Flavone therapeutics

Abstract

Compounds, and pharmaceutically acceptable salts thereof, useful as to treat a disease or disorder affecting cartilage and bone, neural tissue, connective tissue, and internal organ or peripheral tissue are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various diseases or disorders, such as inflammatory diseases or disorders.

Description

Attorney Docket No.93033-425510 FLAVONE THERAPEUTICS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 657,642, filed June 7, 2024. The entire contents of that application are hereby incorporated by reference herein. BACKGROUND

[0002] Continual exposure to exogenous and endogenous sources of reactive oxygen species (ROS) and other oxidants have both beneficial and deleterious effects on the cell. ROS play important roles in a wide range of physiological processes; however, high ROS levels are associated with oxidative stress, redox imbalance, and disease progression. Oxidative stress has been implicated in nearly all major human diseases, from inflammatory disorders, autoimmune diseases, neurogenerative diseases, and cardiovascular diseases to diabetes and cancer. Antioxidant defense systems have evolved as a means of protection against oxidative stress, with the transcription factor Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) as the key regulator. Nrf2 is responsible for regulating an extensive panel of antioxidant enzymes involved in the detoxification and elimination of oxidative stress. Nrf2-mediated antioxidant capabilities have been demonstrated to prevent and treat multiple diseases, including chronic inflammatory diseases characterized by persistent inflammation.

[0003] Patients develop a chronic inflammatory disease because the immune system has an inappropriate response or an over-response to something it has been exposed to. In some cases, this means that the patient develops an autoimmune disease, in which the immune system starts to attack the body. In other instances, the patient experiences chronic inflammation in response to certain foods or environmental factors. The inflammation and associated symptoms may come and go, and many diseases often resist treatment. Some chronic inflammatory diseases impact cartilage and bone, neural tissues, connective tissues, and internal organs or peripheral tissues.

[0004] Inflammation as well as cartilage pain, musculoskeletal (bone) pain, and arthritic pain associated with inflammation are a major problem for many. Pain stemming from these conditions is associated with aberrant inflammation. Examples of cartilage and bone diseases and disorders associated with inflammation and redox potential include osteoarthritis, gout, and rheumatoid arthritis.

[0005] Particularly problematic is osteoarthritis (OA), which is a chronic disease affecting over 27 million people in the United States (U.S.) among many others around the world. Osteoarthritis is recognized to be a multifactorial disease associated with risk factors such as obesity, joint-loading, acute injury, aging and joint misalignment. The incidence of osteoarthritis is increasing significantly as obesity rates increase and the mean age of the population advances. 1Attorney Docket No.93033-425510

[0006] Osteoarthritis is a heterogeneous disease. The metabolic subtype is distinguishable by the presence of its major causative features, adipokines, hyperglycaemia and hormonal imbalance, and its prevalence in middle-aged people. The mechanical subtype means that it is related to movement and physical forces or is caused by these. For example, mechanical osteoarthritis is a joint's pathophysiological response to a mechanical injury, i.e. increased physical force in localized areas of a joint.

[0007] Equine osteoarthritis or degenerative joint disease, is a very common condition in horses of all ages and disciplines. Like in humans, it can lead to damage and deterioration of the surrounding soft tissues, cartilage, and bone if this condition becomes chronic. There is no cure for this degenerative disease process, and current treatments focus on pain management to lengthen the athletic careers of horses.

[0008] Traditionally, osteoarthritis has been treated with over-the-counter (OTC) anti-inflammatory drugs like ibuprofen, aspirin or acetaminophen. While these drugs have a role to play in the management of OA symptoms, unfortunately, a systemic approach with these drugs and other anti-inflammatory agents can have serious adverse side effects. For example, long-term use of ibuprofen can lead to severe problems with the liver and kidneys or even an erosion of the stomach lining (known as gastritis). This last symptom can result in internal bleeding. Other available drugs on the market run into different problems.

[0009] Treatments such as menthol, camphor, wintergreen or capsaicin work by stimulating nerves in the applied area but the result is a temporary cessation of pain that later returns. Other technologies like lidocaine and skin patches only mask the symptoms of osteoarthritis.

[0010] The general management of osteoarthritis has revolved around suppressing its symptoms and keeping the pain at bay. This has meant, however, dealing with medications that provide temporary pain relief at the cost of unwanted side effects. Without addressing the root cause of the pain, the chronic inflammation of OA is lessened but never gone. There are limited options for the safe and effective treatment of conditions stemming from cartilage and musculoskeletal (e.g. bone) pain.

[0011] Gout is a common and complex form of arthritis. It is characterized by sudden, severe attacks of pain, swelling, redness, and tenderness in one or more joints, most often in the big toe. An attack of gout can occur suddenly, and gout symptoms may come and go.

[0012] Rheumatoid arthritis is a chronic inflammatory disorder that can affect more than just your joints. In some people, the condition can damage a wide variety of body systems, including the skin, eyes, lungs, heart and blood vessels. Early rheumatoid arthritis tends to affect smaller joints first, particularly the joints of hands and feet. As the disease progresses, symptoms often spread to the wrists, knees, ankles, elbows, hips and shoulders. Rheumatoid arthritis signs and symptoms may vary in severity and may even come and go. Periods of increased disease activity, called flares, alternate with periods of relative remission, when the swelling and pain fade or disappear. 2Attorney Docket No.93033-425510

[0013] Inflammation of connective tissues as well as associated symptoms can be a major problem for many. Examples of connective tissue and related diseases and disorders associated with inflammation and redox potential include psoriasis and psoriatic arthritis, atopic dermatitis (eczema), and lupus.

[0014] Psoriasis is a common, long-term (chronic) disease with no cure. It can be painful, interfere with sleep and make it hard to concentrate. The condition tends to go through cycles, flaring for a few weeks or months, then subsiding for a while. Psoriatic arthritis is a form of arthritis that affects some people who have psoriasis, a disease that causes red patches of skin topped with silvery scales. Most people develop psoriasis years before being diagnosed with psoriatic arthritis. Fr some, however, the joint problems begin before skin patches appear or at the same time. Joint pain, stiffness and swelling are the main signs and symptoms of psoriatic arthritis. They can affect any part of the body, including your fingertips and spine, and can range from relatively mild to severe. Both psoriatic arthritis and psoriasis are chronic diseases that worsen over time, and disease flares can alternate with periods of remission.

[0015] Atopic dermatitis (eczema) is a condition that causes dry, itchy and inflamed skin. It is common in young children but can occur at any age. Atopic dermatitis is long lasting (chronic) and tends to flare sometimes. Psoriasis is a skin disease that causes a rash with itchy, scaly patches, most commonly on the knees, elbows, trunk and scalp.

[0016] Systemic lupus erythematosus (lupus) is an autoimmune disease. Inflammation caused by lupus can affect many different body systems, including joints, skin, kidneys, blood cells, brain, heart and lungs. Signs and symptoms may come on suddenly or develop slowly, may be mild or severe, and may be temporary or permanent. Most people with lupus have mild disease characterized by flares that alternate with periods of remission.

[0017] Inflammation of neural tissue in the brain and spinal cord can be the result of injury or acquired diseases or disorders of the nervous system that affect. Examples of neural tissue and related diseases and disorders associated with inflammation and redox potential include amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, Multiple Sclerosis, Retinitis Pigmentosa, glaucoma, retinoblastoma, and traumatic brain injury (TBI).

[0018] ALS, Parkinson's disease, Alzheimer ’s disease, Huntington’s disease, Friedreich Ataxia, and Multiple Sclerosis are progressive degenerative disorders. ALS often begins with muscle twitching and weakness in an arm or leg, trouble swallowing or slurred speech. Eventually, ALS affects control of the muscles needed to move, speak, eat and breathe. Parkinson's disease often begins with a slow onset of symptoms. Common symptoms are tremors and slurred speech, but the disorder may also cause stiffness or slowing of movement. Alzheimer's disease is characterized by changes in the brain that lead to deposits of certain proteins. Alzheimer's disease is the most common cause of dementia, a gradual decline in memory, thinking, behavior and social skills. Huntington's disease is a rare, often inherited disease that causes nerve 3Attorney Docket No.93033-425510 cells in the brain to decay over time. The disease affects a person's movements, thinking ability and mental health. Friedreich Ataxia (FA) is a rare, inherited disorder that can cause movement and sensory symptoms and trouble with walking and gait. In FA, nerve fibers in the spinal cord and peripheral nerves break down, becoming thinner. Multiple sclerosis (MS) is an autoimmune disease. Some people with severe MS may lose the ability to walk independently or ambulate at all. Other individuals may experience long periods of remission without any new symptoms depending on the type of MS they have.

[0019] Retinitis pigmentosa, glaucoma, and retinoblastoma are progressive degenerative ocular disorders. Retinitis pigmentosa is affects the retina and causes loss of night and side vision. Glaucoma is a heterogeneous group of ocular disorders including juvenile open-angle glaucoma (JOAG) and primary open-angle glaucoma (POAG) that alters visual acuity due to the loss of optic nerve function. Mutations within myocilin are associated with up to 36% of JOAG and 4% of POAG cases, which can be considered myocilin-associated glaucoma. Retinoblastoma is an eye cancer that starts as a growth of cells in the retina.

[0020] Traumatic brain injury usually results from acute injury, such as a violent blow or jolt to the head or body. A direct injury to brain tissue, such as a bullet or shattered piece of skull, also can cause traumatic brain injury. Mild traumatic brain injury may affect your brain cells temporarily, and more- serious traumatic brain injury can result in bruising, torn tissues, bleeding and other physical damage to the brain.

[0021] Inflammation of internal organs and peripheral tissues as well as associated symptoms can be a major problem for many. Examples of internal organ and peripheral tissue diseases and disorders associated with inflammation and redox potential include cardiovascular disease, restenosis and atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), Celiac’s disease, and type II diabetes.

[0022] Cardiovascular diseases are conditions that affect the structures or function of your heart and blood vessels. Also known as heart disease, cardiovascular disease refers to the following 4 entities: coronary artery disease (CAD) which is also referred to as coronary heart disease (CHD), cerebrovascular disease, peripheral artery disease (PAD), and aortic atherosclerosis. Cardiovascular disease is the leading cause of death in the U.S.

[0023] Stenosis, which includes atherosclerosis and restenosis, is the medical term for the narrowing of a blood vessel, which is made of connective tissue. Connective tissue supports many different parts of your body, such as the heart. Restenosis occurs when an artery that was opened with a stent or angioplasty becomes narrowed again. Atherosclerosis is the buildup of fatty deposits and cholesterol inside of your arteries. This buildup can limit the blood supply to your heart. Stents are often put in place to open the artery so blood can flow freely to the heart again; however, when this area narrows again, restenosis results. 4Attorney Docket No.93033-425510

[0024] Chronic obstructive pulmonary disease is a chronic inflammatory lung disease that causes obstructed airflow from the lungs. People with COPD are at increased risk of developing diseases of internal organs and peripheral tissue such as heart disease, lung cancer, and a variety of other conditions. COPD is a progressive disease, and symptoms often don't appear until significant lung damage has occurred.

[0025] Inflammatory bowel disease is a term that describes disorders involving long-standing (chronic) inflammation of tissues in your digestive tract. Types of IBD include ulcerative colitis and Crohn’s disease. Ulcerative colitis involves inflammation and sores (ulcers) along the lining of your large intestine (colon) and rectum. Crohn's disease is characterized by inflammation of the lining of your digestive tract, which often can involve the deeper layers of the digestive tract. Crohn's disease most commonly affects the small intestine. For some people, IBD is only a mild illness. For others, it's a debilitating condition that can lead to life-threatening complications.

[0026] Celiac’s disease is an illness caused by an immune reaction to gluten. Gluten is a protein found in foods containing wheat, barley or rye. Eating gluten triggers an immune response to the gluten protein in your small intestine. Over time, this reaction damages the small intestine's lining and prevents it from properly absorbing nutrients.

[0027] Type II diabetes used to be known as adult-onset diabetes, but both type I and type II diabetes can begin during childhood and adulthood. Type II is more common in older adults, but the increase in the number of children with obesity has led to more cases of type II diabetes in younger people. Low-grade inflammation is a common feature in subjects with type II diabetes (T2D) and is associated with the development and progression of long-term complications such as nephropathy, neuropathy and retinopathy. Moreover, low-grade inflammation is associated with cardiovascular disease in diabetes, which is the primary cause of morbidity and mortality in individuals with type 2 diabetes. There's no cure for type 2 diabetes; however, losing weight, eating well and exercising can help manage the disease.

[0028] The general management of inflammatory diseases has revolved around suppressing symptoms. This strategy, however, involves using medications that provide temporary relief at the cost of unwanted side effects. Without addressing the root cause of the inflammation, the associated symptoms of chronic inflammation is lessened but never gone.

[0029] Therefore, there is unmet medical need to develop new therapeutic compounds, such as flavone and flavonoid derivatives, that can selectively treat, prevent, or slow progression of symptoms associated with any one or more of the foregoing diseases or disorders of cartilage and bone, connective tissue, neural tissue, and internal organ and peripheral tissue with good in vivo efficacy, safety, and pharmacokinetic profiles for treating patients. 5Attorney Docket No.93033-425510 SUMMARY

[0030] In one aspect, compounds of formula (I), or pharmaceutically acceptable salts thereof, are described herein: I), wherein each of X1, Y, R6, R7, R8, and R

[0031] In another aspect, compounds of formula (II), or pharmaceutically acceptable salts thereof, are described herein: I), wherein each of X1, R1, R6, R7, R8, R9,

[0032] In another aspect, compounds of formula (III), or pharmaceutically acceptable salts thereof, are described herein: I), wherein each of Y, R6, R7, and R9is def

[0033] In another aspect, compounds of formula (IV), or pharmaceutically acceptable salts thereof, are described herein: ), wherein each of Y, R6, and R7is define

[0034] In another aspect, compounds of formula (I), (II), (III), and (IV) in a non-salt form are disclosed.

[0035] In another aspect, compounds of formula (I), (II), (III), and (IV) and pharmaceutically acceptable salts are disclosed. 6Attorney Docket No.93033-425510

[0036] In another aspect, a pharmaceutical composition of a therapeutically effective amount of a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles is disclosed.

[0037] In another aspect, a pharmaceutical composition of a therapeutically effective amount of a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof is disclosed.

[0038] In another aspect, a method of modulating inflammation in a subject by administering to the subject a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof is disclosed.

[0039] In another aspect, a method of treating pain in a subject by administering to the subject a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof is disclosed.

[0040] In another aspect, a method of treating or preventing a disease or disorder in a subject by administering to the subject a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof is disclosed. The disease or disorder may include any one or more of a disease or disorder selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, traumatic brain injury, cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease, inflammatory bowel disease, Celiac’s disease, and type II diabetes.

[0041] In another aspect, a method of modulating inflammation in a subject by administering a compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is disclosed.

[0042] In still another aspect, a method of treating pain in a subject by administering to the subject the compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is disclosed.

[0043] In still another aspect, a method of treating or preventing a disease or disorder in a subject by administering to the subject the compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is disclosed. The disease or disorder may include any one or more of a disease or disorder selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa, glaucoma, retinoblastoma, traumatic brain injury, cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease, inflammatory bowel disease, Celiac’s disease, and type II diabetes. 7Attorney Docket No.93033-425510

[0044] In another aspect, a method of modulating inflammation in a subject by administering a compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, including a therapeutically effective amount of the compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and one or more pharmaceutically acceptable carriers or vehicles is disclosed.

[0045] In another aspect, a method of treating pain in a subject by administering a compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, including a therapeutically effective amount of the compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and one or more pharmaceutically acceptable carriers or vehicles is disclosed.

[0046] In another aspect, a method of treating or preventing a disease or disorder in a subject by administering a compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, including a therapeutically effective amount of the compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and one or more pharmaceutically acceptable carriers or vehicles is disclosed. The disease or disorder may include any one or more of a disease or disorder selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa, glaucoma, retinoblastoma, traumatic brain injury, cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease, inflammatory bowel disease, Celiac’s disease, and type II diabetes.

[0047] In another aspect, a use of a compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, including a therapeutically effective amount of the compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and one or more pharmaceutically acceptable carriers or vehicles, as a medicament is disclosed.

[0048] In another aspect, a use of a compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, including a therapeutically effective amount of the compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and one or more pharmaceutically acceptable carriers or vehicles, in the manufacture of a medicament is disclosed.

[0049] In another aspect, a use of a compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, including a therapeutically effective amount of the compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a 8Attorney Docket No.93033-425510 pharmaceutical composition thereof, and one or more pharmaceutically acceptable carriers or vehicles, in the manufacture of a medicament for the modulation of inflammation is disclosed.

[0050] In another aspect, a use of a compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, including a therapeutically effective amount of the compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and one or more pharmaceutically acceptable carriers or vehicles, in the manufacture of a medicament for treating pain is disclosed.

[0051] In another aspect, a use of a compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, including a therapeutically effective amount of the compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and one or more pharmaceutically acceptable carriers or vehicles, in the manufacture of a medicament for treating or preventing a disease or disorder is disclosed. The disease or disorder may include any one or more of a disease or disorder selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa, glaucoma, retinoblastoma, traumatic brain injury, cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease, inflammatory bowel disease, Celiac’s disease, and type II diabetes.

[0052] In yet another aspect, a method of treating cancer by administering the compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject is disclosed.

[0053] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, illustrative methods and materials are now described. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0054] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. The references cited herein are not admitted to be prior art to the application. 9Attorney Docket No.93033-425510 BRIEF DESCRIPTIONS OF THE FIGURES

[0055] The detailed description particularly refers to the accompanying figures in which:

[0056] Fig.1 shows a graph of the total glutathione, glutathione, including reduced glutathione (GSH) and oxidized glutathione (GSSG), in HepG2 cells after treatment of compound 24.

[0057] Fig. 2 shows a graph of the redox potential (Eh), reduced glutathione (GSH) / oxidized glutathione (GSSG), in HepG2 cells after treatment of compound 24.

[0058] Fig.3A shows a graph of hepatic glutathione dynamics showing total glutathione, including reduced glutathione (GSH) and oxidized glutathione (GSSG), over 72 hours following treatment with 5 mg / kg of compound 24.

[0059] Fig.3B shows a graph of hepatic glutathione dynamics showing glutathione redox potential (Eh), reduced glutathione (GSH) / oxidized glutathione (GSSG), over 72 hours following treatment with 5 mg / kg of compound 24.

[0060] Fig.4A shows a graph of hepatic glutathione dynamics showing total glutathione, including reduced glutathione (GSH) and oxidized glutathione (GSSG), over 72 hours following treatment with 5 mg / kg of compound 24.

[0061] Fig.4B shows a graph of hepatic glutathione dynamics showing glutathione redox potential (Eh), reduced glutathione (GSH) / oxidized glutathione (GSSG), over 72 hours following treatment with 5 mg / kg of compound 24.

[0062] Fig.5 shows a graph of hepatic glutathione dynamics to dose response showing total glutathione, including reduced glutathione (GSH) and oxidized glutathione (GSSG), over 24 hours following treatment with varying concentrations of compound 24.

[0063] Fig.6 shows a graph of the oxygen consumption rate (OCR) track with time. Cells were cultivated in the absence (control) or presence of 200 µM compound 24.

[0064] Fig.7 shows the maximal OCR of cells that were cultivated in the absence (control) or presence of 200 uM compound 24.

[0065] Fig.8 shows a graph of mitochondrial ATP production measured by luciferin–luciferase. Cells were cultivated in the absence (control) or presence of 200 µM, 100 µM, and 50 µM compound 24, or 50 nM omaveloxolone (OMA, Skyclarys).

[0066] Fig.9 shows a graph of the toxicity of compound 24 compared to omaveloxolone (Skyclarys).

[0067] Fig. 10 shows a graph of radical oxygen species (ROS) generation compared to edaravone (Radicava) and omaveloxolone (Skyclarys).

[0068] Fig. 11 shows a graph of GCLC protein expression of compound 24 normalized to B-actin. Column height represents intensity of signal in western blot. 10Attorney Docket No.93033-425510

[0069] Fig.12 shows images of the expression of GCLC and B-actin at 6, 24, and 48 hours (duplicates) used to generate Fig.11.

[0070] Fig. 13 shows a graph of brain glutathione concentration showing total glutathione, including reduced glutathione (GSH) and oxidized glutathione (GSSG), over 72 hours following treatment with 5 mg / kg of compound 24.

[0071] Fig. 14 shows a graph of neurofilament-A plasma concentrations in ALS mice following treatment of compound 24.

[0072] Fig.15 shows a graph of the mean life extension in ALS mice following treatment of compound 24. DETAILED DESCRIPTION

[0073] The present application describes useful flavone and flavonoid compounds and derivatives with pharmaceutical properties, including compounds with anti-inflammatory, antibacterial, anticancer, anti- arthritis, and anti-stroke activities. These features may results in development of an improved therapeutic with anticancer and / or anti-inflammatory activities, or an improved therapeutic for treating or preventing a disease or disorder selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, traumatic brain injury (TBI), cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes. Successful drug discovery relies on the selection of drug candidates with good in vivo pharmacokinetic (PK) properties, as well as appropriate preclinical efficacy and safety profiles.

[0074] In one aspect, the disclosure relates to a compound of formula (I): I), or a pharmaceutically acceptable salt thereNR11; Y is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocyclyl, or 5- to 12-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocyclyl, or 5- to 12-membered heteroaryl is independently optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy; R6is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R7is halogen, hydroxy, RA, 11Attorney Docket No.93033-425510 C1-C6haloalkyl, or C1-C6alkoxy; or two of R6and R7taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12; each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; p is 1, 2, or 3; provided that: (i) R6and R7are not the same, or two of R6and R7taken together with the carbon atoms to which they are bound; (ii) if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy; (iii) Y is not 3-pyridyl; and (iv) if R7and R9is OH, then Y is not unsubstituted phenyl.

[0075] In one aspect, the disclosure relates to a compound of formula (I): I), or a pharmaceutically acceptable salt there NR11; Y is C1-C6alkyl, C3-C10cycloalkyl,C6-C10aryl, 6- to 8-membered heterocycloalkyl, or 5- to 12-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocycloalkyl, or 5- to 12- membered heteroaryl is independently optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy; R6is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R7is halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; or two of R6and R7taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; RAis -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12; RBis -C(O)R12, -C(O)OR12, or -C(O)NR12R13; p is 1, 2, or 3; provided that: (i) R6and R7are not the same, or two of R6and R7taken together with the carbon atoms to which they are bound; (ii) if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy; and (iii) Y is not 3-pyridyl.

[0076] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University 12Attorney Docket No.93033-425510 Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry,” 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. As used herein, the terms “compounds of the invention,” “compounds of the disclosure,” and “compounds as described herein” refer to the compounds of formulas (I)-(IV), and all of the embodiments thereof, as described herein, and to the compounds identified in Table A.

[0077] As described herein, the compounds as described herein comprise multiple variable groups (e.g., Y, X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, RA, RB, n, m, p, etc.). As one of ordinary skill in the art will recognize, combinations of groups envisioned by this disclosure are those combinations that result in the formation of stable or chemically feasible compounds. The term “stable,” in this context, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40^C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0078] As used herein, the term “halo” or “halogen” means fluoro, chloro, bromo, or iodo, each of which may be used interchangeably with the terms F, Cl, Br or I, respectively.

[0079] As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having the specified number of carbon atoms, which is attached to the rest of the molecule by a single bond. In some embodiments, it can be advantageous to limit the number of atoms in an “alkyl” to a specific range of atoms, such as C1-C20alkyl, C1-C12alkyl, or C1-C6alkyl. For example, a “C1-C6alkyl” group is an alkyl group having between one and six carbon atoms. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. It will be appreciated that an alkyl can be unsubstituted or substituted as described herein.

[0080] As used herein, the term “alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, and having the specified number of carbon atoms, which is attached to the rest of the molecule by a single bond. In some embodiments, it can be advantageous to limit the number of atoms in an “alkenyl” to a specific range of atoms, such as C2-C20alkenyl, C2-C12alkenyl, or C2-C6alkenyl. For example, a “C2-C6alkenyl” group is an alkenyl group having between two and six carbon atoms. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl. Included within this term are cis and trans isomers and 13Attorney Docket No.93033-425510 mixtures thereof. It will be appreciated that an alkenyl can be unsubstituted or substituted as described herein.

[0081] As used herein, the term “cycloalkyl” refers to a stable, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, having the specified number of carbon ring atoms, and which is attached to the rest of the molecule by a single bond. In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” to a specific range of atoms, such as having 3 to 12 ring atoms. For example, a “C3-C8cycloalkyl” group is a cycloalkyl group having between three and eight carbon atoms. Examples of cycloalkyl groups include cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. It will be appreciated that a cycloalkyl can be unsubstituted or substituted as described herein.

[0082] As used herein, the term “alkoxy” refers to a radical of the formula -ORawhere Rais an alkyl group having the specified number of carbon atoms. For example, a “C1-C6alkoxy” group is a radical of the formula -ORawhere Rais an alkyl group having the between one and six carbon atoms. Examples, without limitation, of alkoxy groups are methoxy and ethoxy. In some embodiments, it can be advantageous to limit the number of atoms in an “alkoxy” to a specific range of atoms, such as C2-C6alkoxy. For example, a “C2-C6alkoxy” group is an alkoxy group having between two and six carbon atoms.

[0083] As used herein, the term “haloalkyl” refers to an alkyl group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups. For example, a “C1-C6haloalkyl” group is an alkyl group having between one and six carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups. In particular, a C1haloalkyl group may be represented by any one or more of the chemical formulas of CH2F (fluoromethyl), CHF2(difluoromethyl), and CF3(trifluoromethyl).

[0084] As used herein, the term “haloalkenyl” refers to an alkenyl group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the alkenyl group are replaced by halo groups. For example, a “C1-C6haloalkenyl” group is an alkenyl group having between one and six carbon atoms, wherein one or more of the hydrogen atoms of the alkenyl group are replaced by halo groups.

[0085] As used herein, the term “haloalkoxy” refers to an alkoxy group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the of the alkyl group are replaced by halo groups.

[0086] As used herein, the term “alkylene” refers to a divalent, straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having the specified number of carbon atoms, which is attached to the rest of the molecule by two single bonds. For example, a “C1-C6alkylene” group is an alkylene group having between one and six carbon atoms. 14Attorney Docket No.93033-425510

[0087] As used herein, the term “alkenylene” refers to a divalent, straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, and having the specified number of carbon atoms, which is attached to the rest of the molecule by two single bonds. For example, a “C2-C6alkenylene” is an alkenylene group having between one and six carbon atoms.

[0088] As used herein, the term “haloalkylene” refers to an alkylene group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the alkylene group are replaced by halo groups. For example, a “C1-C6haloalkylene” group is an alkylene group having between one and six carbon atoms, wherein one or more of the hydrogen atoms of the alkylene group are replaced by halo groups.

[0089] As used herein, the term “heterocyclyl” refers to a stable, non-aromatic, mono-, bi-, or tricyclic (fused, bridged, or spiro) radical in which one or more ring atoms is a heteroatom (e.g., a heteroatom independently selected from N, O, P, and S), which has the specified number of ring atoms, and which is attached to the rest of the molecule by a single bond. Heterocyclic rings can be saturated, or can contain one or more double or triple bonds. In some embodiments, the “heterocyclyl” group has the indicated number of ring members, in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus, and each ring in the ring system contains 3 to 7 ring members. For example, a 6-membered heterocyclyl includes a total of 6 ring members, at least one of which is a heteroatom (e.g., a heteroatom independently selected from N, O, P, and S). In particular, a 6-membered heterocyclyl may be represented by a dioxane.

[0090] As used herein, the term “aryl” refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. In some embodiments, it can be advantageous to limit the number of atoms in an “aryl” to a specific range of atoms, such as mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C6-C14aryl), or monovalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C6-C10aryl). Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. It will be appreciated that an aryl group can be unsubstituted or substituted as described herein. An aryl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0091] As used herein, the term “heteroaryl” refers to a stable mono-, bi-, or tricyclic ring radical having the specified number of ring atoms, wherein at least one ring in the system is aromatic, at least one aromatic ring in the system contains one or more heteroatoms (e.g., one or more heteroatoms independently selected from N, O, P, and S). In some embodiments, each ring in the system contains 3 to 7 ring members. For example, a 6-membered heteroaryl includes a total of 6 ring members, at least one of which is a 15Attorney Docket No.93033-425510 heteroatom selected from N, S, O, and P. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”. A heteroaryl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. Illustrative examples of 6-membered heteroaryl groups include radicals of the following entities: . Illustrative examples of 5-membered heteroaryl groups includeradicals of the following entities . Illustrative examples of 10-membered heteroaryl group the following entities:. R2, R3, R4, and R are taken together with the5carbon atoms to which they are bound to form a 6-membered heteroaryl,” as used herein, can be used to refer to a structure, for example, , wherein two of R1, R2, R3, R4, and R5are taken together with the carbon atoms to whiund to form a 6-membered heteroaryl (such as pyridyl). Illustratively, a 6-membered heteroaryl structure can be depicted by the structural formula . In particular, it will be appreciated that a structural formula referring to “R2and R3are taken together with the carbon atoms to which they are bound to form a fused pyridyl” can be depicted by the structural formula . It will be appreciated that a heteroaryl group can be unsubstituted or substituted as described herein.

[0093] It will be appreciated that the phrase “two of R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl,” as used herein, can be used to refer to a 16Attorney Docket No.93033-425510 structure, for example, , wherein two of R6, and R7are taken together with the carbon atoms to which they form a 6-membered heterocyclyl. Illustratively, a 6-memberedheterocyclyl structure can be depicted by the structural formul . In particular, it will be appreciated that a structural formula referring to “R6and R7are t her with the carbon atoms towhich they are bound to form a fused dioxane” can be depicted by the structural form .

[0094] In particular, a flavone or flavonoid derivative can be depicted by th rmula, wherein Y is as defined herein.ified, the compounds as described herein, whether identified by chemical name or chemical structure, include all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), conformational isomers, and tautomers of the compounds identified by the chemical names and chemical structures provided herein. In addition, single stereoisomers, double bond isomers, conformational isomers, and tautomers as well as mixtures of stereoisomers, double bond isomers, conformational isomers, and tautomers are within the scope of the disclosure.

[0096] Certain chemical entities of formula (I)-(IV) may be depicted in two or more tautomeric forms. Any and all alternative tautomers are included within the scope of these formulas, and no inference should be made as to whether the chemical entity exists as the tautomeric form in which it is drawn. It will be understood that the chemical entities described herein can exist in different tautomeric forms. It will be readily appreciated by one of skill in the art that because of rapid interconversion, tautomers can generally be considered to be the same chemical compound. Examples of tautomers include but are not limited to enol-keto tautomers, amine-imine tautomers, and the like. 17Attorney Docket No.93033-425510

[0097] A mpound, refers to aracemic mixture of the compound.

[0098] As used herein, the prefix “rel-,” when used in connection with a chiral compound, refers to a single enantiomer of unknown absolute configuration. In a compound bearing the “rel-” prefix, the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound, but do not necessarily reflect the absolute stereochemistry of the compound. Where the relative stereochemistry of a given stereocenter is unknown, no stereochemical designator is provided.

[0099] As used herein, the term “compound,” when referring to the compounds of the disclosure, refers to a collection of molecules having identical chemical structures, except that there may be isotopic variation among the constituent atoms of the molecules. The term “compound” includes such a collection of molecules without regard to the purity of a given sample containing the collection of molecules. Thus, the term “compound” includes such a collection of molecules in pure form, in a mixture (e.g., solution, suspension, colloid, or pharmaceutical composition, or dosage form) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal.

[0100] In some embodiments, the disclosure relates to a compound of formula (I): R6R7X1Y ,

[0101] or a pharmaceutically acceptwherein X1is O or NR11; Y is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocyclyl, or 5- to 12-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocyclyl, or 5- to 12-membered heteroaryl is independently optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1- 18Attorney Docket No.93033-425510 C3alkoxy; R6is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R7is halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; or two of R6and R7taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; RAis -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12; RBis -C(O)R12, -C(O)OR12, or -C(O)NR12R13; and p is 1, 2, or 3.

[0102] In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), X1is O or NR11; Y is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 12-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 12-membered heteroaryl is independently optionally substituted by halogen, C1-C3alkyl, or C1-C3alkoxy; R6is H, halogen, C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; or two of R6and R7taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; R8is H, halogen, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; RAis -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12; RBis -C(O)NR12R13; and p is 1 or 3.

[0103] In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), R6and R7are not the same. In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), R6and R7are not the same, or two of R6and R7taken together with the carbon atoms to which they are bound. In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy. In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), Y is not 3-pyridyl. In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), R6and R7are not the same; and if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy. In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), R6and R7are not the same, or two of R6and R7taken together with the carbon atoms to which they are bound; and Y is not 3-pyridyl. In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), R6and R7are not the same, or two of R6and R7taken together with the carbon atoms to which they are bound; if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy; and Y is not 3-pyridyl.

[0104] In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), R6and R7are not the same, or two of R6and R7taken together with the carbon atoms to which they are bound; and if R7and R9is OH, then Y is not unsubstituted phenyl. In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), R6and R7are not the same, or two of R6and R7taken together with the carbon atoms to which they are bound; if R7is OH or methoxy, then at least one of R6or R8is halogen or 19Attorney Docket No.93033-425510 C1-C6alkoxy; and if R7and R9is OH, then Y is not unsubstituted phenyl. In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), R6and R7are not the same, or two of R6and R7taken together with the carbon atoms to which they are bound; if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy; Y is not 3-pyridyl; and if R7and R9is OH, then Y is not unsubstituted phenyl.

[0105] In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), if R7and R9are the same, then Y is not unsubstituted phenyl. In some embodiments of compounds of formula (I), if R7and R9are the same, then Y is C1-C6alkyl, C3-C10cycloalkyl, 6- to 8-membered heterocyclyl, or 5- to 12-membered heteroaryl. In some embodiments of compounds of formula (I), if R7and R9are the same, then Y is C1-C6alkyl, C3-C10cycloalkyl, or 5- to 12-membered heteroaryl.

[0106] In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), both of R6and R7are not H. In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), both of R6and R7are not methoxy. In some embodiments of compounds of formula (I) (as well as formulas (II)- (IV)), R6and R8are not the same. In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), R7and R9are not the same. In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), both of R7and R9are not hydroxy. In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), both of R7and R9are not methoxy. In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), the compound is n In some embodimentsof compounds of formula (I), the compound is no . In some embodiments ofcompounds of formula (I), the compound is not . In some embodiments of20Attorney Docket No.93033-425510 F O HO O compounds of formula (I), the compound is no . In some embodiments ofcompounds of formula (I), the compound is no In some embodiments ofcompounds of formula (I), the compound is not In some embodiments ofcompounds of formula (I), the compound is no In some embodiments ofcompounds of formula (I), the compound is not In some embodiments ofcompounds of formula (I), the compound is no .

[0107] In some embodiments, the disclosnd of formula (II): ,

[0108] or a pharmaceutically herein: X1is O or NR11; each R1isindependently halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy; R6is H, halogen, or C1-C6alkoxy; R7is 21Attorney Docket No.93033-425510 halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, hydroxy, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; RAis -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OCH3; RBis -C(O)R12, -C(O)OR12, or -C(O)NR12R13; n is 0, 1, 2, or 3; p is 1, 2, or 3; provided that: (i) R6and R7are not the same; (ii) if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy; and (iii) if R7and R9is OH, then Y is not unsubstituted phenyl.

[0109] In some embodiments, the disclosure relates to a compound of formula (II): ,

[0110] or a pharmaceutically herein: X1is O or NR11; each R1is independently halogen, hydroxy, C13y ,3y R6is H, halogen, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, hydroxy, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; RAis -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OCH3; RBis -C(O)R12, -C(O)OR12, or -C(O)NR12R13; n is 0, 1, 2, or 3; p is 1, 2, or 3; provided that: (i) R6and R7are not the same; and (ii) if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy.

[0111] In some embodiments of compounds of formula (I) or (II), R6is H, halogen, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, or C1-C6alkoxy; and R9is H, halogen, hydroxy, or RA.

[0112] In some embodiments, the disclosure relates to a compound of formula (III): ,

[0113] or a pharmaceutically acceptaherein: Y is substituted or unsubstituted 5- to 12-membered heteroaryl; R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or 22Attorney Docket No.93033-425510 C1-C6alkoxy; or two of R6and R7taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; R9is H, halogen, hydroxy, RA, or C1-C6alkoxy; each R10, R12, and R13is independently H or C1-C6alkyl; RAis -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12; RBis -C(O)R12, -C(O)OR12, or -C(O)NR12R13; p is 1, 2, or 3; provided that: (i) R6and R7are not the same, or two of R6and R7taken together with the carbon atoms to which they are bound; and (ii) Y is not 3-pyridyl.

[0114] In some embodiments of compounds of formula (I) or (III), R6is C1-C6alkoxy; R7is hydroxy or RA; or two of R6and R7taken together with the carbon atoms to which they are bound to form a 6- membered heterocyclyl; and R9is H or hydroxy.

[0115] In some embodiments, the disclosure relates to a compound of formula (IIIa): , or a pharmaceutically acceptable sal halogen, hydroxy, or C1-C6alkoxy; R7is Ahalogen, hydroxy, R , or C1-C6alkoxy; or two of R6and R7taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; R9is H, halogen, hydroxy, RA, or C1-C6alkoxy; each R10, R12, and R13is independently H or C1-C6alkyl; RAis -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, - OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12; RBis -C(O)R12, -C(O)OR12, or -C(O)NR12R13; p is 1, 2, or 3; provided that: R6and R7are not the same, or two of R6and R7taken together with the carbon atoms to which they are bound; and

[0116] In some embodiments of compounds of formula (I), (III), or (IIIa), R6is C1-C6alkoxy; R7is hydroxy or RA; or two of R6and R7taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; and R9is H or hydroxy.

[0117] In some embodiments, the disclosure relates to a compound of formula (IV): ,23Attorney Docket No.93033-425510

[0118] or a pharmaceutically acceptable salt thereof, wherein: Y is unsubstituted C1-C6alkyl or unsubstituted C3-C10cycloalkyl; R6is H, halogen, hydroxy, or C1-C6alkoxy; and R7is halogen, hydroxy, or C1-C6alkoxy; provided that: R6and R7are not the same.

[0119] In some embodiments of compounds of formula (I) or (IV), R6is C1-C6alkoxy; and R7is hydroxy.

[0120] In some embodiments of compounds of formula (I) or (II), X1is O or NR11. In some embodiments, X1is O. In some embodiments, X1is NR11. In some embodiments, X1is NH or NMe. In some embodiments, X1is NMe. In some embodiments, X1is O or NMe.

[0121] In some embodiments of compounds of formula (I), Y is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocyclyl, or 5- to 12-membered heteroaryl. In some embodiments, Y is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 12-membered heteroaryl. In some embodiments, Y is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 12-membered heteroaryl, wherein C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 12-membered heteroaryl is optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, Y is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 12-membered heteroaryl, wherein C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 12-membered heteroaryl is optionally substituted by halogen, C1-C3alkyl, or C1-C3alkoxy.

[0122] In some embodiments of compounds of formula (I), Y is C6-C10aryl or 5- to 12-membered heteroaryl. In some embodiments, Y is substituted or unsubstituted C6-C10aryl or substituted or unsubstituted 5- to 12-membered heteroaryl. In some embodiments, Y is C6-C10aryl or 5- to 12-membered heteroaryl, wherein C6-C10aryl or 5- to 12-membered heteroaryl is optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, Y is unsubstituted C6-C10aryl or unsubstituted 5- to 12-membered heteroaryl, or C6-C10aryl or 5- to 12-membered heteroaryl substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, Y is unsubstituted C6-C10aryl or unsubstituted 5- to 12-membered heteroaryl, or C6-C10aryl or 5- to 12-membered heteroaryl substituted by halogen, C1-C3alkyl, or C1-C3alkoxy.

[0123] In some embodiments of compounds of formula (I) or (II), Y is C6-C10aryl. In some embodiments, Y is substituted or unsubstituted C6-C10aryl. In some embodiments, Y is C6-C10aryl, wherein C6-C10aryl is optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, Y is C6-C10aryl, wherein C6-C10aryl is optionally substituted by halogen or C1-C3alkoxy. In some embodiments, Y is unsubstituted C6-C10aryl, or C6-C10aryl substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, Y is unsubstituted C6-C10aryl, or C6-C10aryl substituted by halogen or C1-C3alkoxy. In some embodiments, Y is unsubstituted C6-C10aryl, or C6-C10aryl substituted by R1(n of R1). 24Attorney Docket No.93033-425510

[0124] In some embodiments of compounds of formula (I) or (II), Y is phenyl. In some embodiments, Y is substituted or unsubstituted phenyl. In some embodiments, Y is phenyl, wherein phenyl is optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, Y is phenyl, wherein phenyl is optionally substituted by halogen or C1-C3alkoxy. In some embodiments, Y is phenyl, wherein phenyl is optionally substituted by R1(n of R1). In some embodiments, Y is unsubstituted phenyl, or phenyl substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, Y is unsubstituted phenyl, or phenyl substituted by halogen or C1-C3alkoxy. In some embodiments, Y is unsubstituted phenyl, or phenyl substituted by R1(n of R1). In some embodiments, Y is unsubstituted phenyl.

[0125] In some embodiments of compounds of formula (I) or (II), Y is selected from: .. ) or (II), Y is C6-C10aryl substituted by R1(n of R1), and each R1is independently halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, Y is phenyl substituted by R1(n of R1), and each R1is independently halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, each R1is independently halogen, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, each R1is independently halogen, C1-C2alkyl, or C1-C2alkoxy. In some embodiments, each R1is independently halogen or C1-C2alkoxy. In some embodiments, each R1is independently chloro, fluoro, methoxy, or ethoxy. In some embodiments, R1is not hydroxy. In some embodiments, when two of R1are chloro, each chloro is in a meta position to the other chloro.

[0128] In some embodiments of compounds of formula (I) or (II), n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some embodiments, n is one or more. In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.

[0129] In some embodiments of compounds of formula (I) or (III), Y is 5- to 12-membered heteroaryl. In some embodiments, Y is substituted or unsubstituted 5- to 12-membered heteroaryl. In some embodiments, Y is 5- to 12-membered heteroaryl, wherein 5- to 12-membered heteroaryl is optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, Y is unsubstituted 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryl substituted by halogen, hydroxy, 25Attorney Docket No.93033-425510 C1-C3alkyl, or C1-C3alkoxy. In some embodiments, Y is unsubstituted 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryl substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, Y is unsubstituted 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryl substituted by C1-C3alkyl. In some embodiments, Y is unsubstituted 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryl substituted by R2(m of R2).

[0130] In some embodiments of compounds of formula (I) or (III), Y is pyridyl, quinolinyl, isoquinolinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl. In some embodiments, Y is substituted or unsubstituted pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, or substituted or unsubstituted thiazolyl. In some embodiments, Y is pyridyl, quinolinyl, isoquinolinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, wherein pyridyl, quinolinyl, isoquinolinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl is optionally substituted by R2(m of R2). In some embodiments, Y is quinolinyl, pyrazolyl, or thiazolyl, wherein quinolinyl, pyrazolyl, or thiazolyl is optionally substituted by R2(m of R2). In some embodiments, Y is unsubstituted pyridyl, unsubstituted quinolinyl, unsubstituted isoquinolinyl, unsubstituted pyrrolyl, unsubstituted imidazolyl, unsubstituted pyrazolyl, unsubstituted oxazolyl, or unsubstituted thiazolyl, or pyridyl, quinolinyl, isoquinolinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl substituted by R2(m of R2). In some embodiments, Y is unsubstituted quinolinyl, unsubstituted pyrazolyl, or unsubstituted thiazolyl, or quinolinyl, pyrazolyl, or thiazolyl substituted by R2(m of R2). In some embodiments, Y is unsubstituted quinolinyl. In some embodiments, Y is 6-quinolinyl.

[0131] In some embodiments of compounds of formula (I) or (III), Y is selected from: ,

[0132] whereinund.

[0133] In some embodiments of compounds of formula (I) or (III), Y is ,

[0134] wherein represents a pothe rest of the compound.

[0135] In some embodiments of compounds of formula (I) or (III), Y is selected from: .

[0136] 26Attorney Docket No.93033-425510 .

[0137] In some embodiments of compounds of formula (I) or (III), Y is .

[0138] In some embodiments of compounds of formula (I) or (III), Y , X2 is O, S, orNR11, and each X3and X4is independently N or CH; provided that at l2, X3and X4is a heteroatom (e.g., O, S, or NR11) and at least one of X3and X4is CH. In some embodiments of compoundsof formula (I) or (III), Y is , X2 is O, S, or NR11, and each X3 and X4 is independently N orCH; provided that at least one of X3and X4is CH. In some embodiments, X2is S or NR11, and each X3and X4is independently N or CH; provided that at least one of X3and X4is CH. In some embodiments, X2is S or N(CH3), and each X3and X4is independently N or CH; provided that at least one of X3and X4is CH.

[0139] In some embodiments of compounds of formula (I) or (III), Y is 5- to 12-membered heteroaryl substituted by R2(m of R2), and each R2is independently halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, each R2is independently halogen, C1-C2alkyl, or C1-C2alkoxy. In some embodiments, R2is C1-C2alkyl. In some embodiments, R2is methyl.

[0140] In some embodiments, each R1is independently halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, each R1is independently halogen, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, each R1is independently halogen, C1-C2alkyl, or C1-C2alkoxy. In some embodiments, each R1is independently halogen or C1-C2alkoxy. In some embodiments, each R1is independently chloro, fluoro, methoxy, or ethoxy.

[0141] In some embodiments, each R2is independently halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, each R2is independently halogen, C1-C2alkyl, or C1-C2alkoxy. In some embodiments, R2is C1-C2alkyl. In some embodiments, R2is methyl.

[0142] In some embodiments of compounds of formula (I) or (III), m is 0, 1 or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1.

[0143] In some embodiments of compounds of formula (I) or (IV), Y is C1-C6alkyl or C3-C10cycloalkyl. In some embodiments, Y is C1-C6alkyl or C3-C10cycloalkyl, wherein C1-C6alkyl or 27Attorney Docket No.93033-425510 C3-C10cycloalkyl is optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, Y is unsubstituted C1-C6alkyl or unsubstituted C3-C10cycloalkyl, or C1-C6alkyl or C3-C10cycloalkyl substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. In some embodiments, Y is unsubstituted C1-C6alkyl or unsubstituted C3-C10cycloalkyl. In some embodiments, Y is C1-C6alkyl. In some embodiments, Y is t-butyl. In some embodiments, Y is C3-C10cycloalkyl. In some embodiments, Y is C3-C8cycloalkyl. In some embodiments, Y is cyclopentyl or cyclohexyl.

[0144] In some embodiments of compounds of formula (I) (as well as formulas (II), (III), (IIIa), and (IV)), R6is H, halogen, hydroxy, or C1-C6alkoxy. In some embodiments, R6is H, halogen, or C1-C6alkoxy. In some embodiments, R6is H, halogen, or C1-C3alkoxy. In some embodiments, R6is H, chloro, fluoro, or methoxy. In some embodiments, R6is H or C1-C6alkoxy. In some embodiments, R6is H or methoxy. In some embodiments, R6is H. In some embodiments, R6is C1-C6alkoxy. In some embodiments, R6is C1-C3alkoxy. In some embodiments, R6is methoxy. In some embodiments, R6is halogen. In some embodiments, R6is fluoro.

[0145] In some embodiments of compounds of formula (I) (as well as formulas (II), (III), (IIIa), and (IV)), R7is halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy. In some embodiments, R7is halogen, hydroxy, RA, or C1-C6alkoxy. In some embodiments, R7is hydroxy, RA, or C1-C6alkoxy. In some embodiments, R7is halogen, hydroxy, RA, or C1-C3alkoxy. In some embodiments, R7is hydroxy, RA, or C1-C3alkoxy. In some embodiments, R7is hydroxy. In some embodiments, R7is halogen. In some embodiments, R7is fluoro. In some embodiments, R7is C1-C6alkoxy. In some embodiments, R7is C1-C3alkoxy. In some embodiments, R7is methoxy. In some embodiments, R7is RA. In some embodiments, R7is C1-C3haloalkyl, such as -CHF2. In some embodiments, R7is selected fromand , meme embodiments, R7is fluoro, hydroxy, methoxy, or RA. In some embodiments, R7is hydroxy or RA. In some 28Attorney Docket No.93033-425510 embodiments, R7is hydroxy, methoxy, or RA. In some embodiments, R7is hydroxy . Insome embodiments, R7is hydroxy, , or . In some embodiments, R7ishydroxy, methoxy, , or . In some embodiments, R7is selected from fluoro,therwith the carbon atoms to which they are bound to form a 6-membered heterocyclyl. In some embodiments, two of R6and R7are taken together with the carbon atoms to which they are bound to form a fused dioxane.

[0147] In some embodiments of compounds of formula (I) or (II), R8is H, halogen, or C1-C6alkoxy. In some embodiments, R8is H, halogen, or C1-C3alkoxy. In some embodiments, R8is H or halogen. In some embodiments, R8is H or C1-C6alkoxy. In some embodiments, R8is H. In some embodiments, R8is H, fluoro, or methoxy. In some embodiments, R8is H or methoxy. In some embodiments, R8is H or fluoro. In some embodiments, R8is halogen. In some embodiments, R8is fluoro.

[0148] In some embodiments of compounds of formula (I) (as well as formulas (II) and (III)), R9is H, halogen, hydroxy, or RA. In some embodiments, R9is H, hydroxy, fluoro, or . In some embodiments, R9is H or halogen. In some embodiments, R9is H or fluoro. Inents, R9is H. In some embodiments, R9is hydroxy. In some embodiments, R9is halogen. In some embodiments, R9is fluoro. In some embodiments, R9is RA. In some embodiments, R9is .

[0149] In some embodiments of compounds of formula (I) (aulas (II), (III), (IIIa), and (IV)), each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl. In some embodiments, each R10, R11, R12, and R13is independently H or C1-C6alkyl. In some embodiments, each R10, R11, R12, and R13is independently H or C1-C3alkyl. In some embodiments, each R10, R11, R12, and R13is independently H or methyl. In some embodiments, each R10, R11, R12, and R13is independently H, methyl, or phenyl. 29Attorney Docket No.93033-425510

[0150] In some embodiments of compounds of formula (I) (as well as formulas (II), (III), (IIIa), and (IV)), each R10and R11is independently H, C1-C6alkyl, or C6-C10aryl. In some embodiments, each R10and R11is independently H or C1-C6alkyl. In some embodiments, R10is H or C1-C6alkyl. In some embodiments, R10is H or C1-C3alkyl. In some embodiments, R10is H or methyl. In some embodiments, R10is H. In some embodiments, R10is methyl. In some embodiments, R11is H or C1-C6alkyl. In some embodiments, R11is H or methyl. In some embodiments, R11is H.

[0151] In some embodiments of compounds of formula (I) (as well as formulas (II), (III), (IIIa), and (IV)), each R12and R13is independently H, C1-C6alkyl, or C6-C10aryl. In some embodiments, each R12and R13is independently H or C1-C6alkyl. In some embodiments, each R12and R13is independently H or C1-C3alkyl. In some embodiments, each R12and R13is independently H or methyl. In some embodiments, each R12and R13is independently H, methyl, or phenyl.

[0152] In some embodiments of compounds of formula (I) (as well as formulas (II), (III), (IIIa), and (IV)), RAis -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, or -(OCH2CH2)p-OR12. In some embodiments, RAis -OCH2-RBor -(OCH2CH2)p-OR12. In some embodiments, , meembodiments, .

[0153] Inrmula (I) (as well as formulas (II), (III), (IIIa), and (IV)), p is 1, 2, or 3. In some embodiments, p is 1 or 3. In some embodiments, p is 1.

[0154] In some embodiments of compounds of formula (I) (as well as formulas (II), (III), (IIIa), and (IV)), RBis -C(O)R12, -C(O)OR12, or -C(O)NR12R13. In some embodiments, RBis -C(O)NR12R13. In some embodiments, .

[0155] Inents of compounds of formula (I) (as well as formulas (II), (III), (IIIa), and (IV)), at least one of R6, R8, and R9is H. In some embodiments, at least two of R6, R8, and R9is H. In some embodiments, each of R8and R9are H. In some embodiments, each of R6and R9are independently H, hydroxy, or methoxy. In some embodiments, at least one of R6and R7is methoxy. In some embodiments, R6is methoxy and R7is hydroxy. In some embodiments, R6is H and R7is methoxy or RA. In some 30Attorney Docket No.93033-425510 embodiments, R6is methoxy and R7is hydroxy or RA. In some embodiments, R6is H and R7is methoxy or RA, or R6is methoxy and R7is hydroxy or RA. In some embodiments, R6is methoxy, R8is H, and R9is H. In some embodiments, R6is H, R8is methoxy, and R9is hydroxy. In some embodiments, one of R6or R8is methoxy and the other of R6or R8is H. In some embodiments, R6is H or methoxy, R7is methoxy or RA, R8is H or methoxy, and R9is H or hydroxy. In some embodiments, R6is methoxy, and R7is RA.

[0156] In some embodiments of compounds of formula (I) (as well as formulas (II), (III), (IIIa), and (IV)), one of R6, R7, R8, and R9is C1-C6alkoxy. In some embodiments, two of R6, R7, R8, and R9is C1-C6alkoxy. In some embodiments, one of R6, R7, R8, and R9is halogen. In some embodiments, two of R6, R7, R8, and R9is halogen.

[0157] In some embodiments, a compound of formula (I) is of formula (II), (III), (IIIa), or (IV). In some embodiments, a compound of formula (III) is of formula (IIIa).

[0158] In some embodiments, the disclosure relates to a compound selected from Table A, or a pharmaceutically acceptable salt thereof. In other embodiments, the disclosure relates to a compound selected from Table A, i.e., the compound in non-salt form.

[0159] Table A. Compound Structures and Names. No. Structure Name n- - e31Attorney Docket No.93033-425510 7-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)-5- - 4- - 8- - 4-32Attorney Docket No.93033-425510 2-((8-methoxy-4-oxo-2-phenyl-4H- - e - - - -33Attorney Docket No.93033-425510 8-fluoro-7-(2-methoxyethoxy)-2- 20 8- - - 6- e 6-34Attorney Docket No.93033-425510 9-(quinolin-6-yl)-2,3-dihydro-7H- e - 4- l- ne - y- y-35Attorney Docket No.93033-425510 6-fluoro-7-(2-methoxyethoxy)-2- e 8- - e n-36Attorney Docket No.93033-425510 - e - - n- e37Attorney Docket No.93033-425510 5-fluoro-7-methoxy-2-phenyl-4H- - e

[0160] In some embodiments, the compound is selected from: ,38Attorney Docket No.93033-425510 , ,39Attorney Docket No.93033-425510 ,

[0162] In some embodiments, the compound is selected from: F O , ,40Attorney Docket No.93033-425510 , , nd

[0164] In some embodiments, the compound is selected from: 41Attorney Docket No.93033-425510 ,

[0165] In some embodiments, the compound is selected from

[0166] In some embodiments, the disclosure relates to the compound selected from 2-(3,5- dichlorophenyl)-5-hydroxy-6,7-dimethoxy-4H-chromen-4-one; 5,7-dihydroxy-8-methoxy-2-(quinolin-6- 42Attorney Docket No.93033-425510 yl)-4H-chromen-4-one; 2-((8-methoxy-4-oxo-2-(quinolin-6-yl)-4H-chromen-7-yl)oxy)-N- methylacetamide; and 6-fluoro-7-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one, or a pharmaceutically acceptable salt thereof.

[0167] In other embodiments, the foregoing compounds are in a non-salt form. In other embodiments, the foregoing compounds are pharmaceutically acceptable salts thereof. Salts, Compositions, Uses, Formulation, Administration and Additional Agents Pharmaceutically acceptable salts and compositions

[0168] As discussed herein, the disclosure provides compounds as described herein, and pharmaceutically acceptable salts thereof, that are useful for treating or preventing a disease or disorder including, but not limited to osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, traumatic brain injury (TBI), cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes. In some embodiments, the disease or disorder is osteoarthritis. In some embodiments, the disease or disorder is gout. In some embodiments, the disease or disorder is rheumatoid arthritis. In some embodiments, the disease or disorder is psoriasis. In some embodiments, the disease or disorder is psoriatic arthritis. In some embodiments, the disease or disorder is atopic dermatitis (eczema). In some embodiments, the disease or disorder is systemic lupus erythematosus. In some embodiments, the disease or disorder is amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or disorder is Parkinson's disease. In some embodiments, the disease or disorder is Alzheimer’s disease. In some embodiments, the disease or disorder is Huntington’s disease. In some embodiments, the disease or disorder is Friedreich Ataxia. In some embodiments, the disease or disorder is multiple sclerosis, retinitis pigmentosa (RP). In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is retinoblastoma. In some embodiments, the disease or disorder is traumatic brain injury (TBI). In some embodiments, the disease or disorder is cardiovascular disease, restenosis. In some embodiments, the disease or disorder is atherosclerosis. In some embodiments, the disease or disorder is chronic obstructive pulmonary disease (COPD). In some embodiments, the disease or disorder is inflammatory bowel disease. In some embodiments, the disease or disorder is Celiac’s disease. In some embodiments, the disease or disorder is type II diabetes.

[0169] As discussed herein, the disclosure provides compounds as described herein, and pharmaceutically acceptable salts thereof, that are useful for the treatment of diseases, disorders, and conditions including, but not limited to pain, inflammation, and cancer. In some aspects, the pain is 43Attorney Docket No.93033-425510 musculoskeletal pain or arthritic pain. In another aspect, the disclosure provides compounds as described herein, and pharmaceutically acceptable salts thereof, that are useful for modulating inflammation.

[0170] As discussed herein, the disclosure provides compounds as described herein, and pharmaceutically acceptable salts thereof, that are useful for the treatment of diseases, disorders, and conditions including, but not limited to a disease or disorder associated with a redox imbalance. The disease or disorder may affect an organ or a tissue selected from the group consisting of cartilage and bone, neural tissue, connective tissue, and internal organ or peripheral tissue. The disease or disorder affecting cartilage and bone may include osteoarthritis (metabolic and / or mechanical), gout, or rheumatoid arthritis. The disease or disorder affecting neural tissue may include amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, and traumatic brain injury (TBI). The disease or disorder affecting connective tissue may include psoriasis, psoriatic arthritis, atopic dermatitis (eczema), and systemic lupus erythematosus. The disease or disorder affecting internal organ and peripheral tissue may include cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes. The disease or disorder may be an autoimmune disease selected from rheumatoid arthritis, multiple sclerosis, and lupus. The disease or disorder may include any one or more of a disease or disorder selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, traumatic brain injury (TBI), cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes.

[0171] Accordingly, in another aspect, pharmaceutical compositions are provided, wherein these compositions comprise a compound as described herein, or a pharmaceutically acceptable salt thereof, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0172] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” of a compound includes any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound as described herein or an inhibitorily active metabolite or residue thereof. The salt may be in pure form, in a mixture (e.g., solution, suspension, or colloid) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal. As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a target. 44Attorney Docket No.93033-425510

[0173] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compound as described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0174] As described herein, the pharmaceutically acceptable compositions additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds as described herein such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this disclosure. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as 45Attorney Docket No.93033-425510 protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0175] In another aspect, the disclosure features a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0176] In another aspect, the disclosure features a pharmaceutical composition comprising a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles. Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

[0177] In another aspect, the disclosure features a method of treating pain comprising administering to the subject a compound as described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects of the disclosure, the pain is musculoskeletal pain or arthritic pain.

[0178] In yet another aspect, the disclosure features a method of modulating inflammation comprising administering an effective amount of a compound as described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0179] In another aspect, the disclosure features a method of treating or preventing a disease or disorder comprising administering to the subject a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects of the disclosure, the disease or disorder is a disease or disorder associated with a redox imbalance. The disease or disorder may affect an organ or a tissue selected from the group consisting of cartilage and bone, neural tissue, connective tissue, and internal organ or peripheral tissue. The disease or disorder affecting cartilage and bone may include osteoarthritis (metabolic and / or mechanical), gout, or rheumatoid arthritis. The disease or disorder affecting neural tissue may include amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s 46Attorney Docket No.93033-425510 disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, and traumatic brain injury (TBI). The disease or disorder affecting connective tissue may include psoriasis, psoriatic arthritis, atopic dermatitis (eczema), and systemic lupus erythematosus. The disease or disorder affecting internal organ and peripheral tissue may include cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes. The disease or disorder may be an autoimmune disease selected from rheumatoid arthritis, multiple sclerosis, and lupus. The disease or disorder may include any one or more of a disease or disorder selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, traumatic brain injury (TBI), cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes.

[0180] In yet another aspect, the disclosure features a method of treating cancer comprising administering an effective amount of a compound as described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0181] As used herein, the phrase “upregulate Nrf2 activity” includes, but is not limited to, the process by which a cell increases the activity of the transcription factor of nuclear factor erythroid 2-related factor 2, called NRF2, that is involved in the expression of genes involved in oxidative stress response.

[0182] In one aspect, the disclosure features a method of upregulating Nrf2 activity comprising administering to the subject a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. A compound as described herein may upregulate Nrf2 activity through allosteric interactions in the Kelch domain of KEAP1. For example, allosteric interactions of a compound of the disclosure may include non-oxidative binding (e.g., non-covalent binding) in the Kelch domain of KEAP1. Allosteric binding to the Kelch domain of KEAP1, for example, may provide Nrf2 accummulation and activation of an antioxidant response. Advantages of a non-oxidative binding mechanism include, but are not limited to, a descrease in off-target binding, normal cellular function, low toxicity, and a descrease in undesirable side effects.

[0183] In another aspect, the disclosure features a method of activating Nrf2 comprising administering to the subject a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use

[0184] In another aspect, the disclosure features a compound as described herein, a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, for use as a medicament. 47Attorney Docket No.93033-425510

[0185] In another aspect, the disclosure features a compound as described herein, a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, for use in treating pain. In some aspects of the disclosure, the pain is musculoskeletal pain or arthritic pain.

[0186] In another aspect, the disclosure features a compound as described herein, a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, for use in a method of modulating inflammation.

[0187] In another aspect, the disclosure features a compound as described herein, a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, for use in treating or preventing a disease or disorder. In some aspects of the disclosure, the disease or disorder is a disease or disorder associated with a redox imbalance. The disease or disorder may affect an organ or a tissue selected from the group consisting of cartilage and bone, neural tissue, connective tissue, and internal organ or peripheral tissue. The disease or disorder affecting cartilage and bone may include osteoarthritis (metabolic and / or mechanical), gout, or rheumatoid arthritis. The disease or disorder affecting neural tissue may include amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, and traumatic brain injury (TBI). The disease or disorder affecting connective tissue may include psoriasis, psoriatic arthritis, atopic dermatitis (eczema), and systemic lupus erythematosus. The disease or disorder affecting internal organ and peripheral tissue may include cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes. The disease or disorder may be an autoimmune disease selected from rheumatoid arthritis, multiple sclerosis, and lupus. The disease or disorder may include any one or more of a disease or disorder selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, traumatic brain injury (TBI), cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes.

[0188] In another aspect, the disclosure features a compound as described herein, a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, for use in a method of treating cancer. Manufacture of Medicaments

[0189] In another aspect, the disclosure provides the use of a compound as described herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.

[0190] In another aspect, the disclosure provides the use of a compound as described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a 48Attorney Docket No.93033-425510 medicament for use in treating pain. In some aspects of the disclosure, the pain is musculoskeletal pain or arthritic pain.

[0191] In yet another aspect, the disclosure provides the use of a compound as described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in modulating inflammation.

[0192] In another aspect, the disclosure provides the use of a compound as described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or preventing a disease or disorder. In some aspects of the disclosure, the disease or disorder is a disease or disorder associated with a redox imbalance. The disease or disorder may affect an organ or a tissue selected from the group consisting of cartilage and bone, neural tissue, connective tissue, and internal organ or peripheral tissue. The disease or disorder affecting cartilage and bone may include osteoarthritis (metabolic and / or mechanical), gout, or rheumatoid arthritis. The disease or disorder affecting neural tissue may include amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, and traumatic brain injury (TBI). The disease or disorder affecting connective tissue may include psoriasis, psoriatic arthritis, atopic dermatitis (eczema), and systemic lupus erythematosus. The disease or disorder affecting internal organ and peripheral tissue may include cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes. The disease or disorder may be an autoimmune disease selected from rheumatoid arthritis, multiple sclerosis, and lupus. The disease or disorder may include any one or more of a disease or disorder selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, traumatic brain injury (TBI), cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes.

[0193] In yet another aspect, the disclosure provides the use of a compound as described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating cancer. Administration of Compounds, Pharmaceutically Acceptable Salts, and Compositions

[0194] In certain embodiments, an “effective amount” of a compound of as described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective for treating or lessening the severity of one or more of the conditions, diseases, or disorders as disclosed herein. 49Attorney Docket No.93033-425510

[0195] The compounds, salts, and compositions, according to the methods as described herein, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of pain, inflammation, or cancer as disclosed herein. The compounds, salts, and compositions, according to the methods as described herein, may be administered using any amount and any route of administration effective for treating or lessening the severity of the disease or disorder as disclosed herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition, disease, or disorder, the particular agent, its mode of administration, and the like. The compounds, salts, and compositions as described herein are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compounds, salts, and compositions as described herein will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound or salt employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound or salt employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound or salt employed, and like factors well known in the medical arts.

[0196] The term “subject” or “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0197] The pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intravenously, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the condition being treated. In some embodiments, pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals by a topical, oral, systemic, or inhalation route. In some embodiments, pharmaceutically acceptable compositions of this disclosure can be topically administered to humans and other animals to treat a disease or disorder selected from osteoarthritis (metabolic and / or mechanical), psoriasis, atopic dermatitis (eczema), gout, lupus, and psoriatic arthritis. In some embodiments, pharmaceutically acceptable compositions of this disclosure can be orally, intravenously, and / or intraperitoneally administered to humans and other animals to treat a disease or disorder selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, traumatic brain injury (TBI), cardiovascular disease, 50Attorney Docket No.93033-425510 restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes. In some embodiments, pharmaceutically acceptable compositions of this disclosure can be administered by inhalation to humans and other animals to treat a disease or disorder such as chronic obstructive pulmonary disease (COPD).

[0198] In certain embodiments, the compound, salts, and compositions as described herein may be administered orally or parenterally at dosage levels of about 0.001 mg / kg to about 1000 mg / kg, one or more times a day, effective to obtain the desired therapeutic effect. In certain embodiments, the compound, salts, and compositions as described herein may be administered at dosage levels of about 0.001 mg / kg to about 1000 mg / kg, one or more times a week, effective to obtain the desired therapeutic effect. In certain embodiments, the compound, salts, and compositions as described herein may be administered at dosage levels of about 0.1 mg / kg to about 10 mg / kg, one or more times a week, effective to obtain the desired therapeutic effect.

[0199] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound or salt, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0200] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0201] The injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0202] In order to prolong the effect of the compounds as described herein, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This may be accomplished 51Attorney Docket No.93033-425510 by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0203] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compound or salt as described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0204] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound or salt is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0205] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include 52Attorney Docket No.93033-425510 polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0206] The active compound or salt can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release-controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound or salt may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0207] Dosage forms for topical or transdermal administration of a compound or salt as described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0208] The compounds and salts as described herein, or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the disclosure, in another aspect, includes a composition for coating an implantable device comprising a compound or salt as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the disclosure includes an implantable device coated with a composition comprising a compound or salt as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further 53Attorney Docket No.93033-425510 covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Synthesis of the Compounds of the Disclosure

[0209] The disclosed compounds of formula (I)-(IV) can be prepared from known materials by the methods described in the Examples, other similar methods, and other methods known to one skilled in the art. As one skilled in the art would appreciate, the functional groups of the intermediate compounds in the methods described below may need to be protected by suitable protecting groups. Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art. The use of protecting groups is described in detail in T.G.M. Wuts et al., Greene’s Protective Groups in Organic Synthesis (4th ed.2006). EXAMPLES

[0210] The following examples are offered to illustrate but not to limit the disclosure. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula (I)-(IV). Abbreviations

[0211] Unless otherwise noted, or where the context dictates otherwise, the following abbreviations shall be understood to have the following meanings: Abbreviation Meaning NMR Nuclear magnetic resonance ESI-MS Electrospray mass spectrometry LC / MS Liquid chromatography-mass spectrometry UPLC Ultra performance liquid chromatography HPLC / MS / MS High performance liquid chromatography / tandem mass spectrometry IS Internal standard HPLC High performance liquid chromatography SFC Supercritical fluid chromatography ESI Electrospray ionization kg Kilogram g Grams mg Milligrams L Liter(s) mL Milliliters μL Microliters nL Nanoliters mol Mole mmol Millimoles hr, h Hours 54Attorney Docket No.93033-425510 min Minutes ms Millisecond mm Millimeters μm Micrometers nm Nanometer MHz Megahertz Hz Hertz N Normal (concentration) M Molar (concentration) mM Millimolar (concentration) μM Micromolar (concentration) ppm Parts per million % w / v Weight-volume concentration % w / w Weight-weight concentration IV intravenous injection IP intraperitoneal injection BIW twice weekly SYNTHETIC CHEMICAL EXAMPLES

[0212] The proposed targets, intermediates, and / or starting materials can be prepared via the conventional chemistry or by following the schemes as shown below. Intermediate Table. 1-(2-hydroxy-3-methoxy-4- i A h h h l h n- - 3-Example 1 Preparation of 2-(3,5-dichlorophenyl)-5,7-dihydroxy-8-methoxy-4H-chromen-4-one (1) 55Attorney Docket No.93033-425510 [021dichlorophenyl) prop-2-en-1-one

[0214] A mixture of 1-(4-(benxyphenyl) ethan-1-one (600 mg, 1.98 mmol) and 3,5-dichlorobenzaldehyde (521 mg, 2.98 mmol) in ethanol (5 mL), aq. NaOH solution (238 mg, 5.95 mmol, dissolved in 2 mL H2O) was added dropwise and stirred at room temperature for 16 h. Upon completion of the reaction, the reaction was poured into ice-cold water, acidified with 1.5 N HCl, and extracted with ethyl acetate (2 × 25 mL). The combined organic layer was washed with water (25 mL), and brine solution (25 mL), dried over anhydrous Na2SO4and concentrated under a vacuum to get the crude product. The crude product was purified by column chromatography using 10-30% ethyl acetate in pet ether as eluent to get the (E)-1-(4-(benzyloxy)-2-hydroxy-3,6-dimethoxyphenyl)-3-(3,5- dichlorophenyl) prop-2-en-1-one (800 mg, 1.74 mmol, 88% yield) as pale-yellow solid. MS (ESI) m / z: 461.0 (M+1)+. 56Attorney Docket No.93033-425510

[0215] Step 2: Synthesis of 7-(benzyloxy)-2-(3,5-dichlorophenyl)-5,8-dimethoxy-4H-chromen-4- one.

[0216] To a stirred solution of ( xy-3,6-dimethoxyphenyl)-3-(3,5-dichlorophenyl) prop-2-en-1-one (800 mg, 1.74 mmol) in DMSO ((10 mL) iodine (44.2 mg, 0.17 mmol) was added and the mixture was heated at 120 °C for 4 h. After the completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature and diluted with ice-cold water, the obtained residue was filtered, washed with petroleum ether and dried to afford the 7-(benzyloxy)-2-(3,5- dichlorophenyl)-5,8-dimethoxy-4H-chromen-4-one (0.78 g, 1.70 mmol, 98% yield) as off-white solid.1H- NMR (400 MHz, DMSO-d6): δ 8.05 (s, 2H), 8.04 (s, 1H), 7.87-7.86 (m, 2H), 7.55 – 7.33 (m, 2H), 7.47 – 7.45 (m, 1H), 6.99 (s, 2H), 6.84 (s, 1H), 5.38 (s, 2H), 3.87 (s, 3H).3.85 (s, 3H). MS (ESI) m / z: 459.0 (M+2)+.

[0217] Step 3: 2-(3,5-dichlorophenyl)-7-hydroxy-5,8-dimethoxy-4H-chromen-4-one_(42)

[0218] To a solution of 7-(benzyloxy)-2-(3,5-dichlorophenyl)-5,8-dimethoxy-4H-chromen-4-one (500 mg, 1.09 mmol) was dissolved in a mixture of acetic acid (9 mL) and conc hydrochloric acid (3 mL, 1.09 mmol) (3:1) was added and the reaction mixture was heated at 80 °C for 5 h. After the completion of the reaction, the reaction mixture was cooled to room temperature and poured into ice-cold water, the obtained residue was filtered and dried to get the 2-(3,5-dichlorophenyl)-7-hydroxy-5,8-dimethoxy-4H- chromen-4-one (400 mg, 0.99 mmol, 91% yield) as a brown solid. The obtained solid was used in the next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 3.77 (s, 3H), 3.85 (s, 3H), 6.49 (s, 1H), 6.96 (s, 1H), 7.86 (s, 1H), 8.03 (d, J = 2 Hz, 2H), 10.69 (s, 1H). MS (ESI) m / z: 369.0 (M+2)+.

[0219] Step 4: 2-(3,5-dichlorophenyl)-5,7-dihydroxy-8-methoxy-4H-chromen-4-one_(1) 57Attorney Docket No.93033-425510

[0220] To a stirred solution of aluminum chloride (1.16 g, 8.72 mmol) in acetonitrile (12 mL), was added dropwise the solution of 2-(3,5-dichlorophenyl)-7-hydroxy-5,8-dimethoxy-4H-chromen-4-one (400 mg, 1.09 mmol, dissolved in 3 mL acetonitrile) at room temperature. The reaction mixture was refluxed at 90 °C for 6 h. The progress of the reaction was monitored by TLC. After the completion of the reaction, the solvent was evaporated under vacuum to get the residue, and the residual mass was treated with (10%) aq. HCl, the obtained solid was filtered and dried to afford (300 mg, 0.80 mmol, 74% as a yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 12.36 (s, 1H), 10.92 (s, 1H), 8.08 (d, J = 2 Hz, 2H), 7.92 (s, 1H), 7.20 (s, 1H), 6.33 (s, 1H), 3.85 (s, 3H). MS (ESI) m / z: 355.0 (M+2)+. Example 2 Preparation of 2-(3,5-dichlorophenyl)-5-hydroxy-6,7-dimethoxy-4H-chromen-4-one (2)

[0221] Step 1: Synthesis of (E)-3-(3,5-dichlorophenyl)-1-(6-hydroxy-2,3,4-trimethoxyphenyl)prop- 2-en-1-one. 58Attorney Docket No.93033-425510

[0222] A mixture of (E)-3-(3, ide (1.5 g, 6.37 mmol) and 3,4,5- trimethoxyphenol (1.17 g, 6.37 mmol) was dissolved in BF3OEt2(15 mL, 6.37 mmol) at room temperature. The reaction mixture was stirred at 130 °C for 20 min. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was poured into ice-cold water, and the residue obtained was filtered, washed with water (20 mL), and dried to get the crude. The crude was purified by normal phase column chromatography using 5% ethyl acetate in petroleum ether as eluent to get the (E)-3-(3,5-dichlorophenyl)-1-(6-hydroxy-2,3,4-trimethoxyphenyl) prop-2-en-1-one (1.35 g, 3.10 mmol, 49% yield) as a yellow solid. MS (ESI) m / z: 382.8(M+1)+.

[0223] Step 2: Synthesis of 2-(3,5-dichlorophenyl)-5,6,7-trimethoxy-4H-chromen-4-one.

[0224] To a stirred solution of ( (6-hydroxy-2,3,4-trimethoxyphenyl)prop-2-en-1-one (1.35 g, 3.52 mmol) in DMSO (14 mL) was added iodine (21 mg, 0.09 mmol) at 60 °C. The reaction mixture was allowed to stir at 120 °C for 4 h. After the completion of the reaction, the reaction mixture was poured into ice-cold water (25 mL), and the residue obtained was filtered and dried to get the crude product. The crude product was washed with n-pentane (7 mL) to get the 2-(3,5-dichlorophenyl)-5,6,7-trimethoxy-4H-chromen-4-one (1.0 g, 1.57 mmol, 45% yield) as a brown solid. MS (ESI) m / z: 380.8(M+1)+.

[0225] Step 3: Synthesis of 2-(3,5-dichlorophenyl)-5-hydroxy-6,7-dimethoxy-4H-chromen-4-one (2)

[0226] 2-(3,5-dichlorophenyl)-5,6,7-trimethoxy-4H-chromen-4-one (1.0 g, 2.62 mmol) was treated with 33% HBr in acetic acid (15 mL, 2.62 mmol) at room temperature. The reaction mixture was allowed 59Attorney Docket No.93033-425510 to stir at 110 °C for 2 h. After the completion of the reaction as indicated by TLC, the reaction mixture was poured into ice-cold water (50 mL), and the residue obtained was filtered, and dried to get crude. The crude was purified by preparative HPLC purification to get the 2-(3,5-dichlorophenyl)-5-hydroxy-6,7- dimethoxy-4H-chromen-4-one (10 mg, 0.027 mmol, 1% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 12.61 (s, 1H), 8.22 – 8.22 (d, J = 2.0 Hz, 2H), 7.89 – 7.88 (m, 1H), 7.26 (s, 1H), 7.14 (s, 1H), 3.95 (s, 3H), 3.75 (s, 3H); MS (ESI) m / z: 367.0 (M+1)+. Example 3 Preparation of 5-hydroxy-8-methoxy-7-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one (3)

[0227] Step 1: Synthesis of (E)-1-(4-(benzyloxy)-2-hydroxy-3,6-dimethoxyphenyl)-3-phenylprop-2- en-1-one

[0228] A mixture of 1-(4-(benzoxyphenyl) ethan-1-one (600 mg, 1.98 mmol) and benzaldehyde (211 mg, 1.98 mmol) in ethanol (3 mL), aq. KOH solution (334 mg, 5.95 mmol, dissolved in 3 mL H2O) was added dropwise and kept at room temperature for 16 h. Upon completion of the reaction, the reaction was poured into ice-cold water, acidified with 1.5 N HCl, and extracted with 60Attorney Docket No.93033-425510 ethyl acetate (3 × 25 mL). The combined organic layer was washed with water (30 mL), and brine solution (30 mL), dried over anhydrous Na2SO4,and concentrated under vacuum to get the crude product. The crude product was purified by column chromatography (silica gel) to get the (E)-1-(4-(benzyloxy)-2- hydroxy-3,6-dimethoxyphenyl)-3-phenylprop-2-en-1-one (660 mg, 1.26 mmol, 64% yield) as a pale- yellow solid. MS (ESI) m / z: 391.0 (M+1)+.

[0229] Step 2: Synthesis of 7-(benzyloxy)-5,8-dimethoxy-2-phenyl-4H-chromen-4-one

[0230] A mixture of (E)-1-(4-(be imethoxyphenyl)-4-phenylbut-3-en-1-one(660 mg, 1.63 mmol) and iodine (9.94 mg, 0.039 mmol) was dissolved in DMSO (10 mL), and the mixture was heated at 120 °C for 4 h. After the completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature and diluted with ice-cold water, the obtained residue was filtered, washed with petroleum ether, and dried to get the 7-(benzyloxy)-5,8-dimethoxy-2-phenyl- 4H-chromen-4-one (630 mg, 1.49 mmol, 91% yield) as brown solid. MS (ESI) m / z: 389.1 (M+1)+.

[0231] Step 3: 7-hydroxy-5,8-dimethoxy-2-phenyl-4H-chromen-4-one

[0232] To a solution of 7-(benzyloenyl-4H-chromen-4-one (660 mg, 1.69 mmol) was dissolved in a mixture of acetic acid (6 mL) and hydrochloric acid (2 mL, 1.69 mmol) (3:1) and the reaction mixture was heated at 80 °C for 5 h. After the completion of the reaction, the reaction mixture was cooled to room temperature and poured into ice-cold water (10 mL), the obtained residue was filtered and dried to get the 2-(3,5-dichlorophenyl)-7-hydroxy-5,8-dimethoxy-4H-chromen-4-one (350 mg, 1.12 mmol, 66% yield) as a brown solid. The obtained solid was used in the next step without further purification. MS (ESI) m / z: 299.1 (M+1)+.

[0233] Step 4: Synthesis of 5,8-dimethoxy-7-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one61Attorney Docket No.93033-425510

[0234] To a solution of 7-hydroxy-5,8-dimethoxy-2-phenyl-4H-chromen-4-one (70 mg, 0.23 mmol) in DMF (2 mL) was added potassium carbonate (97 mg, 0.70 mmol) followed by the dropwise addition of 1-chloro-2-methoxyethane (111 mg, 1.17 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 16 h. After the completion of the reaction as indicated by TLC and LCMS, the reaction mixture was poured into ice-cold water, the residue obtained was filtered, washed with petroleum ether, and dried to get the 5,8-dimethoxy-7-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one (40 mg, 0.097 mmol, 41% yield) as a pale-yellow solid. The obtained solid was used in the next step without further purification.1H- NMR (400 MHz, DMSO-d6): δ 8.04 – 8.02 (m, 2H), 7.60 – 7.58 (m, 3H), 6.79 (s, 1H), 6.71 (s, 1H), 4.38 – 4.35 (m, 2H), 3.87 (s, 6H), 3.76 – 3.74 (m, 2H), 3.36 (s, 3H); MS (ESI) m / z: 357.2 (M+1)+.

[0235] Step 5: Synthesis of 5-hydroxy-8-methoxy-7-(2-methoxyethoxy)-2-phenyl-4H-chromen-4- one (3)

[0236] To a stirred solution of 9 mmol) in acetonitrile (2 mL) wasadded 5,8-dimethoxy-7-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one (40 mg, 0.11 mmol) at room temperature and then the mixture was refluxed at 90 °C for 16 h. Upon completion of the reaction, the solvent was completely evaporated under vacuum. The residual mass was diluted with 10% aq. HCl solution at 0 °C, the solid obtained was filtered and washed with water and dried to get 5-hydroxy-8- methoxy-7-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one (12 mg, 0.034 mmol, 31% yield) as a yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 12.62 (s, 1H), 8.10 – 8.08 (m, 2H), 7.63 (d, J = 4 Hz, 3H), 7.06 (s, 1H), 6.64 (s, 1H), 4.30 – 4.27 (m, 2H), 3.87 (s, 3H), 3.73 – 3.72 (m, 2H), 3.34 (s, 3H). Example 4 Preparation of tert-butyl (2-(2-(2-((5-hydroxy-8-methoxy-4-oxo-2-phenyl-4H-chromen-7- yl)oxy)ethoxy)ethoxy)ethyl)carbamate (4)62Attorney Docket No.93033-425510

[0237] l-4H-chromen-7-yl)oxy)ethoxy)ethoxy)ethyl)carbamate:

[0238] To a stirred hromen-4-one (550 mg,1.935 mmol) in DMF (6 mL) was added potassium carbonate (535 mg, 3.87 mmol), followed by tert- butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (725 mg, 2.322 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 hours. After completion, the reaction was quenched with ice- cold water and extracted with EtOAc. The organic layer was dried and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography using 30% PE / EtOAc as eluent to afford the product as a brown liquid. LCMS (m / z): 516.5 [M+1].

[0239] Step 2: Synthesis of 7-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-5-hydroxy-8-methoxy-2- phenyl-4H-chromen-4-one (4):

[0240] To a stirred solution of tert-butyl (2-(2-(2-((5-hydroxy-8-methoxy-4-oxo-2-phenyl-4H- chromen-7-yl)oxy)ethoxy)ethoxy)ethyl)carbamate (100 mg, 0.00019 mmol) in 1,4-dioxane (3 mL) was added 4 M HCl in 1,4-dioxane (3 mL) and the reaction mixture was stirred at room temperature for 1 63Attorney Docket No.93033-425510 hour. The mixture was then concentrated under reduced pressure to afford the crude HCl salt of compound 4. Example 5 Preparation of 8-hydroxy-2-phenyl-4H-chromen-4-one (5)BuLi in hexane (5.78 mL, 14.4 mmol) dropwise under nitrogen atmosphere at -78 °C and the solution was stirred for 1 hour at -78 °C. A solution of 2-hydroxy-3-methoxybenzaldehyde (1.0 g, 6.57 mmol) in THF (8 mL) was then added dropwise into the suspension. The resulting mixture was stirred at -78 °C for 2 h. After the completion of the reaction as indicated by TLC, the reaction mixture was quenched with saturated NH4Cl solution (25 mL) and extracted with ethyl acetate (2 × 40 mL). The combined organic layers were washed with water (40 mL), and brine solution (40 mL), 64Attorney Docket No.93033-425510 dried over anhydrous Na2SO4,and concentrated under reduced pressure to get the crude. The crude was purified by normal phase flash chromatography using 42% ethyl acetate in petroleum ether to afford 2-(1- hydroxy-3-phenylprop-2-yn-1-yl)-6-methoxyphenol (820 mg, 2.8 mmol, 43% yield) as a yellow liquid. MS (ESI) m / z: 253.0 (M-1)-

[0243] Step-2: Synthesis of 8-methoxy-2-phenyl-4H-chromen-4-one.

[0244] To a mixture of Iron (III) nitr .8 mg, 0.08 mmol) and sodium chloride(4.60 mg, 0.08 mmol) was added under an O2atmosphere and a solution of TEMPO (12.29 mg, 0.08 mmol) in dry acetonitrile (4 mL) and a solution of 2-(1-hydroxy-3-phenylprop-2-yn-1-yl)-6- methoxyphenol (400 mg, 1.57 mmol) in dry acetonitrile (5 mL) was added sequentially. The reaction mixture was allowed to stir at the same temperature under O2atmosphere for 3.5 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the O2balloon was removed and DMAP (38.4 mg, 0.31 mmol) was added into the reaction mixture. The reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was diluted with 1.5 N HCl (15 mL) and extracted with ethyl acetate (2 × 20 mL). All the combined organic layers were washed with water (20 mL), brine solution (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get the crude. The crude product was purified by normal phase column chromatography using 18% ethyl acetate in petroleum ether as eluent to get the pure 8-methoxy-2-phenyl-4H-chromen-4-one (200 mg, 0.74 mmol, 47% yield) as a brown solid. MS (ESI) m / z: 253.2 (M+1)+

[0245] Step-3: Synthesis of 8-hydroxy-2-phenyl-4H-chromen-4-one (5)

[0246] To a stirred solution of 8-methoxy-2-phenyl-4H-chromen-4-one (200 mg, 0.79 mmol) in DCM (4 mL) was added 1 M BBr3in DCM (0.87 mL, 0.87 mmol) dropwise under nitrogen atmosphere at -78 °C. After 10 min, the reaction mixture was allowed to warm at room temperature and stirred for 16 h. Upon completion, the reaction mixture was quenched with saturated NaHCO3solution (10 mL) at 0 °C and extracted with DCM (2 × 25 mL). The combined organic layers were washed with water (25 mL), and brine solution (25 mL), dried over anhydrous Na2SO4,and concentrated under reduced pressure to get 65Attorney Docket No.93033-425510 the crude. The crude product was purified by normal phase flash chromatography using 34% ethyl acetate in petroleum ether as an eluent to get pure 8-hydroxy-2-phenyl-4H-chromen-4-one (115 mg, 0.47 mmol, 59% yield) as a brown solid.1H-NMR (400 MHz, DMSO-d6): δ 10.49 (s, 1H), 8.16 – 8.13 (m, 2H), 7.63 – 7.59 (m, 3H), 7.49 – 7.46 (m, 1H), 7.30 – 7.29 (m, 2H), 7.03 (s, 1H) ppm; MS (ESI) m / z: 239.1(M+1)+

[0247] Example 6 Preparation of 7-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one (6).

[0248] in DMF (3mL) was added K2CO3(870 mg, 6.30 mmol) followed by the addition of 1-chloro-2-methoxyethane (1984 mg, 20.99 mmol) at 0 °C. The reaction mixture was stirred at 60 °C for 16 h. After the completion of the reaction, the reaction mixture was diluted with ice-cool water (15 mL) and was extracted with 10% MeOH in DCM (2 × 25 mL). All the combined organic layers were washed with brine solution (2 × 25 mL), dried over anhydrous Na2SO4,and concentrated under vacuum to obtain crude 520 mg (1.63 mmol, 78% yield). The crude product was purified by normal phase flash chromatography using 44% ethyl acetate in petroleum ether to get pure 7-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one (351 mg, 1.18 mmol, 56% yield) as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.12 – 8.09 (m, 2H), 7.96 (d, J = 8.8 Hz, 1H), 7.62 – 7.59 (m, 3H), 7.36 (d, J = 2.4 Hz, 1H), 7.10 – 7.07 (m, 1H), 6.97 (s, 1H), 4.30 – 4.28 (m, 2H), 3.75 – 3.72 (m, 2H), 3.34 (s, 3H) ppm; MS (ESI) m / z: 297.1 (M+1)+Example 7 Preparation of 2-(3,4-difluorophenyl)-7-hydroxy-8-methoxy-4H-chromen-4-one (7).66Attorney Docket No.93033-425510

[0249] Step 1: (E)-3-(3,4-difluorophenyl)-1-(2-hydroxy-3-methoxy-4 (methoxymethoxy)phenyl)prop-2-en-1-one

[0250] To a mixture of 1-(2-h ethoxy)phenyl)ethan-1-one (0.55 g,2.43 mmol) and 3,4-difluorobenzaldehyde (0.86 g, 6.08 mmol) in ethanol (5 mL), 50% aqueous KOH (0.40 g, 7.29 mmol) was added dropwise and kept at ambient temperature for 10 h. After completion of the reaction as indicated by TLC, the reaction mixture was poured into ice-cold water and acidified with 1.5 N HCl, the residue obtained was filtered and dried to give the crude product. The crude product was purified by normal phase column chromatography using 40% ethyl acetate in petroleum ether to get the (E)-3-(3,4-difluorophenyl)-1-(2-hydroxy-3-methoxy-4 (methoxymethoxy)phenyl)prop 2-en-1-one (0.6 g, 1.33 mmol, 55% yield) as a yellow solid. MS (ESI) m / z: 351.1 (M+1)+.

[0251] Step 2: 2-(3,4-difluorophenyl)-7-hydroxy-8-methoxy-4H-chromen-4-one (7)

[0252] To a stirred solution of (E(2-hydroxy-3-methoxy-4- (methoxymethoxy)phenyl)prop-2-en-1-one (0.53 g, 1.51 mmol) in DMSO (6 mL) was added iodine (19 mg, 0.07 mmol) at room temperature. The reaction mixture was stirred at 120 °C for 3.5 h. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature, poured into ice-cold water, and stirred for 10 min. The residue obtained was filtered, washed with ice- cold water, and dried to get the crude product. The crude product was purified by preparative HPLC using the formic acid method to obtain the 2-(3,4-difluorophenyl)-7-hydroxy-8-methoxy-4H-chromen-4-one (20 mg, 0.06 mmol, 4% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.71 (s, 1H), 67Attorney Docket No.93033-425510 8.17 – 8.12 (m, 1H), 7.97 – 7.94 (m, 1H), 7.74 – 7.63 (m, 2H), 7.02 – 7-01 (m, 2H), 3.95 (s, 3H) ppm; MS (ESI) m / z: 305.0 (M+1)+. Example 8 Preparation of 7-hydroxy-8-methoxy-1-methyl-2-phenylquinolin-4(1H)-one (8).

[0253] Step-1: Synthesis of 1-(2-hydroxy-4-methylphenyl)-3-phenylprpane-1,3-dione.

[0254] To an ethyl 3-oxo-3-phenmol) was added 3-bromo-2- methoxyaniline (2.10 g, 10.41 mmol) followed by the addition of indium (III) chloride (0.23 g, 1.04 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was diluted with water (40 mL) and was extracted with ethyl acetate (3 × 40 mL). All the combined organic layers were dried over Na2SO4& concentrated under reduced pressure to get crude. Crude was purified by normal phase column chromatography using petroleum ether / ethyl acetate as an eluent. The desired product was eluted at 2% ethyl acetate in petroleum ether to get a pure (Z)-3-((3- bromo-2-methoxyphenyl)amino)-3-phenylacrylate (1.2 g, 3.03 mmol, 29% yield) as a white solid. MS (ESI) m / z: 376.1 (M+1)+. 68Attorney Docket No.93033-425510

[0255] Step-2: Synthesis of 7-bromo-8-methoxy-2-phenylquinolin-4(1H)-one

[0256] To a stirred solution of ethy ethoxyphenyl)amino)-3-phenylacrylate (1.1 g, 2.92 mmol) with PPA (10 g, 102mmol) at room temperature. The reaction mixture was allowed to stir at 100 °C for 16 h. The reaction mixture was cooled to 0 °C and was quenched with ice water (50 mL). The precipitates were collected by filtration and washed with water (3 × 25 mL) to get crude. Crude was purified by trituration using n-Pentane (3 × 10 mL) to get pure 7-bromo-8-methoxy-2- phenylquinolin-4(1H)-one (1.1 g, 2.82 mmol, 97% yield) as a white solid. MS (ESI) m / z: 330.2 (M+1)+.

[0257] Step-3: Synthesis of 7-bromo-8-methoxy-1-methyl-2-phenylquinolin-4(1H)-one

[0258] To a stirred solution of 7-b ylquinolin-4(1H)-one (1.1 g, 3.33 mmol)with DMF (11 mL) and was added K2CO3(0.69 g, 5 mmol) followed by addition of methyl iodide (0.70 g, 5 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was quenched with ice water (25 mL) & was extracted with ethyl acetate (3 × 25 mL). All the combined organic layers were dried over Na2SO4, and concentrated under reduced pressure to get crude. Crude was purified by normal phase column chromatography using petroleum ether / ethyl acetate as an eluent. The desired product was eluted at 10% ethyl acetate in petroleum ether to get pure 7- bromo-8-methoxy-1-methyl-2-phenylquinolin-4(1H)-one (630 mg, 1.81 mmol, 54% yield) as a brown solid.1H-NMR (400 MHz, DMSO-d6): δ 8.35 – 8.31 (s, 3H), 7.80 (d, J = 12 Hz, 1H), 7.58 – 7.53 (m, 5H), 4.20 (s, 3H), 4.18 (s, 3H). MS (ESI) m / z: 344.2 (M+1)+.

[0259] Step 4: Synthesis of 7-hydroxy-8-methoxy-1-methyl-2-phenylquinolin-4(1H)-one (8).69Attorney Docket No.93033-425510

[0260] To a stirred solution of 7-bromo-8-methoxy-1-methyl-2-phenylquinolin-4(1H)-one (300 mg, 0.87 mmol) with dioxane (6 mL), and was added KOH (147 mg, 2.61 mmol) in water (4 mL) at room temperature. The reaction mixture was purged with N2gas for 15 min. Then, was added tBuBrettphos Pd G3 (37.2 mg, 0.044 mmol) at room temperature. The reaction mixture was allowed to stir in a microwave at 120 °C for 2 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to get crude. The crude was purified by normal phase column chromatography using petroleum ether / ethyl acetate as an eluent. The desired product was eluted at 50% ethyl acetate in petroleum ether to get pure 7-hydroxy-8-methoxy-1-methyl-2-phenylquinolin-4(1H)-one (217 mg, 0.77 mmol, 88% yield) as an off white solid.1H-NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 8.31 (d, J = 1.6 Hz, 2H), 7.73 (d, J = 9.2 Hz, 1H), 7.58 – 7.53 (m, 2H), 7.52 – 7.50 (m, 1H), 7.39 (s, 1H), 7.15 (d, J = 8.8 Hz, 1H), 4.12 (s, 3H), 4.07 (s, 3H). MS (ESI) m / z: 282.1 (M+1)+. Example 10 Preparation of 6,8-difluoro-7-hydroxy-2-phenyl-4H-chromen-4-one (10).

[0261] Step-1: Synthesis of 2,4-difluorobenzene-1,3-diol

[0262] To a stirred solution of 1,3-dimorobenzene (2.3 g, 13.21 mmol) in DCM (80 mL) was added BBr3(1M in DCM, 52.8 mL, 52.8 mmol,) dropwise under nitrogen atmosphere at 0oC. The reaction was stirred at ambient temperature for 28 hours. Upon completion, the reaction mixture was quenched with ice-cold water (dropwise) at 0oC. The mixture was subsequently stirred until all precipitate dissolved completely. DCM layer was seperated, and the water layer was extracted with ethyl 70Attorney Docket No.93033-425510 acetate. The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4and concentrated under vacuum. The resulting crude product was purified by normal phase flash chromatography using 30% ethyl acetate in petroleum ether to get the 2,4-difluorobenzene-1,3-diol (1.6 g, 10.84 mmol, 82% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 9.93 (s, 1H), 9.57 (s, 1H), 6.80 – 6.75 (m, 1H), 6.37 – 6.31 (m, 1H) ppm; LC-MS no ionisation is observed.

[0263] Step-2: Synthesis of 1-(3,5-difluoro-2,4-dihydroxyphenyl)ethan-1-one

[0264] Acetic acid (123 mg, 2.05 mm pwise to a mixture of 2,4-difluorobenzene-1,3-diol (150 mg, 1.027 mmol) in BF3.OEt2(2 mL, 15.78 mmol). The mixture was stirred at 90 °C for 16 h. After the completion of the reaction, the mixture was allowed to cool and poured in a cold 10% solution of NaOAc in water (3 mL). The mixture was stirred for 2 h and extracted with ethyl acetate (2 × 25 mL). The combined organic layers were washed with water (25 mL), brine solution (25 mL), dried over anhydrous Na2SO4and concentrated under vacuum to get the crude product. The crude was purified by normal phase flash chromatography using 30% ethyl acetate in petroleum ether to obtain 1-(3,5- difluoro-2,4-dihydroxyphenyl) ethan-1-one (175 mg, 0.846 mmol, 82% yield) as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 12.29 (s, 1H), 11.65 (s, 1H), 7.65 (dd, J = 12, 2.40 Hz, 1H), 2.57 (s, 3H) ppm; MS (ESI) m / z: 187.1 (M-1)-

[0265] Step-3: Synthesis of (E)-1-(3,5-difluoro-2,4-dihydroxyphenyl)-3-phenylprop-2-en-1-one

[0266] To a mixture of 1-(3,5-di)ethan-1-one (140 mg, 0.74 mmol) and benzaldehyde (158 mg, 1.48 mmol) in ethanol (0.5 mL), 50% aqueous solution of potassium hydroxide (0.5 mL, 0.744 mmol) was added dropwise and kept at ambient temperature for 10 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was poured into ice-cold water and the residue obtained was filtered and dried to give the crude product (85 mg, 0.28 mmol, 39 %) as a yellow solid. The resulting crude product was used in the next step without further purification. MS (ESI) m / z: 275.0 (M-1)-

[0267] Step-4: Synthesis of 6,8-difluoro-7-hydroxy-2-phenyl-4H-chromen-4-one (10) 71Attorney Docket No.93033-425510

[0268] To a solution of (E)-1-(3, henyl)-3-phenylprop-2-en-1-one (85 mg,0.308 mmol) in DMSO (2 mL), was added iodine (3.90 mg, 0.01 mmol) at room temperature. The reaction mixture was stirred at 120 °C for 3 hours. After the completion of the reaction as indicated by TLC, the reaction mixture was poured into ice-cold water and the residue obtained was filtered, washed with MeOH, and dried to give the 6,8-difluoro-7-hydroxy-2-phenyl-4H-chromen-4-one (64 mg, 0.229 mmol, 74.3% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.89 (s, 1H), 8.07 – 8.04 (m, 2H), 7.64 – 7.54 (m, 4H), 7.03 (s, 1H) ppm; MS (ESI) m / z: 275.0 (M+1)+Example 11 Preparation of 2-(4-ethoxy-3-fluorophenyl)-7-hydroxy-8-methoxy-4H-chromen-4-one (11).

[0269] Sfluorophenyl)prop-2-en-1-one

[0270] To a mixture of 1-(2,n-1-one (0.5 g, 2.74 mmol) and 3,4- difluorobenzaldehyde (0.58 g, 4.12 mmol) in EtOH (5 mL), 50% aqueous KOH (1.54 g, 27.4 mmol) was added dropwise and kept at ambient temperature for 10 h. After completion of the reaction, the reaction 72Attorney Docket No.93033-425510 mixture was poured into ice-cold water, then acidified with 1.5 N HCl and stirred for 10 min. The residue obtained was filtered and dried to give the crude product. The crude product was purified by column chromatography using 50% ethyl acetate in petroleum ether as eluent to obtain the (E)-1-(2,4-dihydroxy- 3-methoxyphenyl)-3-(4-ethoxy-3-fluorophenyl)prop-2-en-1-one (150 mg, 0.19 mmol, 7% yield) as a yellow solid. MS (ESI) m / z: 333.1 (M+1)+.

[0271] Step 2: Synthesis of 2-(4-ethoxy-3-fluorophenyl)-7-hydroxy-8-methoxy-4H-chromen-4-one (11)

[0272] To a stirred solution of yphenyl)-3-(4-ethoxy-3-fluorophenyl)prop-2-en-1-one (0.13 g, 0.39 mmol) in DMSO (3 mL) was added iodine (4.96 mg, 0.02 mmol) at room temperature and then stirred at 120 °C for 3.5 h. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature and poured into ice-cold water, the residue obtained was filtered, washed with ice-cold water, and dried to get the crude product. The crude product was eluted with 40% ethyl acetate in petroleum ether as eluent to obtain the 2-(4-ethoxy-3- fluorophenyl)-7-hydroxy-8-methoxy-4H-chromen-4-one (20 mg, 0.05 mmol, 14% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H), 7.87 – 7.93 (m, 2H), 7.63 (t, J = 6.8 Hz, 1H), 7.39 (t, J = 8.8 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.92 (s, 1H), 4.21 (q, J = 6.8 Hz, 2H), 3.95 (s, 3H), 1.40 (t, J = 6.8 Hz, 3H). MS (ESI) m / z: 331.1 (M+1)+. Example 12 Preparation of 2-((8-methoxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)-N-methyl acetamide (12).

[0273] y y y p y mg, 0.93 mmol) in acetone (12 mL), was added potassium carbonate (258 mg, 1.86 mmol) followed by the addition of 2-bromo-N-methylacetamide (142 mg, 0.93 mmol) at room temperature. The reaction mixture was 73Attorney Docket No.93033-425510 stirred at 50 °C for 12 h under N2atmosphere. After completion of the reaction as indicated by TLC, the solvent was completely evaporated in a vacuum. The residual mass was dissolved in 10% methanol in DCM (50 mL) washed with water (25 mL), brine solution (25 mL), dried over anhydrous Na2SO4,and concentrated under reduced pressure to get the crude product. The crude product was purified by preparative HPLC to give 2-((8-methoxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)-N-methylacetamide (40 mg, 0.11 mmol, 13% yield) as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.11 – 8.08 (m, 2H), 8.02 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.65 – 7.61 (m, 3H), 7.17 (d, J = 9.2 Hz, 1H), 7.00 (s, 1H), 4.74 (s, 2H), 4.03 (s, 3H), 2.68 (d, J = 4.8 Hz, 3H). MS (ESI) m / z: 340.1 (M+1)+. Example 15 Preparation of 2-((8-methoxy-1-methyl-4-oxo-2-phenyl-1,4-dihydroquinolin-7-yl)oxy)-N- methylacetamide (15).

[0274] one (180 mg, 0.64 mmol) with acetone (10 mL), was added K2CO3(177 mg, 1.28 mmol) followed by addition of 2-bromo-N-methylacetamide (97 mg, 0.64 mmol) at room temperature. The reaction mixture was allowed to stir at 50 °C for 16 h. The reaction mixture was filtered and the solid was washed with DCM (30 mL). The filtrate was concentrated under reduced pressure to get crude. Crude was purified by normal phase column chromatography using petroleum ether / ethyl acetate as an eluent. The desired product was eluted at 60 % ethyl acetate in petroleum ether to get 2-((8-methoxy-1-methyl-4-oxo-2-phenyl-1,4- dihydroquinolin-7-yl)oxy)-N-methylacetamide (190 mg, 0.53 mmol, 84% yield) compound as an off- white solid.1H-NMR (400 MHz, DMSO-d6): δ 2.70 (s, J = 4.8 Hz, 3H), 3.13 (s, 3H), 4.15 (s, 3H), 4.67 (s, 2H), 7.35 (d, J = 9.2 Hz, 1H), 7.59 – 7.49 (m, 4H), 7.82 (s, 1H), 7.84 (s, 1H), 8.33 – 8.31 (m, 2H). MS (ESI) m / z: 353.1 (M+1)+. Example 16 Preparation of 8-methoxy-7-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one (16). 74Attorney Docket No.93033-425510

[0275] issolved inDMF (8 mL), to that potassium carbonate (309 mg, 2.23 mmol) was added followed by the dropwise addition of 1-chloro-2-methoxyethane (705 mg, 7.46 mmol) at room temperature. The reaction mixture was stirred for 4 h at 90 °C. After completion of the reaction, the reaction is indicated by TLC. The reaction mixture was poured into ice-cold water, and the residue obtained was filtered, washed with petroleum ether, and dried to get the 8-methoxy-7-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one (175 mg, 0.51 mmol, 69% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.10 – 8.08 (m, 2H), 7.77 (d, J = 8.8 Hz, 1H), 7.63 – 7.61 (m, 3H), 7.31 (d, J = 8.8 Hz, 1H), 6.99 (s, 1H), 4.35 – 4.32 (m, 2H), 3.99 (s, 3H), 3.76 – 3.74 (m, 2H), 3.36 (s, 3H). MS (ESI) m / z: 327.1 (M+1)+. Example 17 Preparation of 7-fluoro-5-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one (17).

[0276] , e75Attorney Docket No.93033-425510

[0277] A mixture of 5-fluorobenzene-1,3-diol (850 mg, 6.64 mmol) and cinnamoyl chloride (1.10 g, 6.64 mmol) was dissolved in BF3.OEt2(3.0 mL), at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 15 minutes. Upon completion, the reaction mixture was quenched with saturated NaHCO3solution (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water (30 mL), and brine solution (30 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get the crude product. The crude product was purified by normal phase flash chromatography using 8% ethyl acetate in petroleum ether to get the (E)-1-(4-fluoro-2,6-dihydroxyphenyl)-3-phenylprop-2-en-1-one (1.0 g, 3.83 mmol, 58% yield) as a yellow solid. MS (ESI) m / z: 259.0 (M+1)+

[0278] Step-2: Synthesis of 7-fluoro-5-hydroxy-2-phenyl-4H-chromen-4-one

[0279] To a solution of (E)-1-(4-fl yl)-3-phenylprop-2-en-1-one (1.0 g, 3.87mmol) in DMSO (8 mL) was added iodine (98 mg, 0.38 mmol) at 60 °C. The reaction mixture was allowed to stir at 120 °C for 4 h. After the completion of the reaction as indicated by TLC, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with water (50 mL), and brine solution (50 mL), dried over anhydrous Na2SO4,and concentrated under reduced pressure to get the crude product. The resulting crude product was purified by normal phase flash chromatography using 5% ethyl acetate in petroleum ether as an eluent to get the 7-fluoro-5-hydroxy-2-phenyl-4H-chromen-4-one (130 mg, 0.41 mmol, 10% yield) as an off-white solid. MS (ESI) m / z: 257.1(M+1)+

[0280] Step-3: Synthesis of 7-fluoro-5-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one (17)

[0281] 7-fluoro-5-hydroxy-2-ph0 mg, 0.50 mmol) was dissolved in DMF (2 mL) and a solution K2CO3(210 mg, 1.52 mmol) was added followed by the dropwise addition of 1-chloro-2-methoxyethane (480 mg, 5.07 mmol) at 0 °C. The reaction mixture was stirred at 80 °C for 16 h. After the completion of the reaction as indicated by TLC, water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with 76Attorney Docket No.93033-425510 water, and brine solution, and dried over anhydrous Na2SO4concentrated under reduced pressure to get the crude product. The resulting crude was purified by normal phase flash chromatography using 42% Ethyl acetate in Petroleum ether as an eluent followed by trituration with MTBE to get 7-fluoro-5-(2- methoxyethoxy)-2-phenyl-4H-chromen-4-one (75 mg, 0.21 mmol, 42% yield) as an off-white solid.1H- NMR (400 MHz, DMSO-d6): δ 8.07 – 8.05 (m, 2H), 7.62 – 7.55 (m, 3H), 7.21 (dd, J = 9.2, 2.4 Hz, 1H), 6.99 (dd, J = 12.2, 2.4 Hz, 1H), 6.8 (s, 1H), 424 (t, J = 4.4 Hz, 2H), 3.74 (t, J = 4.8 Hz, 2H), 3.38 (s, 3H) ppm; MS (ESI) m / z: 315.1(M+1)+Example 18 Preparation of 5-fluoro-7-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one (18).

[0282] To a stirred solution of 5-fluoro-7-hydroxy-2-phenyl-4H-chromen-4-one (0.5 g, 1.9 mmol) in DMF (10 mL), was added potassium carbonate (0.8 g, 5.8 mmol) and stirred for 10 min. Then added 1- chloro-2-methoxyethane (1.8 g, 19.5 mmol) slowly dropwise to the reaction mixture at 0 °C, and finally heated at 90 °C for 4 h in a vial. After completion of the reaction (as monitored by TLC), the reaction mixture was reverse quenched with ice-cold water and stirred for 10 min, then filtered the solids, top- washed with ice-cold water, and dried under suction to get the crude product. The crude product was purified by preparative HPLC using the formic acid method to obtain 5-fluoro-7-(2-methoxyethoxy)-2- phenyl-4H-chromen-4-one (0.07 g, 0.22 mmol, 11% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.08 – 8.10 (m, 2H), 7.57 – 7.62 (m, 3H), 7.10 (s, 1H), 6.96 (t, J = 0.8 Hz, 1H), 6.91 – 6.95 (m, 2H), 4.28 – 4.31 (m, 2H), 3.70 – 3.73 (m, 2H), 3.33 (d, J = 5.2 Hz, 1H) ppm; MS (ESI) m / z: 315.1 (M+1)+. Example 19 Preparation of N-(8-methoxy-4-oxo-2-phenyl-4H-chromen-7-yl)benzamide (19).77Attorney Docket No.93033-425510

[0283]

[0284] To a stirred solution of 3-brom nol (3.8 g, 18.72 mmol) was added borontrifluoride–acetic acid complex (12 mL, 18.72 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 2 hours. After completion, the mixture was cooled to room temperature and quenched with saturated NaHCO₃ solution (30 mL). The organic layer was extracted with ethyl acetate (3 × 40 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to afford the crude product. The crude was purified by normal-phase column chromatography using petroleum ether / ethyl acetate as eluent. The desired product was eluted at 0–4% ethyl acetate in petroleum ether to obtain 1-(4-bromo-2-hydroxy-3-methoxyphenyl)ethan-1-one (1.4 g, 4.284 mmol, 22.89% yield) as a colorless liquid. LCMS (ESI) m / z: 245.0 [M+H]⁺.

[0285] Step 2: Synthesis of (E)-1-(4-bromo-2-hydroxy-3-methoxyphenyl)-3-phenylprop-2-en-1-one

[0286] To a stirred solution of 1-thoxyphenyl)ethan-1-one (1.4 g, 5.72 mmol) in ethanol (5 mL) was added potassium hydroxide (KOH, 962 mg, 17.14 mmol) at room temperature. The reaction mixture was stirred for 10 min. Subsequently, benzaldehyde (1.21 g, 11.42 78Attorney Docket No.93033-425510 mmol) dissolved in ethanol (5 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was then directly distilled to afford a crude residue, which was acidified with dilute hydrochloric acid (15 mL). The organic components were extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure to yield a crude product. Purification by normal-phase column chromatography using petroleum ether / ethyl acetate as the eluent (0–8% ethyl acetate in petroleum ether) afforded (E)-1-(4-bromo-2-hydroxy-3-methoxyphenyl)-3-phenylprop-2-en-1- one (360 mg, 0.81 mmol, 14.19% yield) as a colorless liquid. LCMS (m / z): 335.0 (M+2)

[0287] Step 3: Synthesis of 7-bromo-8-methoxy-2-phenyl-4H-chromen-4-one

[0288] To a stirred solution of (E) -methoxyphenyl)-3-phenylprop-2-en-1-one (510 mg, 1.53 mmol) in dimethyl sulfoxide (DMSO, 5.0 mL) was added iodine (38.86 mg, 0.154 mmol) at 60 °C. The reaction mixture was stirred at 120 °C for 4 h. After completion, the mixture was diluted with water (10 mL), and the organic compounds were extracted with ethyl acetate (2 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure to afford a crude product. Purification by trituration with methyl tert-butyl ether (MTBE) and n-pentane yielded 7-bromo-8-methoxy-2-phenyl-4H-chromen-4-one (455 mg, 1.27 mmol, 83% yield) as a light yellow solid. LCMS (m / z): 333.0 (M+3)

[0289] Step 4: Synthesis of N-(8-methoxy-4-oxo-2-phenyl-4H-chromen-7-yl)benzamide (19)

[0290] A mixture of 7-bromon-4-one (90 mg, 0.27 mmol), benzamide (65.8 mg, 0.54 mmol), XPhos (12.96 mg, 0.027 mmol), Tris(dibenzylideneacetone)palladium(0) (12.44 mg, 0.014 mmol) and cesium carbonate (265 mg, 0.81 mmol) in toluene (2 mL) was heated 100 °C for 16 h. After the completion of the reaction, the reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to get residue. The residual mass was purified by column chromatography using 50% 79Attorney Docket No.93033-425510 ethyl acetate in petroleum ether to give the N-(8-methoxy-4-oxo-2-phenyl-4H-chromen-7-yl) benzamide as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 8.13 – 8.10 (m, 2H), 8.04 – 8.00 (m, 3H), 7.82 (d, J = 8 Hz, 1H), 7.65 – 7.64 (m, 4H), 7.63 – 7.56 (m, 2H), 7.07 (s, 1H), 4.11 (s, 3H). MS (ESI) m / z: 372.1 (M+1)+. Example 20 Preparation of 8-fluoro-7-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one (20). [0291 78mmol) in DMF (3 mL) was added K2CO3(324 mg, 2.34 mmol) followed by addition of 1-bromo-2- methoxyethane (119 mg, 0.86 mmol) at room temperature. The reaction mixture was allowed to stir at 90 °C for 3 h. After the completion of the reaction. the reaction mixture was diluted with ice-cold water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with water (20 mL), and brine solution (20 mL), dried over anhydrous Na2SO4,and concentrated under reduced pressure to get the crude product. The resulting crude product was purified by preparative HPLC to get the 8-fluoro-7-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one (100 mg, 0.31 mmol, 41% yield) as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.08 – 8.05 (m, 2H), 7.81 (dd, J = 9.2, 2.0 Hz 1H), 7.64 – 7.59 (m, 3H), 7.43 – 7.38 (m, 1H), 7.03 (s, 1H), 4.40 – 4.38 (m, 2H), 3.75 – 3.73 (m, 2H), 3.34 (s, 3H). MS (ESI) m / z: 315.1 (M+1)+. Example 22 Preparation of 2-(3,5-dichlorophenyl)-5-hydroxy-8-methoxy-7-(2-methoxyethoxy)-4H-chromen-4- one (22).80Attorney Docket No.93033-425510

[0292] To a stirred solution of 2-(3,5-dichlorophenyl)-5,7-dihydroxy-8-methoxy-4H-chromen-4-one (50 mg, 0.14 mmol) in DMF (1 mL) was added potassium carbonate (58.7 mg, 0.42 mmol) followed by the dropwise addition of 1-chloro-2-methoxyethane (134 mg, 1.41 mmol). The reaction mixture was stirred at 90 °C for 16 h. After the completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with water, and brine solution, dried over anhydrous Na2SO4,and concentrated under vacuum to get the crude. The crude product was purified by normal phase column chromatography using 10% ethyl acetate in petroleum ether to get the 2-(3,5-dichlorophenyl)-5-hydroxy-8-methoxy-7-(2-methoxyethoxy)-4H- chromen-4-one (13 mg, 0.03 mmol, 18% yield) as a pale-yellow solid.1H-NMR (400 MHz, DMSO- d6): δ 12.45 (s, 1H), 8.09 (d, J = 1.2 Hz, 2H), 7.92 (s, 1H), 7.23 (s, 1H), 6.66 (s, 1H), 4.29 (t, J = 5.2 Hz, 2H ), 3.86 (s, 3H), 3.72 (t, J = 5.2 Hz, 2H), 3.34 (s, 3H). MS (ESI) m / z: 320.0 (M+1)+. Example 23 Preparation of N-methyl-2-((4-oxo-2-phenyl-4H-chromen-7-yl)oxy)acetamide (23).

[0293] To a stirred solution of 7-hydroxy-2-phenyl-4H-chromen-4-one (500 mg, 2.09 mmol) in DMF (3 mL) was added K₂CO₃ (870 mg, 6.30 mmol), followed by the addition of 2-bromo-N- methylacetamide (478 mg, 3.15 mmol) at 0 °C. The reaction mixture was stirred at 60 °C for 2 hours. After completion, the mixture was diluted with ice-cold water (20 mL), and the resulting solid precipitate was collected by filtration through a Büchner funnel to obtain the crude product. The crude was purified by trituration with n-pentane (4 × 5 mL) to afford N-methyl-2-((4-oxo-2-phenyl-4H-chromen-7- yl)oxy)acetamide (530 mg, 1.70 mmol, 81% yield) as a white solid.

[0294] ¹H-NMR (400 MHz, DMSO-d₆): δ 2.69–2.68 (d, J = 4.8 Hz, 3H), 4.67 (s, 2H), 6.98 (s, 1H), 7.16–7.13 (dd, J = 8.8, 2.4 Hz, 1H), 7.33–7.32 (d, J = 2.4 Hz, 1H), 7.62–7.59 (m, 3H), 8.00–7.98 (d, J = 8.8 Hz, 1H), 8.11–8.09 (m, 2H), 8.16–8.14 (m, 1H). MS (ESI) m / z: 310.1 [M+H]⁺. Example 24 Preparation of 2-((8-methoxy-4-oxo-2-(quinolin-6-yl)-4H-chromen-7-yl)oxy)-N-methylacetamide (24) 81Attorney Docket No.93033-425510

[0295] Step 1: Synthesis of (E)-1-(2-hydroxy-3-methoxy-4-(methoxymethoxy)phenyl)-3- (quinolin-6-yl)prop-2-en-1-one

[0296] l)ethan-1-one (500 mg, 2.21 mmol) in Ethanol (10 mL), was added KOH (744 mg, 6.63 mmol) in Water (1 mL) at 0°C and stirred for 10 minutes. Then was added quinoline-6-carbaldehyde (695 mg, 4.42 mmol) at the same temperature. The reaction mixture was allowed to be stirred at room temperature for 16h. The reaction mixture was concentrated under reduced pressure, then the residue was neutralized with 1.5 N HCl until solid precipitates fell out which was filtered through a Buchner funnel followed by washed with hexane, and dried to get the product (E)-1-(2-hydroxy-3-methoxy-4-(methoxymethoxy)phenyl)-3-(quinolin-6- yl)prop-2-en-1-one (600 mg, 1.199 mmol, 54.2 % yield) as a yellow solid. LCMS (m / z): 366.2 (M+1).

[0297] Step 2: Synthesis of 7-hydroxy-8-methoxy-2-(quinolin-6-yl)-4H-chromen-4-one (26) 82Attorney Docket No.93033-425510 [0 yl)-3-(quinolin-6-yl)prop-2-en-1-one (600 mg, 1.642 mmol) in DMSO (7 mL) and was added iodine (41.7 mg, 0.164 mmol) at 60°C. The reaction mixture was allowed to be stirred at 120°C for 2h. The reaction mixture was poured into ice-cold water (30mL) and the solids were precipitated out, which was filtered through the Buchner funnel to get crude. Crude was triturated with MTBE and ACN to get 7-hydroxy-8-methoxy-2- (quinolin-6-yl)-4H-chromen-4-one (410 mg, 1.117 mmol, 68.0 % yield) as green greyish solid. LCMS (m / z): 320.0(M+1).1H-NMR (400 MHz, DMSO-d6): δ 4.03 (s, 3H), 7.06 (d, J =11.6Hz, 1H), 7.12 (s, 1H), 7.69-7.65 (m, 2H), 8.21 (d, J =12.0Hz, 1H), 8.40 (dd, J =11.6Hz, 2.4Hz, 1H), 8.60 (d, J =10.8Hz, 1H), 8.74 (d, J = 2.0Hz, 1H), 9.03 (d, J = 3.6Hz, 1H), 10.66 (s, 1H).

[0299] Step 3: Synthesis of 2-((8-methoxy-4-oxo-2-(quinolin-6-yl)-4H-chromen-7-yl)oxy)-N- methylacetamide (24)4 g, 1.14 mmol) in acetone (12 mL), was added potassium carbonate (0.47 g, 3.42 mmol) and stirred for 10 min. Then 2-bromo-N-methylacetamide (0.17 g, 1.14 mmol) was added slowly dropwise to the reaction mixture at 0 °C, and the reaction mixture was heated at 50 °C for 16 h. After completion of the reaction as monitored by LCMS, the reaction mixture was poured onto ice-cold water and stirred for 10 min. The residue obtained was filtered, washed with ice-cold water followed by n-pentane, and dried to obtain the 2-((8-methoxy-4- oxo-2-(quinolin-6-yl)-4H-chromen-7-yl)oxy)-N-methylacetamide (0.25 g, 0.62 mmol, 54% yield) as a yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 9.03 – 9.04 (m, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.60 (d, J = 8.0 Hz, 1H), 8.39 – 8.42 (m, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 3.2 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.66 – 7.69 (m, 1H), 7.20 (d, J = 8.4 Hz, 2H), 4.76 (s, 2H), 4.10 (s, 3H), 2.69 (d, J = 4.4 Hz, 3H). MS (ESI) m / z: 391.1 (M+1)+. 83Attorney Docket No.93033-425510 Example 25 / Example 36 Preparation of 5,7-dihydroxy-8-methoxy-2-(quinolin-6-yl)-4H-chromen-4-one (25) and 7-hydroxy- 5,8-dimethoxy-2-(quinolin-6-yl)-4H-chromen-4-one (36) [03in-6- yl)prop-2-en-1-one

[0302] To a stirred solution o-dimethoxyphenyl)ethan-1-one (300 mg, 0.99 mmol) and ethanol (5 mL), followed by the addition of quinoline-6-carbaldehyde (156 mg, 0.99 mmol) at room temperature. The reaction mixture was allowed to be stirred for 10 min. After this was added, NaOH (119 mg, 2.98 mmol) dissolved in water (2 mL) dropwise at 0 °C. The reaction mixture was allowed to be stirred at room temperature for 16 h. The reaction mixture was diluted with water (5 mL) and acidified (pH up to ~5) by 1N HCl solution (3.8 mL). The solid were precipitate out which was filtered through a buchner funnel and washed with ethanol (2 × 4 mL) to get (E)-1-(4-(benzyloxy)-2- hydroxy-3,6-dimethoxyphenyl)-3-(quinolin-6-yl)prop-2-en-1-one (290 mg, 0.62 mmol, 63% yield) as a yellow solid. MS (ESI) m / z: 442.1 (M+1)+.

[0303] Step 2: Synthesis of 7-(benzyloxy)-5,8-dimethoxy-2-(quinolin-6-yl)-4H-chromen-4-one 84Attorney Docket No.93033-425510

[0304] To a stirred solution of y-3,6-dimethoxyphenyl)-3-(quinolin-6- yl)prop-2-en-1-one (290 mg, 0.65 mmol) with DMSO (3 mL) and was added iodine (16.6 mg, 0.06 mmol) at 60 °C. The reaction mixture was allowed to be stirred at 120 °C for 4 h. The reaction mixture was poured into ice-cold water (10 mL) and the solid was precipitated out, which was filtered through a buchner funnel to get 7-(benzyloxy)-5,8-dimethoxy-2-(quinolin-6-yl)-4H-chromen-4-one (260 mg, 0.53 mmol, 81% yield) as a brown solid. MS (ESI) m / z: 440.2 (M+1)+.

[0305] Step 3: 7-hydroxy-5,8-dimethoxy-2-(quinolin-6-yl)-4H-chromen-4-one_(36) and 5,7- dihydroxy-8-methoxy-2-(quinolin-6-yl)-4H-chromen-4-one_(25)

[0306] To a stirred solution of 7-(benzyloxy)-5,8-dimethoxy-2-(quinolin-6-yl)-4H-chromen-4-one (260 mg, 0.59 mmol) with glacial acetic acid (3.6 mL) and was added conc. HCl (1.2 mL) at room temperature. The reaction was allowed to be stirred at 80 °C for 13 h. The reaction mixture was directly evaporated and purified by preparative HPLC to afford 7-hydroxy-5,8-dimethoxy-2-(quinolin-6-yl)-4H- chromen-4-one (59 mg, 0.16 mmol, 28% yield) and 5,7-dihydroxy-8-methoxy-2-(quinolin-6-yl)-4H- chromen-4-one (5 mg, 0.01 mmol, 2% yield) as light-yellow solid.

[0307] 36:1H-NMR (400 MHz, DMSO-d6): δ 3.79 (s, 3H), 3.93 (s, 3H), 6.51 (s, 1H), 6.95 (s, 1H), 7.67 – 7.64 (dd, J = 4.4, 4.4 Hz, 1H), 8.18 – 8.16 (d, J = 8.8 Hz, 1H), 8.35 – 8.33 (dd, J = 2.0, 2.0 Hz, 1H), 8.57 – 8.55 (m, 1H), 8.69 – 8.68 (d, J = 2 Hz, 1H), 9.02 – 9.00 (dd, J = 2.0, 1.6 Hz, 1H), 10.64 (s, 1H). MS (ESI) m / z: 350.0 (M+1)+.

[0308] 25:1H-NMR (400 MHz, DMSO-d6): δ 3.93 (s, 3H), 6.35 (s, 1H), 7.19 (s, 1H), 7.69 – 7.66 (dd, J = 4.0, 4.4 Hz, 1H), 8.22 – 8.20 (d, J = 8.8 Hz, 1H), 8.40 – 8.38 (dd, J=2.0, 2.0 Hz, 1H), 8.60 – 8.58 (d, J = 7.6 Hz, 1H), 8.77 – 8.76 (d, J = 2 Hz, 1H), 9.04 – 9.03 (dd, J = 1.6, 1.6 Hz, 1H), 10.87 (s, 1H), 12.50 (s, 1H). MS (ESI) m / z: 336.0 (M+1)+. Example 28 Preparation of 7-hydroxy-8-methoxy-2-(pyridin-3-yl)-4H-chromen-4-one (28) 85Attorney Docket No.93033-425510

[0309] Step 1: (E)-1-(2-hydroxy-3-methoxy-4-(methoxymethoxy)phenyl)-3-(pyridin-3-yl)prop-2-en- 1-one.

[0310] To a mixture of 1-(2-h ethoxy)phenyl)ethan-1-one (0.5 g,2.21 mmol) and nicotinaldehyde (0.47 g, 4.42 mmol) in ethanol (12 mL), solution of KOH (0.74 g, 6.63 mmol) in water (1.5 mL) was added dropwise and kept at ambient temperature for 16 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure, acidified with 1.5 N HCl, and stirred for 10 minutes, the residue obtained was filtered, washed with ice-cold water followed by hexane wash, and dried under reduced pressure to get the desired product (E)-1 (2-hydroxy-3-methoxy-4-(methoxymethoxy)phenyl)-3-(pyridin- 3-yl)prop-2-en-1-one (0.6 g, 1.65 mmol, 75% yield) as yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 13.01 (s, 1H), 9.05 (s, 1H), 8.64 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 8.39 (dd, J = 8 Hz, 1.6 Hz, 1H), 8.16 – 8.09 (m, 2H), 7.85 (d, J = 20 Hz, 1H), 7.53 – 7.50 (m, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.3 (s, 2H), 3.7 (s, 3H), 3.4 (s, 3H). MS (ESI) m / z: 316.1 (M+1)+.

[0311] Step 2: 7-hydroxy-8-methoxy-2-(pyridin-3-yl)-4H-chromen-4-one (28). 86Attorney Docket No.93033-425510

[0312] To a stirred solution of (E)-1-(2-hydroxy-3-methoxy-4-(methoxymethoxy)phenyl)-3-(pyridin- 3-yl)prop-2-en-1-one (0.5 g, 1.42 mmol) in DMSO (5 mL), and was added iodine (0.036 g, 0.14 mmol) at room temperature and then stirred at 120 °C for 3 h. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature, poured into ice-cold water, and stirred for 10 min. Then the solid obtained was filtered, washed with ice-cold water, and dried under suction to get the crude product. The crude product was purified by preparative HPLC using the FA method to obtain the 7- hydroxy-8-methoxy-2-(pyridin-3-yl)-4H-chromen-4-one (0.04 g, 0.14 mmol, 10% yield) as a yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 9.25 (d, J = 1.6 Hz, 1H), 8.79 – 8.78 (m, 1H), 8.44 – 8.41 (m, 1H), 7.67 – 7.63 (m, 2H), 7.04 – 7.02 (t, J = 8.8 Hz, 2H), 3.96 (s, 3H). MS(ESI) m / z: 270.1 (M+1)+. Example 29 Preparation of 7-hydroxy-8-methoxy-2-(2-methylpyridin-4-yl)-4H-chromen-4-one (29)

[0313] p y y y y y y p y 3-(2- methylpyridin-4-yl)prop-2-en-1-one 87Attorney Docket No.93033-425510

[0314] To a stirred solution oxymethoxy)phenyl)ethan-1-one (100 mg, 0.44 mmol) in EtOH (1mL), 50% aq. KOH solution (KOH 223 mg, 3.98 mmol, in 1 mL H2O) was added. The reaction mixture was stirred at room temperature for 30 min. 2-methylisonicotinaldehyde (80 mg, 0.66 mmol) was then added to the reaction, and the resulting mixture was stirred at room temperature for 16 h. Excess ethanol was completely removed under vacuum and the reaction mixture was added into ice-cold water, acidified with 1.5 N HCl solution, and extracted with ethyl acetate (2 × 25 mL). The combined organic layer was washed with water (25 mL), and brine solution (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get the crude product. The crude was purified by column chromatography using 10% ethyl acetate in petroleum ether to give (E)-1-(2-hydroxy-3-methoxy-4-(methoxymethoxy)phenyl)-3-(2-methylpyridin-4- yl)prop-2-en-1-one (35 mg, 0.098 mmol, 22.12 % yield) as a brown solid. MS (ESI) m / z: 330.2 (M+1)+

[0315] Step 2: Synthesis of 7-hydroxy-8-methoxy-2-(2-methylpyridin-4-yl)-4H-chromen-4-one (29)

[0316] A mixture of (E)-1-(2-hyymethoxy)phenyl)-3-(2-methylpyridin- 4-yl)prop-2-en-1-one (35 mg, 0.10 mmol) and iodine (2 mg, 5.31 µmol) was heated in DMSO (2 mL) at 120 °C for 3 h. The progress of the reaction was monitored by TLC using ethyl acetate / petroleum ether (2:3) as an eluent. Upon completion of the reaction, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with 10% Na2S2O3solution (30 mL), water (30 mL), and brain solution (30 mL), dried over anhydrous, and concentrated under reduced pressure to get the crude product. The crude product was purified by preparative HPLC to give the 7-hydroxy-8-methoxy-2-(2-methylpyridin-4-yl)-4H-chromen-4-one (4 mg, 0.014 mmol, 13% yield) as a yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 8.57 (d, J = 4.8 Hz, 1H), 7.66 (d, J = 5.6 Hz, 2H), 7.33 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 5.2 Hz, 2H), 4.01 (s, 3H), 2.52 (s, 3H). MS (ESI) m / z: 284.1(M+1)+. Example 30 Preparation of 7-hydroxy-8-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4H-chromen-4-one (30). 88Attorney Docket No.93033-425510 l)prop-2-en-1-one.

[0318] A mixture of 1-(2,4-dih an-1-one (500 mg, 2.74 mmol) and 1-methyl 1H-pyrazole-4-carbaldehyde (453 mg, 4.12 mmol) in EtOH (3 mL), 50% aq. KOH solution (1.5 g KOH dissolved in 3 mL H2O) was added dropwise and kept at room temperature for 16 h. Upon completion of the reaction, the reaction was poured into ice-cold water, acidified with 1.5N HCL, and the solid obtained was filtered and dried to get the (E)-1-(2,4-dihydroxy-3-methoxyphenyl)-3-(1-methyl-1H- pyrazol-4-yl) prop-2-en-1-one (380 mg, 1.05 mmol, 38% yield) as a yellow solid. MS (ESI) m / z: 275.2 (M+1)+.

[0319] Step 2: Synthesis of 7-hydroxy-8-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4H-chromen-4-one (30).

[0320] A mixture of (E)-1-(2,4-dihydroxy-3-methoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl) prop-2- en-1-one (380 mg, 1.38 mmol), iodine (18 mg, 0.07 mmol) was added in DMSO (2 mL) and stirred at 120 °C for 3 h. Upon completion of the reaction, the reaction mixture was poured into ice-cold water, and the residue obtained was filtered, washed with petroleum ether and dried to get the 7-hydroxy-8-methoxy-2- (1-methyl-1H-pyrazol-4-yl)-4H-chromen-4-one (240 mg, 0.87 mmol, 63% yield) as an off white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.50 (s, 1H), 8.44 (s, 1H), 8.11 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.61 (s, 1H), 3.94 (s, 3H), 3.93 (s, 3H) ppm; MS m / z 273.1 (M+1)+. Example 31 Preparation of (E)-1-(3-fluoro-2,4-dihydroxyphenyl)-3-phenylprop-2-en-1-one (31). 89Attorney Docket No.93033-425510 -en-1- one

[0322] To a mixture of 1-(2,4-di ethan-1-one (0.5 g, 2.74 mmol) andthiazole-4-carbaldehyde (0.466 g, 4.12 mmol) in ethanol (2 mL), 50% aq. potassium hydroxide (2 mL, 2.74 mmol) was added and stirred at ambient temperature for 10 h. After the completion of the reaction as indicated by TLC, the reaction mixture was poured into ice-cold water and the residue obtained was filtered and dried to get the crude product (310 mg, 0.96 mmol, 35% yield) as a yellow solid. The resulting crude product was used in the next step without further purification. MS (ESI) m / z: 278.0 (M+1)+.

[0323] Step 2: Synthesis of (E)-1-(3-fluoro-2,4-dihydroxyphenyl)-3-phenylprop-2-en-1-one (31)

[0324] A mixture of (E)-1-(2,4-diyl)-3-(thiazol-4-yl)prop-2-en-1-one (250 mg, 0.90 mmol) and iodine (11.4 mg, 0.045 mmol) was stirred in DMSO (3 mL) at 120 °C for 3 h. After the reaction was completed, the reaction mixture was poured into ice-cold water and the residue obtained was filtered, washed with petroleum ether, and dried to give the 7-hydroxy-8-methoxy-2-(thiazol-4-yl)- 4H-chromen-4-one (219 mg, 0.70 mmol, 78% yield) as brown solid.1H-NMR (400 MHz, DMSO-d6): δ 10.80 (bs, 1H), 9.34 (d, J = 1.6 Hz, 1H), 8.49 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.85 (s, 1H), 3.97 (s, 3H); MS (ESI) m / z: 276.0 (M+1)+. Example 32 Preparation of 2-cyclopentyl-7-hydroxy-8-methoxy-4H-chromen-4-one (32). 90Attorney Docket No.93033-425510

[0325] necarboxylate.

[0326] To a stirred solution of 1-(methoxymethoxy)phenyl)ethan-1-one (1.0 g, 4.42 mmol) in DCE (10 mL) was added DMAP (810 mg, 6.64 mmol) followed by the drop wise addition of cyclopentanecarbonyl chloride (1.17 g, 8.84 mmol) dissolved in DCE (5 mL) at room temperature. The reaction mixture was allowed to stir at room temperature for 20 h. Upon completions, the solvent was evaporated under reduced pressure and the residue was dissolved in DCM (2 × 25 mL) and washed with water (25 mL), brine solution (25 mL), dried over anhydrous Na2SO4, concentrated under vacuum to get the crude product. The crude product was purified by normal phase flash chromatography using 21% ethyl acetate in petroleum ether to get 6-acetyl-2-methoxy-3- (methoxymethoxy)phenyl cyclopentanecarboxylate (535 mg, 1.42 mmol, 32% yield) as a colorless liquid. MS (ESI) m / z: 279.2 (M+1)+LCMS showed Without MOM protecting group.

[0327] Step-2: Synthesis of 1-cyclopentyl-3-(2-hydroxy-3-methoxy-4- (methoxymethoxy)phenyl)propane-1,3-dione 91Attorney Docket No.93033-425510

[0328] To a solution of 6-acety xy)phenyl cyclopentanecarboxylate (530 mg, 1.9 mmol) in pyridine (5.5mL) was added potassium tert-butoxide (283 mg, 2.47 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 16 h. After the completion of the reaction, the reaction mixture was acidified with 1.5 N HCl and extracted with ethyl acetate (2 × 25 mL). The combined organic layer was washed with water (25 mL), brine solution (25 mL), dried over anhydrous Na2SO4and concentrated under vacuum to get crude 1-cyclopentyl-3-(2-hydroxy-3-methoxy- 4-(methoxymethoxy)phenyl)propane-1,3-dione (750 mg, 0.29 mmol, 15% yield) as brownish semi-solid. The resulting crude product was used in the next step without further purification. MS (ESI) m / z: 323.0 (M+1)+

[0329] Step-3: Synthesis of 2-cyclopentyl-7-hydroxy-8-methoxy-4H-chromen-4-one (32)

[0330] To a solution of 1-cyclopehoxy-4- (methoxymethoxy)phenyl)propane-1,3-dione (750 mg, 2.32 mmol) in AcOH (16.5 mL, 2.32 mmol) was treated with Con. HCl (2 mL, 2.32 mmol) dropwise at room temperature. The reaction mixture was allowed to stir at 100 °C for 16 h. The reaction mixture was completely evaporated under reduced pressure to removal of acetic acid, then it was neutralized with saturated NaHCO3solution (20 mL) at 0 °C and extracted with ethyl acetate (3 × 35 mL). The combined organic layers were washed with water, brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to get the crude. The crude product was purified by normal phase flash chromatography using 20% ethyl acetate in petroleum ether as eluent to get pure 2-cyclopentyl-7-hydroxy-8-methoxy-4H-chromen-4-one (40 mg, 0.14 mmol, 6% yield) as an off- white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H), 7.58 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.11 (s, 1H), 3.01 (s, 3H), 3.14 – 3.06 (m, 1H), 2.05 – 1.99 (m, 2H), 1.81 – 1.66 (m, 6H) ppm; MS (ESI) m / z: 261.1 (M+1)+Example 33 Preparation of 2-cyclohexyl-7-hydroxy-8-methoxy-4H-chromen-4-one (33) 92Attorney Docket No.93033-425510

[0331] cyclohexanecarboxylate

[0332] To a stirred solution of 1-((methoxymethoxy)phenyl)ethan-1-one (1 g, 4.42 mmol) with DCE (5 mL) and was added DMAP (810 mg, 6.63 mmol) followed by addition of cyclohexanecarbonyl chloride (1.29 g, 8.84 mmol) dissolved in DCE (5 mL) at room temperature. The reaction mixture was allowed to be stirred at room temperature for 20 h. The reaction mixture was directly distilled under reduced pressure to get crude. Crude was purified by normal phase flash chromatography using ethyl acetate in petroleum ether as an eluent. The desired product was eluted at 16% Ethyl acetate in petroleum ether to get 6-acetyl-2-methoxy-3-(methoxymethoxy)phenyl cyclohexanecarboxylate (1.1 g, 2.38 mmol, 54% yield) as a colorless liquid. MS (ESI) m / z: 293.2 (M+1)+LCMS showed Without MOM m / z)

[0333] Step-2: Synthesis of 1-cyclohexyl-3-(2-hydroxy-3-methoxy-4- (methoxymethoxy)phenyl)propane-1,3-dione93Attorney Docket No.93033-425510

[0334] To a stirred solution of 6-acetyl-2-methoxy-3-(methoxymethoxy)phenyl cyclohexanecarboxylate (1.1 g, 3.76 mmol) with pyridine (11 mL) and was added potassium tert-butoxide (560 mg, 4.89 mmol) at room temperature. The reaction mixture was allowed to be stirred at 60 °C for 16 h. The reaction mixture was directly distilled under reduced pressure to get crude 1-cyclohexyl-3-(2- hydroxy-3-methoxy-4-(methoxymethoxy)phenyl)propane-1,3-dione (1.7 g, 1.2 mmol, 32% yield) as a brownish semi-solid. Here Crude was used in the next step without any purification. MS (ESI) m / z: 337.2 (M+1)+

[0335] Step-3: Synthesis of 2-cyclohexyl-7-hydroxy-8-methoxy-4H-chromen-4-one (33)

[0336] To a stirred solution of 1-c-3-methoxy-4- (methoxymethoxy)phenyl)propane-1,3-dione (1.7 g, 5.06 mmol) with AcOH (25 mL) and was added Con. HCl (3 mL) dropwise at room temperature. Con.HCl:AcOH (1:8.3 ratio). The reaction mixture was allowed to be stirred at 100 °C for 16 h. The reaction mixture was directly distilled under reduced pressure to remove AcOH, then it was neutralized with NaHCO3solution (30 mL), and the Organic layer was extracted with ethyl acetate (3 × 50 mL), All the combined organic layers were dried over anhydrous Na2SO4, and concentrated under reduced pressure to get the crude. Crude was purified by normal phase flash chromatography using ethyl acetate in petroleum ether as an eluent. The desired product was eluted at 18% ethyl acetate in petroleum ether to get crude 2-cyclohexyl-7-hydroxy-8-methoxy-4H-chromen-4- one (390 mg, 0.63 mmol, 12% yield) as an off-white solid. Further, it was purified by Prep. HPLC to get pure 2-cyclohexyl-7-hydroxy-8-methoxy-4H-chromen-4-one (80 mg) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): 10.49 (s, 1H), 7.58 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.05 (s, 1H), 3.86 (s, 3H), 2.64 – 2.57 (m, 1H), 1.97 (d, J = 12.0 Hz, 2H), 1.83 (d, J = 12.4 Hz, 2H), 1.72 (d, J = 12.8 Hz, 1H), 1.52 – 1.22 (m, 5H) ppm; MS (ESI) m / z: 275.2 (M+1)+Example 35 Preparation of 6-fluoro-7-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one (35) 94Attorney Docket No.93033-425510

[0337] .97 mmol)in DMF (5 mL), was added potassium carbonate (0.40 g, 2.9 mmol) and stirred for 10 min. Then, was added 1-chloro-2-methoxyethane (0.92 g, 9.76 mmol) slowly dropwise to the reaction mixture at 0 °C, and finally heated at 90 °C for 3 h. After completion of the reaction (as monitored by TLC), the reaction mixture was reverse quenched with ice-cold water and stirred for 10 min. Then filtered the solids, were top-washed with ice-cold water followed by n-pentane, and dried under reduced pressure to obtain the title compound 6-fluoro-7-(2-methoxyethoxy)-2-phenyl-4H-chromen-4-one (0.02 g, 0.07 mmol, 24% yield) as a yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 8.10 – 8.13 (m, 2H), 7.73 (t, J = 4.4 Hz, 2H), 7.60 – 7.68 (m, 4H), 7.03 (s, 1H), 4.37 (d, J = 4.4 Hz, 2H), 3.76 – 3.78 (m, 2H), 3.35 (s, 3H). MS (ESI) m / z: 315.1 (M+1)+. Example 37 Preparation of 2-(4-fluorophenyl)-5,7-dihydroxy-8-methoxy-4H-chromen-4-one (37)95Attorney Docket No.93033-425510 en-1-one.

[0339] To a stirred solution of .1 mmol) in with ethanol (30 mL) andwas added 1-(2-hydroxy-4,6-dimethoxyphenyl)ethan-1-one (3.16 g, 16.1 mmol) at room temperature. The reaction mixture was allowed to be stirred for 10 min. After this, NaOH (1.93 g, 48.3 mmol) in water (4 mL) was added dropwise. The reaction mixture was allowed to be stirred at room temperature for 16 h. The reaction mixture was diluted with water (15 mL) and was acidified (pH up to ~5) by using 1N HCl solution (25 mL). The precipitates were collected by filtration and washed with EtOH (3 × 10 mL) and then dried in a vacuum to obtain pure (E)-3-(4-fluorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2- en-1-one (1.13 g, 3.73 mmol, 22% yield) as a yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 13.37 (s, 1H), 7.83 – 7.81 (m, 2H), 7.70 (q, J = 16 Hz, 2H), 7.29 (q, J = 16 Hz, 2H), 6.17 (d, J = 2 Hz, 1H), 6.13 (d, J = 2.4 Hz, 1H), 3.90 (s, 3H), 3.83 (s, 3H). MS (ESI) m / z: 302.9 (M+H)+.

[0340] Step 2: Synthesis of 2-(4-fluorophenyl)-5,7-dimethoxy-4H-chromen-4-one.

[0341] To a stirred solution of (ydroxy-4,6-dimethoxyphenyl)prop-2- en-1-one (930 mg, 3.08 mmol) with DMSO (9 mL) at 60 °C and was added iodine (18 mg, 0.08 mmol) at 60 °C. The reaction mixture was allowed to be stirred at 120 °C for 16 h. The reaction mixture was 96Attorney Docket No.93033-425510 diluted with water (15 mL). The precipitates were collected by filtration and washed with water (3 × 15 mL) to obtain pure 2-(4-fluorophenyl)-5,7-dimethoxy-4H-chromen-4-one (0.83 g, 2.76 mmol, 82% yield) as a light-yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 8.15 – 8.10 (m, 2H), 7.41 (t, J = 12 Hz, 2H), 6.88 (d, J = 2.8 Hz, 1H), 6.78 (s, 1H), 6.52 (d, J = 2.8 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H). MS (ESI) m / z: 300.9 (M+H)+.

[0342] Step 3: Synthesis of 2-(4-fluorophenyl)-5,7-dihydroxy-4H-chromen-4-one.

[0343] To a stirred solution of 2 methoxy-4H-chromen-4-one (720 mg,2.26 mmol) with DCM (10 mL) and was added BBr3(Neat) (3.0 mL 31.7 mmol) solution dropwise at 0 °C. The reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was cooled at 0 °C and was quenched with sat. NaHCO3solution (15 mL). The reaction mixture was extracted by DCM (3 × 25 mL) to obtain crude. Crude was purified by trituration using petroleum ether (3 × 10 mL) to obtain pure 2-(4-fluorophenyl)-5,7-dihydroxy-4H-chromen-4-one (0.55 g, 2.02 mmol, 74% yield) as a light brown solid. MS (ESI) m / z: 273.1 (M+H)+.

[0344] Step 4: Synthesis of 2-(4-fluorophenyl)-5,7-dihydroxy-4-oxo-4H-chromen-8-yl sulfate tetramethylammonium salt.

[0345] To a stirred solution of 2roxy-4H-chromen-4-one (0.55 g, 2.02 mmol) with water (10 mL), and was added tetramethylammonium hydroxide (1M solution in water) (20.2 mL, 20.2 mmol) at room temperature. After this, potassium persulfate (1.09 g, 4.04 mmol) was added portion-wise over 15 min. The reaction was allowed to stir at room temperature for 20 h. After reaction completion, add saturated potassium dihydrogen phosphate aqueous solution to adjust the pH of the mixture to neutral. The reaction mixture was then stirred at room temperature for another 16 h. After this, was added NaCl (10 eq) and stirred for 15 min. The precipitates were collected by filtration and dried through vacuum to obtain Crude. Crude was purified by trituration using diethyl ether (2 × 10 mL) to 97Attorney Docket No.93033-425510 obtain pure 2-(4-fluorophenyl)-5,7-dihydroxy-4-oxo-4H-chromen-8-yl sulfate tetramethylammonium salt (0.38 g, 1.03 mmol, 41% yield) as a brown solid. MS (ESI) m / z: 289.0 (M+H)+.

[0346] Step 5: Synthesis of 7-(benzyloxy)-2-(4-fluorophenyl)-5,8-dihydroxy-4H-chromen-4-one

[0347] To a stirred solution of 2 oxy-4-oxo-4H-chromen-8-yl sulfate(380 mg, 1.03 mmol) and K2CO3(286 mg, 2.07 mmol) with DMF (4 mL) at room temperature. After stirring for 20 min, was added benzyl bromide (0.12 mL, 1.03 mmol) at room temperature. The reaction mixture was allowed to be stirred at 60 °C for 20 h. The reaction mixture was quenched with ice water (10 mL) and was acidified by 1.5N HCl solution (10 mL) stirred for 30 min at room temperature. The reaction mixture was extracted by ethyl acetate (20 mL), aqueous layer was further extracted by ethyl acetate (2 × 20 mL). All the combined organic layers were washed with brine (20 mL) to obtain crude. Crude was purified by normal phase column chromatography at 50% ethyl acetate in pet ether to obtain pure 7-(benzyloxy)-2-(4-fluorophenyl)-5,8-dihydroxy-4H-chromen-4-one (0.09 g, 0.23 mmol, 21% yield) as a light-yellow solid. MS (ESI) m / z: 379.1 (M+1)+.

[0348] Step 6: Synthesis of 7-(benzyloxy)-2-(4-fluorophenyl)-5-hydroxy-8-methoxy-4H-chromen- 4-one.

[0349] To a stirred a solution ofenyl)-5,8-dihydroxy-4H-chromen-4-one (90 mg, 0.23 mmol) and K2CO3(65.7 mg, 0.47 mmol) with THF (1 mL): DMF (1 mL) at room temperature. The reaction mixture was stirred for 5 min, then was added Me2SO4(0.02 mL, 0.28 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was quenched with ice water (10 mL) and extracted by ethyl acetate (2 × 10 mL). All the combined organic layers were washed with brine (10 mL) to obtain crude. The crude was purified by normal phase column chromatography using 10% ethyl acetate in pet ether to obtain pure 7-(benzyloxy)- 2-(4-fluorophenyl)-5-hydroxy-8-methoxy-4H-chromen-4-one (0.05 g, 0.12 mmol, 57% yield) as light- yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 12.28 (s, 1H), 8.99 (s, 1H), 8.26 – 8.23 (m, 1H), 7.52 – 7.40 (m, 7H), 5.31 (s, 2H), 3.33 (s, 3H). MS (ESI) m / z: 392.6 & 393.6 (M+1)+. 98Attorney Docket No.93033-425510

[0350] Step 7: Synthesis of 2-(4-fluorophenyl)-5,7-dihydroxy-8-methoxy-4H-chromen-4-one (37).

[0351] To a stirred solution of 7-(benzyloxy)-2-(4-fluorophenyl)-5-hydroxy-8-methoxy-4H- chromen-4-one (25 mg, 0.06 mmol) with glacial acetic acid (1.5 mL, 0.06 mmol) and was added conc. HCl (0.5 mL, 0.06 mmol) solution at room temperature. The reaction mixture was allowed to stir at 80 °C for 16 h. The reaction mixture was directly concentrated at a high vacuum. Crude was purified by the preparative HPLC method to obtain pure 2-(4-fluorophenyl)-5,7-dihydroxy-8-methoxy-4H-chromen-4- one (7.0 mg, 0.23 mmol, 36% yield) as a light-yellow solid. MS (ESI) m / z: 303.0 (M+1)+. Example 39 Preparation of 2-(3,4-difluorophenyl)-5,7-dihydroxy-8-methoxy-4H-chromen-4-one (39)

[0352] p y y y y y , yp y (3,4- difluorophenyl)prop-2-en-1-one. 99Attorney Docket No.93033-425510

[0353] To a stirred solution of 6-dimethoxyphenyl)ethan-1-one (0.30 g, 0.99 mmol) and ethanol (6 mL),o owed by t e add t on o 3, -difluorobenzaldehyde (0.14 g, 0.99 mmol) at room temperature. The reaction mixture was allowed to be stirred for 10 min. After this was added NaOH (0.11 g, 2.98 mmol) which was dissolved in water (1 mL) dropwise at 0 °C. The reaction mixture was allowed to be stirred at room temperature for 16 h. The reaction mixture was diluted with water (5 mL) and acidified (pH up to ~5) by 1N HCl solution (2.5 mL). The reaction mixture was extracted with ethyl acetate (15mL), again the aqueous layer was washed with ethyl acetate (2 × 10 mL) and combined all org. layer which was dried over Na2SO4and concentrated through a vacuum to obtain (E)-1-(4-(benzyloxy)-2-hydroxy-3,6-dimethoxyphenyl)-3-(3,4-difluorophenyl)prop-2-en-1-one (0.24 g, 0.56 mmol, 43% yield) as a yellow solid. MS (ESI) m / z: 427.2 (M+1)+.

[0354] Step 2: Synthesis of 7-(benzyloxy)-2-(3,4-difluorophenyl)-5,8-dimethoxy-4H-chromen-4-one

[0355] To a stirred solution of (xy-3,6-dimethoxyphenyl)-3-(3,4- difluorophenyl)prop-2-en-1-one (24 mg, 0.56 mmol) with DMSO (2.5 mL) and was added iodine (3.43 mg, 0.014 mmol) at 60 °C. The reaction mixture was allowed to stir at 120 °C for 16 h. The reaction mixture was diluted with water (7 mL) and org. layer was extracted with ethyl acetate (2 × 10 mL) and combined with both org. layer which was dried over Na2SO4and concentrated through a vacuum to obtain the crude. Crude was triturated with pentane (2 × 1 mL) to obtain the 7-(benzyloxy)-2-(3,4- difluorophenyl)-5,8-dimethoxy-4H-chromen-4-one (180 mg, 0.424 mmol, 60% yield) as a light brown solid. MS (ESI) m / z: 425.1 (M+1)+.

[0356] Step 3: 2-(3,4-difluorophenyl)-7-hydroxy-5,8-dimethoxy-4H-chromen-4-one (38)100Attorney Docket No.93033-425510

[0357] To a stirred solution of 7-(benzyloxy)-2-(3,4-difluorophenyl)-5,8-dimethoxy-4H-chromen-4- one (0.18 g, 0.42 mmol) with glacial acetic acid (3 mL) and was added Conc., HCl (1 mL) at room temperature. The reaction was allowed to stir at 80 °C for 24 h. The reaction mixture was directly evaporated through a vacuum followed by DCM azeotropes and purified by reverse phase purification to obtain the 2-(3,4-difluorophenyl)-7-hydroxy-5,8-dimethoxy-4H-chromen-4-one (52 mg, 0.15 mmol, 36% yield) as a brown solid. From this, 20 mg purified by preparative HPLC to obtain the title compound (6 mg, 0.017 mmol, 4% yield) as a light-yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 3.77 (s, 3H), 3.85 (s, 3H), 6.48 (s, 1H), 6.85 (s, 1H), 7.72 – 7.65 (m, 1H), 7.92 – 7.88 (m, 1H), 8.12 – 8.06 (m, 1H), 10.66 (bs, 1H). MS (ESI) m / z: 335.1 (M+1)+.

[0358] Step 4: Synthesis of 2-(3,4-difluorophenyl)-5,7-dihydroxy-8-methoxy-4H-chromen-4-one (39). F F O O HO O HO O F

[0359] hromen-4-one (30 mg, 0.09 mmol) in acetonitrile (2 mL), was added aluminum chloride (95.7 mg, 0.71 mmol) at room temperature. The reaction mixture was allowed to be stirred at 80 °C for 16 h. ACN was directly distilled out, and was added dilute HCl (1 mL), and diluted with water (3 mL); Org. layer was extracted with ethyl acetate (3 × 5 mL) and combined all org. layer which was dried over Na2SO4and concentrated through a vacuum to obtain the crude. Crude was purified by normal phase column chromatography; the product was eluted at 13% ethyl acetate in pet. ether followed by trituration with n-pentane to obtain the 2-(3,4- difluorophenyl)-5,7-dihydroxy-8-methoxy-4H-chromen-4-one (8 mg, 0.024 mmol, 28% yield) as yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 3.85 (s, 3H), 6.33 (s, 1H), 7.08 (s, 1H), 7.75 – 7.68 (m, 1H), 7.96 – 7.94 (m, 1H), 8.18 – 8.13 (m, 1H), 10.88 (s, 1H), 12.41 (s, 1H). MS (ESI) m / z: 321.0 (M+1)+. Example 40 / Example 41 Preparation of 2-(3,5-dichlorophenyl)-5,8-dihydroxy-7-methoxychroman-4-one (40) and 2-(3,5- dichlorophenyl)-5,6-dihydroxy-7-methoxychroman-4-one (41) 101Attorney Docket No.93033-425510

[0360] Step 1: Synthesis of (E)-3-(35-di hl r h n l) r l l hl ride.

[0361] To a stirred solution of (E)-acrylic acid (3 g, 13.8 mmol) with DCM (30 mL) and was added catalytic amount of DMF (10 mg, 1.38 µmol) at 0 °C. After this was added oxalyl chloride (5.9 mL, 69 mmol) dropwise over 15 min. The reaction mixture was allowed to be stirred at room temperature for 4 h. The reaction mixture was directly concentrated through a high vacuum to obtain the (E)-3-(3,5-dichlorophenyl)acryloyl chloride (3.7 g, 15.7 mmol, 57% yield) as a white solid. Crude was used for the next step without purification. LCMS(m / z): LCMS does not support product mass, so confirmed by TLC.

[0362] Step 2: Synthesis of (E)-3-(3,5-dichlorophenyl)-1-(6-hydroxy-2,3,4-trimethoxyphenyl)prop- 2-en-1-one 102Attorney Docket No.93033-425510

[0363] To a stirred solution of loyl chloride (3 g, 12.7 mmol) and 3,4,5-trimethoxyphenol (2.34 g, 12.7 mmol) with BF3OEt2(30 mL, 12.7 mmol) at room temperature. The reaction mixture was allowed to reflux at 130 °C for 10 min. The reaction mixture was poured into ice- cooled water, so solids were precipitated out and filtered through buchner funnel. Solid was washed with water (30 mL); again solid was washed with petroleum ether (3 × 10 mL) to obtain the (E)-3-(3,5- dichlorophenyl)-1-(6-hydroxy-2,3,4-trimethoxyphenyl)prop-2-en-1-one (4.3 g, 11.22 mmol, 98% yield) as a dark brown solid. MS (ESI) m / z: 384.8 (M+1)+.

[0364] Step 3: 2-(3,5-dichlorophenyl)-5,8-dihydroxy-7-methoxychroman-4-one_(40) and 2-(3,5- dichlorophenyl)-5,6-dihydroxy-7-methoxychroman-4-one_(41).

[0365] To a stirred solution of (E)-3-(3,5-dichlorophenyl)-1-(6-hydroxy-2,3,4- trimethoxyphenyl)prop-2-en-1-one (1.0 g, 2.61 mmol) in glacial acetic acid (50 mL), HBr in 47% water (25 mL) was added in dropwise at room temperature. The reaction mixture was allowed to be stirred at 130 °C for 2 h. After 2 h, reaction mixture was poured into ice-cold water (150 mL) and the solid residue is filtered through buchner funnel. The crude purified by preparative HPLC to obtain 2-(3,5- dichlorophenyl)-5,8-dihydroxy-7-methoxychroman-4-one (46 mg, 0.12 mmol, 5% yield) and 2-(3,5- dichlorophenyl)-5,6-dihydroxy-7-methoxychroman-4-one_ (255 mg, 0.71 mmol, 27% yield) as brown solid.

[0366] 40:1H-NMR (400 MHz, DMSO-d6): δ 2.97 – 2.92 (m, 1H), 3.30 – 3.22 (m, 1H), 3.85 (s, 3H), 5.63 – 5.59 (dd, J = 15.2 Hz, 1H), 6.24 (s, 1H), 7.69 – 7.68 (m, 2H), 7.64 – 7.63 (m, 1H), 8.32 (s, 1H), 11.74 (s, 1H). MS (ESI) m / z: 356.9 (M+1)+.

[0367] 41:1H-NMR (400 MHz, DMSO-d6): δ 2.90 – 2.855 (m, 1H), 3.32 – 3.25 (m, 1H), 3.83 (s, 3H), 5.62 – 5.58 (dd, J = 15.6 Hz, 1H), 6.36 (s, 1H), 7.63 – 7.60 (m, 2H), 7.65 – 7.65 (d, J = 1.6 Hz, 1H). MS (ESI) m / z: 356.9 (M+1)+. 103Attorney Docket No.93033-425510 Example 43 Preparation of 7-hydroxy-8-methoxy-2-phenyl-4H-chromen-4-one (43)

[0369] Cinnamoyl chloride (594 to a mixture of 2-methoxybenzene-1,3-diol (500 mg, 3.57 mmol) in boron trifluoride etherate (10 mL, 3.57 mmol). The mixture was stirred at room temperature for 20 min. After the completion of the reaction, was added ice-cold water (20 mL) at 0 °C and extracted with ethyl acetate (2 × 30 mL). The combined organic layer was washed with sat. NaHCO3solution (20 mL), water, brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to get the crude product (E)-1-(2,4-dihydroxy-3-methoxyphenyl)-3-phenylprop-2-en-1- one (507 mg, 1.82 mmol, 51% yield) as yellow solid, which was used in the next step without further purification.1H-NMR (400 MHz, DMSO- d6): δ 10.54 (s, 1H), 8.02 – 7.99 (m, 5H), 7.49 – 7.46 (m, 3H), 6.52 (d, J = 12 Hz, 1H ), 3.74 (s, 3H). MS (ESI) m / z: 271.2 (M+1)+.

[0370] Step 2: Synthesis of 7-hydroxy-8-methoxy-2-phenyl-4H-chromen-4-one (43).

[0371] To a stirred solution of (E), hoxyphenyl)-3-phenylprop-2-en-1-one (500 mg, 1.85 mmol) in DMSO (4 mL), was added iodine (23.48 mg, 0.092 mmol) at room temperature. The reaction mixture was stirred at 120 °C for 3 h. Upon completion, the reaction mixture was poured into ice-cold water (20 mL), and the residue obtained was filtered, washed with petroleum ether, and dried to get the 7-hydroxy-8-methoxy-2-phenyl-4H-chromen-4-one (500 mg, 1.75 mmol, 95% yield) as a 104Attorney Docket No.93033-425510 yellow solid.1H-NMR (400 MHz, DMSO- d6): δ 10.76 (s, 1H), 8.09 – 8.06 (m, 2H), 7.66-7.60 (m, 4H), 7.03 (d, J = 11.8 Hz, 1H ), 6.94 (s, 1H), 3.96 (s, 3H). MS (ESI) m / z: 269.1 (M+1)+. Example 44 Preparation of 5,7-difluoro-2-phenyl-4H-chromen-4-one (44)

[0372] Step 1: Synthesis of 1-phenyl-3-(2,4,6-trifluorophenyl) propane-1,3-dione.

[0373] To a stirred solution of ac mmol) in THF (7 mL), was addeddropwise LiHMDS (2.83 mL, 2.83 mmol) at 0 °C under N2atmosphere. After 30 min, 2,4,6- trifluorobenzoyl chloride (0.5 g, 2.57 mmol) was slowly added, which was stirred at room temperature for 16 h. After the reaction was completed, the reaction mixture was quenched with saturated ammonium chloride (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with water (20 mL), and brine solution, (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to get the crude. The crude product was purified by normal phase column chromatography using 5% ethyl acetate in petroleum ether to give the 1-phenyl-3-(2,4,6-trifluorophenyl) propane-1,3-dione (650 mg, 2.24 mmol, 87% yield) as an off-white solid. MS (ESI) m / z: 279.0 (M+1)+.

[0374] Synthesis of 5,7-difluoro-2-phenyl-4H-chromen-4-one (44).

[0375] To a stirred solution of 1-phy , , phenyl) propane-1,3-dione (100 mg, 0.35 mmol) in DMSO (1.5 mL) was stirred at 100 °C for 1 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was poured into ice-cold water 40 mL, and the residue obtained was filtered and dried to get the 5,7-difluoro-2-phenyl-4H-chromen-4-one (71 mg, 0.27 mmol, 105Attorney Docket No.93033-425510 76% yield) as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.11 – 8.093 (m, 2H), 7.68 – 7.60 (m, 4H), 7.59 – 7.36 (m, 1H), 7.01 (s, 1H). MS (ESI) m / z: 259.0 (M+1)+. Example 45 Preparation of 6,8-dichloro-2-phenyl-4H-chromen-4-one (45)

[0377] To a stirred solution of 1- enyl)ethan-1-one (1 g, 4.88 mmol) withEtOH (20 mL) and was added benzaldehyde (0.51 g, 4.88 mmol) dropwise at room temperature. The reaction mixture was allowed to stir for 10 min. After this, was added NaOH (0.58 g, 14.63 mmol) in Water (4 mL) dropwise. The reaction mixture was allowed to stir at room temperature for 16 h The reaction mixture was diluted with water (15 mL) and was acidified (pH up to ~ 5) by using 1.5N HCl solution (15 mL). The precipitates were collected by filtration, then washed with EtOH (3 × 10 mL) and dried in vacuo to obtain pure (E)-1-(3,5-dichloro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (1.08 g, 74% yield) as a yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 13.2 (s, 1H), 8.48 (d, J = 3.2 Hz, 1H), 8.13 (d, J = 20.4 Hz, 1H), 8.01 – 7.90 (m, 5H), 7.52 – 7.50 (m, 3H) ppm; MS (ESI) m / z: 293 (M+1)+; MS (ESI) m / z: 295 (M+2)+

[0378] Step-2: Synthesis of 6,8-dichloro-2-phenyl-4H-chromen-4-one (45)

[0379] To a stirred solution of (E)-1-(3,5-dichloro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (400 mg, 1.36 mmol) with DMSO (4 mL) at 60 °C and was added iodine (8.31 mg, 0.03 mmol) at 60 °C. The reaction mixture was allowed to stir at 120 °C for 16 h. The reaction mixture was diluted with water (15 106Attorney Docket No.93033-425510 mL). The precipitates were collected by filtration and washed with water (3 × 15 mL) to obtain pure 6,8- dichloro-2-phenyl-4H-chromen-4-one (0.15 g, 36% yield) as a light yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 8.22 (d, J = 2.4 Hz, 1H) 8.14 – 8.12 (dd, J = 5.6, 1.6 Hz, 2H), 7.94 (d, J = 2.8 Hz, 1H), 7.66 – 7.61 (m, 3H), 7.21 (s, 1H) ppm; MS (ESI) m / z: 291.3 (M+1)+Example 46 Preparation of 7-(difluoromethyl)-2-phenyl-4H-chromen-4-one (46)

[0380]

[0381] To a stirred solution of 1l) ethan-1-one (4.0 g, 26.6 mmol) in acetone (40 mL) was added K2CO3(11.04 g, 80 mmol) followed by the addition of benzoyl chloride (7.49 g, 53.3 mmol) at room temperature. The reaction mixture was allowed to stir at 60 °C for 24 h. Upon completion, the reaction mixture was cooled to room temperature and filtered through the celite. The filtrate was concentrated under a vacuum to obtain crude. The crude was purified by normal phase flash chromatography using ethyl acetate / petroleum ether (9:1) as an eluent to give the 1-(2-hydroxy-4- methylphenyl)-3-phenylpropane-1,3-dione (2.7 g, 3.82 mmol, 14% yield) as a yellow solid. MS (ESI) m / z: 253.1 (M-1)+.

[0382] Step-2: Synthesis of 7-methyl-2-phenyl-4H-chromen-4-one 107Attorney Docket No.93033-425510

[0383] To a stirred solution of 1- nyl)-3-phenylpropane-1,3-dione (2.7 g, 10.62 mmol) in acetic acid (15 mL) was added sodium acetate (2.61 g, 31.9 mmol) at room temperature. The reaction mixture was allowed to stir at 130 °C for 16 h. After the completion the of reaction, the reaction mixture was cooled to room temperature and was basified with sat. NaHCO3solution (10 mL) at 0 °C. The reaction mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with water, and brine solution, dried over anhydrous Na2SO4,and concentrated under reduced pressure to get crude. The resulting crude product was purified by normal phase column chromatography using ethyl acetate / petroleum ether as an eluent. The desired product was eluted at 10% ethyl acetate in petroleum ether to get 7-methyl-2-phenyl-4H-chromen-4-one (870 mg, 3.67 mmol, 34% yield) compound as a brown solid.1H-NMR (400 MHz, DMSO-d6): δ 8.10 – 8.09 (m, 2H), 7.95 (d, J = 10 Hz, 1H), 7.62 – 7.58 (m, 4H), 7.34 – 7.32 (m, 1H), 7.0 (s, 1H), 2.49 (s, 3H). MS (ESI) m / z: 237.1 (M+1)+.

[0384] Step-3: Synthesis of 7-(bromomethyl)-2-phenyl-4H-chromen-4-one

[0385] To a stirred solution of 7-momen-4-one (1.15 g, 4.87 mmol) in CHCl3(20 mL) was added NBS (1.56 g, 8.76 mmol) and benzoyl peroxide (0.118 g, 0.48 mmol) at room temperature. The reaction mixture was allowed to stir at 60 °C for 16 h. progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature, diluted with water, and extracted by DCM (3 × 20 mL). All the combined organic layer was washed with water (30 mL), and the brine solution (30 mL) was dried over anhydrous Na2SO4and concentrated under reduced pressure to get crude. The crude product was purified by normal phase column chromatography using 10% ethyl acetate in petroleum ether to get 7-(bromomethyl)-2-phenyl-4H-chromen-4-one (770 mg, 1.15 mmol, 24% yield) as a white solid. MS (ESI) m / z: 315 (M+1)+and 317 (M+2)+.

[0386] Step-4: Synthesis of 4-oxo-2-phenyl-4H-chromene-7-carbaldehyde108Attorney Docket No.93033-425510

[0387] To a stirred solution of 7-(bromomethyl)-2-phenyl-4H-chromen-4-one (750 mg, 2.38 mmol) in acetonitrile (20 mL) was added NMO (418 mg, 3.57 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 16 h. After the completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4,and concentrated under reduced pressure to get crude. The resulting crude product was purified by normal phase column chromatography using ethyl acetate / petroleum ether as an eluent. The desired product was eluted at 8% ethyl acetate in petroleum ether to get 4-oxo-2-phenyl-4H-chromene-7-carbaldehyde (110 mg, 0.38 mmol, 16% yield) compound. MS (ESI) m / z: 251.1 (M+1)+.

[0388] Step-5: Synthesis of 7-(difluoromethyl)-2-phenyl-4H-chromen-4-one (46)

[0389] To a stirred solution of 4-oxo-2-phenyl-4H-chromene-7-carbaldehyde (80 mg, 0.32 mmol) in DCM (3 mL) was added DAST (258 mg, 1.59 mmol) at -78 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 10 h. The reaction mixture was quenched with aq. NaHCO3solution (10 mL) and extracted with DCM (3 × 10 mL). All the combined organic layer was washed with water (15 mL), and the brine solution (15 mL) was dried over anhydrous Na2SO4and concentrated under reduced pressure to get crude. The crude product was purified by normal phase column chromatography using ethyl acetate / petroleum ether as an eluent. The desired product was eluted at 7% ethyl acetate in petroleum ether to get 7-(difluoromethyl)-2-phenyl-4H-chromen-4-one (68 mg, 0.241 mmol, 75% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.20 – 8.15 (m, 3H), 8.06 (s, 1H), 7.70 – 7.59 (m, 4H), 7.38 (d, J = 54 Hz, 1H), 7.1 (s, 1H). MS (ESI) m / z: 273.1 (M+1)+. Example 47 Preparation of 8-fluoro-7-hydroxy-2-phenyl-4H-chromen-4-one (47) 109Attorney Docket No.93033-425510

[0390] Step 1: Synthesis of 1-(3-fluoro-2,4-dihydroxyphenyl) ethan-1-one.

[0391] To a stirred solution of 2-fluo l (1.0 g, 7.81 mmol) in acetic acid (15 mL)and was added BF3OEt2(3.32 g, 23.42 mmol) dropwise at ambient temperature. The reaction mixture was stirred at 130 °C for 16 h. After the completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with water (30 mL), and brine solution (30 mL), dried over anhydrous Na2SO4,and concentrated to remove solvent under reduced pressure to get crude. The crude was then purified by normal phase column chromatography using 12% ethyl acetate in petroleum ether to get 1-(3- fluoro-2,4-dihydroxyphenyl)ethan-1-one (1.27 g, 7.19 mmol, 92% yield) as a brown solid MS (ESI) m / z: 171.1 (M+1)+.

[0392] Step 2: Synthesis of (E)-1-(3-fluoro-2,4-dihydroxyphenyl)-3-phenylprop-2-en-1-one

[0393] A mixture of 1-(3-fluoro-n-1-one (1.17 g, 6.88 mmol) and benzaldehyde (1.09 g, 10.32 mmol) in EtOH (20 mL), added dropwise ethanolic solution KOH (1.54 g, 27.5 mmol) was stirred at 70 °C for 24 h. Upon completion, the reaction mixture was cooled to room 110Attorney Docket No.93033-425510 temperature and directly concentrated to remove ethanol under reduced pressure. The mixture was diluted with water (10 mL), acidified with 1.5 N HCl solution (15 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with water (30 mL), and brine solution (30 mL), dried over anhydrous Na2SO4,and concentrated under vacuum. The crude product was purified by normal phase column chromatography using 10% ethyl acetate in petroleum ether to get pure (E)-1-(3-fluoro-2,4- dihydroxyphenyl)-3-phenylprop-2-en-1-one (450 mg, 0.88 mmol, 13% yield) as a yellow solid. MS (ESI) m / z: 257.0 (M-1)+.

[0394] Step 3: Synthesis of 8-fluoro-7-hydroxy-2-phenyl-4H-chromen-4-one (47)

[0395] A mixture of (E)-1-(3-fluo-3-phenylprop-2-en-1-one (450 mg, 1.74 mmol) and iodine (44 mg, 0.17 mmol) was stirred in DMSO (5 mL) at room temperature. The reaction mixture was allowed to stir at 120 °C for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature and quenched with ice-cold water (15 mL), and the residue obtained was filtered, washed with water (3 × 15 mL), and dried. The crude was purified by preparative HPLC to get pure 8-fluoro-7-hydroxy-2-phenyl-4H-chromen-4-one (310 mg, 1.20 mmol, 69% yield) as an off-white solid.1H-NMR (400 MHz, MeOD): δ 8.07 – 8.05 (m, 2H), 7.80 (dd, J = 9.2, 2.0 Hz, 1H), 7.62 – 7.60 (m, 3H), 7.11 – 7.07 (m, 1H), 6.89 (s, 1H). MS (ESI) m / z: 257.1 (M+1)+. Example 48 Preparation of 9-phenyl-2,3-dihydro-7H-[1,4]dioxino[2,3-h]chromen-7-one (48). 111Attorney Docket No.93033-425510

[0396] Step-1: Synthesis of 1-(5-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one

[0397] Acetic acid (0.47 g, 7.89 mmo pwise to a mixture of 2,3-dihydrobenzo[b][1,4]dioxin-5-ol (0.6 g, 3.94 mmol) in BF3.OEt2(3 mL, 23.66 mmol) and chloroform (6 mL) at room temperature. The reaction mixture was stirred at 90 °C for 16 h. Upon completion of the reaction, the mixture was allowed to cool and poured into a cold 10% solution of NaOAc in water (3 mL). The mixture was stirred for 2 h and extracted with ethyl acetate (3 × 25 mL). The organic layer was washed with saturated NaHCO3(25 mL), water (25 mL) brine solution (25 mL) and dried over anhydrous Na2SO4and concentrated under reduced pressure to get the crude product. The resulting crude product was purified by normal phase flash chromatography using 30% ethyl acetate in hexane, to obtain 1-(5-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one (0.6 g, 3.09 mmol, 78% yield) as a white solid. MS (ESI) m / z: 195.0 (M+1)+

[0398] Step-2: (E)-1-(5-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-phenylprop-2-en-1-one

[0399] To a mixture of 1-(5-hydr, 1,4]dioxin-6-yl)ethan-1-one (0.6 g, 3.09 mmol) and benzaldehyde (0.39 g, 3.71 mmol)) in ethanol (1 mL), 20% aqueous solution of potassium 112Attorney Docket No.93033-425510 hydroxide (2 mL, 3.09 mmol) was added dropwise and kept at ambient temperature for 12 h. After completion of the reaction, the reaction mixture was poured into ice-cold water, acidified with 1.5 N HCl, and extracted with ethyl acetate (2 × 25 mL). The combined organic layer was washed with water (25 mL), and brine solution (25 mL), dried over anhydrous Na2SO4,and concentrated under a vacuum at 45oC to get the crude product. The crude product was purified by normal phase flash chromatography using 10% ethyl acetate in petroleum ether to obtain (E)-1-(5-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3- phenylprop-2-en-1-one (0.8 g, 2.45 mmol, 80% yield) as a yellow solid. MS (ESI) m / z: 283.1 (M+1)+

[0400] Step-3: 9-phenyl-2,3-dihydro-7H-[1,4]dioxino[2,3-h]chromen-7-one

[0401] To a solution of (E)-1-(5-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-phenylprop-2-en- 1-one (100 mg, 0.35 mmol) in DMSO (2 mL), was added iodine (4.50 mg, 0.02 mmol) at room temperature. The reaction mixture was stirred at 120 °C for 3 h. After the completion of the reaction as indicated by TLC, the reaction mixture was poured into ice-cold water and the residue obtained was filtered, washed with petroleum ether, and dried to give the 9-phenyl-2,3-dihydro-7H- [1,4] dioxino[2,3- h] chromen-7-one (54 mg, 0.2 mmol, 53% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.08 – 8.05 (m, 2H), 7.62 – 7.60 (m, 3H), 7.53 (d, J = 8.80 Hz, 1H), 7.05 (d, J = 8.80 Hz, 1H), 7.00 (s, 1H), 6.55 (d, J = 8.80 Hz, 1H), 4.50 – 4.45 (m, 4H) ppm; MS (ESI) m / z: 281.1 (M+1)+Example 49 Preparation of 5-fluoro-7-methoxy-2-phenyl-4H-chromen-4-one (49). 113Attorney Docket No.93033-425510

[0402] Step-1: Synthesis of 2,6-difluoro-4-methoxybenzoyl chloride

[0403] To a stirred solution of 2,6-dif enzoic acid (4 g, 21.3 mmol) in DCM (40mL), added 1-2 drops of DMF and then added oxalyl chloride (9 g, 70.9 mmol) at 0 °C under nitrogen atmosphere, finally allowed to stir at room temperature for 4 h. After completion of the reaction (as monitored by TLC), the reaction mixture was concentrated under reduced pressure and co-distilled with pentane to get the crude 2,6-difluoro-4-methoxybenzoyl chloride (4 g, 19.3 mmol, 91% yield) as crude. The crude was taken for the next step without any further purification.

[0404] Step-2: Synthesis of 1-(2,6-difluoro-4-methoxyphenyl)-3-phenylpropane-1,3-dione

[0405] To a stirred solution of aol) in THF (50 mL) under nitrogen, was added lithium bis(trimethylsilyl)amide (21.3 mL, 21.3 mmol) drop-wise at 0 °C and allowed to stir for 15 minutes. Then added 2,6-difluoro-4-methoxybenzoyl chloride (4 g, 19.3 mmol) dissolved in THF (10 mL) slowly dropwise at the same temperature. Finally, the reaction mixture was warmed up to room temperature and stirred for 16 h. After completion of the reaction (as monitored by TLC), the reaction mixture was quenched with saturated Aq.NH4Cl (50 mL) solution and separated the organic layer. The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layer was dried over 114Attorney Docket No.93033-425510 anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get crude. The crude product was purified by normal phase flash chromatography using 5% ethyl acetate in petroleum ether as eluent to obtain 1-(2,6-difluoro-4-methoxyphenyl)-3-phenylpropane-1,3-dione (2.9 g, 9.4 mmol, 48% yield) as an off-white solid. MS (ESI) m / z: 291.0 (M+1)+

[0406] Step-3: Synthesis of 5-fluoro-7-methoxy-2-phenyl-4H-chromen-4-one (49)

[0407] 1-(2,6-difluoro-4-methoxyphenyl)-3-phenylpropane-1,3-dione (2.9 g, 9.39 mmol) was taken in a 100 mL sealed tube and dissolved in DMSO (29 mL) at room temperature and then stirred for 16 h at 100 °C. After the completion of the reaction (as monitored by TLC), the reaction mixture was cooled to RT, reverse quenched with ice-cold water, and stirred for 10 min. Then filtered the solids and top-washed with pentane, and dried under suction to obtain 5-fluoro-7-methoxy-2-phenyl-4H-chromen-4-one (2.5 g, 9.2 mmol, 98% yield).1H-NMR (400 MHz, DMSO-d6): δ 8.08 – 8.11 (m, 2H), 7.57 – 7.62 (m, 3H), 7.23 (m, 1H), 6.91 (d, J = 2.40 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 3.93 (s, 3H) ppm; MS (ESI) m / z: 271.1 (M+1)+Example 50 Preparation of 5-fluoro-7-hydroxy-2-phenyl-4H-chromen-4-one (50).

[0408] To a stirred solution of 5-fluoro-7-methoxy-2-phenyl-4H-chromen-4-one (0.5 g, 1.8 mmol) in DCM (25 mL), was added BBr3(18.5 mL, 18.5 mmol) slowly dropwise at 0 °C and then the reaction mixture stirred at room temperature for 16 h. After completion of the reaction (as monitored by TLC), the reaction mixture was quenched with ice-cold (100 mL) water under cooling and stirred for 20 min. Then filtered the solids, top-washed with ice-cold water followed by pentane, and dried under suction to get the crude product. The crude product was purified by normal phase flash chromatography 20% MeOH in DCM as eluent to obtain 5-fluoro-7-hydroxy-2-phenyl-4H-chromen-4-one (0.07 g, 0.2 mmol, 11% yield) 115Attorney Docket No.93033-425510 as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.30 (s, 1H), 8.04 – 8.07 (m, 2H), 7.55 – 7.61 (m, 3H), 6.87 (t, J = 0.80 Hz, 1H), 6.87 (s, 1H), 6.64 – 6.67 (m, 1H) ppm; MS (ESI) m / z: 257.1 (M+1)+Example 51 Preparation of 6-fluoro-7-hydroxy-2-phenyl-4H-chromen-4-one (51).

[0409]

[0410] To a stirred solution of 4-fluol (2 g, 15.61 mmol) in BF3OEt2(15 mL) was added acetic acid (1.78 mL, 31.2 mmol) dropwise at 0 °C. The reaction mixture was heated to 90 °C for 12 h. Upon completion of the reaction, the reaction mixture was quenched with 10% aqueous NaOAc solution and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with water (40 mL), brine solution (40 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to get the 1-(5-fluoro-2,4-dihydroxyphenyl)ethan-1-one (2.1 g, 12.17 mmol, 78% yield).1H-NMR (400 MHz, DMSO-d6): δ 12.31 (s, 1H), 11.22 (s, 1H), 7.71 (d, J = 12.0 Hz, 1H), 6.43 (d, J = 7.6 Hz, 1H), 3.35 (s, 3H). MS (ESI) m / z: 171.0 (M+1)+.

[0411] Step 2: Synthesis of (E)-1-(5-fluoro-2,4-dihydroxyphenyl)-3-phenylprop-2-en-1-one116Attorney Docket No.93033-425510

[0412] To a mixture of 1-(5-fluoro-2,4-dihydroxyphenyl) ethan-1-one (2.1 g, 12.3 mmol) and benzaldehyde (1.44 g, 13.5 mmol) in ethanol (20 mL), aqueous KOH (3 g, 37 mmol) in water (2 mL) at 0 °C and stirred for 10 min. Then benzaldehyde (1.44 g, 13.5 mmol) was added at the same temperature and then the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (as monitored by TLC), the reaction mixture was concentrated under reduced pressure, and the residue was acidified with 1.5 N aqueous HCl solution, then stirred for 10 min, and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to get the crude. Crude was purified by normal phase column chromatography using petroleum ether / ethyl acetate as an eluent. The desired product was eluted at 30% ethyl acetate in petroleum ether to get (E)-1-(5-fluoro-2,4-dihydroxyphenyl)-3-phenylprop-2-en-1- one (2.2 g, 4.77 mmol, 38% yield) as a yellow solid. MS (ESI) m / z: 259.1 (M+1)+.

[0413] Step 3: Synthesis of 6-fluoro-7-hydroxy-2-phenyl-4H-chromen-4-one

[0414] To a stirred solution of (Exyphenyl)-3-phenylprop-2-en-1-one (500 mg, 1.08 mmol) in DMSO (6 mL), and was added iodine (27.5 mg, 0.10 mmol) and reaction mixture was allowed to be stirred at 120 °C for 4 h. After completion of the reaction (as monitored by TLC), the reaction mixture was cooled to room temperature, diluted with ice-cold water, and stirred for 10 min. Then the solids were top-washed in a buchner funnel with ice-cold water, and dried under suction to get the crude product. The crude product was purified by preparative HPLC using the FA method to obtain the 6-fluoro-7-hydroxy-2-phenyl-4H-chromen-4-one (20 mg, 0.078 mmol, 7% yield) as a yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 11.56 (s, 1H), 8.07 – 8.10 (m, 2H), 7.68 (d, J = 10.8 Hz, 1H), 7.57 – 7.61 (m, 3H), 7.23 (d, J = 7.2 Hz, 1H), 6.95 (s, 1H). MS (ESI) m / z: 257.1 (M+1)+. Example 52 Preparation of 7-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-2-phenyl-4H-chromen-4-one (52). 117Attorney Docket No.93033-425510ethoxy)ethyl)carbamate.

[0416] To a soluti 1.04 mmol) in DMF (2mL) was added K2CO3(290 mg, 2.09 mmol) followed by addition of tert-butyl (2-(2-(2- bromoethoxy)ethoxy)ethyl)carbamate (393 mg, 1.25 mmol) at 0 °C. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with ice-cool water (10 mL) and extracted with 10% MeOH in DCM (2 × 25 mL). All the combined organic layers were washed with brine solution (2 × 20 mL), dried over anhydrous Na2SO4and concentrated under vacuum to obtain crude tert-butyl (2-(2-(2-((4- oxo-2-phenyl-4H-chromen-7yl)oxy)ethoxy)ethoxy)ethyl)carbamate (500 mg, 1.04 mmol, 99% yield) as colorless sticky solids. The resulting crude product was used in the next step without further purification. MS (ESI) m / z: 470.3 (M+1)+

[0417] Step-2: Synthesis of 7-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-2-phenyl-4H-chromen-4-one

[0418] To a solutionn- 7yl)oxy)ethoxy)ethoxy)ethyl)carbamate (100 mg, 0.21 mmol) in DCM (2 mL), was added 4 M Hydrogen 118Attorney Docket No.93033-425510 chloride in 1,4-dioxane (2.5 mL, 0.21 mmol) at 0 °C and then the mixture was stirred at 0 °C to room temperature for 4 h. After the completion of the reaction as indicated by TLC, the solvent was evaporated through a vacuum to get the crude product. The crude product was purified by preparative HPLC using the FA method to get the 7-(2-(2-(2-aminoethoxy)ethoxy) ethoxy)-2-phenyl-4H-chromen-4-one (15 mg, 0.04 mmol, 19% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.12 – 8.09 (m, 2H), 7.95 (d, J = 8.8 Hz, 1H), 7.62 – 7.57 (m, 3H), 7.37 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 8.8, 2.4 Hz, 1H), 6.98 (s, 1H), 4.30 – 4.28 (m, 2H), 3.83 – 3.81 (m, 2H), 3.64 – 3.62 (m, 2H), 3.56 – 3.53 (m, 2H), 3.37 (t, J = 5.6 Hz, 2H), 2.64 (t, J = 5.6 Hz, 2H) ppm; MS (ESI) m / z: 370.1 (M+1)+(Note: Two protons merged with the DMSO moisture peak) Example 53 Preparation of 8-methoxy-7-(2-methoxyethoxy)-2-(quinolin-6-yl)-4H-chromen-4-one (53). [0414 g, 1.25 mmol) in DMF (15 mL), was added potassium carbonate (0.51 g, 3.76 mmol) and stirred for 10 min. Then 1-chloro-2-methoxyethane (1.18 g, 12.53 mmol) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was heated at 90 °C for 4 h. After completion of the reaction as indicated by LCMS, the reaction mixture was poured onto ice-cold water and stirred for 10 minutes. The residue obtained was filtered, washed with ice-cold water followed by n-pentane, and dried to obtain the 8- methoxy-7-(2-methoxyethoxy)-2-(quinolin-6-yl)-4H-chromen-4-one (300 mg, 0.77 mmol, 61% yield) as a yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 9.03 – 9.04 (m, 1H), 8.76 (d, J = 2.00 Hz, 1H), 8.59 (d, J = 7.60 Hz, 1H), 8.39 – 8.41 (m, 1H), 8.21 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.66 – 7.69 (m, 1H), 7.33 (d, J = 9.2 Hz, 1H), 7.17 (s, 1H), 4.34 – 4.36 (m, 2H), 4.05 (s, 3H), 3.75 – 3.78 (m, 2H), 3.37 (s, 3H). MS (ESI) m / z: 378.1 (M+1)+.

[0420] The following examples were prepared via conventional chemistry and / or following the general methods above: 119Attorney Docket No.93033-425510 No. Compound1H NMR MS (m / z) (400 MHz, DMSO-d6): δ 12.36 )+)++)+120Attorney Docket No.93033-425510 No. Compound1H NMR MS (m / z) (400 MHz, DMSO-d6): δ 10.71 )+)+)+)+)+121Attorney Docket No.93033-425510 No. Compound1H NMR MS (m / z) (400 MHz, DMSO-d6): δ 2.70 (s, )+)++)+)+122Attorney Docket No.93033-425510 No. Compound1H NMR MS (m / z) (400 MHz, DMSO-d6): δ 8.08 – )+)+]⁺ )+123Attorney Docket No.93033-425510 No. Compound1H NMR MS (m / z) (400 MHz, DMSO-d6): δ 3.93 (s, )+)+)++124Attorney Docket No.93033-425510 No. Compound1H NMR MS (m / z) (400 MHz, DMSO-d6): δ 10.50 )+)+)+)+)+125Attorney Docket No.93033-425510 No. Compound1H NMR MS (m / z) (400 MHz, DMSO-d6): δ 3.79 (s, )+)+)++. )+126Attorney Docket No.93033-425510 No. Compound1H NMR MS (m / z) (400 MHz, DMSO-d6): δ 2.90 – )+)++. )+)++.127Attorney Docket No.93033-425510 No. Compound1H NMR MS (m / z) (400 MHz, MeOD): δ 8.07 – 8.05 )+)+)+)+)+128Attorney Docket No.93033-425510 No. Compound1H NMR MS (m / z) (400 MHz, DMSO-d6): δ 8.12 – )+)+BIOLOGICAL EXAMPLES

[0421] Many modifications and variations of the embodiments described herein may be made without departing from the scope, as is apparent to those skilled in the art. The specific embodiments described herein are offered by way of example only. Example 1 In vitro Glutathione Dynamics

[0422] Glutatione concentrations following treatment in HepG2 cells of varying concentrations of Compound 24 for over 24 hours is shown in FIGs.1-2.

[0423] Compound 24 generated an increase in total glutathione (GSH + GSSG, which is an indicator of NRF2 activation) (FIG. 1). Redox potentials (Eh) showed that with Compound 24 treatment, Eh was reduced (FIG.2). 129Attorney Docket No.93033-425510 Example 2 Hepatic Glutathione Dynamics

[0424] Hepatic glutathione dynamics following single IV treatment of 5 mg / kg in wild type C57B6 mice with Compound 24 for over 72 hours is shown in FIGs. 3-5. Methods for GSH / GSSG detection are as described herein. In order to evaluate changes in the intracellular redox environment, treated livers were collected in perchloric acid (5% v / v; Sigma-Aldrich) and boric acid (0.2 M; Sigma-Aldrich) containing γ- glutamylglutamate (10 µM; Sigma-Aldrich). Intracellular concentrations of cysteine (Cys), cystine (CySS), glutathione (GSH), and glutathione disulfide (GSSG) were measured by reverse-phase, high-performance liquid chromatography as S-carboxymethyl, N-dansyl derivatives normalized to γ-glutamylglutamate. Proteins were acid precipitated and samples were centrifuged at 16,000 × g for 5 min, after which the soluble fraction containing free Cys, CySS, GSH, and GSSG was derivatized with dansyl chloride (Sigma- Aldrich). Samples were separated using an e2695 Separations Module (Waters) fitted with a Supelcosil LC- NH25 µm column (Sigma-Aldrich) and peak detection was determined using a 2474 FLR Detector (Waters). The Cys / CySS and GSH / GSSG redox potentials (Eh) were calculated by the Nernst equation using Cys, CySS, GSH, and GSSG intracellular concentrations.

[0425] GSH is the largest single thiol antioxidant in most cells, including the liver where it is the highest. Changes to GSH levels suggest changes to Nrf2 activity, increasing GSH de novo synthesis.

[0426] Compound 24 generated an increase in total glutathione (GSH + GSSG, which is an indicator of NRF2 activation) that persists with a single dose even up to 72 hours at 5 mg / kg (FIGs. 3A and 4A). Redox potentials (Eh) showed that with Compound 24 treatment, Eh was significantly reduced and sustained for up to 72 hours (FIGs.3B and 4B).

[0427] Dose response effects following treatment of Compound 24 to hepatic glutathione dynamics over a 24 hour period is shown in FIG. 5. Compared to vehicle treated controls, Compound 24 increased total glutathione (FIG.5) by about 20%. Example 3 Mitochondrial Function

[0428] A Seahorse XFp Cell Mito Stress Test assay using a Seahorse XF Mini Analyzer was performed to assess mitochondrial function / dynamics, including as basal respiration, ATP respiration, and maximal and reserve capacity. HepG2 cells were treated with 200 µM compound 24 for 24 hours, after which they were assayed for mitochondrial dynamics via the MitoStress assay kit (FIG.6). Treatment increased maximal respiration rates compared to controls, indicating an increase in mitochondrial activity (FIG.7). 130Attorney Docket No.93033-425510

[0429] Mitochondrial ATP production in HepG2 cells was measured using an ATP Determination Kit (Thermofisher Scientific) and results are shown in FIG. 8. Treatment with compound 24 significantly increased mitochondrial ATP production, as shown in FIG.8. Example 4 In vitro Toxicity

[0430] An MTT toxicity assay was performed to compoare compound 24 and Skyclarys (omaveloxolone), as shown in FIG.9. HepG2 cells were exposed to compound 24 at concentrations up to 800 µM for 24 hours. The LD50 of compound 24 and Skyclarys was 3854 µM and 73 µM, respectively.

[0431] A DCF assay was performed in an in vitro experiment with HepG2 cells to compare compound 24 to Skyclarys (omaveloxolone) and Radicava (edaravone) (FIG.10). Concentrations of 200 µM for compound 24, 100 µM of edaravone, 5 µM of omaveloxolone, and 100 µM of hydrogen peroxide were used. Skyclarys (omaveloxolone) is a Nrf2 activator, a cysteine modifier, that increases ROS. Radicava (edaravone) is used in the treatment of ALS, and is understood as a ROS scavenger but is shown as increasing ROS. Offsite oxidation leads to the production of reactive oxygen species (ROS), which impair cellular function. Excessive ROS levels are linked to toxicity. Compound 24 reduced ROS production, minimizing potential toxicity. Example 5 Nrf2-dependent protein expression (brain)

[0432] An immunoblotting assay was performed to show the expression of glutamate-cysteine ligase catalytic subunit (GCLC) following single IV injection treatment of 5 mg / kg of compound 24 in wild type C57B6 mice (FIGs.11-12). Mice were sacrificed and brains were removed for analysis. GCLC is the rate limiting enzyme for synthesis of the antioxidant glutathione. NRF2 activation has been shown to upregulate GCLC in multiple systems. These data suggest that compound 24 crosses the blood brain barrier and had a direct effect on expression of NRF2 associated genes in the brain. Example 6 Glutathione Concentration (brain)

[0433] Glutatione concentration following single IV injection treatment of 5 mg / kg of Compound 24 in wild type C57B6 mice for over 72 hours is shown in FIG. 13. Mice were sacrificed and brains were removed for analysis. A 30% improvement in glutathione concentration indicates improved ability to manage oxidative stress and remove ROS, which is critical for neuroprotection and cell survival. 131Attorney Docket No.93033-425510 Example 7 Neurofilament Concentrations in ALS Mice

[0434] The hemizygous mutant SOD1 mice (B6SJL-Tg(SOD1*G93A)1Gur / J) are commercially available (Jackson Labs, https: / / www.jax.org / strain / 002726) and are considered to mimic the human amyotrophic lateral sclerosis (ALS) condition. Mice hemizygous for this SOD1-G93A (also called G93A- SOD1) transgene are viable and fertile, with transgenic expression of a G93A mutant form of human SOD1. This founder line (often referred to as G1H) is reported to have high transgene copy number. Hemizygotes exhibit a phenotype similar to ALS in humans; becoming paralyzed in one or more limbs with paralysis due to loss of motor neurons from the spinal cord. Transgenic mice have an abbreviated life span: 50% survive at 128.9+ / -9.1 days (in contrast to C57BL / 6J background where 50% survival is observed at 157.1+ / -9.3 days). The pattern of gene expression in SOD1G93A activated microglia represents a unique ALS-specific signature. These SOD1-G93A (also called G93A-SOD1) transgenic mice may be useful in studying neuromuscular disorders, including Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease).

[0435] The effect of compound 24 treatment in ALS mice is shown in FIGs. 14-15. ALS mice were injected via IV with 5mg / kg of compound 24 at 2X / week. Dosing started when mice turned 8 weeks of age. Death was the endpoint. Blood was collected every 2 weeks for the neurofilament assay.

[0436] An ALS NfL (neurofilament light chain) Assay was performed using an NfL ELISA assay. NfL is a biomarker of neuronal damage. Neurofilament A plasma concentrations in ALS mice with treatment of Compound 24 is shown in FIG. 14. Compound 24 stabilized neurofilament in ALS treated mice to levels similar to the WT control mice. Data illustrate that treatment with compound 24 also extended the life span of ALS mice (FIG.15). STATEMENTS

[0437] 1. A compound of formula (I): , or a pharmaceutically acceptable salt thereof,X1is O or NR11; Y is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocyclyl, or 5- to 12- membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 132Attorney Docket No.93033-425510 8-membered heterocyclyl, or 5- to 12-membered heteroaryl is independently optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy; R6is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R7is halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12, each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; p is 1, 2, or 3; provided that: (i) R6and R7are not the same, or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; (ii) if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy; (iii) Y is not 3-pyridyl; and (iv) if R7and R9is OH, then Y is not unsubstituted phenyl.

[0438] 2. The compound of clause 1, wherein Y is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 12-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 12-membered heteroaryl is independently optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy.

[0439] 3. The compound of clause 1 or 2, wherein Y is C6-C10aryl or 5- to 12-membered heteroaryl, wherein each hydrogen atom in C6-C10aryl or 5- to 12-membered heteroaryl is independently optionally substituted by halogen, C1-C2alkyl, or C1-C2alkoxy.

[0440] 4. The compound of any one of the previous clauses, wherein the compound is of formula (II): ,or a pharmaceutically acceptable salt thereof, wherein: 133Attorney Docket No.93033-425510 X1is O or NR11; each R1is independently halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy; R6is H, halogen, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, hydroxy, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OCH3, each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; n is 0, 1, 2, or 3; p is 1, 2, or 3; provided that: (i) R6and R7are not the same; (ii) if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy; and (iii) if R7and R9is OH, then Y is not unsubstituted phenyl.

[0441] 5. The compound of any one of the previous clauses, wherein R6is H, halogen, or C1-C6alkoxy.

[0442] 6. The compound of any one of the previous clauses, wherein R6is H, halogen, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, or C1-C6alkoxy; and R9is H, halogen, hydroxy, or RA.

[0443] 7. The compound of any one of the previous clauses, wherein R6is H, fluoro, or methoxy.

[0444] 8. The compound of any one of the previous clauses, wherein R6is H or methoxy.

[0445] 9. The compound of any one of the previous clauses, wherein R6is methoxy.

[0446] 10. The compound of any one of clauses 1-8, wherein R6is H.

[0447] 11. The compound of any one of the previous clauses, wherein R7is selected from fluoro, hydroxy, methoxy, 134Attorney Docket No.93033-425510 , y.

[0449] 13. The compound of any one of the previous clauses, wherein R8is H or methoxy.

[0450] 14. The compound of any one of the previous clauses, wherein R9is H, halogen, hydroxy, or RA.

[0451] 15. The compound of any one of the previous clauses, wherein R9is H, fluoro, hydroxy, or . . The compound of any one of the previous clauses, wherein R is H or hydroxy.9

[0453] 17. The compound of any one of clauses 4-16, wherein each R1is independently halogen or C1-C2alkoxy.

[0454] 18. The compound of any one of clauses 4-17, wherein each R1is independently chloro, fluoro, methoxy, or ethoxy.

[0455] 19. The compound of any one of clauses 4-16, wherein n is 0 or 2.

[0456] 20. The compound of any one of clauses 4-16, wherein Y is selected from: .und is of formula (III): , or a pharmaceutically acceptable salt therY is substituted or unsubstituted 5- to 12-membered heteroaryl; R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; 135Attorney Docket No.93033-425510 R9is H, halogen, hydroxy, RA, or C1-C6alkoxy; each R10, R12, and R13is independently H or C1-C6alkyl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, - (OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12, each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; p is 1, 2, or 3; provided that: (i) R6and R7are not the same, or R6and R7are taken together with the carbon atoms to which they are bound; and (ii) Y is not 3-pyridyl.

[0458] 22. The compound of clause 21, wherein R6is C1-C6alkoxy; R7is hydroxy or RA; or two of R6and R7taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; and R9is H or hydroxy.

[0459] 23. The compound of clause 21 or 22, wherein R6is methoxy.

[0460] 24. The compound of any one of clauses 21-23, wherein R7is hydroxy or RA.

[0461] 25. The compound of any one of clauses 21-24, wherein R7is hydroxy . of clause 21, wherein two of R6and R7are taken together with the carbonatoms to which they are bound to form dioxane.

[0464] 27. The compound of any one of clauses 21-26, wherein Y selected from ,X2is O, S, or NR11; each X3and X4is independently N or CH; provided that at least one of X3and X4is CH; each R2is independently halogen, hydroxy, C1-C2alkyl, or C1-C2alkoxy; m is 0, 1 or 2.

[0465] 28. The compound of any one of clauses 21-27, wherein each R2is independently C1-C2alkyl. 136Attorney Docket No.93033-425510

[0466] 29. The compound of any one of clauses 21-27, wherein m is 0 or 1.

[0467] 30. The compound of any one of clauses 21-27, wherein Y is selected from: is f formula (IV):, or a pharmaceutically acceptable salt ther Y is unsubstituted C1-C6alkyl or usu s u e3-C10cycloalkyl; R6is H, halogen, hydroxy, or C1-C6alkoxy; and R7is halogen, hydroxy, or C1-C6alkoxy; provided that: R6and R7are not the same.

[0470] 33. The compound of clause 32, wherein R6is C1-C6alkoxy; and R7is hydroxy.

[0471] 34. The compound of clause 32 or 33, wherein R6is methoxy.

[0472] 35. The compound of any one of clauses 32-33, wherein Y is t-butyl.

[0473] 36. The compound of any one of clauses 32-33, wherein Y is C3-C8cycloalkyl.

[0474] 37. The compound of clause 36, wherein Y is cyclopentyl or cyclohexyl.

[0475] 38. The compound of any one of clauses 1-20, wherein R11is H or methyl.

[0476] 39. The compound of any one of clauses 1-31, wherein each R12and R13is independently H, methyl, or phenyl.

[0477] 40. The compound of any one of clauses 1-4, wherein at least one of R6, R8, and R9is H.

[0478] 41. The compound of any one of clauses 1-4, wherein at least two of R6, R8, and R9is H.

[0479] 42. The compound of any one of clauses 1-4, wherein each of R8and R9are H. 137Attorney Docket No.93033-425510

[0480] 43. The compound of any one of clauses 1-4, wherein each of R6and R9are independently H, hydroxy, or methoxy.

[0481] 44. The compound of any one of clauses 1-4, wherein at least one of R6and R7is methoxy.

[0482] 45. The compound of any one of clauses 1-4, 21, and 32, wherein R6is methoxy and R7is hydroxy.

[0483] 46. The compound of any one of clauses 1-4, wherein R6is methoxy, R8is H, and R9is H.

[0484] 47. The compound of any one of clauses 1-4, wherein R6is H, R8is methoxy, and R9is hydroxy.

[0485] 48. The compound of any one of clauses 1-4, wherein one of R6or R8is methoxy and the other of R6or R8is H.

[0486] 49. The compound of clause 1, wherein the compound is selected from the group consisting of: , ,138Attorney Docket No.93033-425510 ,139Attorney Docket No.93033-425510 ,

[0487] 50. The compound of clause 1, wherein the compound is selected from the group consisting of: , ,140Attorney Docket No.93033-425510 nd

[0488] 51. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of clauses 1-50, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

[0489] 52. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I: I), or a pharmaceutically acceptable salt thereofX1is O or NR11; Y is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocyclyl, or 5- to 12- membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocyclyl, or 5- to 12-membered heteroaryl is independently optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy; R6is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R7is halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12, 141Attorney Docket No.93033-425510 each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; p is 1, 2, or 3; provided that: (i) R6and R7are not the same, or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; (ii) if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy; and (iii) if if R7and R9is OH, then Y is not unsubstituted phenyl.

[0490] 53. The pharmaceutical composition of clause 52, comprising a therapeutically effective amount of the compound of formula II: I), or a pharmaceutically acceptable salt tX1is O or NR11; each R1is independently halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy; R6is H, halogen, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, hydroxy, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OCH3, each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; n is 0, 1, 2, or 3; p is 1, 2, or 3; provided that: (i) R6and R7are not the same; (ii) if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy; and (iii) if R7and R9is OH, then Y is not unsubstituted phenyl.

[0491] 54. The pharmaceutical composition of clause 52, comprising a therapeutically effective amount of the compound of formula III: 142Attorney Docket No.93033-425510 I), or a pharmaceutically acceptable salt thereo Y is substituted or unsubstituted 5- to -mem ere eteroaryl; R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; R9is H, halogen, hydroxy, RA, or C1-C6alkoxy; each R10, R12, and R13is independently H or C1-C6alkyl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12, each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; p is 1, 2, or 3; provided that: R6and R7are not the same, or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl.

[0492] 55. The pharmaceutical composition of clause 52, comprising a therapeutically effective amount of the compound of formula IV: ), or a pharmaceutically acceptable salt thereoY is unsubstituted C1-C6alkyl or unsubstituted C3-C10cycloalkyl; R6is H, halogen, hydroxy, or C1-C6alkoxy; and R7is halogen, hydroxy, or C1-C6alkoxy; provided that: R6and R7are not the same.

[0493] 56. The pharmaceutical composition of any one of clauses 51-55, wherein the compound is in a non-salt form.

[0494] 57. A compound of any one of clauses 1-50, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of clauses 51-56, for use in treating or preventing a disease or 143Attorney Docket No.93033-425510 disorder wherein the disease or disorder is selected from the group consisting of cartilage and bone, neural tissue, connective tissue, and internal organ or peripheral tissue.

[0495] 58. The compound of clause 57, wherein the disease or disorder is selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, traumatic brain injury (TBI), cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes.

[0496] 59. A method of treating or preventing a disease or disorder in a subject, wherein the disease or disorder of an organ or tissue is selected from the group consisting of cartilage and bone, neural tissue, connective tissue, and internal organ or peripheral tissue, comprising administering to the subject a compound of formula I: I), or a pharmaceutically acceptable salt thereofX1is O or NR11; Y is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocyclyl, or 5- to 12- membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocyclyl, or 5- to 12-membered heteroaryl is independently optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy; R6is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R7is halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12, each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; p is 1, 2, or 3; provided that: 144Attorney Docket No.93033-425510 (i) R6and R7are not the same, or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; and (ii) if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy.

[0497] 60. The method of modulating a disease or disorder in a subject of clause 59, comprising administering to the subject a compound of formula II: I), or a pharmaceutically acceptable salt X is O or1 NR11; each R1is independently halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy; R6is H, halogen, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, hydroxy, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, - (OCH2CH2)p-NR12R13, -(OCH2CH2)p-OCH3, each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; n is 0, 1, 2, or 3; p is 1, 2, or 3; provided that: (i) R6and R7are not the same; (ii) if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy.

[0498] 61. The method of modulating a disease or disorder in a subject of clause 59, comprising administering to the subject a compound of formula III: I), or a pharmaceutically acceptable salt thereoY is substituted or unsubstituted 5- to 12-membered heteroaryl; 145Attorney Docket No.93033-425510 R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; R9is H, halogen, hydroxy, RA, or C1-C6alkoxy; each R10, R12, and R13is independently H or C1-C6alkyl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, - (OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12, each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; p is 1, 2, or 3; provided that: R6and R7are not the same, or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl.

[0499] 62. The method of modulating a disease or disorder in a subject of clause 59, comprising administering to the subject a compound of formula IV: ), or a pharmaceutically acceptable salt thereoY is unsubstituted C1-C6alkyl or unsubstituted C3-C10cycloalkyl; R6is H, halogen, hydroxy, or C1-C6alkoxy; and R7is halogen, hydroxy, or C1-C6alkoxy; provided that: R6and R7are not the same.

[0500] 63. The method of clause 59, comprising administering to the subject a compound selected from the group consisting of: ,146Attorney Docket No.93033-425510 , ,147Attorney Docket No.93033-425510 ,a pharmaceutically acceptable salt thereof.use 59, comprising administering to the subject a compound selected from the group consisting of: 148Attorney Docket No.93033-425510 , ,steoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, traumatic brain injury (TBI), cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes.

[0503] 66. A method of treating or preventing a disease in a subject, wherein the disease or disorder is of an organ or tissue is selected from the group consisting of cartilage and bone, neural tissue, connective tissue, and internal organ or peripheral tissue, comprising administering to the subject the 149Attorney Docket No.93033-425510 compound of any one of clauses 1-50, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of clauses 51-56.

[0504] 67. The method of clause 66, wherein the disease or disorder is selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, traumatic brain injury (TBI), cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes.

[0505] 68. Use of the compound of any one of clauses 1-50, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of clauses 51-56, as a medicament for treating or preventing a disease, wherein the disease or disorder is of an organ or tissue is selected from the group consisting of cartilage and bone, neural tissue, connective tissue, and internal organ or peripheral tissue.

[0506] 69. The use of the compound of clause 68, wherein the disease or disorder is selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, traumatic brain injury (TBI), cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes.

[0507] 70. Use of the compound of any one of clauses 1-50, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of clauses 51-56, in the manufacture of a medicament for treating or preventing a disease, wherein the disease or disorder is of an organ or tissue is selected from the group consisting of cartilage and bone, neural tissue, connective tissue, and internal organ or peripheral tissue.

[0508] 71. The use of the compound of clause 70, wherein the disease or disorder is selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, traumatic brain injury (TBI), cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes. 150

Claims

Attorney Docket No.93033-425510 CLAIMS 1. A compound of formula (I): , or a pharmaceutically acceptable salt thereof, X1is O or NR11;Y is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocyclyl, or 5- to 12- membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocyclyl, or 5- to 12-membered heteroaryl is independently optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy; R6is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R7is halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12, each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; p is 1, 2, or 3; provided that: (i) R6and R7are not the same, or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; (ii) if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy; (iii) Y is not 3-pyridyl; and (iv) if R7and R9is OH, then Y is not unsubstituted phenyl.

2. The compound of claim 1, wherein Y is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 12- membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, or 5- to 12-membered heteroaryl is independently optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy. 151Attorney Docket No.93033-425510 3. The compound of claim 1, wherein Y is C6-C10aryl or 5- to 12-membered heteroaryl, wherein each hydrogen atom in C6-C10aryl or 5- to 12-membered heteroaryl is independently optionally substituted by halogen, C1-C2alkyl, or C1-C2alkoxy.

4. The compound of claim 1, wherein the compound is of formula (II): , or a pharmaceutically acceptable salt theX1is O or NR11; each R1is independently halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy; R6is H, halogen, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, hydroxy, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OCH3, each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; n is 0, 1, 2, or 3; p is 1, 2, or 3; provided that: (i) R6and R7are not the same; (ii) if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy; and (iii) if R7and R9is OH, then Y is not unsubstituted phenyl.

5. The compound of claim 1, wherein R6is H, halogen, or C1-C6alkoxy.

6. The compound of claim 1, wherein R6is H, halogen, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, or C1-C6alkoxy; and R9is H, halogen, hydroxy, or RA.

7. The compound of claim 1, wherein R6is H, fluoro, or methoxy.

8. The compound of claim 1, wherein R6is H or methoxy. 152Attorney Docket No.93033-425510 9. The compound of claim 1, wherein R6is methoxy.

10. The compound of claim 1, wherein R6is H.

11. The compound of claim 1, wherein R7is selected from fluoro, hydroxy, methoxy, ,and .

12. The compound of claim 1, wherein R8is H, fluoro, or methoxy.

13. The compound of claim 1, wherein R8is H or methoxy.

14. The compound of claim 1, wherein R9is H, halogen, hydroxy, or RA.

15. The compound of claim 1, wherein R9is H, fluoro, hydroxy, or .

16. The compound of claim 1, wherein R9is H or hydroxy.

17. The compound of claim 14, wherein each R1is independently halogen or C1-C2alkoxy.

18. The compound of claim 14, wherein each R1is independently chloro, fluoro, methoxy, or ethoxy.

19. The compound of claim 4, wherein n is 0 or 2.

20. The compound of claim 4, wherein Y is selected from: .formula (III): , or a pharmaceutically acceptable salt therY is substituted or unsubstituted 5- to 12-membered heteroaryl; R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; 153Attorney Docket No.93033-425510 R9is H, halogen, hydroxy, RA, or C1-C6alkoxy; each R10, R12, and R13is independently H or C1-C6alkyl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, - (OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12, each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; p is 1, 2, or 3; provided that: (i) R6and R7are not the same, or R6and R7are taken together with the carbon atoms to which they are bound; and (ii) Y is not 3-pyridyl.

22. The compound of claim 21, wherein R6is C1-C6alkoxy; R7is hydroxy or RA; or two of R6and R7taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; and R9is H or hydroxy.

23. The compound of claim 21, wherein R6is methoxy.

24. The compound of claim 21, wherein R7is hydroxy or RA.

25. The compound of claim 21, wherein R7is hydroxy .ound of claim 21, wherein two of R6and R7are taken together with the carbon atoms to which they are bound to form dioxane.

27. The compound of claim 21, wherein Y selected from ,X2is O, S, or NR11; each X3and X4is independently N or CH; provided that at least one of X3and X4is CH; each R2is independently halogen, hydroxy, C1-C2alkyl, or C1-C2alkoxy; m is 0, 1 or 2.

28. The compound of claim 21, wherein each R2is independently C1-C2alkyl.

29. The compound of claim 21, wherein m is 0 or 1. 154Attorney Docket No.93033-425510 30. The compound of claim 21, wherein Y is selected from: is compound is of formula (IV):, or a pharmaceutically acceptable salt ther Y is unsubstituted C1-C6alkyl or3C10cycloalkyl; R6is H, halogen, hydroxy, or C1-C6alkoxy; and R7is halogen, hydroxy, or C1-C6alkoxy; provided that: R6and R7are not the same.

33. The compound of claim 32, wherein R6is C1-C6alkoxy; and R7is hydroxy.

34. The compound of claim 32, wherein R6is methoxy.

35. The compound of claim 32, wherein Y is t-butyl.

36. The compound of claim 32, wherein Y is C3-C8cycloalkyl.

37. The compound of claim 36, wherein Y is cyclopentyl or cyclohexyl.

38. The compound of claim 1, wherein R11is H or methyl.

39. The compound of claim 1, wherein each R12and R13is independently H, methyl, or phenyl.

40. The compound of claim 1, wherein at least one of R6, R8, and R9is H.

41. The compound of claim 1, wherein at least two of R6, R8, and R9is H.

42. The compound of claim 1, wherein each of R8and R9are H.

43. The compound of claim 1, wherein each of R6and R9are independently H, hydroxy, or methoxy.

44. The compound of claim 1, wherein at least one of R6and R7is methoxy.

45. The compound of claim 1, wherein R6is methoxy and R7is hydroxy. 155Attorney Docket No.93033-425510 46. The compound of claim 1, wherein R6is methoxy, R8is H, and R9is H.

47. The compound of claim 1, wherein R6is H, R8is methoxy, and R9is hydroxy.

48. The compound of claim 1, wherein one of R6or R8is methoxy and the other of R6or R8is H.

49. The compound of claim 1, wherein the compound is selected from the group consisting of: , ,156Attorney Docket No.93033-425510 , ,157Attorney Docket No.93033-425510 50. The compound of claim 1, wherein the compound is selected from the group consisting of: , ,51. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

52. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I: 158Attorney Docket No.93033-425510 I), or a pharmaceutically acceptable salt thereof X1is O or NR11;Y is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocyclyl, or 5- to 12- membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocyclyl, or 5- to 12-membered heteroaryl is independently optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy; R6is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R7is halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12, each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; p is 1, 2, or 3; provided that: (i) R6and R7are not the same, or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; (ii) if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy; and (iii) if if R7and R9is OH, then Y is not unsubstituted phenyl.

53. The pharmaceutical composition of claim 52, comprising a therapeutically effective amount of the compound of formula II: I), or a pharmaceutically acceptable salt tX1is O or NR11; 159Attorney Docket No.93033-425510 each R1is independently halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy; R6is H, halogen, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, hydroxy, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OCH3, each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; n is 0, 1, 2, or 3; p is 1, 2, or 3; provided that: (i) R6and R7are not the same; (ii) if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy; and (iii) if R7and R9is OH, then Y is not unsubstituted phenyl.

54. The pharmaceutical composition of claim 52, comprising a therapeutically effective amount of the compound of formula III: I), or a pharmaceutically acceptable salt thereoY is substituted or unsubstituted 5- to 12-membered heteroaryl; R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; R9is H, halogen, hydroxy, RA, or C1-C6alkoxy; each R10, R12, and R13is independently H or C1-C6alkyl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12, each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; p is 1, 2, or 3; provided that: R6and R7are not the same, or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl. 160Attorney Docket No.93033-425510 55. The pharmaceutical composition of claim 52, comprising a therapeutically effective amount of the compound of formula IV: ), or a pharmaceutically acceptable salt thereo Y is unsubstituted C1-C6alkyl or unsubst tuted C3-C10cyc oalkyl; R6is H, halogen, hydroxy, or C1-C6alkoxy; and R7is halogen, hydroxy, or C1-C6alkoxy; provided that: R6and R7are not the same.

56. The pharmaceutical composition of claim 51, wherein the compound is in a non-salt form.

57. A compound of claim 1, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 51-56, for use in treating or preventing a disease or disorder wherein the disease or disorder is selected from the group consisting of cartilage and bone, neural tissue, connective tissue, and internal organ or peripheral tissue.

58. The compound of claim 57, wherein the disease or disorder is selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa (RP), glaucoma, retinoblastoma, traumatic brain injury (TBI), cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes.

59. A method of treating or preventing a disease or disorder in a subject, wherein the disease or disorder of an organ or tissue is selected from the group consisting of cartilage and bone, neural tissue, connective tissue, and internal organ or peripheral tissue, comprising administering to the subject a compound of formula I: I), or a pharmaceutically acceptable salt thereofX1is O or NR11; 161Attorney Docket No.93033-425510 Y is C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocyclyl, or 5- to 12- membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 6- to 8-membered heterocyclyl, or 5- to 12-membered heteroaryl is independently optionally substituted by halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy; R6is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R7is halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12, each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; p is 1, 2, or 3; provided that: (i) R6and R7are not the same, or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; and (ii) if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy.

60. The method of modulating a disease or disorder in a subject of claim 59, comprising administering to the subject a compound of formula II: I), or a pharmaceutically acceptable saltX1is O or NR11; each R1is independently halogen, hydroxy, C1-C3alkyl, or C1-C3alkoxy; R6is H, halogen, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, hydroxy, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, or C1-C6alkoxy; each R10, R11, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OCH3, 162Attorney Docket No.93033-425510 each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; n is 0, 1, 2, or 3; p is 1, 2, or 3; provided that: (i) R6and R7are not the same; (ii) if R7is OH or methoxy, then at least one of R6or R8is halogen or C1-C6alkoxy.

61. The method of modulating a disease or disorder in a subject of claim 59, comprising administering to the subject a compound of formula III: I), or a pharmaceutically acceptable salt thereoY is substituted or unsubstituted 5- to 12-membered heteroaryl; R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is halogen, hydroxy, RA, or C1-C6alkoxy; or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl; R9is H, halogen, hydroxy, RA, or C1-C6alkoxy; each R10, R12, and R13is independently H or C1-C6alkyl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, - (OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12, each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; p is 1, 2, or 3; provided that: R6and R7are not the same, or R6and R7are taken together with the carbon atoms to which they are bound to form a 6-membered heterocyclyl.

62. The method of modulating a disease or disorder in a subject of claim 59, comprising administering to the subject a compound of formula IV: ), or a pharmaceutically acceptable salt thereoY is unsubstituted C1-C6alkyl or unsubstituted C3-C10cycloalkyl; 163Attorney Docket No.93033-425510 R6is H, halogen, hydroxy, or C1-C6alkoxy; and R7is halogen, hydroxy, or C1-C6alkoxy; provided that: R6and R7are not the same.

63. The method of claim 59, comprising administering to the subject a compound selected from the group consisting of: , ,164Attorney Docket No.93033-425510 ,165Attorney Docket No.93033-425510 nd . t a compound selectedfrom the group consisting of: , ,166Attorney Docket No.93033-425510 or a pharmaceutically acceptable salt thereof.

65. The method of claim 59, wherein the disease or disorder is selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa, glaucoma, retinoblastoma, traumatic brain injury, cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease, inflammatory bowel disease, Celiac’s disease, and type II diabetes.

66. A method of treating or preventing a disease in a subject, wherein the disease or disorder is of an organ or tissue is selected from the group consisting of cartilage and bone, neural tissue, connective tissue, and internal organ or peripheral tissue, comprising administering to the subject the compound of claim 1.

67. The method of claim 66, wherein the disease or disorder is selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa, glaucoma, retinoblastoma, traumatic brain injury, cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease, inflammatory bowel disease, Celiac’s disease, and type II diabetes.

68. Use of the compound of claim 1, as a medicament for treating or preventing a disease, wherein the disease or disorder is of an organ or tissue is selected from the group consisting of cartilage and bone, neural tissue, connective tissue, and internal organ or peripheral tissue.

69. The use of the compound of claim 68, wherein the disease or disorder is selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa, glaucoma, retinoblastoma, traumatic brain injury, cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease, inflammatory bowel disease, Celiac’s disease, and type II diabetes.

70. Use of the compound of claim 1, in the manufacture of a medicament for treating or preventing a disease, wherein the disease or disorder is of an organ or tissue is selected from the group consisting of cartilage and bone, neural tissue, connective tissue, and internal organ or peripheral tissue.

71. The use of the compound of claim 70, wherein the disease or disorder is selected from osteoarthritis, gout, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis (eczema), systemic lupus erythematosus, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Friedreich Ataxia, multiple sclerosis, retinitis pigmentosa, glaucoma, retinoblastoma, traumatic brain injury, cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease, inflammatory bowel disease, Celiac’s disease, and type II diabetes. 167

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