Quinazolinone therapeutics

Abstract

Compounds, and pharmaceutically acceptable salts or tautomers 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 or tautomers and methods of using the compounds, pharmaceutically acceptable salts or tautomers, and pharmaceutical compositions in the treatment of various diseases or disorders, such as inflammatory diseases or disorders.

Description

Attorney Docket No.93033-425511 QUINAZOLINONE THERAPEUTICS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 657,673, 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.93033-425511

[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 osteoarthritis 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 keeps coming back. 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 osteoarthritis 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's 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.93033-425511

[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. For 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's 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 (FA), Multiple Sclerosis (MS), 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.93033-425511 cells in the brain to decay over time. The disease affects a person's movements, thinking ability and mental health. Friedreich Ataxia 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 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.93033-425511

[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 quinazolinone 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.93033-425511 SUMMARY

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

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

[0032] In another aspect, compounds of formula (III), or pharmaceutically acceptable salts or tautomers thereof, are described herein: I), wherein each of X1, Y, R6, R7, R9,

[0033] In another aspect, compounds of formula (IV), or pharmaceutically acceptable salts or tautomers thereof, are described herein: 6Attorney Docket No.93033-425511 V), wherein each of Y, R6, R7, R9,and

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

[0035] In another aspect, compounds of formula (I), (II), (III), and (IV) and pharmaceutically acceptable salts or tautomers are disclosed.

[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 or tautomer 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 or tautomer 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 or tautomer 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 or tautomer 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 or tautomer 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.

[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 or tautomer thereof, or a pharmaceutical composition thereof is disclosed. 7Attorney Docket No.93033-425511

[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 or tautomer 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 or tautomer 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.

[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 or tautomer thereof, or pharmaceutical composition thereof, including a therapeutically effective amount of the compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt or tautomer 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 or tautomer thereof, or pharmaceutical composition thereof, including a therapeutically effective amount of the compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt or tautomer 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 or tautomer thereof, or pharmaceutical composition thereof, including a therapeutically effective amount of the compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt or tautomer 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. 8Attorney Docket No.93033-425511

[0047] In another aspect, a use of a compound of formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt or tautomer 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 or tautomer 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 or tautomer 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 or tautomer 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 or tautomer 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 or tautomer thereof, or a 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 or tautomer 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 or tautomer 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 or tautomer 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 or tautomer 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 (COPD), 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 or tautomer thereof, or a pharmaceutical composition thereof to the subject is disclosed. 9Attorney Docket No.93033-425511

[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. BRIEF DESCRIPTIONS OF THE FIGURES

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

[0056] Fig.1 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 12 and 25.

[0057] Fig.2 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 12 and 25.

[0058] Fig. 3 shows a graph of radical oxygen species (ROS) generation compared to edaravone (Radicava) and omaveloxolone (Skyclarys).

[0059] Fig.4A shows a graph of GCLC protein expression in the liver of compound 12 normalized to B-actin. Column height represents intensity of signal in western blot.

[0060] Fig.4B shows a graph of GCLC protein expression in the liver of compound 25 normalized to B-actin. Column height represents intensity of signal in western blot.

[0061] Fig. 5 shows images of the expression of GCLC and B-actin at 6, 24, 48, 72, and 96 hours (triplicates) used to generate Figs.4A and 4B.

[0062] Fig. 6A shows a graph of HO-1 protein expression in the liver of compound 12 normalized to B-actin. Column height represents intensity of signal in western blot.

[0063] Fig. 6B shows a graph of HO-1 protein expression in the liver of compound 25 normalized to B-actin. Column height represents intensity of signal in western blot. 10Attorney Docket No.93033-425511

[0064] Fig. 7 shows images of the expression of HO-1 and B-actin at 6, 24, 48, 72, and 96 hours (triplicates) used to generate Figs.6A and 6B.

[0065] Fig. 8 shows a graph of GCLC protein expression in the brain of compound 12 normalized to B-actin. Column height represents intensity of signal in western blot.

[0066] Fig.9 shows images of the expression of GCLC and B-actin at 6, 24, and 48 hours (duplicates) used to generate Fig.8.

[0067] Fig. 10 shows a graph of neurofilament-A plasma concentrations in ALS mice following treatment of compound 12.

[0068] Fig.11 shows a graph of the mean life extension in ALS mice following treatment of compound 12.

[0069] Fig. 12 shows a graph of retinal thickness (µm) in RP mice following treatment of compound 25. DETAILED DESCRIPTION

[0070] The present application describes useful quinazolinone 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.

[0071] In one aspect, the disclosure relates to a compound of formula (I): I),11Attorney Docket No.93033-425511 or a pharmaceutically acceptable salt or tautomer thereof, wherein: X1is =O, =N-OR10, or -C1-C6alkoxy,wherein when X1 is =O or =N-OR10, then “ ” is a single bond, and when X1 is -C1-C6 alkoxy, then“ ” is a double bond; Y is C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, 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 H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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; and p is 1, 2, or 3; provided that (i) R6and R7are not the same; and (ii) when R9is methoxy, then R7is halogen, hydroxy, or RA.

[0072] 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 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.

[0073] 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.

[0074] 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. 12Attorney Docket No.93033-425511

[0075] 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.

[0076] 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 mixtures thereof. It will be appreciated that an alkenyl can be unsubstituted or substituted as described herein.

[0077] 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.

[0078] 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. 13Attorney Docket No.93033-425511

[0079] 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).

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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. 14Attorney Docket No.93033-425511 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.

[0086] 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.

[0087] 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 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 include radicalsof the following entities . Illustrative examples of 10-memberedheteroaryl groupsof the following entities: .pp p , R2, R3, R4, and R5are taken together with the carbon atoms to which they are bound to form a 6-membered heteroaryl,” as used herein, can be used to 15Attorney Docket No.93033-425511 refer to a structure, for example , wherein two of R1, R2, R3, R4, and R5are taken together with the carbon atoms re bound to form a 6-membered heteroaryl (such aspyridyl). 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 with the carbon atoms to which they are bound to form a fused pyridyl” can be depicted by thestructural formula It will be appreciated that a heteroaryl group can be unsubstituted or substituted as desc

[0089] 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 structure, for example, , wherein two of R6, and R7are taken together with the carbon atoms to which theform a 6-membered heterocyclyl. Illustratively, a 6-membered heterocyclyl structure can be depicted by the structural formu . In particular, it will be appreciated that a structural formula referring to “R6and R7aether with the carbon atoms to which they are bound to form a fused dioxane” can be depicted by the structural form .16Attorney Docket No.93033-425511

[0090] As used herein, the terms “quinazolinone” and “quinazolinone derivative” refers to a compound with the general core structure depicted by the structural formu , wherein each of X1and R11is as defined herein.

[0091] In particular, a quinazolinone or quinazolinone derivative can be depicted by the structural N Nformula nedherein. edepicted by the structural formu ,wherein R10is as defined herein

[0092] Unless otherwise specified, 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.

[0093] 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.93033-425511

[0094] In automers:H N N N N H .

[0095] As useund, refers to a racemic mixture of the compound.

[0096] 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.

[0097] As used herein, the structural moiety represented by “ ” when used in connection with abond between two atoms, refers to a single bond or a double bond between two atoms. It will beappreciated that the phrase “when X1 is =O or =N-OR10, then “ ” is a single bond” as used herein, canN N be used to refer to respective structures, for example N11, depicted in a structural formul , represents a single bond. Additionally, it will beappreciated that the phrase “whe1 s 1- 6 a o y, then “ ” is a double bond” as used herein, can18Attorney Docket No.93033-425511 be used to refer to a structure, for example , wherein , depicted in a structuralformula , represents a double bond, and X1is C1-C6alkoxy (e.g. –O-C1-C6alkyl).

[0098] 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.

[0099] In some embodiments, the disclosure relates to a compound of formula (I): , or a pharmaceutically acceptabl, wherein: X1is =O, =N-OR10, or-C1-C6 alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a single bond, and when X1 is-C1-C6 alkoxy, then “ ” is a double bond; Y is C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, 6- to8-membered heteroor 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 H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, H, or C1-C6alkyl; RAis -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, 19Attorney Docket No.93033-425511 -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12; RBis -C(O)R12, -C(O)OR12, or -C(O)NR12R13; and p is 1, 2, or 3.

[0100] In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), wherein X1is =O, =N-OR10, or -C1-C6 alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a single bond, andwhen X1 is C1-C6 alkoxy, then “ ” is a double bond; Y is C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, or5- 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; R6is H or C1-C6alkoxy; R7is halogen, hydroxy, or RA; R8is H; R9is H, halogen, or RA; each R10, R12, and R13is independently H or C1-C6alkyl; R11is absent, H, or C1-C6alkyl; RAis -OCH2-RBor -(OCH2CH2)p-OR12; RBis -C(O)NR12R13; and p is 1.

[0101] 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)), if R9is methoxy, then R7is halogen, hydroxy, or RA. In some embodiments of compounds of formula (I) (as well as formulas (II)-(IV)), R6and R7are not the same; and if R9is methoxy, then R7is halogen, hydroxy, or RA.

[0102] 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)), 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 no .

[0103] In some embodiments, the disclosure relaof formula (II): ,20Attorney Docket No.93033-425511 or a pharmaceutically acceptable salt or tautomer thereof, wherein: X1is =O, =N-OR10, or C1-C6alkoxy,wherein when X1 is =O or =N-OR10, then “ ” is a single bond, and when X1 is C1-C6 alkoxy, then“ ” is a double bond; R6 is H, halogen, hydroxy, or C1-C6 alkoxy; R7 is H, halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, hydroxy, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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; n is 0, 1, or 2; and p is 1, 2, or 3; provided that R6and R7are not the same.

[0104] In some embodiments of compounds of formula (I) or (II), R6is H, or C1-C6alkoxy; R7is halogen, hydroxy, or RA; R8is H; and R9is H, halogen, or RA.

[0105] In some embodiments, the disclosure relates to a compound of formula (III): , or a pharmaceutically acceptable sa in: Y is substituted or unsubstituted 5- to12-membered heteroaryl; X1is =O, =N-OR10, or -C1-C6alkoxy, wherein when X1is =O or =N-OR10, then“ ” is a single bond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond; R6 is H, halogen,hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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.

[0106] In some embodiments of compounds of formula (I) or (III), R6is H or C1-C6alkoxy; R7is halogen or RA; and R9is H or halogen.

[0107] In some embodiments, the disclosure relates to a compound of formula (IIIa): ,21Attorney Docket No.93033-425511 (IIIa) or a pharmaceutically acceptable salt or tautomer thereof, wherein: X1is =O, =N-OR10, or -C1-C6alkoxy, wherein when X1is =O or =N-OR10, then“ ” is a single bond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond; R6 is H, halogen,hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R10, R12, an13s independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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.

[0108] In some embodiments of compounds of formula (I), (III), or (IIIa), R6is H or C1-C6alkoxy; R7is halogen or RA; and R9is H or halogen.

[0109] In some embodiments, the disclosure relates to a compound of formula (IV): , or a pharmaceutically acceptable s rein: Y is unsubstituted C1-C6alkyl orunsubstituted C3-C10cycloalkyl; R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R12and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is 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; and p is 1, 2, or 3; provided that: R6and R7are not the same.

[0110] In some embodiments of compounds of formula (I) or (IV), R6is H; R7is halogen or RA; and R9is halogen or RA.

[0111] In some embodiments of compounds of formula (I), (II), or (III), X1is =O, =N-OR10, or-C1-C6 alkoxy (e.g. –O-C1-C6 alkyl), wherein when X1 is =O or =N-OR10, then “ ” is a single bond, andwhen X1 is -C1-C6 alkoxy, then “ ” is a double bond. In some embodiments, X1 is =O or =N-OR10 and“ ” is a single bond, or X1 is -C1-C6 alkoxy and “ ” is a double bond.

[0112] In some embodiments of compounds of formula (I), (II), or (III), X1is =O or =N-OR10and“ ” is a single bond. In some embodiments, X1 is =N-OH, and “ ” is a single bond. In someem odiments, X1 is =O, and “ ” is a single bond. In some embodiments, X1 is -C1-C6 alkoxy and22Attorney Docket No.93033-425511“ ” is a double bond. In some embodiments, X1 is -C1-C3 alkoxy and “ ” is a double bond. In someembodiments, X1 is -methoxy, and “ ” is a double bond.

[0113] 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.

[0114] 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.

[0115] 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).

[0116] 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 23Attorney Docket No.93033-425511 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.

[0117] In some embodiments of compounds of formula (I) or (II), Y is selected from: . tituted 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.

[0119] 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.

[0120] 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, 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).

[0121] 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, 24Attorney Docket No.93033-425511 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.

[0122] In some embodiments of compounds of formula (I) or (III), Y is selected from: , wherein represen

[0123] In some embodiments of compounds of formula (I) or (III), Y is , wherein represents a point of attache compound.

[0124] In some embodiments of compounds of formula (I) or (III), Y is selected from: .

[0125] .

[0126] .

[0127] In some embodiments of compounds of formula (I) or (III), Y is , X2 is O, S, orNR11, and each X3and X4is independently N or CH; provided that at least one of X2, X3and X4is a heteroatom (e.g., O, S, or NR11) and at least one of X3and X4is CH. In some embodiments of compounds 25Attorney Docket No.93033-425511of 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 oneof 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.

[0128] 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.

[0129] 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.

[0130] 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 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.

[0131] 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 or C1-C6alkoxy. In some embodiments, R6is H or C1-C3alkoxy. 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.

[0132] In some embodiments of compounds of formula (I) (as well as formulas (II), (III), (IIIa), and (IV)), R7is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy. In some embodiments, R7is halogen, hydroxy, RA, or C1-C6alkoxy. In some embodiments, R7is halogen, hydroxy, or RA. In some embodiments, R7is H. In some embodiments, R7is hydroxy. In some embodiments, R7is halogen. In some embodiments, R7is fluoro. In some embodiments, R7is RA. In some embodiments, R7is , or26Attorney Docket No.93033-425511 . In some embodiments, R7is fluoro or hydroxy. In some embodiments, R7is hydroxy orRA. In some embodiments, R7is fluoro, hydroxy, , or .

[0133] In some embodiments of compoun logen, 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.

[0134] In some embodiments of compounds of formula (I) (as well as formulas (II), (III), (IIIa), and (IV)), R9is H, halogen, hydroxy, or RA. In some embodiments, R9is H, halogen, or RA. In some embodiments, R9is H or halogen. In some embodiments, R9is halogen or RAIn some embodiments, R9is H, hydroxy, fluoro, or . In some embodiments, R9is H or fluoro. In some embodiments, R9is H. In some embodiments droxy. In some embodiments, R is halogen. In some embodiments9, R9is fluoro. In some embodiments, R9is RA. In some embodiments, R9is .

[0135] In some embodiments of compounds of formula (I) (ass (II), (III), (IIIa), and (IV)), each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl. In some embodiments, each R10, R12, and R13is independently H or C1-C6alkyl. In some embodiments, each R10, R12, and R13is independently H or C1-C3alkyl. In some embodiments, each R10, R12, and R13is independently H or methyl.

[0136] In some embodiments of compounds of formula (I) (as well as formulas (II) and (III)), R10is H, C1-C6alkyl, or C6-C10aryl. 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.

[0137] In some embodiments of compounds of formula (I) (as well as formulas (II), (III), (IIIa), and (IV)), R11is absent, H, or C1-C6alkyl. In some embodiments, R11is absent. In some embodiments, R11, when present, is H or C1-C3alkyl. In some embodiments, R11, when present, is H or methyl. In some embodiments, R11is H. In some embodiments, R11is methyl.

[0138] 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.

[0139] In some embodiments 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 27Attorney Docket No.93033-425511 embodiments, each of R8and R9are H. In some embodiments, each of R6and R9are independently H, hydroxy, or methoxy. In some embodiments, one of R6and R7is methoxy. In some embodiments, R6is methoxy and R7is hydroxy. In some embodiments, R6is methoxy and R7is hydroxy, or R6is H and R7is fluoro. In some embodiments, R6is methoxy, R8is H, and R9is H. In some embodiments, R6is H, R8is halogen, and R9is H. In some embodiments, one of R6or R8is methoxy and the other of R6or R8is H. In some embodiments, at least one of R6, R7, R8, and R9is fluoro. In some embodiments, at two of R6, R7, R8, and R9is fluoro. In some embodiments, R6is H or methoxy, R7is halogen or hydroxy, R8is H, and R9is H or halogen. In some embodiments, R6is H or methoxy, R7is hydroxy or RA, R8is H, and R9is H or fluoro.

[0140] 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.

[0141] 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, RAis -OCH2-RBor -(OCH2CH2)p-OCH3. In some embodiments, RAis,.and (IV)), p is 1, 2, or 3. In some embodiments, p is 1 or 3. In some embodiments, p is 1.

[0143] 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 O embodiments, .

[0144] Inents, 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).

[0145] In some embodiments, the disclosure relates to a compound selected from Table A, or a pharmaceutically acceptable salt or tautomer thereof. In other embodiments, the disclosure relates to a compound selected from Table A, i.e., the compound or tautomer in non-salt form. 28Attorney Docket No.93033-425511

[0146] Table A. Compound Structures and Names. No. Structure Name - e e e e n- e - - e29Attorney Docket No.93033-425511 No. Structure Name 2-((8-methoxy-3-methyl-4- - - - e e e30Attorney Docket No.93033-425511 No. Structure Name e - e - - -31Attorney Docket No.93033-425511 No. Structure Name -

[0147] , p , ,32Attorney Docket No.93033-425511 ,

[0148] In some embodiments, the compound is 33Attorney Docket No.93033-425511 a pharmaceutically acceptable salt or tautomer thereof. odiments, the compound is selected from,

[0151] In some embodiments, the disclosure relates to the compound selected from 5,7-difluoro-2- (quinolin-6-yl)quinazolin-4(3H)-one; 7-hydroxy-8-methoxy-2-phenylquinazolin-4(1H)-one; and (Z)-7- hydroxy-8-methoxy-3-methyl-2-phenylquinazolin-4(3H)-one oxime, or a pharmaceutically acceptable salt thereof.

[0152] In other embodiments, the foregoing compounds are in a non-salt form. In other embodiments, the foregoing compounds or tautomers are pharmaceutically acceptable salts thereof. Salts, Compositions, Uses, Formulation, Administration and Additional Agents Pharmaceutically acceptable salts and compositions

[0153] 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, 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. 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. 34Attorney Docket No.93033-425511 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.

[0154] As discussed herein, the disclosure provides compounds as described herein, and pharmaceutically acceptable salts or tautomers 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 musculoskeletal pain or arthritic pain. In another aspect, the disclosure provides compounds as described herein, and pharmaceutically acceptable salts or tautomers thereof, that are useful for modulating inflammation.

[0155] As discussed herein, the disclosure provides compounds as described herein, and pharmaceutically acceptable salts or tautomers 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, 35Attorney Docket No.93033-425511 retinoblastoma, traumatic brain injury (TBI), cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes.

[0156] Accordingly, in another aspect, pharmaceutical compositions are provided, wherein these compositions comprise a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0157] 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.

[0158] 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. 36Attorney Docket No.93033-425511

[0159] 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 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.

[0160] In another aspect, the disclosure features a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable carrier.

[0161] 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 or tautomer thereof, and one or more pharmaceutically acceptable carriers or vehicles. Uses of Compounds and Pharmaceutically acceptable salts or tautomers and Compositions 37Attorney Docket No.93033-425511

[0162] 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 or tautomer thereof, or a pharmaceutical composition thereof. In some aspects of the disclosure, the pain is musculoskeletal pain or arthritic pain.

[0163] 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 or tautomer thereof, or a pharmaceutical composition thereof.

[0164] 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 or tautomer 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 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.

[0165] 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 or tautomer thereof, or a pharmaceutical composition thereof.

[0166] 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. 38Attorney Docket No.93033-425511

[0167] 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 or tautomer 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.

[0168] 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 or tautomers, and Compositions for Use

[0169] In another aspect, the disclosure features a compound as described herein, a pharmaceutically acceptable salt or tautomer thereof, or pharmaceutical composition thereof, for use as a medicament.

[0170] In another aspect, the disclosure features a compound as described herein, a pharmaceutically acceptable salt or tautomer thereof, or pharmaceutical composition thereof, for use in treating pain. In some aspects of the disclosure, the pain is musculoskeletal pain or arthritic pain.

[0171] In another aspect, the disclosure features a compound as described herein, a pharmaceutically acceptable salt or tautomer thereof, or pharmaceutical composition thereof, for use in a method of modulating inflammation.

[0172] In another aspect, the disclosure features a compound as described herein, a pharmaceutically acceptable salt or tautomer 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. 39Attorney Docket No.93033-425511 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.

[0173] In another aspect, the disclosure features a compound as described herein, a pharmaceutically acceptable salt or tautomer thereof, or pharmaceutical composition thereof, for use in a method of treating cancer. Manufacture of Medicaments

[0174] In another aspect, the disclosure provides the use of a compound as described herein, or a pharmaceutically acceptable salt or tautomer or pharmaceutical composition thereof, for the manufacture of a medicament.

[0175] In another aspect, the disclosure provides the use of a compound as described herein, a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating pain. In some aspects of the disclosure, the pain is musculoskeletal pain or arthritic pain.

[0176] In yet another aspect, the disclosure provides the use of a compound as described herein, a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in modulating inflammation.

[0177] In another aspect, the disclosure provides the use of a compound as described herein, a pharmaceutically acceptable salt or tautomer 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), 40Attorney Docket No.93033-425511 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.

[0178] In yet another aspect, the disclosure provides the use of a compound as described herein, a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating cancer. Administration of Compounds, Pharmaceutically acceptable salts or tautomers, and Compositions

[0179] In certain embodiments, an “effective amount” of a compound of as described herein, a pharmaceutically acceptable salt or tautomer 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.

[0180] 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 41Attorney Docket No.93033-425511 combination or coincidental with the specific compound or salt employed, and like factors well known in the medical arts.

[0181] The term “subject” or “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0182] 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, 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).

[0183] 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, tautomers, 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.

[0184] 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 42Attorney Docket No.93033-425511 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.

[0185] 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.

[0186] 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.

[0187] 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 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.

[0188] 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. 43Attorney Docket No.93033-425511

[0189] 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.

[0190] 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 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.

[0191] 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. 44Attorney Docket No.93033-425511

[0192] 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.

[0193] 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 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

[0194] The disclosed compounds of formula (I)-(IV), or tautomers thereof, 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). 45Attorney Docket No.93033-425511 EXAMPLES

[0195] 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

[0196] 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 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 46Attorney Docket No.93033-425511 SYNTHETIC CHEMICAL EXAMPLES

[0197] The proposed targets, intermediates, and / or starting materials can be prepared via the conventional chemistry or by following the schemes as shown below. Intermediate Synthesis Schemes Scheme 1: Synthesis of methyl 4-(benzyloxy)-3-methoxy-2-nitrobenzoatedExample 1 Preparation of 5-fluoro-2-phenylquinazolin-4(1H)-one (1) 47Attorney Docket No.93033-425511

[0198] A mixture of 2-bromo-6-fluorobenzoic acid (100 mg, 0.45 mmol) and benzimidamide hydrochloride (107 mg, 0.68 mmol) was dissolved in DMF (3 mL) and added cesium carbonate (298 mg, 0.91 mmol) and then allowed to nitrogen purging for 15 minutes at room temperature. To this mixture with stirring was added copper(I) iodide (17 mg, 0.01 mmol) and nitrogen purged for 5 minutes. The reaction mixture was stirred at 50 °C for 16 h. After the completion of the reaction (as monitored by TLC), the reaction mixture was diluted with ice-cold water and stirred for 10 minutes, filtered the solids, and washed with water to get the crude. The crude product was suspended in methanol and cooled slowly to 0 °C. After stirring for 5 minutes, the solids were filtered, washed with cold methanol, and dried under vacuum to obtain the pure compound 5-fluoro-2-phenylquinazolin-4(1H)-one (100 mg, 0.41 mmol, 91% yield) as a blue-white solid.1H-NMR (400 MHz, DMSO-d6): δ 12.55 (s, 1H), 8.18 (d, J = 7.2 Hz, 2H), 7.80 – 7.78 (m, 1H), 7.61 – 7.56 (m, 4H), 7.26 – 7.22 (m, 1H). MS (ESI) m / z: 241.2 (M+1)+. Example 2 Preparation of 5-fluoro-2-phenylquinazolin-4(1H)-one (2)

[0199] A stirreol) in DMF (3 mL) was added benzimidamide hydrochloride (0.59 g, 3.80 mmol) followed by addition of cesium carbonate (1.65 g, 5.06 mmol) at room temperature. The mixture was allowed to N2purging for 15 min. Subsequently, copper(I) iodide (0.096 g, 0.50 mmol) was added at room temperature and was allowed to stir at room temperature for 16 h under an N2atmosphere. After completion of the reaction (as monitored by TLC), the reaction mixture was poured into ice-cold water and stirred for 10 min, the residue obtained was filtered, washed with water, and dried to get the crude product. The crude product was suspended in methanol and cooled slowly to 0 °C. After stirring for 5 min, the solid was filtered, washed with cold methanol, and dried under vacuum to obtain the 5,7-difluoro-2-phenylquinazolin-4(1H)-one (0.1 g, 0.38 48Attorney Docket No.93033-425511 mmol, 15% yield) as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 12.67 (s, 1H), 8.17 – 8.10 (m, 2H), 7.64 – 7.55 (m, 3H), 7.41 – 7.37 (m, 2H). MS (ESI) m / z: 259.2 (M+1)+. Example 3 Preparation of 8-methoxy-7-(2-methoxyethoxy)-2-phenylquinazolin-4(1H)-one (3) [020

[0201] To a stirred solution of 4-robenzaldehyde (2 g, 10.14 mmol in DMF (20 mL), and to the stirred solution potassium carbonate (4.21 g, 30.4 mmol) was added followed by the dropwise addition of 1-bromo-2-methoxyethane (2.1 g, 15.2 mmol). The reaction mixture was stirred at 80 °C for 5 h. After the completion of the reaction as indicated by TLC, water (50 mL) was added to the reaction mixture and extracted with ethyl acetate of (2 × 50 mL). The combined organic layer was washed with water, and brine solution, dried over anhydrous Na2SO4concentrated under reduced pressure to get the crude product 3-methoxy-4-(2-methoxyethoxy)-2-nitrobenzaldehyde (2.5 g, 10.14 mmol, 98% yield) as brown solid. The crude product was used in the next step without further purification. MS (ESI) m / z: 256.2 (M+1)+.

[0202] Step 2: 3-methoxy-4-(2-methoxyethoxy)-2-nitrobenzoic acid 49Attorney Docket No.93033-425511

[0203] To a stirred solution of 3- oxy)-2-nitrobenzaldehyde (500 mg, 1.96 mmol) in DMF (10 mL) was added oxone ( .3 g, . 5 mmo ). The reaction mixture was stirred for 4 h at room temperature. Upon completion of the reaction, water (25 mL) was added, and extracted with ethyl acetate (2 × 25 mL). The combined organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4,filtered, and concentrated under reduced pressure to get the crude product 3-methoxy-4-(2- methoxyethoxy)-2-nitrobenzoic acid (540 mg, 1.96 mmol, 97% yield) as yellow solid. The crude product was used in the next step without further purification. MS (ESI) m / z: 270.0 (M+1)+.

[0204] Step 3: Synthesis of 3-methoxy-4-(2-methoxyethoxy)-2-nitrobenzamide

[0205] To a stirred solution of 3 xy)-2-nitrobenzoic acid (550 mg, 2.02mmol) in DMF (8 mL), DIPEA (1.06 mL, 6.08 mmol) was added followed by the addition of HATU (1157 mg, 3.04 mmol) and ammonium chloride (325 mg, 6.08 mmol). The reaction mixture was allowed to stir at room temperature for 5 h. Upon completion of the reaction, the reaction mixture was diluted with ice-cold water (25 mL) and extracted with ethyl acetate (2 × 25 mL). The combined organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get the crude. The crude product was purified by normal phase flash column chromatography using ethyl acetate / petroleum as an eluent to give 3-methoxy-4-(2-methoxyethoxy)-2-nitrobenzamide (590 mg, 1.98 mmol, 98% yield) as yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.57 (s, 1H), 7.54 (s, J = 12 Hz, 1H), 7.35 (d, J =12 Hz, 1H). MS (ESI) m / z: 271.0 (M+1)+.

[0206] Step 4: Synthesis of 2-amino-3-methoxy-4-(2-methoxyethoxy)benzamide

[0207] 3-methoxy-4-(2-methoxy630 mg, 2.33 mmol) was dissolved in MeOH (10 mL) and in the stirred solution 50% wet Pd / C (400 mg, 0.37 mmol) was added. The solution was stirred for 16 h under an H2atmosphere. Upon completion, the reaction mass was filtered through 50Attorney Docket No.93033-425511 celite bed and washed with methanol (50 mL). The filtrate was concentrated under a vacuum to get the 2- amino-3-methoxy-4-(2-methoxyethoxy)benzamide (500 mg, 1.89 mmol, 81% yield) as an off-white solid. MS (ESI) m / z: 241.1(M+1)+.

[0208] Step 5: Synthesis of 8-methoxy-7-(2-methoxyethoxy)-2-phenylquinazolin-4(1H)-one (3)

[0209] A mixture of 2-amino- benzamide (150 mg, 0.62 mmol),benzaldehyde (80 mg, 0.75 mmol) was dissolved in EtOH (20 mL) and added iodine (174 mg 0.68 mmol) at room temperature. The reaction mixture was stirred and refluxed at 90 °C for 3 h. After completion of the reaction as indicated by TLC, the solvent was evaporated under a vacuum. The residual mass was purified by normal phase column chromatography using ethyl acetate / petroleum ether as an eluent to get the 8-methoxy-7-(2-methoxyethoxy)-2-phenylquinazolin-4(3H)-one (110 mg, 0.33 mmol, 54% yield) as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 12.37 (s, 1H), 8.22 – 8.20 (m, 2H), 7.88 (d, J = 9.2 Hz, 1H), 7.60 – 7.54 (m, 3H), 7.31 (d, J = 8.8 Hz, 1H), 4.31 (t, J = 3.2 Hz, 2H), 3.98 (s, 3H), 3.75 (d, J = 2.8 Hz, 2H), 3.36 (s, 3H). MS (ESI) m / z: 327.1 (M+1)+. Example 5 Preparation of 5-fluoro-7-(2-methoxyethoxy)-2-phenylquinazolin-4(3H)-one (5) 51Attorney Docket No.93033-425511 h

[0211] To a stirred solution of 2,6-zoic acid (500 mg, 2.87 mmol) in MeOH (10 mL), was added thionyl chloride (0.042 mL, 0.57 mmol) at 0 °C. The reaction mixture was stirred at 65 °C for 5 h. After completion of the reaction as indicated by TLC, the reaction mixture was completely evaporated, the residue was dissolved in water, basified with 10% sodium bicarbonate solution, 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 reduced pressure to get the crude of methyl 2,6-difluoro-4-hydroxybenzoate (440 mg, 81% yield) as a white solid. The crude product was used in the next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 6.57 – 6.54 (m, 2H), 3.81 (s, 3H). 52Attorney Docket No.93033-425511

[0212] Step 2: Synthesis of methyl 2,6-difluoro-4-(2-methoxyethoxy)benzoate

[0213] To a stirred solution of benzoate (450 mg, 2.39 mmol) in DMF (10 mL), was added potassium carbonate (992 mg, 7.18 mmol), followed by the addition of 1-bromo-2- methoxyethane (499 mg, 3.59 mmol) at 0 °C. the reaction mixture was stirred at room temperature for 5 h. Upon completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL) 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 reduced pressure to get the crude product methyl 2,6-difluoro-4-(2-methoxyethoxy)benzoate (490 mg, 83% yield) as brown oily liquid. The crude product was used in the next step without further purification.1H-NMR (400 MHz, DMSO-d6): δ 6.92 – 6.88 (m, 2H), 4.22 – 4.19 (m, 2H), 3.84 (s, 3H), 3.67 – 3.64 (m, 2H), 3.30 (s, 3H).

[0214] Step 3: Synthesis of methyl 2-((2,4-dimethoxybenzyl)amino)-6-fluoro-4-(2- methoxyethoxy)benzoate

[0215] Methyl 2,6-difluo.47 mmol) was dissolved in NMP (8 mL) to the stirred solution potassium carbonate (0.74 g, 5.36 mmol) was added, followed by the addition of (2,4-dimethoxyphenyl)methanamine (0.82 g, 4.91 mmol). The reaction mixture was stirred at 80 °C for 16 h. After the completion of the reaction as indicated by TLC, water (50 mL) was added to the reaction mixture and extracted with ethyl acetate of (2 × 50 mL). The combined organic layer was washed with water (50 mL), and brine solution (50 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get the crude product. The crude product was purified by normal phase column chromatography using 20% ethyl acetate in petroleum ether to get the methyl 2-((2,4- dimethoxybenzyl)amino)-6-fluoro-4-(2-methoxyethoxy)benzoate (1.4 g, 3.56 mmol, 80% yield) as white solid.

[0216] Step 4: Synthesis of 2-((2,4-dimethoxybenzyl)amino)-6-fluoro-4-(2-methoxyethoxy)benzoic acid 53Attorney Docket No.93033-425511

[0217] To a stirred solutio mino)-6-fluoro-4-(2- methoxyethoxy)benzoate (1.3 g, 3.30 mmol) in a mixture of methanol (8 mL), THF (8 mL), water (4 mL) was added lithium hydroxide hydrate (1.38 g, 33 mmol) to 0 °C. The reaction mixture was stirred at 65 °C for 16 h. Upon completion of the reaction, the reaction mixture was completely evaporated under vacuum and acidified with 1.5 N HCL, the residue obtained was filtered and dried to get the 2-((2,4- dimethoxybenzyl) amino)-6-fluoro-4-(2-methoxyethoxy) benzoic acid (1.2 g, 3.16 mmol, 96% yield) as a yellow solid. MS (ESI) m / z: 378.0 (M-1)+.

[0218] Step 5: Synthesis of 2-((2,4-dimethoxybenzyl)amino)-6-fluoro-4-(2-methoxyethoxy) benzamide

[0219] To a stirred soluti fluoro-4-(2-methoxyethoxy)benzoic acid (75 mg, 0.19 mmol) in DMF (2 mL), DIPEA (0.104 mL, 0.59 mmol) was added, followed by the addition of HATU (113 mg, 0.29 mmol) and ammonium chloride (31.7 mg, 0.59 mmol). The reaction mixture was allowed to stir at room temperature for 16 h. After the completion of the reaction as indicated by TLC, added water (10 mL) and extracted with ethyl acetate (2 × 15 mL). The combined organic layer was washed with water (10 mL), and brine solution (10 mL), dried over anhydrous Na2SO4,and concentrated under reduced pressure to get the crude. The crude product was purified by normal phase column chromatography using 35% ethyl acetate in petroleum ether to get 2- ((2,4-dimethoxybenzyl)amino)-6-fluoro-4-(2-methoxyethoxy)benzamide (60 mg, 0.14 mmol, 73% yield) as white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.01 – 7.98 (m, 1H), 7.41 (s, 1H), 7.32 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.50 – 6.47 (m, 1H), 6.05 – 6.01 (m, 1H), 5.93 (d, J = 2.0 Hz, 1H), 4.19 (d, J = 5.6 Hz, 2H), 4.06 – 4.04 (m, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 3.61 – 3.59 (m, 2H), 3.28 (s, 3H).

[0220] Step 6: Synthesis of 2-amino-6-fluoro-4-(2-methoxyethoxy)benzamide 54Attorney Docket No.93033-425511

[0221] To a solution of 2-((2,4- fluoro-4-(2 methoxyethoxy) benzamide (60 mg, 0.16 mmol) in DCM (5 mL),was treated w t TF (0.5 mL, 6.49 mmol) at 0 °C for 1 h. After the completion of the reaction as indicated by TLC, the solvent was removed in a vacuum, basified with 10% sodium bicarbonate solution, and extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with water (10 mL), and brine solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under a vacuum to get the 2-amino-6-fluoro-4-(2- methoxyethoxy) benzamide (40 mg, 0.15 mmol, 99% yield) as a white solid. MS (ESI) m / z: 229.2 (M+1)+.

[0222] Step 7: Synthesis of 5-fluoro-7-(2-methoxyethoxy)-2-phenylquinazolin-4(3H)-one (5)

[0223] A mixture of 2-aminoenzamide (50 mg, 0.22 mmol), and benzaldehyde (0.027 mL, 0.26 mmol) was dissolved in EtOH (10 mL), iodine (61.2 mg, 0.24 mmol) was added at room temperature. The reaction mixture was stirred and refluxed at 90 °C for 8 h. After completion of the reaction as indicated by TLC, the solvent was evaporated under a vacuum. The residual mass was dissolved in ethyl acetate (25 mL) and washed with thiosulphate solution (10 mL), water (10 mL), and brine solution (10 mL), dried and concentrated under reduced pressure to get the crude product. The crude product was purified by preparative HPLC to get the isolated 5-fluoro-7-(2-methoxyethoxy)-2- phenylquinazolin-4(3H)-one (15 mg, 0.04 mmol, 21% yield) as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 12.41 (s, 1H), 8.18 – 8.16 (m, 2H), 7.63 – 7.53 (m, 3H), 7.05 (d, J = 2.4 Hz, 1H), 6.95 – 6.92 (m, 1H), 4.30 – 4.28 (m, 2H), 3.72 – 3.70 (m, 2H), 3.33 (s, 3H). Example 8 / Example 14 Preparation of 8-methoxy-7-(2-methoxyethoxy)-3-methyl-2-phenylquinazolin-4(3H)-one (8) and 4,8-dimethoxy-7-(2-methoxyethoxy)-2-phenylquinazoline (14) 55Attorney Docket No.93033-425511

[0224] T -4(3H)-one (90mg, 0.27 mmol) in DMF (10 mL), was added sodium hydride (60 % on mineral oil; 26.5 mg, 0.55 mmol), portion-wise at 0 °C under N2atmosphere. The slurry was stirred for 30 min before iodomethane (0.02 mL, 0.33 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 4 h. After the completion of the reaction, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with ethyl acetate (2 × 20 mL). All the combined organic layer was washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to get the crude product. The crude product was purified by preparative HPLC, and the isolated fraction was concentrated, dried, and lyophilized to get the (regioisomer A) 8-methoxy-7-(2-methoxyethoxy)-3- methyl-2-phenylquinazolin-4(3H)-one (22.78 mg, 0.06 mmol, 24% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 7.91 (d, J = 8.8 Hz, 1H), 7.70 – 7.68 (m, 2H), 7.58 – 7.56 (m, 3H), 7.36 (d, J = 8.8 Hz, 1H), 4.31 – 4.28 (m, 2H), 3.87 (s, 3H), 3.74 – 0.72 (m, 2H), 3.34 (s, 3H), 3.33 (s, 3H). MS m / z: 341.1 (M+1)+and (regioisomer B) 4,8-dimethoxy-7-(2-methoxyethoxy)-2-phenylquinazoline (9.67 mg, 0.02 mmol, 10% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.58 – 8.55 (m, 2H), 7.89 (d, J = 8.8 Hz, 1H), 7.57 (t, J = 2.0 Hz, 3H), 7.50 (d, J = 9.2 Hz, 1H), 4.37 – 4.34 (m, 2H), 4.25 (s, 3H), 4.08 (s, 3H), 3.76 – 3.74 (m, 2H), 3.36 (s, 3H). MS (ESI) m / z: 341.2 (M+1)+. Example 11 / Example 13 Preparation of 5,7-difluoro-3-methyl-2-phenylquinazolin-4(3H)-one (11) and 5,7-difluoro-4- methoxy-2-phenylquinazoline (13) 56Attorney Docket No.93033-425511 [02 l) inDMF (1.5 mL) was added NaH (20 mg, 0.58 mmol) at 0 ⁰C. After 10 min, was added iodomethane (0.03 mL, 0.58 mmol) dropwise at 0 ⁰C. The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with ice-cold water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layer was with water (10 mL), and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to get the crude product. The resulting crude product was purified by preparative HPLC using the formic acid method to get the 5,7-difluoro-3-methyl-2-phenylquinazolin-4(3H)- one_regioisomer A (14 mg, 0.05 mmol, 13% yield) and 5,7-difluoro-4-methoxy-2- phenylquinazoline_regioisomer B (7 mg, 0.02 mmol, 6% yield) as off-white solid. Regioiosmer A1H- NMR (400 MHz, MeOD): δ 7.90 – 7.60 (m, 5H), 7.24 – 7.14 (m, 2H), 3.45 (s, 3H). MS (ESI) m / z: 273.1 (M+1)+; Regioiosmer B1H-NMR (400 MHz, DMSO-d6): δ 8.55 – 8.53 (m, 2H), 7.64 – 7.53 (m, 5H), 4.27 (s, 3H). MS (ESI) m / z: 273.1 (M+1)+. Example 12A Route 1: Preparation of 7-hydroxy-8-methoxy-2-phenylquinazolin-4(3H)-one (12) [p y y y y y 57Attorney Docket No.93033-425511

[0227] To a (0.9 g, 2.97 mmol) in DMF (15 mL) wasadded Cs2CO3(2.9 g, 8.9 mmol) followed by dropwise addition of MeI (0.55 mL, 8.9 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice water (30 mL), and the residue obtained was filtered and dried to get pure methyl 4- (benzyloxy)-3-methoxy-2-nitrobenzoate (870 mg, 2.74 mmol, 92% yield) as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 7.83 (d, J= 15 Hz, 1H), 7.53 – 7.45 (m, 3H), 7.44 – 7.38 (m, 3H), 5.34 (s, 2H), 3.85 (s, 3H), 3.81 (s, 3H).

[0228] Step 2: Synthesis of methyl 2-amino-4-(benzyloxy)-3-methoxybenzoate

[0229] To a s0 mg, 2.74 mmol) in a mixture of MeOH (10 mL), H2O (3 mL) was added iron (1.07 g, 19.19 mmol) and ammonium chloride (367 mg, 6.85 mmol) at room temperature. The resulting solution was refluxed at 80 °C for 8 h. After the completion of the reaction as indicated by TLC, the reaction mixture was filtered through a celite bed and washed with 10% MeOH in DCM (3 × 20 mL) and the filtrate was concentrated under reduced pressure. The residual mass was dissolved in DCM (50 mL) and washed with water (25 mL), and brine solution (25 mL), dried over anhydrous Na2SO4,and concentrated under a vacuum to get crude. The crude product was purified by trituration using n-pentane (3 × 10 mL) to get pure methyl 2-amino-4-(benzyloxy)-3- methoxybenzoate (680 mg, 2.31 mmol, 84% yield) compound as a brown solid. MS (ESI) m / z: 288.2 (M+1)+.

[0230] Step 3: Synthesis of 7-(benzyloxy)-8-methoxy-2-phenylquinazolin-4(3H)-one 58Attorney Docket No.93033-425511 CN OMe OMe BnO NH2BnO N

[0231] Ag, 1.04 mmol) and benzonitrile (538 mg, 5.22 mmol) were dissolved in 4 M HCl in dioxane (3 mL, 1.044 mmol) at room temperature. The reaction mixture was refluxed at 120 °C for 24 h. Upon completion of the reaction, the solvent was directly concentrated under vacuum, and the residual mass was basified with sat. NaHCO3solution (30 mL) and was extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with water (30 mL), and brine solution (30 mL), dried over anhydrous Na2SO4, and concentrated to give a crude product. The crude product was purified by normal phase flash column chromatography using ethyl acetate and petroleum ether as eluent to get the product 7-(benzyloxy)-8-methoxy-2-phenylquinazolin- 4(3H)-one (100 mg, 28%) as a white solid. MS (ESI) m / z: 357.8 (M-1)+.

[0232] Step 4: Synthesis of 7-hydroxy-8-methoxy-2-phenylquinazolin-4(3H)-one.

[0233] To a stirred solution of 7-(benzyloxy)-8-methoxy-2-phenylquinazolin-4(3H)-one (100 mg, 0.28 mmol) in methanol (4 mL) was added palladium 10% on carbon (148 mg, 1.39 mmol) and the reaction mixture was allowed to stir at room temperature for 12 h. After the completion of the reaction as indicated by TLC and LCMS, the reaction mixture was filtered and washed with MeOH and the resulting filtrate was concentrated under reduced pressure to get crude, The crude product was purified by column chromatography using ethyl acetate and petroleum ether as eluent to get the pure 7-hydroxy-8-methoxy-2- phenylquinazolin-4(3H)-one (33 mg, 0.12 mmol, 44% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 12.25 (s, 1H), 10.07 (s, 1H), 8.22 – 8.19 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.59 – 7.54 (m, 3H), 7.05 (d, J = 12.0 Hz, 1H), 3.99 (s, 3H). Example 12B Route 2: Preparation of 7-hydroxy-8-methoxy-2-phenylquinazolin-4(3H)-one (12) 59Attorney Docket No.93033-425511

[0235] To 3 g, 42.9 mmol) inDMF (150 ml) were added HATU (24.45 g, 64.3 mmol) and DIPEA (22.46 ml, 129 mmol) at 0 °C. The reaction mixture was stirred at rt for 5min, and ammonium chloride (6.88 g, 129 mmol) was added at 0 °C. The reaction mixture was stirred at rt for 16h. The reaction mixture was diluted with ice-cold water (200 mL) and was extracted by DCM (3 x 200 mL) and washed with brine solution (100 mL). The combined organic layer was dried over sodium sulfate and concentrated at a high vacuum to obtain crude 4- (benzyloxy)-3-methoxy-2-nitrobenzamide (13 g, 13.0 mmol, 79% Yield) as pale brown solid. LCMS(m / z): 303.1 (M+1).1H-NMR (400 MHz, DMSO-d6): δ 8.07 (s, 1H), 7.57 (m, 6H), 5.30 (s, 2H), 3.83 (s, 3H).

[0236] Step 2: Synthesis of 2-amino-4-(benzyloxy)-3-methoxybenzamide:

[0237] Tog, 43.0 mmol) in Ethanol (462 ml) and Water (114 ml) were added ammonium chloride (11.50 g, 215 mmol) and iron (12.01 g, 215 mmol) at rt. The resulting reaction mixture was refluxed at 85 °C for 2h. The solvent was directly removed at a high vacuum. Crude was purified by flash column chromatography using 50-60% EtOAc in pet ether to afford 2-amino-4-(benzyloxy)-3-methoxybenzamide (10.8 g, 33.7 mmol, 78% Yield). 60Attorney Docket No.93033-425511 LCMS(m / z): 273.1 (M+1).1H-NMR (400 MHz, DMSO-d6): δ 7.81 – 7.56 (m, 1H), 7.48 – 7.31 (m, 6H), 7.24 (s, 1H), 7.07 – 6.90 (m, 1H), 6.66 – 6.41 (m, 1H), 6.40 – 6.32 (m, 1H), 5.15 (s, 2H), 3.68 (s, 3H).

[0238] Step 3: Synthesis of 7-(benzyloxy)-8-methoxy-2-phenylquinazolin-4(3H)-one:

[0239] To 8 g, 39.7 mmol) inEthanol (600 ml) were added iodine (11.07 g, 43.6 mmol) and benzaldehyde (5.05 g, 47.6 mmol) at rt. The resulting reaction mixture was refluxed at 90 °C for 2h. The solvent was directly removed at a high vacuum. The crude was diluted with saturated Sodium thiosulfate pentahydrate solution (300 ml) and extracted with 20% MeOH in DCM (3 x 300 ml). The combined organic layer was washed with brine (100 ml), dried over sodium sulfate, and concentrated to get crude. It was triturated with hexane (2 x 100 ml) and the solid was dried to get 7-(benzyloxy)-8-methoxy-2-phenylquinazolin-4(3H)-one (11 g, 30.69 mmol, 77.41 % yield). LCMS(m / z): 359.2 (M+1).1H-NMR (400 MHz, DMSO-d6): ppm 12.39 (brs, 1H), 8.22 – 8.19 (m, 2H), 7.89 – 7.86 (m, 1H), 7.60 – 7.42 (m, 9H), 5.31 (s, 2H), 3.99 (s, 3H).

[0240] Step 4: Synthesis of 7-hydroxy-8-methoxy-2-phenylquinazolin-4(1H)-one (12)

[0241] H)-one (3.2 g, 8.75 mmol) in a mixture of THF (5 ml) and MeOH (15 ml). The reaction mixture was degassed for 2 min, palladium on carbon (0.931 g, 4.38 mmol) and palladium hydroxide on carbon (1.229 g, 4.38 mmol) were added under nitrogen atm. The reaction mixture was stirred at rt for 4h under H2atm. The reaction mixture was filtered through celite pad and the solid was washed with MeOH (2 x 500 ml). The filtrate was concentrated to get crude. MTBE (100 ml) was added to the crude product and stirred for 30 min. The suspension was filtered and the solid was washed with MTBE (2 x 100 ml). The solid was dried to get 7- hydroxy-8-methoxy-2-phenylquinazolin-4(1H)-one as an off-white solid. LCMS: 0.73 min, 99.42 %, 269.2 (M+H)+; Column: CSH C-18 (30x2.1mm) 1.7 μm, Mobile phase A: 0.1% HCOOH in H2O B: 0.1% HCOOH in ACN, Flow rate: 1.0 mL / min. HPLC: 3.90 min, 99.87%; (Column: X-Bridge C8 (50 X 4.6)mm ,3.5μm, Mobile phase A: 0.1% FA in water, Mobile phase B : ACN, Flow: 1.0 mL / min).1H-NMR (400 61Attorney Docket No.93033-425511 MHz, DMSO-d6): ppm 12.32 (brs, 1H), 10.11 (brs, 1H), 8.21 (dd, J = 8.0, 2.0 Hz, 2H), 7.77 (d, J = 8.8 Hz, 1H), 7.60 – 7.56 (m, 3H), 7.04 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H). Example 15 Preparation of 2-cyclohexyl-5,7-difluoroquinazolin-4(3H)-one (15)

[0242] To a stirred solution of 2-bromo-4,6-difluorobenzoic acid (100 mg, 0.42 mmol) in DMF (2.5 mL) was added cyclohexanecarboximidamide hydrochloride (0.10 g, 0.63 mmol), cesium carbonate (270 mg, 0.84 mmol) and copper(I) iodide (16 mg, 0.08 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was stirred at 100 °C for 16 h. After the completion of the reaction as monitored by TLC, the reaction mixture was poured into ice-cold water and stirred for 20 min, the residue obtained was filtered, washed with ice n-pentane, and dried to get the crude. The crude product was purified by preparative HPLC using the formic acid method to give the 2-cyclohexyl-5,7- difluoroquinazolin-4(3H)-one (40 mg, 0.14 mmol, 34% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 12.21 (s, 1H), 7.31 – 7.21 (m, 2H), 2.55 – 2.53 (m, 1H), 1.89 – 1.80 (m, 2H), 1.80 – 1.75 (m, 2H), 1.68 – 1.62 (m, 1H), 1.56 – 1.51 (m, 2H), 1.35 – 1.25 (m, 3H). MS (ESI) m / z: 265.1 (M+1)+. Example 16 / Example 17 Preparation of 2-cyclohexyl-7-fluoro-5-(2-methoxyethoxy)quinazolin-4(3H)-one (16) and 2- cyclohexyl-5,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (17)y g, . ded NaH (90 mg, 2.27 mmol) under nitrogen atmosphere. After 10 min, was added 2-cyclohexyl-5,7- difluoroquinazolin-4(3H)-one (0.15 g, 0.56 mmol) (dissolved in 1 mL DMF) dropwise at 0 °C. The 62Attorney Docket No.93033-425511 reaction mixture was stirred at 100 °C for 2.5 h. The progress of the reaction is monitored by TLC. Upon completion, the reaction mixture was diluted with ice-cold water and extracted with 10% MeOH in ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to get the crude. The crude product was purified by preparative HPLC using the formic acid method to obtain the mono-alkylated compound 2-cyclohexyl-7- fluoro-5-(2-methoxyethoxy)quinazolin-4(3H)-one (30 mg, 0.09 mmol, 16% yield);1H-NMR (400 MHz, DMSO-d6): δ 11.77 (s, 1H), 6.90 – 6.83 (m, 2H), 4.20 (t, J = 4.8 Hz, 2H), 3.73 (t, J = 4.4 Hz, 2H), 3.37 (s, 3H), 2.55 (q, J = 3.6 Hz, 1H), 1.88 – 1.77 (m, 4H), 1.99 – 1.49 (m, 2H), 1.34 – 1.23 (m, 2H). MS(ESI) m / z: 321.1 (M+1)+; 2-cyclohexyl-5,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (40 mg, 0.10 mmol, 18% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.53 (s, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 4.21 – 4.13 (m, 4H), 3.71 – 3.67 (m, 4H), 3.36 (s, 6H), 2.90 – 2.88 (m, 1H), 1.87 – 1.77 (m, 5H), 1.58 – 1.50 (m, 2H), 1.33 – 1.19 (m, 3H). MS (ESI) m / z: 377.2 (M+1)+. Example 18 Preparation of 2-cyclopentyl-5,7-difluoroquinazolin-4(3H)-one (18)

[0244] To a sti4 mmol) in DMF (5 mL) was added cyclopentanecarboximidamide hydrochloride (180 mg, 1.26 mmol), cesium carbonate (550 mg, 1.68 mmol) and copper(I) iodide (30 mg, 0.17 mmol) under N2atmosphere at room temperature. The reaction mixture was stirred at 100 °C for 16 h. After the completion of the reaction (as monitored by TLC), the reaction mixture was poured into ice-cold water and stirred for 20 min, the residue obtained was filtered, washed with n-pentane, and dried to get the crude. The crude product was purified by preparative HPLC using the formic acid method to get the 2-cyclopentyl-5,7-difluoroquinazolin-4(3H)- one (0.03 g, 0.12 mmol, 14% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 12.27 (s, 1H), 7.30 – 7.21 (m, 2H), 3.01 – 2.98 (m, 1H), 1.99 – 1.96 (m, 2H), 1.90 – 1.85 (m, 2H), 1.76 – 1.73 (m, 2H), 1.62 – 1.59 (m, 2H). MS (ESI) m / z: 251.1 (M+1)+. 63Attorney Docket No.93033-425511 Example 19 / Example 20 Preparation of 2-cyclopentyl-7-fluoro-5-(2-methoxyethoxy)quinazolin-4(3H)-one (19) and 2- cyclopentyl-5,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (20)added NaH (60 % on mineral oil; 0.09 g, 2.34 mmol) portionwise at 0 °C under nitrogen atmosphere. After 10 min, the solution of 2-cyclopentyl-5,7-difluoroquinazolin-4(3H)-one (150 mg, 0.56 mmol) in DMF (1 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 100 °C for 3.5 h. After the completion of the reaction as indicated by TLC, the reaction mixture was diluted with ice-cold water (10 mL) and extracted with 10% MeOH in ethyl acetate (2 × 20 mL). The combined organic layers were washed with water (20 mL), and brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to get the crude. The crude product was purified by preparative HPLC using the formic acid method to obtain the mono-alkylated compound 2-cyclopentyl-7-fluoro-5-(2- methoxyethoxy)quinazolin-4(3H)-one (70 mg, 0.22 mmol, 37% yield) as off-white solids.1H-NMR (400 MHz, DMSO-d6): δ 11.83 (s, 1H), 6.90 – 6.83 (m, 2H), 4.21 (t, J = 4.8 Hz, 2H), 3.72 (t, J = 4.8 Hz, 2H), 3.37 (s, 3H), 2.98 (q, J = 8.4 Hz, 1H), 1.98 – 1.92 (m, 2H), 1.89 – 1.80 (m, 2H), 1.77 – 1.72 (m, 2H), 1.63 – 1.58 (m, 2H); MS (ESI) m / z: 307.1 (M+1)+and dialkylated 2-cyclopentyl-5,7-bis(2- methoxyethoxy)quinazolin-4(3H)-one (50 mg, 0.13 mmol, 23% yield) as off-white solids.1H-NMR (400 MHz, DMSO-d6): δ 11.53 (s, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 4.21 – 4.13 (m, 4H), 3.71 – 3.67 (m, 4H), 3.36 (s, 6H), 2.47 – 2.46(m, 1H), 1.87 – 1.77 (m, 4H), 1.58 – 1.50 (m, 2H), 1.33 – 1.19 (m, 2H). MS (ESI) m / z: 363.2 (M+1)+. Example 21 Preparation of 2-(tert-butyl)-5,7-difluoroquinazolin-4(3H)-one (21)64Attorney Docket No.93033-425511

[0246] To a solution of 2-bromo-4,6-difluorobenzoic acid (50 mg, 0.21 mmol) and pivalimidamide hydrochloride (40 mg, 0.31 mmol) in the DMF (2.5 mL), was added cesium carbonate (0.13 g, 0.42 mmol) and copper(I)iodide (8.04 mg, 0.04 mmol) under N2atmosphere at room temperature. The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction as monitored by TLC, the reaction mixture was diluted with ice-cold water (15 mL) and extracted with ethyl acetate (2 × 25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to get the crude. The crude product was purified by preparative HPLC using the FA method to get the 2-(tert-butyl)-5,7-difluoroquinazolin-4(3H)-one (17 mg, 0.07 mmol, 34% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.99 (s, 1H), 7.33 – 7.22 (m, 2H), 1.34 (s, 9H). MS (ESI) m / z: 239.1 (M+1)+. Example 22 Preparation of 5-fluoro-7-(2-methoxyethoxy)-2-(quinolin-6-yl)quinazolin-4(3H)-one (22)

[0247] A mixture of 2-amino-6-fluoro-4-(2-methoxyethoxy)benzamide (150 mg, 0.65 mmol) and quinoline-6-carbaldehyde (114 mg, 0.72 mmol) was dissolved in EtOH (20 mL), iodine (183 mg, 0.72 mmol) was added at room temperature. After completion of the reaction as indicated by TLC, the solvent was evaporated under a vacuum. The residual mass was dissolved in ethyl acetate (2 × 20 mL) and washed with sodium thiosulphate solution (20 mL), water (20 mL), and brine solution (20 mL), dried and concentrated under reduced pressure to get the crude product. The crude product was purified by preparative HPLC using method B to get the 5-fluoro-7-(2-methoxyethoxy)-2-(quinolin-6-yl)quinazolin- 4(3H)-one (24 mg, 0.06 mmol, 10% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 12.62 (s, 1H), 9.04 – 9.02 (m, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.52 – 8.49 (m, 2H), 8.16 (d, J = 9.2 Hz, 1H), 7.68 – 7.65 (m, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.99 – 6.96 (m, 1H), 4.32 – 4.30 (m, 2H), 3.73 – 3.71 (m, 2H), 3.34 (s, 3H). MS (ESI) m / z: 366.0 (M+1)+. Example 23 / Example 26 Preparation of 8-methoxy-7-(2-methoxyethoxy)-3-methyl-2-(quinolin-6-yl)quinazolin-4(3H)-one 65Attorney Docket No.93033-425511 (23) and 4,8-dimethoxy-7-(2-methoxyethoxy)-2-(quinolin-6-yl)quinazoline (26)

[0248] zolin-4(3H)-one (110 mg, 0.29 mmol) in a mixture of DMF and THF (3:1, 20 mL) was added sodium hydride (60 % on mineral oil; 28.0 mg, 0.58 mmol) portionwise at 0 °C under N2atmosphere. The slurry was stirred for 30 min before iodomethane (0.02 mL, 0.35 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 4 h. After the completion of the reaction, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to get the crude product. The crude product was purified by preparative HPLC, the isolated fraction was concentrated, dried, and lyophilized to get the (regioisomer A) 8-methoxy-7-(2-methoxyethoxy)-3-methyl-2-(quinolin-6-yl)quinazolin-4(3H)-one (23.6 mg, 0.058 mmol, 20% yield) as white solid.1H-NMR (400 MHz, DMSO-d6): δ 9.04 – 9.02 (m, 1H), 8.54 – 8.52 (m, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.08 – 8.06 (m, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.68 – 7.65 (m, 1H), 7.39 (d, J = 8.8 Hz, 1H), 4.32 – 4.30 (m, 2H), 3.89 (s, 3H), 3.75 – 3.73 (m, 2H), 3.41 (s, 3H), 3.37 (s, 3H). MS (ESI) m / z: 392.1(M+1)+and (regioisomer B) 4,8-dimethoxy-7-(2-methoxyethoxy)- 2-(quinolin-6-yl)quinazoline (25.05 mg, 0.064 mmol, 22% yield) as a green solid.1H-NMR (400 MHz, DMSO-d6): δ 9.19 (d, J = 2.0 Hz, 1H), 9.02 – 9.01 (m, 1H), 8.96 – 8.94 (m, 1H), 8.69 (d, J = 7.6 Hz, 1H), 8.21 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.69 – 7.65 (m, 1H), 7.54 (d, J = 9.2 Hz, 1H), 4.39 – 4.36 (m, 2H), 4.33 (s, 3H), 4.13 (s, 3H), 3.77 – 3.75 (m, 2H), 3.37 (s, 3H). MS (ESI) m / z: 392.2 (M+1)+. Example 24 Preparation of 8-methoxy-7-(2-methoxyethoxy)-2-(quinolin-6-yl)quinazolin-4(3H)-one (24) 66Attorney Docket No.93033-425511 [0 ) andquinoline-6-carbaldehyde (204 mg, 1.29 mmol) was dissolved in EtOH (20 mL) and added iodine (302 mg, 1.19 mmol) at room temperature. The reaction mixture was stirred and refluxed at 90 °C for 3 h. After completion of the reaction as indicated by TLC, the solvent was evaporated under a vacuum. The residual mass was dissolved in 10% MeOH in DCM (25 mL) and washed with sodium thiosulphate solution (10 mL), water (10 mL), brine solution (10 mL), and dried over anhydrous Na2SO4and concentrated to get crude. The crude product was purified by normal phase column chromatography using ethyl acetate / petroleum ether as an eluent to get the 8-methoxy-7-(2-methoxyethoxy)-2-(quinolin-6- yl)quinazolin-4(3H)-one (120 mg, 0.30 mmol, 28% yield) as a yellow solid.1H-NMR (400 MHz, DMSO- d6): δ 12.57 (s, 1H), 9.02 – 9.01 (m, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.60 – 8.58 (m, 1H), 8.51 – 8.49 (m, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.67 – 7.64 (m, 1H), 7.32 (d, J = 9.2 Hz, 1H), 4.32 – 4.30 (m, 2H), 4.03 (s, 3H), 3.76 – 3.74 (m, 2H), 3.37 (s, 3H). MS (ESI) m / z: 378.1 (M+1)+. Example 25 Preparation of 5,7-difluoro-2-(quinolin-6-yl)quinazolin-4(3H)-one (25)

[0250] Al) in DMF (1 mL) was added quinoline-6-carboximidamide hydrochloride (0.08 g, 0.38 mmol), cesium carbonate (0.24 g, 0.76 mmol) and CuI (0.014 g, 0.076 mmol) under N2atmosphere at room temperature. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (as monitored by TLC), the reaction mixture was poured into ice-cold water and stirred for 10 min, the residue obtained was filtered, washed with water, and dried to get the crude product. The crude product was dissolved in MeOH / formic acid (3:1) and stirred for 5 min at room temperature (for removal of Cu impurities). The resulting solution 67Attorney Docket No.93033-425511 was concentrated under vacuum, diluted with MeOH, and the pure solid obtained was filtered, and dried to get 5,7-difluoro-2-(quinolin-6-yl) quinazolin-4(3H)-one (0.025 g, 0.08 mmol, 21% yield) brown-yellow solid.1H-NMR (400 MHz, DMSO-d6, 80 °C): δ 9.00 – 8.93 (m, 2H), 8.70 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.0 (d, J = 16.0 Hz, 1H), 7.60 – 7.57 (m, 1H), 7.22 (d, J = 10.0 Hz, 1H), 6.97 (s, 1H). MS (ESI) m / z: 310.1 (M+1)+. Example 27 Preparation of 2-(tert-butyl)-7-fluoro-5-(2-methoxyethoxy)quinazolin-4(3H)-one (27)

[0251] To a s F (5 mL) was addedNaH (60 % on mineral oil; 0.20 g, 5.04 mmol) portionwise at 0 °C under N2atmosphere. The slurry was stirred for 30 min after that was added 2-(tert-butyl)-5,7-difluoroquinazolin-4(3H)-one (0.3 g, 1.26 mmol) dropwise at 0 °C. After completion of the reaction as monitored by TLC, the reaction mixture was diluted with ice-cold water and extracted with 10% MeOH in ethyl acetate (2 × 25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to get the crude. The crude product was purified by column chromatography using 15% MeOH in DCM to obtain the 2-(tert-butyl)-7-fluoro-5-(2-methoxyethoxy)quinazolin-4(3H)-one (0.19 g, 0.64 mmol, 51% yield) as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.57 (s, 1H), 6.93 – 6.85 (m, 2H), 4.23 (t, J = 4.4 Hz, 2H), 3.74 (t, J = 4.4 Hz, 2H), 3.38 (s, 3H), 1.32 (s, 9H). MS (ESI) m / z: 295.1 (M+1)+.

[0252] The following examples were prepared via conventional chemistry and / or following the general methods above: No. Compound1H NMR MS (m / z) +68Attorney Docket No.93033-425511 No. Compound1H NMR MS (m / z) ++. +++69Attorney Docket No.93033-425511 No. Compound1H NMR MS (m / z) +++++70Attorney Docket No.93033-425511 No. Compound1H NMR MS (m / z) (400 MHz, DMSO-d6): δ 12.27 (s, +. ++++71Attorney Docket No.93033-425511 No. Compound1H NMR MS (m / z) (400 MHz, DMSO-d6): δ 9.04 – +++72Attorney Docket No.93033-425511 No. Compound1H NMR MS (m / z) (400 MHz, DMSO-d6): δ 9.19 (d, ++BIOLOGICAL EXAMPLES

[0253] 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 Hepatic Glutathione Dynamics

[0254] Hepatic glutathione dynamics following single IV treatment of 5 mg / kg in wild type C57B6 mice with Compound 12 and 25 for up to 96 hours. Data is shown for up to 72 hours in FIGs.1-2. 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 73Attorney Docket No.93033-425511 (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.

[0255] 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.

[0256] Compounds 12 and 25 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 (FIG. 1). Redox potentials (Eh) showed that with Compound 12 and 25 treatment, Eh was significantly reduced and sustained for up to 72 hours (FIG.2). Example 2 ROS Generation

[0257] A DCF assay was performed in an in vitro experiment with HepG2 cells to compare compound 12 and 25 to Skyclarys (omaveloxolone) and Radicava (edaravone) (FIG.3). Concentrations of 200 µM for compounds 12 and 25, 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 12 and 25 reduced ROS production, minimizing potential toxicity. Example 3 Nrf2-dependent protein expression (liver and brain)

[0258] An immunoblotting assay (FIG.5) was performed to show the expression of glutamate- cysteine ligase catalytic subunit (GCLC) in the liver following single IV injection treatment of 5 mg / kg of compound 12 (FIG.4A) and 25 (FIG.4B) in wild type C57B6 mice. Mice were sacrificed and livers 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.

[0259] An immunoblotting assay (FIG.7) was performed to show the expression of Heme oxygenase-1 (HO-1) in the liver following single IV injection treatment of 5 mg / kg of compound 12 (FIG.6A) and 25 (FIG.6B) in wild type C57B6 mice. Mice were sacrificed and livers were removed for analysis. HO-1 plays a role in the body's response to oxidative stress and inflammation. HO-1 breaks down heme into biliverdin, carbon monoxide (CO), and iron, and these breakdown products have anti- inflammatory and antioxidant properties. 74Attorney Docket No.93033-425511

[0260] An immunoblotting assay (FIG.9) was performed to show the expression of glutamate- cysteine ligase catalytic subunit (GCLC) in the brain following single IV injection treatment of 5 mg / kg of compound 12 (FIG.8) in wild type C57B6 mice. 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 12 crosses the blood brain barrier and had a direct effect on expression of NRF2 associated genes in the brain. Example 4 Neurofilament Concentrations in ALS Mice

[0261] 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).

[0262] The effect of compound 12 treatment in ALS mice is shown in FIGs. 10-11. ALS mice were injected via IV with 5mg / kg of compound 12 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.

[0263] 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 12 is shown in FIG. 11. Compound 24 stabilized neurofilament in ALS treated mice to levels similar to the WT control mice. Data illustrate that treatment with compound 12 also extended the life span of ALS mice (FIG.12). Example 5 Retinal Effects in RP Mice

[0264] The RhoP23Hmouse model (B6.129S6(Cg)-Rhotm1.1Kpal / J) is commercialy available (https: / / www.jax.org / strain / 017628). These mice carry the P23H mutation of the Rho (rhodopsin) gene and exhibit progressive retinal degeneration observed in patients with autosomal dominant retinitis pigmentosa 75Attorney Docket No.93033-425511 (RP). Significance: There is an approximately 5% decline in visual fields per year in RP patients. Patients with RP generally become legally blind by 20 years after onset of symptoms. Assuming that the average longevity of a mouse is ~2 years and of a human ~80 years, a human life is ~40-fold the length of a mouse life. These data show that treatment of RP mice with compound 25, delays progression of RP by about 4 weeks. Thus, without being bound by any theory, the treatment of humans with compound 25 could delay the onset of blindness by 3 years in humans. Currently there are no treatments that have been shown to be effective for all genetic forms of RP. Gene therapy for RP is currently limited to a few forms and FDA approval is currently required for each genetic form. RP is an oxidative stress disorder and compound 25 could potentially be used as a therapy for most forms of RP, and potentially more common retinal degenerative disorders such as age related macular degeneration (AMD) that is also associated with oxidative stress.

[0265] The effect of compound 25 treatment in RP mice is shown in FIG. 12. RP mice were injected subcutaneously with 5mg / kg of compound 25 at 2X / week. Dosing started when mice turned 4 weeks of age. Duration of the study was four months, and clinical observations were taken 2X / month using optical coherence tomography. OCT is an imaging method used to generate a picture of the back of the retina. Blood was collected every 2 weeks for plasma redox assay. Translational Insight: Dosing at 4 weeks in mice aligns with clinical realities, allowing assessment of therapeutic impact on disease progression post- symptom onset.

[0266] By 35 days of age, heterozygotes have a shorter rod outer segment when compared to controls. At day 63, heterozygotes have half the rod nuclei compared to controls and decreased length of the rod outer segment.

[0267] As shown in FIG. 12, the arrow indicates initiation of treatment (4 weeks of age). Retinal thickness nadir occurred at 12 weeks. Retinal thickness nadir is the lowest point or the thinnest point of the retinal nerve fiber layer (RNFL) thickness, often measured by optical coherence tomography (OCT). This nadir point is significant because it's a key indicator of the severity and progression of conditions that can affect the retina. After 12 weeks, retinas in vehicle mice continued to decline in thickness. After 12 weeks, retinas in control (omaveloxolone) and compound 25-treated mice are nearly identical. Vehicle mice have highly significant thinner retinas compared to control (omaveloxolone) and compound 25-treated mice. P< 0.01 76Attorney Docket No.93033-425511 STATEMENTS

[0268] 1. A compound of formula (I): , or a pharmaceutically acceptable sa : X1 is =O, =N-OR10, or -C1-C6alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;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 H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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; and p is 1, 2, or 3; provided that (i) R6and R7are not the same; and (ii) if R9is methoxy, then R7is halogen, hydroxy, or RA.

[0269] 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. 77Attorney Docket No.93033-425511

[0270] 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.

[0271] 4. The compound of clause 1, wherein the compound is of formula (II): , or a pharmaceutically acceptable salt X1 is =O, =N-OR10, or -C1-C6alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;R6is H, halogen, hydroxy, or C1-C alkoxy;6R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, hydroxy, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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; n is 0, 1, or 2; and p is 1, 2, or 3; provided that R6and R7are not the same.

[0272] 5. The compound of any one of the preceding clauses, wherein R7is halogen, hydroxy, RA, or C1-C6alkoxy.

[0273] 6. The compound of any one of the preceding clauses, wherein R9is H, halogen, or RA.

[0274] 7. The compound of any one of the preceding clauses, wherein R6is H or C1-C6alkoxy; R7is halogen, hydroxy, or RA; R8is H; and R9is H, halogen, or RA. 78Attorney Docket No.93033-425511

[0275] 8. The compound of any one of the preceding clauses, wherein R6is H or C1-C6alkoxy.

[0276] 9. The compound of any one of the preceding clauses, wherein R6is H or methoxy.

[0277] 10. The compound of any one of the preceding clauses, wherein R7is halogen, hydroxy, or RA.

[0278] 11. The compound of any one of the preceding clauses, wherein R7is fluoro, hydroxy, . ny one of the preceding clauses, wherein R8is H.

[0280] 13. The compound of any one of the preceding clauses, wherein R9is H, halogen, or RA.

[0281] 14. The compound of any one of the preceding clauses, wherein R9is H, fluoro, or . . The compound of clause 1, wherein the compound is of formula (III):, or a pharmaceutically acceptable sal n:Y is substituted or unsubstituted 5- to 12-membered heteroaryl; X1 is =O, =N-OR10, or -C1-C6 alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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. 79Attorney Docket No.93033-425511

[0283] 16. The compound of clause 15, wherein R6is H or C1-C6alkoxy; R7is halogen or RA; and R9is H or halogen.

[0284] 17. The compound of clause 15 or 16, wherein R6is H or C1-C3alkoxy.

[0285] 18. The compound of any one of clauses 15-17, wherein R6is H or methoxy.

[0286] 19. The compound of any one of clauses 15-18, wherein R7is halogen or RA.

[0287] 20. The compound of any one of clauses 15-19, wherein R7is fluoro or . he compound of any one of clauses 15-20, wherein R9is H or fluoro.

[0289] 22. The compound of any one of clauses 15-21, wherein Y selected from quinoline, isoquinoline, pyridine, imidazole, pyrazole, oxazole, and thiazole.

[0290] 23. The compound of any one of clauses 15-22, wherein Y is .The compound of clause 1, wherein the compound is of formula (IV): , or a pharmaceutically acceptable sal: Y is unsubstituted C1-C6alkyl or unsubstituted C3-C10cycloalkyl; R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R12and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is 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; and 80Attorney Docket No.93033-425511 p is 1, 2, or 3; provided that: R6and R7are not the same.

[0292] 25. The compound of clause 24, wherein R6is H; R7is halogen or RA; and R9is halogen or RA.

[0293] 26. The compound of clause 24 or 25, wherein R6is H.

[0294] 27. The compound of any one of clauses 24-26, wherein R7is halogen or RA.

[0295] 28. The compound of any one of clauses 24-27, wherein R7is fluoro or . e compound of any one of clauses 24-28, wherein R9is halogen or RA.

[0297] 30. The compound of any one of clauses 24-29, wherein R9is fluoro or . e compound of any one of clauses 24-30, wherein Y is t-butyl.

[0299] 32. The compound of any one of clauses 24-30, wherein Y is C3-C8cycloalkyl.

[0300] 33. The compound of any one of clauses 24-30, wherein Y is cyclopentyl or cyclohexyl.

[0301] 34. The compound of any one of clauses 1-23, wherein R10is H or methyl.

[0302] 35. The compound of any one of clauses 1-23, wherein R10is H.

[0303] 36. The compound of any one of clauses 1-23, wherein R10is methyl.

[0304] 37. The compound of any one of the preceding clauses, wherein R11is absent, H, or methyl.

[0305] 38. The compound of any one of the preceding clauses, wherein each R12and R13is independently H or methyl.

[0306] 39. The compound of any one of clauses 1-23, wherein X1is =O, =N-OH, or -C1-C3alkoxy.

[0307] 40. The compound of any one of clauses 1-23, wherein X1is =O, =N-OH, or -methoxy.

[0308] 41. The compound of clause 1, wherein the compound is selected from the group consisting of: 81Attorney Docket No.93033-425511 , ,82Attorney Docket No.93033-425511 ,

[0309] 42. The compound of clause 1, wherein the compound is a pharmaceutically acceptable salt or tautomer thereof. ceutical composition comprising a therapeutically effective amount of thecompound of any one of clauses 1 to 42, or a pharmaceutically acceptable salt or tautomer thereof, and one or more pharmaceutically acceptable carriers or vehicles.

[0311] 44. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I: I), or a pharmaceutically acceptable salt oX1 is =O, =N-OR10, or -C1-C6 alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;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 83Attorney Docket No.93033-425511 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 H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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; and p is 1, 2, or 3; provided that (i) R6and R7are not the same; and (ii) when R9is methoxy, then R7is halogen, hydroxy, or RA.

[0312] 45. The pharmaceutical composition of clause 44, comprising a therapeutically effective amount of the compound of formula II: I), or a pharmaceutically acceptable sX1 is =O, =N-OR10, or -C1-C6 alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, hydroxy, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, H, or C1-C6alkyl; each RAis independently -C(O)NR12R13, NR12C(O)R13, -NR12S(O)2R13, -OCH2-RB, -(OCH2CH2)p-NR12R13, -(OCH2CH2)p-OR12, 84Attorney Docket No.93033-425511 each RBis independently -C(O)R12, -C(O)OR12, or -C(O)NR12R13; n is 0, 1, or 2; and p is 1, 2, or 3; provided that R6and R7are not the same.

[0313] 46. The pharmaceutical composition of clause 44, comprising a therapeutically effective amount of the compound of formula III: I), or a pharmaceutically acceptable saltY is substituted or unsubstituted 5- to 12-membered heteroaryl; X1 is =O, =N-OR10, or -C1-C6 alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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.

[0314] 47. The pharmaceutical composition of clause 44, comprising a therapeutically effective amount of the compound of formula IV: V), or a pharmaceutically acceptable salt85Attorney Docket No.93033-425511 Y is unsubstituted C1-C6alkyl or unsubstituted C3-C10cycloalkyl; R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R12and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is 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; and p is 1, 2, or 3; provided that R6and R7are not the same.

[0315] 48. The pharmaceutical composition of any one of clauses 43-47, wherein the compound or tautomer is in a non-salt form.

[0316] 49. A compound of any one of clauses 1-42, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of any one of clauses 43-47, for use in treating or preventing a disease or disorder 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.

[0317] 50. The compound of clause 49, 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.

[0318] 51. 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),86Attorney Docket No.93033-425511 or a pharmaceutically acceptable salt or tautomer thereof, wherein: X1 is =O, =N-OR10, or -C1-C6 alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;Y is C -C alkyl, C -C cycloalkyl, C -C aryl, 6- to 8-membered het16 3 10 6 10erocyclyl, 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 H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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; and p is 1, 2, or 3; provided that: (i) R6and R7are not the same; and (ii) when R9is methoxy, then R7is halogen, hydroxy, or RA.

[0319] 52. The method of clause 51, comprising administering to the subject a compound of formula II: I),X1 is =O, =N-OR10, or -C1-C6 alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, hydroxy, or C1-C6alkoxy; 87Attorney Docket No.93033-425511 R9is H, halogen, hydroxy, or RA; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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; n is 0, 1, or 2; and p is 1, 2, or 3; provided that R6and R7are not the same.

[0320] 53. The method of clause 51, comprising administering to the subject a compound of formula III: I), or a pharmaceutically acceptable saltY is substituted or unsubstituted 5- to 12-membered heteroaryl; X1 is =O, =N-OR10, or -C1-C6 alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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.

[0321] 54. The method of clause 51, comprising administering to the subject a compound of formula IV: 88Attorney Docket No.93033-425511 ), or a pharmaceutically acceptable salt Y is unsubstituted C1-C6alkylor unsubst tuted C3-C10cyc oa y ; R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R12and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is 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; and p is 1, 2, or 3; provided that R6and R7are not the same.

[0322] 55. The method of clause 51, comprising administering to the subject a compound selected from the group consisting of: , , ,89Attorney Docket No.93033-425511 , , , , ,90Attorney Docket No.93033-425511 a pharmaceutically acceptable salt or tautomer thereof. od of clause 51, 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.

[0325] 58. 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 any one of clauses 1-42, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of any one of clauses 43-47.

[0326] 59. The method of clause 58, 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.

[0327] 60. Use of the compound of any one of clauses 1-42, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of any one of clauses 43-47, 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.

[0328] 61. The use of the compound of clause 60, 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, 91Attorney Docket No.93033-425511 retinoblastoma, traumatic brain injury (TBI), cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Celiac’s disease, and type II diabetes.

[0329] 62. Use of the compound of any one of clauses 1-42, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of any one of clauses 43-47, 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.

[0330] 63. The use of the compound of clause 62, 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. 92

Claims

Attorney Docket No.93033-425511 CLAIMS What is claimed is:

1. A compound of formula (I): , or a pharmaceutically acceptable sa : X1 is =O, =N-OR10, or -C1-C6alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;Y is C1-C6alkyl, C3-C10cycloalkyl, C6-C aryl, 6- to 8-membered heterocyclyl, or 5- to 12-10membered 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 H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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; and p is 1, 2, or 3; provided that (i) R6and R7are not the same; and (ii) if R9is methoxy, then R7is halogen, hydroxy, or RA.

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. 93Attorney Docket No.93033-425511 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 X1 is =O, =N-OR10, or -C1-C6alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;R6is H, halogen, hydroxy, or C1-C alkoxy;6R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, hydroxy, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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; n is 0, 1, or 2; and p is 1, 2, or 3; provided that R6and R7are not the same.

5. The compound of claim 1, wherein R7is halogen, hydroxy, RA, or C1-C6alkoxy.

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

7. The compound of claim 1, wherein R6is H or C1-C6alkoxy; R7is halogen, hydroxy, or RA; R8is H; and R9is H, halogen, or RA. 94Attorney Docket No.93033-425511 8. The compound of claim 1, wherein R6is H or C1-C6alkoxy.

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

10. The compound of claim 1, wherein R7is halogen, hydroxy, or RA. .

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

15. The compound of claim 1, wherein the compound is ):, or a pharmaceutically acceptable sal n:Y is substituted or unsubstituted 5- to 12-membered heteroaryl; X1 is =O, =N-OR10, or -C1-C6 alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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.

16. The compound of claim 15, wherein R6is H or C1-C6alkoxy; R7is halogen or RA; and 95Attorney Docket No.93033-425511 R9is H or halogen.

17. The compound of claim 15, wherein R6is H or C1-C3alkoxy.

18. The compound of claim 15, wherein R6is H or methoxy.

19. The compound of claim 15, wherein R7is halogen or RA.

20. The compound of claim 15, wherein R7is fluoro or .

21. The compound of claim 15, wherein R9is H or fluo22. The compound of claim 15, wherein Y selected from quinoline, isoquinoline, pyridine, imidazole, pyrazole, oxazole, and thiazole.

23. The compound of claim 15, wherein Y i .

24. The compound of claim 1, wherein the c formula (IV):, or a pharmaceutically acceptable sal n:Y is unsubstituted C1-C6alkyl or unsubstituted C3-C10cycloalkyl; R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R12and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is 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; and p is 1, 2, or 3; provided that: R6and R7are not the same.

25. The compound of claim 24, wherein R6is H; R7is halogen or RA; and 96Attorney Docket No.93033-425511 R9is halogen or RA.

26. The compound of claim 24, wherein R6is H.

27. The compound of claim 24, wherein R7is halogen or RA.

28. The compound of claim 24, wherein R7is fluoro or .

29. The compound of claim 24, wherein R9is halogen r RA30. The compound of claim 24, wherein R9is fluoro or .

31. The compound of claim 24, wherein Y is t-butyl.

32. The compound of claim 24, wherein Y is C3-C8cycloalkyl.

33. The compound of claim 24, wherein Y is cyclopentyl or cyclohexyl.

34. The compound of claim 1, wherein R10is H or methyl.

35. The compound of claim 1, wherein R10is H.

36. The compound of claim 1, wherein R10is methyl.

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

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

39. The compound of claim 1, wherein X1is =O, =N-OH, or -C1-C3alkoxy.

40. The compound of claim 1, wherein X1is =O, =N-OH, or -methoxy.

41. The compound of claim 1, wherein the compound is selected from the group consisting of: ,97Attorney Docket No.93033-425511 ,42. The compound of claim 1, wherein the compound is 98Attorney Docket No.93033-425511 a pharmaceutically acceptable salt or tautomer thereof.l composition comprising a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or tautomer thereof, and one or more pharmaceutically acceptable carriers or vehicles.

44. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I: I), or a pharmaceutically acceptable salt oX1 is =O, =N-OR10, or -C1-C6 alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;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 H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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; and 99Attorney Docket No.93033-425511 p is 1, 2, or 3; provided that (i) R6and R7are not the same; and (ii) when R9is methoxy, then R7is halogen, hydroxy, or RA.

45. The pharmaceutical composition of claim 44, comprising a therapeutically effective amount of the compound of formula II: I), or a pharmaceutically acceptable s X1 is =O, =N-OR10, or -C1-C6 alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, hydroxy, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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; n is 0, 1, or 2; and p is 1, 2, or 3; provided that R6and R7are not the same.

46. The pharmaceutical composition of claim 44, comprising a therapeutically effective amount of the compound of formula III: 100Attorney Docket No.93033-425511 I), or a pharmaceutically acceptable salt Y is substituted or unsubstitute5- to -mem ere eteroary ; X1 is =O, =N-OR10, or -C1-C6 alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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.

47. The pharmaceutical composition of claim 44, comprising a therapeutically effective amount of the compound of formula IV: V), or a pharmaceutically acceptable saltY is unsubstituted C1-C6alkyl or unsubstituted C3-C10cycloalkyl; R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R12and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is H or C1-C6alkyl; 101Attorney Docket No.93033-425511 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; and p is 1, 2, or 3; provided that R6and R7are not the same.

48. The pharmaceutical composition claim 44, wherein the compound or tautomer is in a non-salt form.

49. A compound of claim 1, for use in treating or preventing a disease or disorder 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.

50. The compound of claim 49, 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.

51. 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 oX1 is =O, =N-OR10, or -C1-C6 alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;Y is C1-C6alkyl, C3-C10cycloalky ,6-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; 102Attorney Docket No.93033-425511 R6is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R8is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; R9is H, halogen, hydroxy, RA, C1-C6haloalkyl, or C1-C6alkoxy; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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; and p is 1, 2, or 3; provided that: (i) R6and R7are not the same; and (ii) when R9is methoxy, then R7is halogen, hydroxy, or RA.

52. The method of claim 51, comprising administering to the subject a compound of formula II: I), or a pharmaceutically acceptable salX1 is =O, =N-OR10, or -C1-C6 alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R8is H, halogen, hydroxy, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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; n is 0, 1, or 2; and p is 1, 2, or 3; 103Attorney Docket No.93033-425511 provided that R6and R7are not the same.

53. The method of claim 51, comprising administering to the subject a compound of formula III: I), or a pharmaceutically acceptable salt Y is substituted or unsubstituted 5- to 12-membered heteroaryl; X1 is =O, =N-OR10, or -C1-C6 alkoxy, wherein when X1 is =O or =N-OR10, then “ ” is a singlebond, and when X1 is -C1-C6 alkoxy, then “ ” is a double bond;R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; R9is H, halogen, hydroxy, or RA; each R10, R12, and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is absent, 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.

54. The method of claim 51, comprising administering to the subject a compound of formula IV: ), or a pharmaceutically acceptable saltY is unsubstituted C1-C6alkyl or unsubstituted C3-C10cycloalkyl; R6is H, halogen, hydroxy, or C1-C6alkoxy; R7is H, halogen, hydroxy, RA, or C1-C6alkoxy; 104Attorney Docket No.93033-425511 R9is H, halogen, hydroxy, or RA; each R12and R13is independently H, C1-C6alkyl, or C6-C10aryl; R11is 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; and p is 1, 2, or 3; provided that R6and R7are not the same.

55. The method of claim 51, comprising administering to the subject a compound selected from the group consisting of: , , , , ,105Attorney Docket No.93033-425511 , , ,56. The method of claim 51, comprising administering to the subject a compound that is a pharmaceutically acceptable salt or tautomer thereof.

57. The method of claim 51, 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, 106Attorney Docket No.93033-425511 cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease, inflammatory bowel disease, Celiac’s disease, and type II diabetes.

58. 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.

59. The method of claim 58, 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.

60. 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.

61. The use of the compound of claim 60, 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.

62. 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.

63. The use of the compound of claim 62, 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 107Attorney Docket No.93033-425511 brain injury, cardiovascular disease, restenosis, atherosclerosis, chronic obstructive pulmonary disease, inflammatory bowel disease, Celiac’s disease, and type II diabetes. 108

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