.26 (m, 2 H), 3.11 - 3.22 (m, 2 H), 3.02 (s, 6 H), 2.61 (s, 3 H)

[0086] Procedure for preparation of Compound 7

[0087] Step 1: To a solution of compound 7a (0.30 g, 1.70 mmol, 1.00 eq) in toluene (20 mL) and H2SO4 (0.80 mL) was added NaNa (140 mg, 2.15 mmol, 1.26 eq). The mixture was stirred at 60 °C for 4 hrs. LC-MS showed compound 7a was consumed completely and the desired mass was detected. The reaction mixture was adjusted to pH>7 with 2M NaOH solution, quenched with NaClO aqueous solution (100 mL), and extracted with ethyl acetate (50 mx3). The combined organic layers were washed with saturated NaCl (20 mL x2) solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / ethyl acetate=l / l to 0 / 1). Compound 7b (300 mg, 1.57 mmol, 46.0% yield) was obtained as a yellow solid. Step 2: A mixture of compound 7b (0.30 g, 1.57 mmol, 1.00 eq), compound 7c (348 mg, 1.57 mmol, 1.00 eq) , Pd2(dba)3 (215 mg, 235 pmol, 0.15 eq), XantPhos (272 mg, 470 pmol, 0.30 eq), and CS2CO3 (1.02 g, 3.14 mmol, 2.00 eq) in dioxane (5 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 110 °C for 12 hrs under an N2 atmosphere. LC-MS showed compound 7b was consumed completely and the desired mass was detected. The reaction mixture was filtered and extracted with ethyl acetate (50 mL x3). The combined organic layers were washed with saturated NaCl solution (20 mL x2), dried overNa2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD06-Waters Xbidge C18 150*40*10um; mobile phase:[water (NtLHCChj-ACN]; gradient: 42%-72% B over 10 min). Compound 7 (271 mg, 814 pmol, 51.9% yield, 100% purity) was obtained as a white solid.!H NMR: (400 MHz, DMSO) d ppm 8.33 (d, 7=8.38 Hz, 1 H), 7.93 (dd, 7=8.13, 1.25 Hz, 1 H), 7.72 (dd, 7=7.32, 1.31 Hz, 1 H), 7.55 - 7.62 (m, 1 H), 7.47 (d, 7=8.38 Hz, 1 H), 7.35 (d, 7=7.63 Hz, 1 H), 7.04 (d, 7=7.63 Hz, 1 H), 3.69 - 3.98 (m, 5 H), 3.03 - 3.31 (m, 2 H), 2.60 (s, 3 H), 2.24 (s, 3 H)

[0088] Procedure for preparation of Compound 8

[0089] Step 1: To a solution of compound 8a (10.0 g, 37.9 mmol, 1.00 eq) in CCU (100 mL) was added BPO (459 mg, 1.90 mmol, 0.05 eq) and NBS (6.75 g, 37.9 mmol, 1.00 eq) and the mixture was stirred at 85 °C for 12 hrs. LCMS showed compound 8a was consumed completely and the desired mass was detected. The reaction mixture was quenched by addition H2O (20 mL) and extracted with DCM (20 mL x3). The combined organic layers were washed with saturated NaCl (120 mL x2) solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate=l / O to 20 / 1). Compound 8b (11.0 g, 32.1 mmol, 84.6% yield) was obtained as a yellow oil. Step 2: To a solution of compound 8b (8.00 g, 23.3 mmol, 1.00 eq) in EtOH (100 mL) and H2O (10 mL) was added NaCN (0.87 g, 17.7 mmol, 0.76 eq) at 0 °C. The mixture was stirred at 20 °C for 12 hrs. LC-MS showed compound 8b was consumed completely and the desired mass was detected. The reaction solution was adjusted to pH>7 with NaOH and extracted with Ethyl acetate (50 mL x3). The combined organic layers were washed with saturated NaCl (50 mL x2) solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S i O2, Petroleum ether / Ethyl acetate=l / O to 20 / 1).

[0090] Compound 8c (1.89 g, 6.55 mmol, 28.0 % yield) was obtained as a white solid. Step 3: Compound 8c (1.80 g, 6.24 mmol, 1.00 eq) was dissolved in a mixed solution of THF (20 mL) and MeOH (10 mL), and COQ2.6H2O (2.97 g, 12.4 mmol, 2.00 eq) and NaBPE (1.47 g, 38.8 mmol, 6.23 eq) were added at 0 °C. The mixture was stirred at 20 °C for 1 hr. LC-MS showed compound 8c was consumed completely and the desired mass was detected. The reaction mixture was cooled to 0~5 °C and quenched drop-wise with saturated aqueous NH4CI (30 mL). After addition, the resulting mixture was stirred at 0~5 °C for 0.5 h, then slowly warmed to room temperature and extracted with ethyl acetate (50 mL x3). The combined organic layers were washed with saturated NaCl aqueous (20 mL x2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=2 / l to 0 / 1). Compound 8d (0.680 g, 2.61 mmol, 41.8% yield) was obtained as a white solid. Step 4: To a solution of compound 8d (0.60 g, 2.30 mmol, 1.00 eq) in H2O (2 mL) and dioxane (10 mL) was added MeBF3'K+(1.12 g, 9.21 mmol, 4.00 eq), K2CO3 (954 mg, 6.91 mmol, 3.00 eq), and Pd(dppf)Ch (168 mg, 230 pmol, 0.10 eq) under nitrogen. The mixture was stirred at 110 °C for 2 hrs. LC-MS showed compound 8d was consumed completely and the desired mass was detected. The reaction mixture was filtered and extracted with Ethyl acetate (50 mL x3). The combined organic layers were washed with saturated NaCl (20 mL x2) aqueous, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate=l / l to 0 / 1). Compound 8e (450 mg, 2.30 mmol, 99.8% yield) was obtained as a yellow oil. Step 5: A mixture of compound 8e (0.40 g, 2.04 mmol, 1.00 eq), compound 8f (454 mg, 2.04 mmol, 1.00 eq), Pd2(dba)3 (187 mg, 2.04 pmol, 0.10 eq), XantPhos (213 mg, 817 pmol, 0.40 eq), and CS2CO3 (2.00 g, 6.13 mmol, 3.00 eq) in dioxane (10 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 110 °C for 12 hr under an N2 atmosphere. LC- MS showed compound 8e was consumed completely and the desired mass was detected. The reaction mixture was filtered and extracted with Ethyl acetate (50 mL x3). The combined organic layers were washed with saturated NaCl solution (20 mL x2), dried overNa2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD02-Waters Xbidge BEH C18 150*25*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 40%-70% B over 10 min). Compound 8 (85 mg, 242 pmol, 11.8% yield, 96.2% purity) was obtained as a yellow solid. NMR: (400 MHz, DMSO) 3 ppm 8.32 (d, 7=8.50 Hz, 1 H), 7.93 (d, 7=8.13, 1 H), 7.71 (d, 7=7.32, 1 H), 7.55 - 7.61 (m, 1 H), 7.47 (d, 7=8.50 Hz, 1 H), 7.29 (s, 1 H), 7.21 (s, 1 H), 3.74 - 3.97 (m, 2 H), 3.05 - 3.26 (m, 2 H), 2.63 (s, 3 H), 2.36 (s, 3 H)

Claims

CLAIMSWhat is claimed is:

1. A compound represented by Formula (I):or a pharmaceutically acceptable salt thereof, wherein:X is O, NR3, or SY1, Y2, Y3, and Y4are independently selected from CR2, and N, wherein at least two of Y1, Y2, Y3, and Y4are CR2;R1is selected from the group consisting of H, halogen, Ci-ealkyl, Ci-ehaloalkyl, and Ci-6alkoxy; each R2is independently selected from the group consisting of H, halogen, C i -ealky 1, Ci-6haloalkyl, Ci-6alkoxy, -CN, -OH, -NO2, -NR2aR2b, -OR4, -C(O)R4, -C(S)R4, -C(O)OR4, -OC(O)R4, -C(O)NR2aR2b, -C(S)NR2aR2b, -OC(O)NR2aR2b, -SR4, -S(O)R4, -S(O)2R4, -SO2NR2aR2b, -NR4C(O)R4, -NR4C(O)OR4, -NR4C(O)NR2aR2b, -NR4SO2NR2aR2b, and -NR4SO2R4;R2aand R2bare each independently hydrogen, Ci-ealkyl or Ci-ealkyl substituted with - OH or Ci -3 alkoxy; orR2aand R2btogether with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl;R3is H or Ci-ealkyl; each R4is independently selected from the group consisting of H and Ci-ealkyl, wherein said Ci-ealkyl is optionally substituted with -OH or Ci-aalkoxy; and m is 1 or 2.

2. The compound of claim 1, wherein the compound is represented by Formula (la):or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound is represented by Formula (lb):or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein X is O.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R1is Ci -ealkyl.

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

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Y1, Y2, Y3, and Y4is CR2.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein each R2is independently selected from the group consisting of H, halogen, Ci-6alkyl,Ci-6haloalkyl, Ci-6alkoxy, NR2aR2b, CN, and NO2.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein each R2is independently selected from the group consisting of H, halogen, Ci-6alkyl,Ci-6alkoxy, and NR2aR2b.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each R2is independently selected from the group consisting of H, Cl, methyl, -OCH3,-OCH(CH3)2, and N(CH3)2.

11. The compound of any one of claims 1-10, wherein the compound is represented by a compound in Table 1, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

13. A method of treating a disease or disorder mediated by sarcoplasmic / endoplasmic reticulum Ca2+ATPase (SERCA) in a subject, comprising administering to a subject an effective amount of a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 12.

14. The method of claim 13, wherein the disease or disorder is a heart disease, stroke, stenosis, restenosis, a disease associated with vascular smooth muscle cell proliferation, a disease associated with neointima formation, a disease associated with calcineurin PP2B, a disease associated with NF AT, arteriovenous fistula failure, a cardiac disease, a disease associated with a cardiac disease, urinary incontinence, cancer, asthma, pulmonary hypertension, chronic obstructive pulmonary disease, diabetes, a neurodegenerative disease, bipolar disorder, atherosclerosis, muscle degeneration, or an autoimmune disease.

15. The method of claim 14, wherein the disease or disorder is diabetes.

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

17. The method of claim 15, wherein the diabetes is type 2.

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