Methods of treating metabolic disorders

Abstract

The present invention relates to methods and compositions for the treatment of disorders associated with CBP function such as type 2 diabetes mellitus, refractory type 2 diabetes, obesity, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, dyslipidemia, chronic kidney disease, atherosclerosis, diabetic kidney disease, a cognitive disorder, and / or metabolic syndrome.

Description

[0001] PATENT

[0002] ATTORNEY DOCKET NO.: 51121-108WO2

[0003] METHODS OF TREATING METABOLIC DISORDERS

[0004] Background

[0005] The present disclosure relates to methods of modulating CBP for use in the treatment of disorders associated with CBP function. In particular, this invention relates to methods for treatment of type 2 diabetes mellitus, refractory type 2 diabetes, obesity, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, dyslipidemia, chronic kidney disease, atherosclerosis, diabetic kidney disease, a cognitive disorder, and / or metabolic syndrome.

[0006] Type 2 Diabetes mellitus (also referred to as noninsulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes) is a metabolic disorder that is characterized by high blood glucose in the presence of insulin resistance and relative insulin deficiency. Type 2 diabetes is a progressive disease in which the risks of myocardial infarction, stroke, microvascular events and mortality are all strongly associated with hyperglycemia. Type 2 diabetes is also a silent disease with significant declines in p-cell function and kidney damage often occurring before any symptoms of the disease manifest.

[0007] Glycated hemoglobin (HbA1c) is considered a key marker of glycemic control in diabetology. The American Diabetes Association (ADA) guidelines indicate that a subject with HbA1 c less than or equal to 5.7% is considered normal glycemia. Subject treatment goals for HbA1c may vary by subject; however, persistently poorly controlled HbA1c contributes disproportionately to the development of complications associated with diabetes. Subjects with type 2 diabetes often fail to achieve normal glycemia despite treatment using the ADA treatment paradigm. Despite not within normal range, the ADA guidelines suggest a reasonable HbA1c treatment goal of less than or equal to 7% following current treatment options of diet, exercise, metformin, oral diabetes treatments, followed by basal insulin. However, many subjects fail to reach their HbA1c goals despite clinical treatment and are considered to have refractory type 2 diabetes.

[0008] Refractory type 2 diabetes is generally explained by an insulin secretory defect, or beta cell damage, becoming more and more profound with time, against a background of (relatively stable) insulin resistance. Subjects living with type 2 diabetes for at least 8 years are more likely to suffer from refractory type 2 diabetes. Therefore, there is a desire for a treatment method providing normal, or near normal glycemia, in a subject with refractory type 2 diabetes. There is a desire for a treatment method providing normal, or near normal glycemia, in a subject with refractory type 2 diabetes, wherein the subject has been treated for type 2 diabetes at least 8 years.

[0009] Nearly half of American adults have high blood pressure. High blood pressure is a risk factor for stroke, coronary heart disease (CHD), and other significant health threats. Many subjects with type 2 diabetes and obesity experience high blood pressure; however, approved treatments for diabetes typically have little or no effect on controlling high blood pressure. There is a desire for treatment options to manage high blood pressure. There is a desire for a method to treat high blood pressure in a subjects with diabetes.

[0010] Low serum levels of high-density lipoprotein cholesterol (HDL-C) is another known risk factor for coronary heart disease (CHD). Subjects with type 2 diabetes often experience low serum levels of HDL-C; however, approved diabetes treatments generally fail to raise HDL-C. Longitudinal population studies have confirmed that HDL-C is inversely and independently associated with the risk of developing CHD. PATENT

[0011] ATTORNEY DOCKET NO.: 51121-108WO2

[0012] There is a desire for a drug therapy to increase HDL-C levels. There is a desire for a treatment method to raise HDL-C in a subject with type 2 diabetes.

[0013] Obesity is associated with an increase in the overall amount of adipose tissue (i.e., body fat), especially adipose tissue localized in the abdominal area. Obesity has reached epidemic proportions in the United States. The prevalence of obesity has steadily increased over the years among all racial and ethnic groups. The most recent data from the Centers for Disease Control and Prevention, and the National Center for Health Statistics report 66% of the adult population overweight (BMI, 25.0-29.9), 31% obese (BMI, 30-39.9), and 5% extremely obese (BMI, >40.0). Among children aged 6 through 19 years, 32% were overweight and 17% were obese. This translates to 124 million Americans medically overweight, and 44 million of these deemed obese. Obesity is responsible for more than 300,000 deaths annually and will soon overtake tobacco usage as the primary cause of preventable death in the United States. Obesity is a chronic disease that contributes directly to numerous dangerous co-morbidities, including type 2 diabetes, cardiometabolic diseases, hepatic disorders, cardiovascular disease, inflammatory diseases, premature aging, and some forms of cancer. Since more than 80% of subjects with type 2 diabetes are overweight, obesity is the greatest risk factor for developing type 2 diabetes. Increasing clinical evidence indicates that the best way to control type 2 diabetes is to reduce weight. Accordingly, there is a continuing need for the development of improved medications that treat or prevent obesity.

[0014] Obesity is also considered a state of mild chronic inflammation, characterized by a high production of cytokines, adipokines and other pro-inflammatory proteins in adipose tissue, as well as in other peripheral tissues and at the systemic level, which contribute to metabolic disorders that can suffer these individuals permanently, such as type 2 diabetes Mellitus and cardiovascular pathologies. Among the inflammatory factors related to obesity and metabolic disorders, the pro-inflammatory cytokine TNF-a stands out. In particular, TNF-a reduces the expression of genes involved in the action of insulin (for example, that of its receptor gene), atenuates insulin signaling and inhibits the action of insulin-stimulated lipoprotein lipase. This favors the development of insulin resistance and hepatic steatosis. The role of proinflammatory cytokines in this process has also been demonstrated through the use of drugs based on anti-TNF-a antibodies to improve pathologies such as liver steatosis and type 2 diabetes Mellitus. Insulin is the most important hormone in regulating the proper functioning of adipose tissue and the accumulation of triglycerides in it, and in the uptake of glucose. In normal insulin-sensitive adipose tissue, fat storage occurs here, in response to insulin and other hormones (leptin), by stimulating lipoprotein lipase and inhibiting lipolysis. However, excessive accumulation of fatty acids in adipose tissue associated with obesity reduces insulin sensitivity, which promotes the accumulation of free fatty acids in the form of triglycerides in other organs and tissues (liver, muscle, heart, etc..), and causes alterations in the production or sensitivity to leptin, and increased synthesis of pro-inflammatory cytokines, which in turn carries an increased risk of development of associated diseases (metabolic syndrome, hypertension, diabetes, cardiovascular diseases, etc.), in the central nervous system, insulin signaling is also essential for the control of energy balance and glucose homeostasis, and is dependent on its interaction with other regulatory factors, such as leptin, which act together as anorexigenic factors, reducing the intake. PATENT

[0015] ATTORNEY DOCKET NO.: 51121-108WO2

[0016] Obesity is also characterized by alterations in the functions of various cells of the immune system, such as macrophages, dendritic cells and T cells, associated with deficiencies in defense against pathogens and other antigens, and an increased risk of infections and complications, postoperative. The macrophages of the adipose tissue show less phagocytic capacity and reduced respiratory burst, which are processes involved in the response of the innate immune system against infectious agents.

[0017] Furthermore, dendritic cells have alterations in their ability to stimulate T cells, involved in the adaptive immune response responsible, for example, for the production of antibodies in vaccination and responsible for the memory T-cell response in cases of infection.

[0018] Hepatic steatosis or non-alcoholic fatty liver is an alteration with a high degree of association with obesity and occurs in upto 50% of obese individuals, both children and adults, constituting the main liver disease at present.

[0019] Non-alcoholic steatohepatitis (NASH) is a progressive liver disease characterized histologically by fatty acid accumulation, hepatocyte damage, and inflammation that resembles alcoholic hepatitis. NASH is a critical stage in the process that extends from hepatic steatosis to cirrhosis and liver failure. Obesity and type 2 diabetes are associated with NASH.

[0020] Dyslipidemia is a disorder of lipoprotein metabolism involving lipoprotein overproduction (hyperlipidemia) or deficiency. Dyslipidemia can be manifested by elevated levels of total blood cholesterol, i.e., "bad" low-density lipoprotein cholesterol and triglycerides, and decreased levels of "good" high-density lipoprotein cholesterol. Dyslipidemia is considered in many situations, including diabetes, which is a common cause of dyslipidemia. Dyslipidemia (hypertriglyceridemia and hypercholesterolemia) are associated with obesity, type 2 diabetes mellitus and hypertension and constitute the main risk factor for cardiovascular pathologies. The reduction of serum triglyceride and cholesterol concentrations in subjects with abnormally high concentrations of these biochemical parameters are beneficial and, especially, the reduction of LDL cholesterol since it is considered a clear risk factor for cardiovascular pathologies and its decrease is related to a reduction in morbidity and total mortality from long-term cardiovascular diseases. Cholesterol levels are kept at a constant level by different Mechanisms, including (i) regulation of the activity and concentration of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (ii) regulation of the enzyme acyl-CoA: cholesterol acyltransferase, ACAT, which it controls the excess of free intracellular cholesterol and its transformation into cholesterol esters, which is the way in which they are transported, and (iii) the regulation of the expression of hepatic LDL receptors that allow the absorption of cholesterol from plasma and the reverse transport of it by HDL. The newly formed cholesterol in the liver is initially released into the blood in the form of very low-density lipoprotein (VLDL) and may contribute to its increase.

[0021] Chronic kidney disease has several underlying reasons and involves the glomeruli, tubules or interstitial tissue surrounding the glomeruli and tubules. The glomerulus is a network (tuft) of capillaries that performs the first step of blood filtration. The renal tubule is the part of nephron containing the fluid filtered through the glomerulus. Glomerulonephritis (GN) is inflammation of glomeruli. GN may lead to serious kidney damage and, in some subjects, kidney failure. The causes of glomerulonephritis are complex and diverse, some have a genetic basis, and others are associated with systemic diseases. PATENT

[0022] ATTORNEY DOCKET NO.: 51121-108WO2

[0023] Atherosclerosis is a chronic disease that causes thickening of the innermost layer (intima) of the aorta or middle artery. This reduces blood flow and can cause ischemia and tissue destruction in organs supplied by affected blood vessels. Atherosclerosis is a major cause of heart disease including myocardial infarction, stroke and surrounding arterial disease.

[0024] Diabetic kidney disease is a form of chronic kidney disease that occurs in nearly 30% of diabetic subjects. Diabetic kidney disease is defined as diabetes with the presence of proteinuria and / or impaired renal function (i.e., reduced glomerular filtration rate).

[0025] Cognitive disorders of interest include, but are not limited to, attention deficit hyperactivity disorder (ADHD), traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD), substance dependence disorder (SDD), depression (e.g., major depressive disorder), dementia, Alzheimer's disease, Parkinson's disease, autism, and schizophrenia.

[0026] Metabolic syndrome is a collection of health barriers or risks that increase the likelihood of suffering from heart disease, stroke, and diabetes. This condition is also known by other names such as syndrome X and metabolic failure syndrome. Metabolic syndrome may include any of a variety of potential metabolic and / or obese constitutional phenotypes, including insulin resistance. Metabolic syndrome is often characterized by any of a number of metabolic diseases or risk factors, which are generally most metabolized when two or more of these factors are present in a single individual. These factors include central obesity (disproportionate adipose tissue in and around the abdomen), atherogenic dyslipidemia (these include a group of blood fatty diseases, which include, for example, high triglycerides, low HDL cholesterol, and high LDL cholesterol (which may promote plaque accumulation in the vascular system including the arterial wall), hypertension, insulin resistance or glucose intolerance (appropriate availability of insulin or blood sugar), Chronic prothrombotic conditions (e.g. characterized by high fibrinogen or plasminogen activation inhibitor concentration in the blood) and chronic pro-inflammatory conditions (e.g. higher than normal levels in the blood, highly sensitive C-reactive protein characterized by reactive protein concentration). People suffering from metabolic syndrome are at high risk of suffering from coronary heart disease, other diseases associated with plaque accumulation in the arterial wall (e.g., stroke and peripheral vascular disorders) and type II diabetes.

[0027] Summary

[0028] The present invention features methods to treat diabetes, type 2 diabetes, type 2 diabetes mellitus, refractory type 2 diabetes, obesity, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, dyslipidemia, chronic kidney disease, atherosclerosis, diabetic kidney disease, a cognitive disorder, and / or metabolic syndrome e.g., in a subject in need thereof.

[0029] In one aspect, the invention features a method of treating diabetes, type 2 diabetes, type 2 diabetes mellitus, obesity, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, dyslipidemia, chronic kidney disease, atherosclerosis, diabetic kidney disease, a cognitive disorder, and / or metabolic syndrome in a subject in need thereof, the method including administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein (CBP). PATENT

[0030] ATTORNEY DOCKET NO.: 51121-108WO2

[0031] In another aspect, the invention features a method of treating diabetes in a subject in need thereof, the method including administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein (CBP).

[0032] In another aspect, the invention features a method of inducing remission or regression of diabetes in a subject in need thereof, the method including administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein (CBP).

[0033] In another aspect, the invention features a method of treating high blood pressure in a subject in need thereof, the method including administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein (CBP). In some embodiments, the subject has type 2 diabetes and is non-obese. in some embodiments, the subject has type 2 diabetes and obesity. In some embodiments, the subject has refractory type 2 diabetes. In some embodiments, the subject has type 2 diabetes for at least 8 years.

[0034] In another aspect, the invention features a method of raising HDL-C in a subject in need thereof, the method including administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein (CBP).

[0035] In another aspect, the invention features a method of treating low HDL-C in a subject in need thereof, the method including administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein (CBP).

[0036] In any of the aspects described herein, the subject has diabetes. In any of the aspects described herein, the subject has type 2 diabetes mellitus. In any of the aspects described herein, the subject has refractory type 2 diabetes. In any of the aspects described herein, the diabetes is refractory. In any of the aspects described herein, the subject has had diabetes for at least 8 years. In any of the aspects described herein, the subject has obesity. In any of the aspects described herein, the subject has nonalcoholic fatty liver disease. In any of the aspects described herein, the subject has nonalcoholic steatohepatitis. In any of the aspects described herein, the subject has dyslipidemia. In any of the aspects described herein, the subject has chronic kidney disease. In any of the aspects described herein, the subject has atherosclerosis. In any of the aspects described herein, the subject has diabetic kidney disease. In any of the aspects described herein, the subject has a cognitive disorder. In any of the aspects described herein, the subject has metabolic syndrome. In any of the aspects described herein, the subject has any one or more of the following: diabetes, type 2 diabetes, type 2 diabetes mellitus, refractory type 2 diabetes, obesity, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, dyslipidemia, chronic kidney disease, atherosclerosis, diabetic kidney disease, a cognitive disorder, and metabolic syndrome.

[0037] In some embodiments, the subject age is at least 46 years. In some embodiments, the subject age is at least 60 years old. In some embodiments, the subject is taking an SGLT2 inhibitor. In some embodiments, the subject is taking metformin. In some embodiments, the subject is not administered a basal insulin. In some embodiments, the subject failed to reach their HbA1c goal while taking metformin and an SGLT2 inhibitor. In some embodiments, the subject is not obese. In some embodiments, the subject has comorbid high blood pressure, in some embodiments, the subject has comorbid low HDL-C. In some embodiments, the subject has comorbid obesity. In some embodiments, the subject has at least PATENT

[0038] ATTORNEY DOCKET NO.: 51121-108WO2

[0039] two cardiovascular risk factors. In some embodiments, the subject has no cardiovascular risk factors. In some embodiments, the subject has comorbid high blood pressure.

[0040] In another aspect, the invention features a method of improving glycemic control in a subject with type 2 diabetes mellitus, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

[0041] In another aspect, the invention features a method of reducing the risk of major adverse cardiovascular events in a subject with type 2 diabetes mellitus, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

[0042] In another aspect, the invention features a method of treating obesity in a subject, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

[0043] In another aspect, the invention features a method for chronic weight management in a subject, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

[0044] In another aspect, the invention features a method of improving weight management in a subject, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

[0045] In any of the aspects described herein, the subject has an initial body mass index of at least 30 kg / m2or greater (e.g., at least 30 kg / m2, 31 kg / m2, 32 kg / m2, 33 kg / m2, 34 kg / m2, 35 kg / m2, 36 kg / m2, 37 kg / m2, 38 kg / m2, 39 kg / m2, 40 kg / m2, 41 kg / m2, 42 kg / m2, 43 kg / m2, 44 kg / m2, or 45 kg / m2), or about 27 kg / m2(26.5 kg / m2, 27.5 kg / m2, 28 kg / m2, 28.5 kg / m2, 29 kg / m2, or 29.5 kg / m2)in the presence of at least one weight-related comorbid condition. In any of the aspects described herein, the at least one weight-related comorbid condition is hypertension, type 2 diabetes mellitus, or dyslipidemia, in any of the aspects described herein, the agent that reduces the level and / or activity of CREB-binding protein is administered as an adjunct to diet and exercise. In any of the aspects described herein, the agent that reduces the level and / or activity of CREB-binding protein is administered as an adjunct to a reduced-calorie diet and increased physical activity.

[0046] In any of the aspects described herein, the agent that reduces the level and / or activity of CREB-binding protein is administered in combination with a glucagon-like peptide 1 receptor agonist or a glucagon-like peptide 1 receptor agonist and glucose-dependent insulinotropic polypeptide receptor agonist.

[0047] In another aspect, the invention features a method of treating a cognitive disorder in a subject, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

[0048] In another aspect, the invention features a method of preventing or delaying cognitive decline in a subject, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

[0049] In another aspect, the invention features a method of improving glycemic control and preventing or delaying cognitive decline in a subject in a subject with type 2 diabetes mellitus, the method comprises PATENT

[0050] ATTORNEY DOCKET NO.: 51121-108WO2

[0051] administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

[0052] In some embodiments, the cognitive disorder is selected from the group consisting of MCI and dementia. In some embodiments, the method results in a reduction in the risk of the subject experiencing cognitive decline. In some embodiments, the subject's risk of cognitive decline is reduced by about 14% (e.g., about 23.5%, about 23%, about 22.5%, about 22%, about 21.5%, about 21%, about 20.5%, about 20%,.about 19.5%, about 19%, about 18.5%, about 18%, about 17.5%, about 17%, about 16.5%, about 16%, about 15.5%, about 15%, about 14.5%, about 13.5%, about 13%, about 12.5%, about 12%, about 11.5%, about 11%, about 10.5%, about 10%,.about 9.5%, about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, or about 5%).

[0053] In another aspect, the invention features a method of improving glycemic control in a subject with type 2 diabetes mellitus, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

[0054] In some embodiments, the subject’s risk of the occurrence of a composite of the following outcomes is reduced: cognitive decline, stroke, transient ischemic attack or death. In some embodiments, the subject has either: multiple cardiovascular risk factors without established cardiovascular disease; or established cardiovascular disease.

[0055] In another aspect, the invention features a method of treating, preventing or delaying development of heart failure in a subject, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

[0056] In some embodiments, the heart failure is selected from the group consisting of HFrEF and HFpEF. In some embodiments, the heart failure is HFpEF.

[0057] In another aspect, the invention features a method of preventing or delaying HFpEF in a subject, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

[0058] In another aspect, the invention features a method of improving weight management and preventing or delaying HFpEF in a subject in a subject with type 2 diabetes mellitus, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

[0059] In some embodiments, the method provides a reduced risk of hospitalization for HFpEF. In some embodiments, the subject’s six minute walk test is improved by about 10%. In some embodiments, the subject’s risk of the occurrence of a composite of the following outcomes is reduced: cognitive decline, hospitalization for HFpEF, or death.

[0060] In another aspect, the invention features a method of treating high blood pressure in a subject receiving clinical treatment for type 2 diabetes using oral antidiabetic agents for at least 1 year, 2 years, 3, year, 4 year or 5 years wherein the subject's HbA1c is > 7% (e.g., 7.10%, 7.20%, 7.30%, 7.40%, 7.50%, 7.60%, 7.70%, 7.80%, 7.90%, 8.00%, 8.10%, 8.20%, 8.30%, 8.40%, 8.50%, 8.60%, 8.70%, 8.80%, 8.90%, 9.00%, 9.10%, 9.20%, 9.30%, 9.40%, 9.50%, 9.60%, 9.70%, 9.80%, 9.90%, 10.00%, 10.50%, 11.00%, 11.50%, 12.00%, 12.50%, 13.00%, 13.50%, 14.00%, 14.50%, or 15.00%), the method including PATENT

[0061] ATTORNEY DOCKET NO.: 51121-108WO2

[0062] administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein (CBP).

[0063] In another aspect, the invention features a method of treating refractory type 2 diabetes in a subject having type 2 diabetes for at least 8 years, the method including administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein (CBP).

[0064] In some embodiments of any of the above aspects, the diabetes, the type 2 diabetes, the type 2 diabetes mellitus, obesity, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, dyslipidemia, chronic kidney disease, atherosclerosis, diabetic kidney disease, a cognitive disorder, and / or metabolic syndrome is in a subject.

[0065] In some embodiments of any of the above aspects, the effective amount of the agent reduces the level and / or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%), as compared to a reference. In some embodiments, the effective amount of the agent that reduces the level and / or activity of CBP by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%), as compared to a reference. In some embodiments, the effective amount of the agent that reduces the level and / or activity of CBP by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0066] In some embodiments of any of the above aspects, the effective amount of the agent reduces the level and / or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more). In some embodiments, the effective amount of the agent that reduces the level and / or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%), as compared to a reference for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more).

[0067] In some embodiments, the subject has diabetes. In some embodiments, the subject has type 2 diabetes. In some embodiments, the subject has type 2 diabetes mellitus. In some embodiments, the subject has obesity. In some embodiments, the subject has nonalcoholic fatty liver disease. In some embodiments, the subject has nonalcoholic steatohepatitis. In some embodiments, the subject has dyslipidemia. In some embodiments, the subject has chronic kidney disease. In some embodiments, the subject has atherosclerosis. In some embodiments, the subject has diabetic kidney disease. In some embodiments, the subject has a cognitive disorder. In some embodiments, the subject has metabolic syndrome.

[0068] In some embodiments, the subject has refractory type 2 diabetes. In some embodiments, the subject has an HbA1c of greater than 10% (e.g., 10.00%, 10.25% 10.50%, 10.75% 11.00%, 11.25% 11.50%, 11.75%, 12.00%, 12.25%, 12.50%, 12.75%, 13.00%, 13.25%, 13.50%, 13.75%, 14.00%, 14.25%, 14.50%, 14.75%, 15.00%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%). In some embodiments, the subject has an HbA1c of greater than 11% (e.g., 11.00%, 11.25% 11.50%, 11.75%, 12.00%, 12.25%, 12.50%, 12.75%, 13.00%, 13.25%, 13.50%, 13.75%, 14.00%, 14.25%, 14.50%, 14.75%, 15.00%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%). In some embodiments, the subject has an HbA1c treatment goal of 5.7%. In some embodiments, the subject has an HbA1c PATENT

[0069] ATTORNEY DOCKET NO.: 51121-108WO2

[0070] treatment goal of less than or equal to 5.7% (e.g., 5.70%, 5.60%, 5.50%, 5.40%, 5.30%, 5.20%, 5.10%, 5.00%, 4.90%, 4.80%, 4.70%, 4.60%, 4.50%, 4.40%, 4.30%, 4.20%, 4.10%, 4.00%, 3.90%, 3.80%, 3.70%, 3.60%, 3.50%, 3.40%, 3.30%, 3.20%, 3.10%, 3.00%, 2.90%, 2.80%, 2.70%, 2.60%, or 2.50%). In some embodiments, the subject has an HbA1c treatment goal of 6%. In some embodiments, the subject has an HbA1 c treatment goal of 7%.

[0071] In another aspect, the present invention provides a method for treating refractory type 2 diabetes in a subject who is non-responsive to metformin, SGLT-2 or metformin plus an SGLT-2 inhibitor, the method including administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein (CBP). In some embodiments, the subject has type 2 diabetes and is non-obese. In some embodiments, the subject has type 2 diabetes and obesity. In some embodiments, the subject has refractory type 2 diabetes. In some embodiments, the subject has type 2 diabetes for at least 8 years.

[0072] In another aspect, the present invention provides a method of treating a hypertensive crisis in a subject with refractory type 2 diabetes, the method including administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein (CBP).

[0073] In another aspect, the invention provides a method of treating high blood pressure in a subject with type 2 diabetes, the method including administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein (CBP).

[0074] In another aspect, the invention provides a method of improving glycemic control and increasing HDL-C, in a subject with type 2 diabetes meilitus, the method including administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein (CBP).

[0075] In another aspect, the invention provides a method of improving glycemic control and treating high blood pressure in a subject in a subject diagnosed with type 2 diabetes meilitus, an agent that reduces the level and / or activity of CREB-binding protein (CBP).

[0076] In some embodiments, the method results in a reduction in the risk of the subject experiencing high blood pressure. In some embodiments, the method results in a reduction in the risk of the subject experiencing hypertensive crisis. In some embodiments, the method results in a reduction in the risk of the subject experiencing clinically low HDL-C.

[0077] In another aspect, the invention provides a method of improving glycemic control in a subject with type 2 diabetes meilitus, an agent that reduces the level and / or activity of CREB-binding protein (CBP).

[0078] In any one of the aspects described herein, the subject has one or more of the following: T2DM; high blood pressure; reduced HDL-C; and obesity. In any one of the aspects described herein, the subject has: multiple cardiovascular risk factors without high blood pressure or clinically significant high blood pressure. In any one of the aspects described herein, the subject has: multiple cardiovascular risk factors or HbA1c level above 11% (e.g., 11.25% 11.50%, 11.75%, 12.00%, 12.25%, 12.50%, 12.75%, 13.00%, 13.25%, 13.50%, 13.75%, 14.00%, 14.25%, 14.50%, 14.75%, 15.00%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%).

[0079] In some embodiments, the subject’s risk of hypertensive crisis is reduced by at least about 10% (e.g., about 10.00%, about 10.25%, about 10.50%, about 10.75% about 11.00%, about 11.25% about 11.50%, about 11.75%, about 12.00%, about 12.25%, about 12.50%, about 12.75%, about 13.00%, about PATENT

[0080] ATTORNEY DOCKET NO.: 51121-108WO2

[0081] 13.25%, about 13.50%, about 13.75%, about 14.00%, about 14.25%, about 14.50%, about 14.75%, about 15.00%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25%). In some embodiments, the HDL-C levels are increased. In some embodiments, HDL-C levels are increased to a clinically desired level. an agent that reduces the level and / or activity of CREB-binding protein (CBP). In some embodiments, the risk of the occurrence of a composite of the following outcomes is reduced: hospitalization for high blood pressure or death. In some embodiments, the risk of death or hospitalization for high blood pressure is reduced.

[0082] In some embodiments, the risk of the occurrence of a composite of the following outcomes is reduced: high blood pressure and HbA1c above 5.7%. In some embodiments, the risk of the occurrence of a composite of the following outcomes is reduced: low HDL-C, high blood pressure, and HbA1c above 7%.

[0083] In some embodiments, the risk of the occurrence of a composite of the following outcomes is reduced: low HDL-C, high blood pressure and HbA1c above 5.7%. In some embodiments, the risk of the occurrence of a composite of the following outcomes is reduced: low HDL-C, high blood pressure, and HbA1c above 6%.

[0084] In some embodiments, the subject fails to achieve HbAIC < 7% using one or two oral diabetes agents for at least one year prior to treatment using an agent that reduces the level and / or activity of CREB-binding protein (CBP)an agent that reduces the level and / or activity of CREB-binding protein (CBP), or pharmaceutically acceptable salt thereof. In some embodiments, the subject fails to achieve HbAIC < 8% using one or two oral agents for at least one year prior to treatment using an agent that reduces the level and / or activity of CREB-binding protein (CBP), or pharmaceutically acceptable salt thereof. In some embodiments, the subject fails to achieve HbAIC <10% using one or two oral agents for at least one year prior to treatment using an agent that reduces the level and / or activity of CREB-binding protein (CBP), or pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the subject is at least 46 years old. In some embodiments, the subject is at least 55 years old. In some embodiments, the subject is at least 60 years old.

[0086] In some embodiments, the subject is also administered metformin and an SGLT2 oral agent. In some embodiments, the subject is also administered an SGLT2 oral agent. In some embodiments, the subject is also administered metformin. In some embodiments, the subject is also administered a basal insulin. In some embodiments, the subject is also administered metformin and a basal insulin. In an embodiment the subject is also administered an SGLT2 and a basal insulin. In an embodiment the subject is also administered metformin, an SGLT2, and a basal insulin. In some embodiments, the basal insulin is insulin glargine. In some embodiments, the basal insulin is insulin Degludec. In some embodiments, the subject is also administered an SGLT2 oral pharmaceutical. In some embodiments, the subject is also administered metformin, an SGLT2 oral, and insulin Degludec. In some embodiments, the subject is also administered metformin, an SGLT2 oral, and insulin Degludec.

[0087] In any of the aspects described herein, the agent that reduces the level and / or activity of CREB-binding protein (CBP) is a small molecule compound, or pharmaceutically acceptable salt thereof. In any of the aspects described herein, the agent that reduces the level and / or activity of CREB-binding protein (CBP) is a CBP degrader, or pharmaceutically acceptable salt thereof. PATENT

[0088] ATTORNEY DOCKET NO.: 51121-108WO2

[0089] In any of the aspects described herein, the agent that reduces the level and / or activity of CREB-binding protein (CBP) is a compound, or pharmaceutically acceptable salt thereof having the structure of Formula I:

[0090] A-L-B

[0091] Formula I,

[0092] wherein

[0093] A is a CBP binding moiety;

[0094] B is a degradation moiety; and

[0095] L is a linker.

[0096] In some embodiments, L has the structure of Formula II:

[0097] A1-(F)-(E)m-C-A2,

[0098] Formula II

[0099] wherein

[0100] A1is a bond between the linker and A;

[0101] A2is a bond between B and the linker;

[0102] m is, independently, 0 or 1;

[0103] C is absent, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl;

[0104] each E is, independently, absent, O, S, NRN, optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1-C10 heteroalkylene wherein any C1-C10 alkylene, C2-C10 alkenylene, C2-C10 alkynylene, C2-C10 polyethylene glycol, or C1-C10 heteroalkylene is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, C(O)Rf, S(O)2Rf, C(O)N(Rf)2, N(Rf)2, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, carbocycle, and Ci Cs alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0105] each RNis, independently, H, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alky ny I, optionally substituted C2-C0 heterocyclyl, optionally substituted C6-C12 aryl, or optionally substituted C1-C7 heteroalkyl wherein any C1-C4 alkyl, C2 C4 alkenyl, C2-C4 alkynyl, C2-C6 heterocyclyl, C6-C 2 aryl, or C1-C7 heteroalkyl is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(0)N(Rf)2, S(O)2N(Rf)2, 0Rf, SRf, C(O)Rf, S(O)2Rf, C(O)N(Rf)2, N(Rf)2, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, carbocycle, and C Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0106] F is optionally substituted C3-C10 carbocyclylene, optionally substituted C2-C 0 heterocyclylene, optionally substituted Ce-Cio arylene, or optionally substituted C2-C9 heteroarylene, wherein any C3-C10 carbocyclylene, C2-C10 heterocyclylene, Ce-Cio arylene, or C2-C9 heteroarylene is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(Rf)2, CN, C(0)N(Rf)2, S(0)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, C(0)Rf, S(O)2Rf, C(0)0Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, carbocycle, and Ci-C6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; PATENT

[0107] ATTORNEY DOCKET NO.: 51121-108WO2

[0108] each Rfis, independently, hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, carbocyclyl, or heterocyclyl, wherein any Ci-Ce alkyl, C2-C6 alkenyl, C2-Cealkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(R9)2, CN, C(O)N(Ra)2, S(O)N(R9)2, S(O)2N(Ra)2, OR8, SR8, C(O)R8, S(O)2R8, C(O)N(R8)2, N(RS)2, N(Rs)S(O)R8, N(RS)S(O)2R3, and Ci. Ce alkyl, which carbocyclyl and Ci-Ce alkyl are optionally substituted with one or more groups independently selected from oxo, halo, Ci-Ce alkyl, cyano, N(R8)2, OR8, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and Ci-Ce alkyl;

[0109] each Rs is, independently, hydrogen, Ci-Ce alkyl, C -Ce alkenyl, C2-Cealkynyl, Ci-Cs alkoxy, carbocyclyl, or heterocyclyl, wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-Cealkynyl, Ci-Ce alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Ce alkoxy, carbocyclyl, heterocyclyl, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R8are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo.

[0110] In some embodiments, m is 0.

[0111] In some embodiments, E is absent.

[0112] In some embodiments, m is 1.

[0113] In some embodiments, E is optionally substituted C1-10 alkylene.

[0114] In some embodiments, E is methylene or ethylene.

[0115]

[0116] In some embodiments, F is optionally substituted C2-C9 heteroarylene.

[0117] In some embodiments, F is the structure:

[0118]

[0119] wherein X? and Xs are each independently C or N; and

[0120] R15 and Rie combine with the atoms to which they are attached to form an optionally substituted 3-12 membered heteroaryl, wherein the heteroaryl is optionally substituted with A' and / or one or more of the following groups: halogen or Ci-Ce alkyl.

[0121]

[0122] PATENT

[0123] ATTORNEY DOCKET NO.: 51121-108WO2

[0124]

[0125] In some embodiment,

[0126]

[0127] In some embodiments, F is optionally substituted C2-C10 heterocyclylene.

[0128]

[0129] In some embodiments, C is carbonyl.

[0130] In some embodiments, L is a linker having the structure of Formula Ila:

[0131] AI-CF'HT-A2.

[0132] Formula Ila

[0133] Ci is carbonyl;

[0134] F1is optionally substituted C2-C9 heteroarylene.;

[0135] In some embodiments, L has the structure:

[0136]

[0137] PATENT

[0138] ATTORNEY DOCKET NO.: 51121-108WO2

[0139]

[0140] In some embodiments, L has the structure of Formula lib:

[0141] A1-(F2)-(E2)mi-C2-A2,

[0142] Formula lib

[0143] rm is 0 or 1;

[0144] C2is absent, or carbonyi;

[0145] each E2is, independently, optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1-C10 heteroalkylene wherein any C1-C10 alkylene, C2-C10 alkenylene, C2-C10 alkynylene, C2-C10 polyethylene glycol, or C1-C10 heteroalkylene is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(R11a)2, CN, C(O)N(R1a)2, S(O)N(R11a)2, S(O)2N(R1 a)2, OR11a, SR113, OC(O)R11a, C(O)R1'a, C(O)ORl1a, S(O)Rl1a, S(O)2R11a, C(O)N(R11a)2, N(Ra)C(O)R11a, N(R11a)S(O)R11a, N(R11a)S(O)2R'1a, carbocycle, and Ci-C6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0146] F2is optionally substituted C3-C10 carbocyclylene, optionally substituted C2-C10 heterocyclylene, optionally substituted Ce-Cio arylene, or optionally substituted C2-C9 heteroarylene, wherein any C3-C10 carbocyclylene, C2-C10 heterocyclylene, Cs-Cio arylene, or C2-C9 heteroarylene is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(Ra)2, CN, C(O)N(Ra)2, , C(O)OR'1a, S(O)R'1a, S(O)2R11a,

[0147]

[0148] carbocycle, and Ci-C6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo,

[0149] each R11ais, independently, hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-Cs alkoxy, carbocyclyl, or heterocyclyl, wherein each Ci-Cs alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-Ce alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Ce alkoxy, carbocyclyl, heterocyclyl, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Raare taken together with the atom to which they are attached to form a carbocyclyl or heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo. PATENT

[0150] ATTORNEY DOCKET NO.: 51121-108WO2

[0151] In some embodiments, C2is absent.

[0152] In some embodiments, C2is carbonyl.

[0153] In some embodiments, mi is 0.

[0154] In some embodiments, E2is absent.

[0155] In some embodiments, m is 1.

[0156] In some embodiments, E2is optionally substituted C1-C10 alkylene.

[0157] In some embodiments, E2is methylene or ethylene.

[0158] In some embodiments, F2is optionally substituted C2-C9 heteroarylene.

[0159]

[0160] In some embodiments, the CBP binding moiety has the structure of Formula III: PATENT

[0161] ATTORNEY DOCKET NO.: 51121-108WO2

[0162]

[0163] Formula III,

[0164] wherein

[0165] Xais, independently, C or N;

[0166] X2ais, independently, C or N;

[0167] R1aand R1bcombine with the atoms to which they are attached to form an optionally substituted C3-C10 carbocycle, an optionally substituted C5-C10 aryl,anoptionally substituted C3-C9 heteroaryl, or optionally substituted C3-C9 heterocycle, wherein the carbocycle, aryl, heteroaryl or heterocycle is optionally substituted with A1and / or one or more of the following groups: halogen, Ci-Ce alkyl, C5-C10 aryl, C2-C9 heteroaryl, C2-C9 heterocycle, C3-C10 carbocycle, C(O)N(Rle)2, S(O)N(R1e)2, S(O)2N(R1e)2, ORle,

[0168]

[0169] N(R1e)S(O)N(R1e)2; wherein any Ci-Ce alkyl, C5-C10 aryl, C2-C9 heteroaryl, C2-C9 heterocycle, C3-C10 carbocycle is optionally substituted A1and / or one or more substituent groups independently selected from halogen, Ci-Ce alkyl, C2-C9 heteroaryl, C3-C12 carbocycle, C2-C9 heterocycle, C(O)N(R1e)2, S(O)N(R1e)2, S(O)2N(R1e)2, C(O)R1e, C(O)OR1e, S(O)R1e, or S(O)2R1e.

[0170] R1cis A1, NR2aR3a, Cs-C2oaryl, C2-C9 heterocyle, C1-C20 heteroaryl, (Ce-C2oaryl)(Ci-C2o heteroaryl), (C1-C20 heteroaryl)-(Ce-C2oaryl), and (C1-C20 heteroaryl)(Ci-C2o heteroaryl), wherein each Ce-C2oaryl, C1-C20 heteroaryl, (Ce-C2oaryl)(Ci-C2oheteroaryl) and (C1-C20 heteroaryl)-(Ci-C2o heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from R1h, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(R1CN, C(O)N(R1f)2, S(O)N(R1f)2, S(O)2N(R1f)2, OR1f, SR1f, OC(O)R1f, OC(O)OR1f, C(O)R1f, C(O)OR1f, S(O)R1f, S(O)2R1f, OC(O)N(R1f)2, N(R1f)C(O)OR1f, N(R1f)C(O)N(R1f)2, N(R1f)C(O)R1f, N(R1f)S(O)R1f, N(R1f)S(O)2R1f, N(R1f)S(O)N(R1f)2, and N(Rir)S(O)2N(R1f)2;

[0171] R1dis C1-C12 alkyl, C2-C12 alkenyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R1dis optionally substituted with one or more groups RT;

[0172] each R1eis, independently, hydrogen, C1 C4 alkyl, C2 C4 alkenyl, C2-C4alkynyl, or C2-C5 cycloalkyl, wherein each C1 C4 alkyl, C2C4 alkenyl, C2-C alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1 C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; R2ais, independently, H, C1-C12 alkyl, C5-C2oaryl, C1-C20 heteroaryl, (Ce-C2oaryl)(Ci-C2o heteroaryl), (C -C20 heteroaryl)(Cs-C2oaryl), and (C1-C20 heteroaryl)(Ci-C2o heteroaryl), wherein each Ce-C2oaryl, C -C20 heteroaryl, (Ce-C2oaryl)(Ci-C2o heteroaryl) and (C1-C20 heteroaryl)(Ci-C2o heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from R1k, oxo, PATENT

[0173] ATTORNEY DOCKET NO.: 51121-108WO2

[0174]

[0175] R3ais Ci~Ci2alkyl, C2Ci2alkenyl, C2Ci2alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each Ci Ci2alkyl, C2Ci2alkenyl, C2Ci2alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3ais optionally substituted with A' and / or one or more groups R1k; or R2aand R3aof Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1and / or one or more groups Rl;

[0176] each Rfis, independently, hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Cealkynyl, C3-C9 carbocyclyl, and C2-Cs heterocyciyl, wherein each Ci-Ce alkyl, C2-Ce alkenyl, C2-Csalkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Ce alkoxy, carbocyclyl, heterocyclyl, or Ci-Ce alkyl that is optionally substituted with A and / or one or more groups independently selected from oxo and halo; or two R1fare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0177] each R^ is, independently, oxo, Ci-Ce alkyl, C2-Ce alkenyl, C2-Cealkynyl, C3-C9 carbocyclyl, C2-Cg heterocyclyl, C5-C9 aryl, Ci-C20heteroaryl, F, Cl, Br, I, NO2, N(R1L)2, CN, C(O)N(R1L-)2, S(O)N(R1L)2, S(O)2N(R°)2, OR1L, SR1L, OC(O)OR1L, OC(O)OR1L, C(O)R1L, C(O)OR1L, S(O)R1L, S(O)2R1L, OC(O)N(R1L)2, N(R1L)C(O)OR1L, N(R1L)C(O)N(R1L)2, N(R1L)C(O)R1i-, N(R1LS(O)R1L, N(R1L)S(O)2R1L, N(R1L)S(O)N(R1L)2, or N(R1i-)S(O)2N(R1L)2, wherein any Ci-Ce alkyl, C2-Cs alkenyl, C2-Ce alky ny I, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(R1L)2, CN, C(O)N(R1L)2, S(O)N(R1L)2, S(O)2N(R1i-)2, OR11-, SR1L, OC(O)R1L, C(O)R1L, S(O)R1L, S(O)2R1L, C(O)N(R1L)2, N(R1L)C(O)R1L, N(R1L)S(O)R1L, N(R1L)S(O)2R1Land Ci Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0178] each R1his, independently, hydrogen, Ci Ce alkyl, C2Ce alkenyl, C2Cealkynyl, carbocyclyl, or heterocyclyl, wherein any Ci Ce alkyl, C2-Ce alkenyl, C2Cealkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(R1 M)2, CN, C(O)N(R1M)2, S(O)N(R1M)2, S(O)2N(R1M)2, OR1M, SR1M, OC(O)R1M, C(O)R1M, C(O)OR1M, S(O)R1M, S(O)R1M, C(O)N(R1M)2, N(R1M)C(O)R1M, N(R1M)S(O)R1M, N(R1 M)S(O)2R1 M, and Ci-Ce alkyl, which carbocyclyl and Ci Ce alkyl are optionally substituted with one or more groups independently selected from oxo, halo, Ci-Ce alkyl, cyano, N(R1M)2, OR1M, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and Ci-Ce alkyl;

[0179] each R1jis, independently, hydrogen, Ci Ce alkyl, C2-Ce alkenyl, C2Cealkynyl, carbocyclyl, and heterocyclyl, wherein each Ci-Ce alkyl, C2Ce alkenyl, C2Cealkynyl, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, CvCe alkoxy, carbocyclyl, heterocyciyl, or C -Ce alkyl that is optionally substituted with A1and / or one or more groups independently selected from oxo and halo; or two R1^ are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with A and / or one PATENT

[0180] ATTORNEY DOCKET NO.: 51121-108WO2

[0181] or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with A1and / or one or more groups independently selected from oxo and halo;

[0182] each R1kis, independently, hydrogen, Ci Co alkyl, C2-C6 alkenyl, C2-C6alkynyl, carbocyclyl, or heterocyclyl, wherein any Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(R1N)2, CN, CHF2, CF3, C(O)N(R1N)2, S(O)N(R1N)2, S(O)2N(R1N)2, OR'N, SR1N, OC(O)RIN, C(O)RIN, C(O)OR1N, S(O)R1N, S(O)2RINd, C(O)N(R1N)2, N(R1N)C(O)R1N, N(R1N)S(O)R1N, N(R1N)S(O)2R1N, and C1-C6 alkyl, which carbocyclyl and Ci-Ce alkyl are optionally substituted with A' and / or one or more groups independently selected from oxo, halo, Ci-Cs alkyl, cyano, N(R1N)2, OR1N, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and Ci-Cs alkyl;

[0183] each RMis, independently, hydrogen, Ci-Cs alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-Cs alkoxy, carbocyclyl, or heterocyclyl, wherein each Ci-Cs alkyl, C2-C6 alkenyl, C2-CsalkynylCsalkynyl, Ci-Ce alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Cs alkoxy, carbocyclyl, heterocyclyl, and Ci-Cs alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd2are taken together with the nitrogen to which they are atached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0184] each R1Nis, independently, hydrogen, Ci-Cs alkyl, C2-C6 alkenyl, C2-Csalkynyl, C -Cs alkoxy, carbocyclyl, or heterocyclyl, wherein each Ci-Cs alkyl, C2-C6 alkenyl, C2-Csalkynyl, Ci-Cs alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Cs alkoxy, carbocyclyl, heterocyclyl, and C1-C salkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R1Nare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0185] and one and only one of R1a, R1b, R1c, or R1dcomprises A1. PATENT

[0186] ATTORNEY DOCKET NO.: 51121-108WO2

[0187]

[0188] PATENT

[0189] ATTORNEY DOCKET NO.: 51121-108WO2

[0190] In some embodiments, the CBP binding moiety of Formula III has the structure:

[0191]

[0192] IIn some embodiments, the CBP binding moiety has the structure: PATENT

[0193] ATTORNEY DOCKET NO.: 51121-108WO2

[0194]

[0195] PATENT

[0196] ATTORNEY DOCKET NO.: 51121-108WO2

[0197]

[0198] PATENT

[0199] ATTORNEY DOCKET NO.: 51121-108WO2

[0200]

[0201] IIn some embodiments, the CBP binding moiety has the structure:

[0202]

[0203] PATENT

[0204] ATTORNEY DOCKET NO.: 51121-108WO2

[0205] IIn some embodiments, the CBP binding moiety has the structure:

[0206]

[0207] In some embodiments, the CBP binding moiety has the structure of Formula (I I l-A):

[0208]

[0209] Formula lll-A

[0210] wherein

[0211] R8is C1 C12 alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each Ci C12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R8is optionally substituted with one or more groups R°;

[0212] R9is C Caalkyl, C2-C6heteroaryl, C2-C9 heterocycle, C(O)N(Rh2)2, S(O)N(Rh2)2, S(O)2, C(O)Rh2, C(O)ORh2, S(O)Rh2, or S(O)2Rh2, wherein any Ci-C4alkyl, C2C 6 heteroaryl, or C2 C9 heterocycle is optionally substituted one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh2)2, S(O)N(Rh2)2, N(Rh2)C(O)ORh2, N(Rh2)C(O)N(Rh2)2, N(Rh2)C(O)Rh2, N(Rh2)2, N(Rh2)S(O)2Rh2, N(Rh2)S(O)N(Rh2)2, and N(Rh2)S(O)2N(Rh2)2; PATENT

[0213] ATTORNEY DOCKET NO.: 51121-108WO2

[0214] R10is Ce-C2oaryl, C1-C20 heteroaryl, (C6-C2oaryl)(Ci-C2o heteroaryl), (Ci-2o heteroaryl)(C6-C2oaryl), and (C1-C20 heteroaryl)(Ci-C2o heteroaryl), wherein each Ce-C2oaryl, C1-C20 heteroaryl, (C6-C2oaryl)(Ci-C20 heteroaryl) and (C1-C20 heteroaryl)(Ci-C2o heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Rpp, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(Ra2)2, CN, C(O)N(Ra2)2, S(O)N(Ra2)2, S(O)2N(Ra2)2, N(Ra2)C(O)ORa2)C(O)N(Ra2)C(O)N(Ra2)S(O)2Ra2, N(Ra2)S(O)N(Ra2)2, and N(Ra2)S(O)2N(Ra2)2;

[0215] each Ra2is, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-Cealkynyl, carbocyclyl, and heterocyclyl, wherein each Ci-Ce alkyl, C2-C6alkenyl, C2-C6alkynyl, carbocyclyl, and heterocyclyi is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Cs alkoxy, carbocyclyl, heterocyclyl, or Ci-Cs alkyl that is optionally substituted with A1and / or one or more groups independently selected from oxo and halo; or two Ra2are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0216] each R°is, independently, oxo, Ci-Cs alkyl, C2-Cs alkenyl, C2-Csalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(RP)2, CN, C(O)N(RP)2, S(O)N(RP)2, S(O)2N(RC)2, C(O)ORP, OCOC(O)RP, C(O)ORP, S(O)RP, S(O)2RP, OCRP(O)2, N(RP)2, N(RP)RPC(O)RPN(RP)2, RPN(RP)2, N(RPS(O)RP, N(RPS(O)RPPN(RPRPRP)2, or N(RP)S(O)2N(RP)2, wherein any Ci-C6alkyl, C2-C3alkenyl, C2-Cealkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(RP)2, CN, C(O)N(RP)2, S(O)RP, S(O)2N(RP)S(O)RP, N(Rp)S(O)2Rpand Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0217] each Rpis, independently, hydrogen, Ci-Cs alkyl, C2-Ce alkenyl, C2-Csalkynyl, carbocyclyl, or heterocyclyl, wherein any Ci Cs alkyl, C2-Cs alkenyl, C2Cealkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd2)2, CN, C(O)N(Rd2)2, S(O)N(Rd2)2, S(O)2N(Rd2)2, ORd2, SRd2, C(O)R C(O)N(Rd2)2, N(Rd2)C(O)Rd2, N(Rd2)S(O)Rd2, N(Rd2)S(O)2Rd2, and Ci-Ce alkyl, which

[0218]

[0219] alkyl are optionally substituted with one or more groups independently selected from oxo, halo, Ci ealkyl, cyano, N(Rd2)2, ORd2, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and Ci -ealkyl;

[0220] each Rd2is, independently, hydrogen, Ci-Ce alkyl, C2Cs alkenyl, C2-Cealkynyl, Ci Cs alkoxy, carbocyclyl, or heterocyclyl, wherein each Ci CsC alkyl, C2Ce alkenyl, C2-Cealkynyl, Ci-Ce alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci Ce alkoxy, carbocyclyl, heterocyclyl, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd2are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1 C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0221] each Rh2is, independently, hydrogen, C1 C4 alkyl, C2C-i alkenyl, C2-C-ialkynyl, or C2-Cs cycloalkyl, wherein each C1 C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, and C2Cs cycloalkyl is optionally substituted with PATENT

[0222] ATTORNEY DOCKET NO.: 51121-108WO2

[0223] one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; and wherein R10comprises A1.

[0224] In some embodiments, R8is methyl, oxetanyl, tetra hydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidiny I, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrroiidinyl of Rsis optionally substituted with one or more groups Rb2.

[0225]

[0226] In some embodiments, R9is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.

[0227] In some embodiments, R9has the structure:

[0228]

[0229] IIn some embodiments, the CBP binding moiety has the structure:

[0230]

[0231]

[0232] IIn some embodiments, the CBP binding moiety has the structure:

[0233]

[0234] PATENT

[0235] ATTORNEY DOCKET NO.: 51121-108WO2

[0236] In some embodiments, NR2R3taken together has the structure:

[0237]

[0238] wherein

[0239] X3is NRN2, CH2, or O;

[0240] X4is N, or CH;

[0241] X5is N, or CH;

[0242] Xe is NRN2, CH2, or O;

[0243] R14is H, halogen, optionally substituted C1-3 alkyl, optionally substituted C1-3 heteroalkyl, C1-3 alkoxy, or CN; and

[0244] RN2is C1-C3 alkyl or H.

[0245] In some embodiments, NR2R3taken together has the structure:

[0246]

[0247] wherein

[0248] X3is NRN2, CH2, or O;

[0249] X4is N, or CH;

[0250] X5is N, or CH;

[0251] Xe is NRN2, CH2, or O;

[0252] R14is H, halogen, optionally substituted C1-3 alkyl, optionally substituted C1-3 heteroalkyl, C1-3 alkoxy, or CN; and

[0253] RN2is C1-C3 alkyl or H.

[0254] In some embodiments, X3 is CH2, X4is CH, and Xsis CR14.

[0255] In some embodiments, X3 is O, X4is CH, and X9is CR14.

[0256] In some embodiments, X3 is O, X4is N, and X9is CR14.

[0257] In some embodiments, X3is O, X4is CH, and X9is N.

[0258] In some embodiments, X3is CH2, X4is N, and X9is N.

[0259] In some embodiments, X3is CH2, X4is N, and X9is CR14.

[0260] In some embodiments, X3is NRN2, X4is CH, and X9 is CR14.

[0261] In some embodiments, X3is NRN2, X4is CH, and X9is N.

[0262] In some embodiments, X3is CH(COOH), X4is CH, and X9is CR14.

[0263] In some embodiments, R14is optionally substituted C1-C3 alkyl.

[0264] In some embodiments, R14is CHF2, CF3, CHCI2, or CH3. PATENT

[0265] ATTORNEY DOCKET NO.: 51121-108WO2

[0266] In some embodiments, R14is optionally substituted C1-C3 alkoxy.

[0267] In some embodiments, R14is OCHs

[0268] In some embodiments, R14is halo

[0269] In some embodiments, R14is F or Cl.

[0270] In some embodiments, R14is CN.

[0271] In some embodiments, RN2is H.

[0272] In some embodiments, RN2is C1-C3 alkyl.

[0273] In some embodiments, C1-C3 alkyl is methyl.

[0274]

[0275] PATENT

[0276] ATTORNEY DOCKET NO.: 51121-108WO2

[0277] IIn some embodiments, the CBP binding moiety has the structure:

[0278]

[0279] In some embodiments, the CBP binding moiety has the structure of Formula (lll-B):

[0280]

[0281] Formula lll-B

[0282] wherein R1is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R is optionally substituted with A and / or one or more groups Rb;

[0283] R2is Ce-C oaryl, C1-C20 heteroaryl, (C6- oaryl)(Ci-C2o heteroaryl), (Ci-C2o heteroaryl)(C6-C2oaryl), and (C1-C20 heteroaryl)(Ci-C2o heteroaryl), wherein each Ce-C oaryl, C1-C20 heteroaryl, (Cs-C2oaryl)(Ci-C20 heteroaryl) and (C1-C20 heteroaryl)(Ci-C2o heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from R°, oxo, F, Cl, Br, I, NO2, N(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, N(Ra)C(O)ORa)C(O)N(Ra)2, N(Ra)2, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2;

[0284] R3is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each Ci-Ci2alkyl, C2-Ci2alkenyl, C2-Ci2alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3is optionally substituted with A1and / or one or more groups Re;

[0285] or R2and R3taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1and / or one or more groups Re;

[0286] R4is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with A1and / or one or more substituent groups independently selected from F, Cl, Br, I, C3-C5 carbocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(R )2, ORh, SRh, OC(O)Rh, OC(O)ORh, C(O)Rh, C(O)ORh, S(O)Rh, S(O)2Rh, OC(O)N(R )2, N(Rh)C(O)ORh, N(Rh)C(O)N(Rh)2, N(Rh)C(O)Ra, N(Rh)S(O)Rh, N(Rh)S(O)2R, N(R )S(O)N(R )2, and N(Rh)S(O)2N(Rh)2;

[0287] each Rais, independently, hydrogen, Ci-Cs alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1 C6 alkyl, C2 C6 alkenyl, C2-C0 alkynyl, carbocyclyl, and heterocyclyl is PATENT

[0288] ATTORNEY DOCKET NO.: 51121-108WO2

[0289] optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Ce alkoxy, carbocyclyl, heterocyclyl, or Ci-Ce alkyl that is optionally substituted with A1and / or one or more groups independently selected from oxo and halo; or two Raare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with A1and / or one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionaily substituted with A1and / or one or more groups independently selected from oxo and halo;

[0290] each Rbis, independently, oxo, Ci-Ce alkyl, C2-Ce alkenyl, C2-Cealkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-Cio aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, N(R°)2, CN, C(O)N(R°)2, S(O)N(R°)2, S(O)2N(R°)2, OR0, SR°, OC(O)OR°, OC(O)OR°, C(O)R°, C(O)OR°, S(O)R°, S(O)2RC, OC(O)N(R°)2, N(R°)C(O)OR°, N(R°)C(O)N(R°)2, N(R°)C(O)R°, N(R°)S(O)R°, N(RC)S(O)2RC, N(R°)S(O)N(R0)2, or N(RC)S(O)2N(RC)2, wherein any Ci-Ce alkyl, C2-Ce alkenyl, C2-Cealkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, Ce-Cio aryl, and C2-C12 heteroaryl is optionally substituted with A' and / or one or more groups independently selected from oxo, halo, NO2, N(R°)2, CN, C(O)N(R°)2, S(O)N(R°)2, S(O)2N(R0)2, OR0, SR°, OC(O)R°, C(O)R°, S(O)R°, S(O)2R°, C(O)N(RC)2, N(R°)C(O)R°, N(R°)S(O)R°, N(R0)S(O)2R°and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0291] each R°is, independently, hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Cealkynyl, carbocyclyl, or heterocyclyl, wherein any Ci-Ce alkyl, C2-Ce alkenyl, C2-Cealkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, C(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)2, N(Rd)S(O))Rd, N(Rd)S(O)2Rd, and Ci-Ce alkyl, which carbocyclyl and Ci-Ce alkyl are optionally substituted with A1and / or one or more groups independently selected from oxo, halo, Ci-Ce alkyl, cyano, N(Rd)2, ORd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and Ci-Ce alkyl;

[0292] each Rdis, independently, hydrogen, Ci-Ce alkyl, C2Ce alkenyl, C2Cealkynyl, Ci-Ce alkoxy, carbocyclyl, or heterocyclyl, wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-Cealkynyl, Ci-Ce alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Ce alkoxy, carbocyclyl, heterocyclyl, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rdare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and Ci-C salkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0293] each Reis, independently, oxo, Ci-Ce alkyl, C2-Ce alkenyl, C2-Csalkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(R?)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, or N(Rf)S(O)2N(Rt)2, wherein any C -Ce alkyl, C2-Ce alkenyl, C2-Cealkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, and C2-Cio heteroaryl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, NO2, N(R2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rr)2, ORf, SRf, OC(O)Rf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, C(O)N(Rf)2, N(Rt)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, PATENT

[0294] ATTORNEY DOCKET NO.: 51121-108WO2

[0295] carbocycle, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0296] each Rfis, independently, hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl (e.g. C3-C12 carbocyclyl), or heterocyclyl (C3-C12 heterocyclyl), wherein any Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, C3-C12 carbocyclyl, C3-C12 heterocyclyl, halo, NO2, N(Rg)2, CN, C(O)N(Rg)2, S(O)N(Rg)2, S(O)2N(Rg)2, ORg, SRg, OC(O)Rg, C(O)Rg, C(O)ORg, S(O)Rg, S(O)2Rg, C(O)N(Rg)2, N(Rg)C(O)Rg, N(Rg)S(O)Rg, N(Rg)S(O)2Rg, and C -Ce alkyl, in which C3-C12 carbocyclyl and Ci-Ce alkyl are optionally substituted with A1and / or one or more groups independently selected from oxo, halo, Ci-Ce alkyl, cyano, N(R9)2, ORs, C3-C12 heterocyclyl (C3-C12 heterocyclyl), and C3-C12 carbocyclyl (C3-C12 carbocyclyl) that is optionally substituted with one or more groups independently selected from halo, and Ci-Cealkyl;

[0297] each R9 is, independently, hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cs alkoxy, carbocyclyl, or heterocyclyl, wherein each Ci-Cs alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Cs alkoxy, carbocyclyl, heterocyclyl, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg1are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0298] each Rhis, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and Ci-Cs alkyl that is optionally substituted with one or more groups independently selected from halo; and wherein and only one of R1, R2, R3, or R4comprises A1.

[0299] In some embodiments, R1is C1 C12 alkyl or 3-12 membered heterocycle.

[0300] In some embodiments, R1methyl, oxetanyl, tetrahydrofuranyl, tetra hydro pyranyl, dioxothiolanyl, cyclopropanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R1is optionally substituted with one or more groups Rb.

[0301] In some embodiments,

[0302]

[0303] In some embodiments, R1is Methyl.

[0304] In some embodiments, R1is 3-12 membered heterocycle, e.g.,

[0305]

[0306] In some embodiments, Rbis H.

[0307] In some embodiments, R2is C6-C20aryl that is optionally substituted with one or more substituent groups independently selected from Rc. PATENT

[0308] ATTORNEY DOCKET NO.: 51121-108WO2

[0309] In some embodiments, R2comprises A1.

[0310] In some embodiments,

[0311]

[0312] In some embodiments,

[0313]

[0314] In some embodiments, Rcis C1-C4alkyl that is optionally substituted with one or more groups independently selected from halo.

[0315] In some embodiments, Rcis CHF2.

[0316] In some embodiments, R3is a C1-C12 alkyl or 3-12 membered heterocycle that is optionally substituted with one or more groups Re.

[0317] In some embodiments, R2and R3taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups Re.

[0318] In some embodiments, R2and R3taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups Re; and wherein the 9- or 10-membered bicyclic heterocycle comprises at least one aromatic ring.

[0319]

[0320] PATENT

[0321] ATTORNEY DOCKET NO.: 51121-108WO2

[0322]

[0323] In some embodiments, NR2R3taken together has the structure:

[0324]

[0325]

[0326] PATENT

[0327] ATTORNEY DOCKET NO.: 51121-108WO2

[0328]

[0329] In some embodiments, Reis H.

[0330] In some embodiments, R4is C(O)Rh.

[0331] In some embodiments, R4has the structure:

[0332]

[0333] In some embodiments, Rhis methyl.

[0334] IIn some embodiments, the CBP binding moiety has the structure:

[0335]

[0336]

[0337] PATENT

[0338] ATTORNEY DOCKET NO.: 51121-108WO2

[0339] IIn some embodiments, the CBP binding moiety has the structure:

[0340]

[0341] In some embodiments, the CBP binding moiety has the structure:

[0342]

[0343] IIn some embodiments, the CBP binding moiety has the structure:

[0344]

[0345] IIn some embodiments, the CBP binding moiety has the structure:

[0346]

[0347] PATENT

[0348] ATTORNEY DOCKET NO.: 51121-108WO2

[0349] In some embodiments, the CBP binding moiety has the structure of Formula (lll-C):

[0350]

[0351] Formula III-C

[0352] wherein:

[0353] Xi is C or N;

[0354] X2 is C or N;

[0355] R5is C1-C12 alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R5is optionally substituted with one or more groups Rk1;

[0356] R6is C1-4alkyl, C6-C20aryl, C1-C20 heteroaryl, (C6-C20aryl)(C1-C20heteroaryl), (C1-C20heteroaryl)-(C6-C20aryl), and (C1-C20 heteroaryl)(C1-C20heteroaryl), C(O)N(Rh1)2, S(O)N(Rh1)2, S(O)2, C(O)Rh1, C(O)ORh1, S(O)Rh1, or S(O)2Rh1, wherein C1-C4 alkyl, Cs-C2oaryl, C1-C20 heteroaryl, (C6-C2oaryl)-(Ci-C2o heteroaryl) and (Ci-C2oheteroaryl)-(Ci-C2o heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh1)2, S(O)2N(Rh1)2, ORh1, S(O)2Rh1, OC(O)Rh1, C(O)ORh1, N(Rh1)2, N(Rh1)2, N(Rh1)C(O)N(Rh1)2, N(Rh1)S(O)2Rh1, N(Rh1)S(O)N(Rh1)2, and N(Rh1)S(O)2N(Rh1)2;

[0357] R7is C6-C2oaryl, C1-C20 heteroaryl, (C6-C2oaryl)(Ci-C2o heteroaryl), (C1-C20 heteroaryl)-(Ce-C2o aryl), and (C1-C20 hetero aryl) (C1-C20 hetero ary I), wherein each Cs-C2oaryl, C1-C20 heteroaryl, (C6-C20 aryl)(Ci -C20 heteroaryl) and (Ci-C2oheteroaryl)(Ci-C2o heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from RL1, oxo, F, Cl, Br, I, NO2, N(Ra1)2, CN, C(O)N(Ra1)2, S(O)N(Ra1)2, S(O)2N(Ra1)2, N(Ra1)C(O)Ra1, C(O)ORa1, S(O)Ra1, N(Ra1)S(O)2Ra1, N(Ra1)S(O)N(Ra1)2, and N(Ra1)S(O)2N(Ra1)2;

[0358] each Ra1is, independently, hydrogen, Ci-Cs alkyl, C2-C6 alkenyl, C2-Cealkynyl, carbocyclyl, and heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C Ce alkoxy, carbocyclyl, heterocyclyl, or C1-C6 alkyl that is optionally substituted with A1and / or one or more groups independently selected from oxo and halo; or two Ra1are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1 C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0359] each Rk1is, independently, oxo, Ci Ce alkyl, C2-C6 alkenyl, C2 Cealkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(RL1)2, CN, C(O)N(RL1)2, S(O)N(RL1)2, S(O)2N(RL1)2, ORL1, OC(O)RL1, OC(O)ORL1, C(O)ORL1, N(RL1)C(O)RL1, N(RL1)2, N(RL1)2, N(RL1)S(O)RL1, N(RL1)S(O)2RL1, N(RL1)S(O)N(RL1)2, or N(RL1)S(O)2N(RL1)2, wherein any Ci-C6alkyl, C2-C6alkenyl, C2-Cealkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or PATENT

[0360] ATTORNEY DOCKET NO.: 51121-108WO2

[0361] more groups independently selected from oxo, halo, NO2, N(RL1)2, CN, C(O)N(RL1)2, S(O)N(RL1)2, S(O)2N(RL1)2, S(O)RL1, S(O)2RL1and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0362] each RL1is, independently, hydrogen, C1-C6 alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, or heterocyclyl, wherein any Ci-Ce alkyl, C2-Ce alkenyl, C2Cealkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd1)2, CN, C(O)N(Rd1)2, S(O)N(Rd1)2, S(O)2N(Rd1)2, ORd1, SRd1, C(O)Rd1, S(O)Rd1, C(O)N(Rd1)2, N(Rd1)C(O)Rd1, N(Rd1)S(O)Rd1, N(Rd1)S(O)2Rd1, and Ci-Ce alkyl, which carbocyclyl and Ci-Ce alkyl are optionally substituted with one or more groups independently selected from oxo, halo, Ci-Ce alkyl, cyano, N(Rd1)2, ORd1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and Ci-Ce alkyl;

[0363] each Rd1is, independently, hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Cealkynyl, Ci-Ce alkoxy, carbocyclyl, or heterocyclyl, wherein each Ci-Ce alkyl, C2-Ce alkenyl, C2-Cealkynyl, Ci-Ce alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Ce alkoxy, carbocyclyl, heterocyclyl, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd1are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0364] each Rh1is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, and C2-C5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C4 alkyl that is optionally substituted with one or more groups independently selected from halo; and wherein R7comprises A1.

[0365] In some embodiments, the CBP binding moiety has the structure of Formula III-D:

[0366]

[0367] Formula III-D

[0368] wherein:

[0369] R11is C1-C12 alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each Ci-C12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R11is optionally substituted with one or more groups RM;

[0370] R12is C1-C4 alkyl, C(O)N(Rh3)2, S(O)N(Rh3)2, S(O)2N(Rh3)2, C(O)Rh3, C(O)ORh3, S(O)Rh3, or S(O)2Rh3, wherein any C1-C4alkyl is optionally substituted one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh3)2, S(O)N(Rh3)2, PATENT

[0371] ATTORNEY DOCKET NO.: 51121-108WO2

[0372] N(Rh3)C(O)Rh3, C(O)N(Rh3)2, N(Rh3)C(O)Rd3, N(Rh3)S(O)Rh3, N(Rd3)S(O)2Rh3, N(Rh3)S(O)N(Rh3)2, and N(Rh3)S(O)2N(Rh3)2;

[0373] R13is NR2R3, C6-C20aryl, C1-C20heteroaryl, (C6-C20aryl)(C1-C20heteroaryl), (C1-C20heteroaryl)(C6-C20aryl), and (C1-C20heteroaryl)(C1-C20heteroaryl), wherein each C6-C20aryl, C1-C20heteroaryl, (C6-C20aryl)(C1-C20heteroaryl) and (C1-C20heteroaryl)(C1-C20heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from RN1, oxo, F, Cl, Br, I, NO2, N(Ra3)2, CN, C(O)N(Ra3)2, S(O)N(Ra3)2, S(O)2N(Ra3)2, N(Ra3)C(O)ORa3, S(O)Ra3, N(Ra3)2, N(Ra3)S(O)N(Ra3)2, and N(Ra3)S(O)2N(Ra3)2;

[0374] R2is C6-C20aryl, C1-C20heteroaryl, (C6-C20aryl)(C1-C20heteroaryl), (C1-C20heteroaryl)(C6-C20aryl), and (C1-C20heteroaryl)(C1-C20heteroaryl), wherein each C6-C20aryl, C1-C20heteroaryl, (C6-C20aryl)(C1-C20heteroaryl) and (C1-C20heteroaryl)(C1-C20heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Rc, oxo, F, Cl, Br, I, NO2, N(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2;

[0375] R3is Ci-Ci2alkyl, C2-Ci2alkenyl, C2-Ci2alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each Ci-Ci2alkyl, C2-Ci2alkenyl, C2-Ci2alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3is optionally substituted with A1and / or one or more groups Re;

[0376] or R2and R3taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1and / or one or more groups Re;

[0377] each Rais, independently, hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, carbocyclyl, and heterocyclyl, wherein each Ci-Ce alkyl, C2-Ce alkenyl, C2-C6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci Ce alkoxy, carbocyclyl, heterocyclyl, or Ci-Ce alkyl that is optionally substituted with A1and / or one or more groups independently selected from oxo and halo; or two Raare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with A1and / or one or more groups independently selected from oxo, halo and C1 C3 alkyl that is optionally substituted with A1and / or one or more groups independently selected from oxo and halo;

[0378] each Rcis, independently, hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, carbocyclyl, or heterocyclyl, wherein any C1-C6alkyl, C2-Ce alkenyl, C2Cealkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, OC(O)Rd, C(O)Rd, C(O)ORd, S(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)C(O)Rd, N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1-C6alkyl, which carbocyclyl and C1-C6alkyl are optionally substituted with A1and / or one or more groups independently selected from oxo, halo, C1-C6alkyl, cyano, N(Rd)2, ORd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and Ci-Ce alkyl;

[0379] each Rdis, independently, hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, carbocyclyl, or heterocyclyl, wherein each Ci-Ce alkyl, C2Ce alkenyl, C2-Cealkynyl, Ci-Ce alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Ce alkoxy, carbocyclyl, heterocyclyl, and C1-C6alkyl that is PATENT

[0380] ATTORNEY DOCKET NO.: 51121-108WO2

[0381] optionally substituted with one or more groups independently selected from oxo and halo; or two Rdare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0382] each Reis, independently, oxo, C1-C6alkyl, C2-C6 alkenyl, C2-C6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, OC(O)ORf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, OC(O)N(Rf1)2, N(Rf1)C(O)ORf1, N(Rf1)C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, N(Rf1)S(O)N(Rf1)2, or N(Rf1)S(O)2N(Rf1)2, wherein any Ci-Ce alkyl, C2-C6 alkenyl, C2-Cealkynyl, carbocyciyl, heterocyciyl, aryl, and heteroaryl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, carbocycle, and C1-C6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0383] each Rf1is, independently, hydrogen, C1-C6alkyl, C2-C6 alkenyl, C2-C6alkynyl, carbocyciyl, or heterocyciyl, wherein any Ci-Ce alkyl, C2-C6 alkenyl, C2-Cealkynyl, carbocyciyl, and heterocyciyl is optionally substituted with one or more groups independently selected from oxo, carbocyciyl, heterocyciyl, halo, NO2, N(Rg1)2, CN, C(O)N(Rg1)2, S(O)N(Rg1)2, S(O)2N(Rg1)2, ORg1, SRg1, OC(O)Rg1, C(O)Rg1, C(O)ORg1, S(O)Rg1, S(O)2Rg1, C(O)N(Rg1)2, N(Rg1)C(O)Rg1, N(Rg1)S(O)Rg1, N(Rg1)S(O)2Rg1, and Ci-Ce alkyl, which carbocyciyl and Ci-Ce alkyl are optionally substituted with A1and / or one or more groups independently selected from oxo, halo, Ci-Ce alkyl, cyano, N(Rg1)2, ORg1, heterocyclyl, and carbocyclyl

[0384] that is optionally substituted with one or more groups independently selected from halo, and Ci-Ce alkyl;

[0385] each Rg1is, independently, hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Cealkynyl, Ci-Ce alkoxy, carbocyciyl, or heterocyciyl, wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-Cealkynyl, Ci-Ce alkoxy, carbocyciyl, and heterocyciyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Ce alkoxy, carbocyciyl, heterocyciyl, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg1are taken together with the nitrogen to which they are attached to form a heterocyciyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0386] each Ra3is, independently, hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-Cealkynyl, carbocyciyl, and heterocyciyl, wherein each Ci-Ce alkyl, C2-C6 alkenyl, Ce-Cealkynyl, carbocyciyl, and heterocyciyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Ce alkoxy, carbocyciyl, heterocyciyl, or Ci-Ce alkyl that is optionally substituted with A1and / or one or more groups independently selected from oxo and halo; or two Ra3are taken together with the nitrogen to which they are attached to form a heterocyciyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1 C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; PATENT

[0387] ATTORNEY DOCKET NO.: 51121-108WO2

[0388] each RMis, independently, oxo, C1-C6alkyl, C2-C6 alkenyl, C2-C6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, C(RN1OC(O)O)RN1, S N(RN1)S(O)R

[0389]

[0390] wherein any C1-C6alkyl, C2-C6 alkenyl, C2-C6alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(RN1)2, CN, C(O)N(RN1)2, S(O)N(RN1)2, S(O)2N(RN1)2, S(O)RN1, S(O)2RN1and Ci-C6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0391] each RN1is, independently, hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-Cealkynyl, carbocyclyl, or heterocyclyl, wherein any Ci-Ce alkyl, C2-C6 alkenyl, C2-Csalkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd3)2, CN, C(O)N(Rd3)2, S(O)N(Rd3)2, S(O)2N(Rd3)2, ORd3, SRd3, C(O)Rd3, S(O)2Rd3, C(O)N(Rd3)2, N(Rd3)2, N(Rd3)S(O)Rd3, N(Rd3)S(O)2Rd3, and Ci-6alkyl, which carbocyclyl and Ci-Ce alkyl are optionally substituted with one or more groups independently selected from oxo, halo, Ci-Ce alkyl, cyano, N(Rd3)2, ORd3, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and Ci-Ce alkyl;

[0392] each Rd3is, independently, hydrogen, Ci-Cs alkyl, C2-C6 alkenyl, C2-Cealkynyl, Ci-Ce alkoxy, carbocyclyl, or heterocyclyl, wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-Cealkynyl, Ci-Ce alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Ce alkoxy, carbocyclyl, heterocyclyl, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd3are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3alkyl that is optionally substituted

[0393] with one or more groups independently selected from oxo and halo;

[0394] each Rh3is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1 C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; and wherein R13comprises A1.

[0395] In some embodiments,

[0396]

[0397] In some embodiments

[0398]

[0399] PATENT

[0400] ATTORNEY DOCKET NO.: 51121-108WO2

[0401]

[0402] PATENT

[0403] ATTORNEY DOCKET NO.: 51121-108WO2

[0404]

[0405] PATENT

[0406] ATTORNEY DOCKET NO.: 51121-108WO2

[0407]

[0408] PATENT

[0409] ATTORNEY DOCKET NO.: 51121-108WO2

[0410]

[0411] PATENT

[0412] ATTORNEY DOCKET NO.: 51121-108WO2

[0413]

[0414] PATENT

[0415] ATTORNEY DOCKET NO.: 51121-108WO2

[0416]

[0417]

[0418] one or more groups Rc.

[0419] In some embodiments, R3is C1 C12 alkyl. PATENT

[0420] ATTORNEY DOCKET NO.: 51121-108WO2

[0421] IIn some embodiments, the CBP binding moiety has the structure:

[0422]

[0423] PATENT

[0424] ATTORNEY DOCKET NO.: 51121-108WO2

[0425]

[0426] PATENT

[0427] ATTORNEY DOCKET NO.: 51121-108WO2

[0428]

[0429] PATENT

[0430] ATTORNEY DOCKET NO.: 51121-108WO2

[0431]

[0432] PATENT

[0433] ATTORNEY DOCKET NO.: 51121-108WO2

[0434]

[0435] PATENT

[0436] ATTORNEY DOCKET NO.: 51121-108WO2

[0437]

[0438] PATENT

[0439] ATTORNEY DOCKET NO.: 51121-108WO2

[0440]

[0441] PATENT

[0442] ATTORNEY DOCKET NO.: 51121-108WO2

[0443]

[0444] In some embodiments, the CBP binding moiety has the structure of Formula III-E:

[0445]

[0446] Formula III-E

[0447] wherein

[0448] Y is CR4z, or N;

[0449] Z is CR4zor N; PATENT

[0450] ATTORNEY DOCKET NO.: 51121-108WO2

[0451] R1zis, independently, C1 C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C1-C9 heteroalkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with one or more groups Rzb;

[0452] R2zis, independently, C1-C12 alkyl, C2-C12 alkenyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1 C12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with one or more groups Rzb;

[0453] R3zis, independently, ORzf, NRzcRzd, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C2oaryl, C3-C12 carbocycle, C2-C9 heterocycle, C1-C20 heteroaryl, (Ce-C2oaryl)(Ci-C2o heteroaryl), (C1-C20 heteroaryl)-(Cs-C2oaryl), and (C1-C20 heteroaryl)(Ci-C2o heteroaryl), wherein each C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, Ce-C2oaryl, C3-C12 carbocycle, Cs-C2oaryl, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(Ci -C20 heteroaryl) and (Ci-C2oheteroaryl)-(Ci-C2o heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Rze, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(Rzf)2, CN, C(O)N(Rzf)2, S(O)N(Rzf)2, S(O)2N(Rzf)2, ORzf, SRzf,

[0454]

[0455] R4zis, independently, ORzf, NRzcRzd, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, Ce-C2oaryl, C3-C12 carbocycle, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C2oaryl)(Ci-C2o heteroaryl), (C1-C20 heteroaryl)-(C6-C2oaryl), and (C1-C20 heteroaryl)(Ci-C2o heteroaryl), wherein each C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, Ce-C2oaryl, C3-C12 carbocycle, C6-C2oaryl, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(Ci -C20 heteroaryl) and (Ci-C2oheteroaryl)-(Ci-C2o heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Rze, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(Rzf)2, CN, C(O)N(Rzf)2, S(O)N(Rzf)2, S(O)2N(Rzf)2, ORzf, SRzf, OC(O)Rzf, OC(O)ORzf, C(O)Rzf, C(O)ORzf, S(O)Rzf, S(O)2Rzf, OC(O)N(Rzf)2, N(Rzf)C(O)ORzf, N(Rzf)C(O)N(Rzf)2, N(Rzf)C(O)Rzf, N(Rzf)S(O)Rzf, N(Rzf)S(O)2Rzf, N(Rzf)S(O)N(Rzf)2, and N(Rzf)S(O)2N(Rzf)2;

[0456] each Rzbis, independently, C1 C12 alkyl, C2 C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1 C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with A1and / or one or more groups Rze;

[0457] Rzcis, independently, C1 C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1 C12 alkyl, C2C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with A1and / or one or more groups Re;

[0458] Rzdis, independently, C1 C12 alkyl, C2-C12 alkenyl, C2 C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with A1and / or one or more groups Rze;

[0459] or Rzcand Rzdtaken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1and / or one or more groups Rze; PATENT

[0460] ATTORNEY DOCKET NO.: 51121-108WO2

[0461] each Rzeis, independently, H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1 C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo;

[0462] each Rzfis, independently, H, C1 C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1 C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C(O)OH, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; or a pharmaceutically acceptable salt thereof.

[0463] In some embodiments, the CBP binding moiety of Formula III has the structure:

[0464]

[0465] In some embodiments, R3zis NRzcRzd.

[0466]

[0467] PATENT

[0468] ATTORNEY DOCKET NO.: 51121-108WO2

[0469]

[0470] In some embodiments, R3zis C1 C12 alkyl.

[0471] In some embodiments, R3zis methyl.

[0472] In some embodiments, R3zis C1-C9 heteroalkyl.

[0473] In some embodiments, R3zis OMe.

[0474] In some embodiments, R3zis C2-C9 heterocycle.

[0475]

[0476] PATENT

[0477] ATTORNEY DOCKET NO.: 51121-108WO2

[0478]

[0479] In some embodiments, R4zis C1 C12 alkyl.

[0480] In some embodiments, R4zis methyl.

[0481] In some embodiments, R4zis C1-C9 heteroalkyl.

[0482] In some embodiments, R4zis OMe.

[0483] In some embodiments, R4zis C2-C9 heterocycle.

[0484] In some embodiments,

[0485]

[0486] IIn some embodiments, the CBP binding moiety has the structure:

[0487]

[0488] PATENT

[0489] ATTORNEY DOCKET NO.: 51121-108WO2

[0490]

[0491] PATENT

[0492] ATTORNEY DOCKET NO.: 51121-108WO2

[0493]

[0494] PATENT

[0495] ATTORNEY DOCKET NO.: 51121-108WO2

[0496]

[0497] PATENT

[0498] ATTORNEY DOCKET NO.: 51121-108WO2

[0499]

[0500] In some embodiments, the degradation moiety (B) is a ubiquitin ligase binding moiety.

[0501] In some embodiments, the degradation moiety (B) comprises Cereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2), or von Hippel-Lindau (VHL) ligands, or derivatives or analogs thereof. PATENT

[0502] ATTORNEY DOCKET NO.: 51121-108WO2

[0503] In some embodiments, the degradation moiety is a ubiquitin iigase moiety. In some embodiments, the ubiquitin ligase binding moiety includes Cereblon iigands, IAP (Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2), hydrophobic tag, or von Hippel-Lindau ligands, or derivatives or analogs thereof.

[0504] In another aspect, the disclosure features a compound having the structure of Formula I:

[0505] A-L-B

[0506] Formula I,

[0507] or a pharmaceutically acceptable salt thereof, wherein

[0508] A is a CBP binding moiety;

[0509] B is a degradation moiety; and

[0510] L is a linker between the EP300 binding moiety and the degradation moiety having the structure of Formula lie:

[0511] A1-(F)-C-A2.

[0512] Formula He,

[0513] wherein

[0514] C is carbonyl;

[0515] F is optionally substituted C2-C9 heteroarylene;

[0516] A1is a bond between the linker and A;

[0517] A2is a bond between B and the linker;

[0518] wherein A has the structure of Formula IIIF:

[0519]

[0520] Formula IIIF,

[0521] wherein:

[0522] is C3-C12 carbocyclyl, or C2-C12 heterocyclyl, wherein the C3-C12 carbocyclyl, or C2-C12 heterocyclyl is optionally substituted one or more groups of Rb”;

[0523] R1” is C(O)OH, or carboxylic acid bioisostere;

[0524] R2afis Cs-C2oaryl, C1-C20 heteroaryl, (C6-C2oaryl)(Ci-C2o heteroaryl), (C1-C20 hetero ary I) (C6-C20 aryl), and (C1-C20 hetero aryl) (C1-C20 hetero ary I), wherein each Cs-C2oaryl, C1-C20 heteroaryl, (C6-C20 aryl)(Ci -C20 heteroaryl) and (C -C2oheteroaryl)(Ci-C2o heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Rc", oxo, F, Cl, Br, I, NO2, N(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra')2, S(O)2N(Ra')2, OR3”, SRa”, OC(O)Ra”, OC(O)ORa”, C(O)Ra”, C(O)ORa”, S(O)Ra”, S(O)2Ra”, OC(O)N(R3)2, N(R3')C(0)0Ra”, N(Ra")C(O)N(Ra')2, N(Ra”)C(O)Ra”, N(Ra)S(O)Ra”, N(Ra)S(O)2Ra”, N(Ra”)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra")2; PATENT

[0525] ATTORNEY DOCKET NO.: 51121-108WO2

[0526] R3afis C1-C12 alkyl, C2-C12 alkenyl, C2-Ci2alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-Ci2alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3afis optionally substituted with A1and / or one or more groups of Re”'; or R2afand R3afof Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1and / or one or more groups of Re”;

[0527] R4afis C1 C4 alkyl, C2-C4 alkenyl, C2-C alkynyl, C3-C5 carbocycle, C1-C5 heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2. C(O)Rh’, C(O)ORh\ S(O)Rh’, or S(O)2Rh", wherein any C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C3-C5 carbocycle, and C2-C5 heterocycle is optionally substituted with A and / or one or more substituent groups independently selected from F, Cl, Br, I, C3-C5 carbocycle, C(O)N(Rh’)2, S(O)N(Rh)2, S(O)2N(Rh')2, ORh, SRh, OC(O)Rh, OC(O)ORh, C(O)Rd, C(O)ORh, S(O)Rh”, S(O)2Rh”, OC(O)N(Rh)2, N(Rh")C(O)ORh”, N(Rh)C(O)N(Rh’)2, N(Rh”)C(O)Rh”, N(Rh)S(O)Rh”, N(Rh’)S(O)2Rh”, N(Rh)S(O)N(Rh)2, and N(Rh")S(O)2N(Rh>2;

[0528] each Ra’is, independently, hydrogen, C Cs alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl, wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyi, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Cs alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, or C1-C6 alkyl that is optionally substituted with A1and / or one or more groups independently selected from oxo and halo; or two Ra” are taken together with the nitrogen to which they are attached to form a C2-C12 heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0529] each Rb”is, independently, oxo, Ci-Ce alkyl, C2-C6 alkenyl, C2-Cealkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, Cs-Cio aryl, C1-C12 heteroaryl, F, Cl, Br, I, NO2, N(R0’)2, CN, C(O)N(R°’)2, S(O)N(R°”)2,

[0530]

[0531] N(R°’)S(O)2N(R°’)2, wherein any Ci Co alkyl, C2 C6 alkenyl, C2-Cealkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, CsCio aryl, and C2-C12 heteroaryl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, NO2, N(R°”)2, CN, C(O)N(R°”)2, S(O)N(R°”)2, S(O)2N(R°”)2, OR0”, SR° ”, OC(O)R°”, C(O)RC", S(O)R° ”, S(O)2RC”, C(O)N(R° ”)2, N(RC")C(O)RC', N(R°’)S(O)R°, N(R0”)S(O)2R0’ ”, and Ci Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0532] each R°”is, independently, hydrogen, CN, Ci-Ce alkyl, C2-C6 alkenyl, C2 Cealkynyl, C3C12 carbocyclyl, or C3-C12 heterocyclyl, wherein any Ci-Ce alkyl, C2-C6 alkenyl, C2 Cealkynyl, C3 C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd”)2, CN, C(O)N(Rd’)2, S(O)N(Rd”)2, S(O)2N(Rd”)2, ORd”, SRd”, OC(O)Rd”, C(O)Rd”, C(O)ORd”, S(O)Rd”, S(O)2Rd”, C(O)N(Rd”)2, N(Rd”)C(O)Rd’, N(Rd”)S(O)Rd’, N(Rd)S(O)2Rd”, and Ci-Ce alkyl, which C3-C12 carbocyclyl and Ci-Ce alkyl are optionally substituted with one or more groups independently selected from oxo, halo, Ci-Ce alkyl, cyano, N(Rd”)2, ORd”, C3-C12 heterocyclyl, and C3-C12 carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and CvCe alkyl; PATENT

[0533] ATTORNEY DOCKET NO.: 51121-108WO2

[0534] each Rd" is, independently, hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-Ce alkoxy, C3-C12 carbocyclyi, or C3C12 heterocyclyi, wherein each Ci-Ce alkyl, C2 C6 alkenyl, C2-Cealkynyl, Ci-Ce alkoxy, C3-C12 carbocyclyi, and C3-C12 heterocyclyi is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Ce alkoxy, C3-C12 carbocyclyi, C3-C12 heterocyclyi, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rdare taken together with the nitrogen to which they are attached to form a C2-C12 heterocyclyi that is optionally substituted with one or more groups independently selected from oxo, halo and C1 C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0535] each Re” is, independently, oxo, Ci-Ce alkyl, C2-C6 alkenyl, C2-Cealkynyl, C3-C12 carbocyclyi, C3-C12 heterocyclyi, C2-C9 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, N(Rf)2, CN, C(O)N(Rf')2, S(O)N(Rr)2, S(O)2N(Rf)2, ORf, SRf”, OC(O)Rf, OC(O)ORf”, C(O)Rf, C(O)ORf’, S(O)Rf, S(O)2Rf, OC(O)N(Rf’)2, N(Rf')C(O)ORf", N(Rf)C(O)N(Rf)2, N(Rf')C(O)Rf', N(Rf)S(O)Rf", N(Rf”)S(O)2Rf", N(Rf')S(O)N(Rf')2, or N(Rf’)S(O)2N(Rf')2, wherein any Ci-Ce alkyl, C2-C6 alkenyl, C2-Cealkynyl, C3-C12 carbocyclyi, C3-C12 heterocyclyi, C2-C9 aryl, and C2-C10 heteroaryl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, NO2, N(Rf)2, CN, C(O)N(Rf”)2, S(O)N(Rf")2, S(O)2N(Rf”)2, ORfSRf, OC(O)Rf", C(O)Rf", C(O)ORf, S(O)Rf", S(O)2Rf", C(O)N(Rf)2, N(Rf')C(O)Rf, N(Rf)S(O)Rf”, N(Rf’)S(O)2Rf”, C3-C12 carbocycle, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0536] each Rf"is, independently, hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-Cealkynyl, C3-C12 carbocyclyi, or C3-C12 heterocyclyi, wherein any Ci-Ce alkyl, C2-C6 alkenyl, C2-Cealkynyl, C3-C12 carbocyclyi, and C3-C12 heterocyclyi is optionally substituted with one or more groups independently selected from oxo, C3-C12 carbocyclyi, C3-C12 heterocyclyi, halo, NO2, N(R9”)2, CN, C(O)N(R9”)2, S(O)N(R9”)2, S(O)2N(R9”)2, ORT, SR9", OC(O)RT, C(O)R9", C(O)ORs", S(O)RT, S(O)2R9", C(O)N(R0”)2, N(R9")C(O)R9", N(Rs")S(O)R0”, N(R9’)S(O)2Rg", and Ci-Ce alkyl, which C3-C12 carbocyclyi and Ci Ce alkyl are optionally substituted with A1and / or one or more groups independently selected from oxo, halo, Ci-Ce alkyl, cyano, N(R9")2, OR9", C2-C12 heterocyclyi, and C3-C12 carbocyclyi that is optionally substituted with one or more groups independently selected from halo, and Ci-Ce alkyl;

[0537] each Rs" is, independently, hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-Cealkynyl, Ci-Ce alkoxy, C3-C12 carbocyclyi, or C3-Ci2 heterocyclyi, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 carbocyclyi, and C3-C12 heterocyclyi is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C Ce alkoxy, C3-C12 carbocyclyi, C3-C12 heterocyclyi, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R9are taken together with the nitrogen to which they are attached to form a C2-C12 heterocyclyi that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and

[0538] each Rh”is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C3-C12 heterocyclyi, or C2-C5 cycloalkyl, wherein each C1 C alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C12 heterocyclyi and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, PATENT

[0539] ATTORNEY DOCKET NO.: 51121-108WO2

[0540] hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with A1and / or one or more groups independently selected from halo; and

[0541] wherein one and only one of R2af, R3af, or R4afcomprises A1.

[0542] In an aspect, the disclosure features a compound having the structure of Formula I:

[0543] A-L-B

[0544] Formula I,

[0545] wherein

[0546] A is a CBP binding moiety;

[0547] B is a degradation moiety; and

[0548]

[0549] wherein,

[0550] A1is a bond between the linker and A; and

[0551] A2is a bond between B and the linker;

[0552] or a pharmaceutically acceptable salt thereof.

[0553] In an aspect, the disclosure features a compound having the structure of Formula I:

[0554] A-L-B

[0555] Formula I,

[0556] wherein

[0557] A is a CBP binding moiety;

[0558] B is a degradation moiety; and

[0559]

[0560] wherein,

[0561] A1is a bond between the linker and A; and

[0562] A2is a bond between B and the linker;

[0563] or a pharmaceutically acceptable salt thereof.

[0564] In an aspect, the disclosure features a compound having the structure of Formula I:

[0565] A-L-B

[0566] Formula I,

[0567] wherein

[0568] A is a CBP binding moiety;

[0569] B is a degradation moiety; and PATENT

[0570] ATTORNEY DOCKET NO.: 51121-108WO2

[0571] L has the structure

[0572]

[0573] wherein,

[0574] A1is a bond between the linker and A; and

[0575] A2is a bond between B and the linker;

[0576] or a pharmaceutically acceptable salt thereof.

[0577] In some embodiments of any aspects described herein, wherein A has the structure of Formula IMF:

[0578]

[0579] wherein:

[0580] ( C )

[0581] is C3-C12 carbocyclyl, or C2-C12 heterocyclyi, wherein the C3-C12 carbocyciyl, or C2-C12 heterocyclyl is optionally substituted one or more groups of Rb”;

[0582] R1” is C(O)OH, or carboxylic acid bioisostere;

[0583] R2afis C6-C2oaryl, C -C20 heteroaryl, (C6-C2oaryl)(Ci-C2o heteroaryl), (C1-C20 hetero ary I) (C0-C20 aryl), and (C1-C20 hetero aryl) (C1-C20 hetero ary I), wherein each C6-C2oaryl, C -C20 heteroaryl, (C6-C20 aryl)(Ci-C2o heteroaryl) and (Ci-C2oheteroaryl)(Ci-C2o heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Rc, oxo, F, Cl, Br, I, NO2,

[0584]

[0585] R3afis C1-C12 alkyl, C2-C12 alkenyl, C2-Ci2alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1 C12 alkyl, C2-C12 alkenyl, C2-Ci2alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3is optionally substituted with A1and / or one or more groups of Re”; or R2afand R3afof Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1and / or one or more groups of Re;

[0586] R4ais C1-C4 alkyl, C2-C4 alkenyl, C2-C alkynyl, C3-C5 carbocycle, C1-C5 heterocycle, C(O)N(Rh')2, S(O)N(Rh)2, S(O)2N(Rh')2. C(O)Rh”, C(O)OR ", S(O)Rh”, or S(O)2Rh", wherein any C1-C4 alkyl, C2-C4 alkenyl, C2-C alkynyl, C3-C5 carbocycle, and C2-C5 heterocycle is optionally substituted with A and / or one or more substituent groups independently selected from F, Cl, Br, I, C3-C5 carbocycle, C(O)N(Rh’)2, S(O)N(Rh)2, S(O)2N(Rh')2, ORh, SRh, OC(O)Rh”, OC(O)ORh, C(O)Rb, C(O)ORh, S(O)Rh”, S(O)2Rh”, PATENT

[0587] ATTORNEY DOCKET NO.: 51121-108WO2

[0588] OC(O)N(Rh)2, N(Rh”)C(O)ORh”, N(Rh”)C(O)N(Rh’)2, N(Rd’)C(O)Rh’, N(Rh')S(O)Rh’, N(Rh')S(O)2Rh', N(Rh')S(O)N(Rh')2, and N(Rh”)S(O)2N(Rd”)2;

[0589] each Ra’is, independently, hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, 02-Cealkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl, wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Cs alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, or C1-C0 alkyl that is optionally substituted with A1and / or one or more groups independently selected from oxo and halo; or two Ra” are taken together with the nitrogen to which they are attached to form a C2-C12 heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0590] each Rb’is, independently, oxo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-Cio aryl, C1-C12 heteroaryl, F, Cl, Br, I, NO2, N(R°’)2, CN, C(O)N(R° )2, S(O)N(R°”)2,

[0591]

[0592] N(R° )S(O)2N(R° )2, wherein any Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, Cs-Cio aryl, and C2-C12 heteroaryl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, NO2, N(R° ”)2, CN, C(O)N(R°”)2, S(O)N(R°’)2, S(O)2N(R° ”)2, OR0", SR° ", OC(O)R°", C(O)R°", S(O)R°", S(O)2R°’, C(O)N(R° ”)2, N(R°")C(O)R°', N(R°")S(O)R°", N(R0”)S(O)2R°”, and Ci-Cs alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0593] each R°’is, independently, hydrogen, CN, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd”)2, CN, C(O)N(Rd’)2, S(O)N(Rd”)2, S(O)2N(Rd”)2, ORd”, SRd”, OC(O)Rd”, C(O)Rd”, C(O)ORd”, S(O)Rd”, S(O)2Rd”, C(O)N(Rd”)2, N(Rd")C(O)Rd", N(Rd”)S(O)Rd”, N(Rd’)S(O)2Rd”, and Ci Ce alkyl, which C3-C12 carbocyclyl and Ci Ce alkyl are optionally substituted with one or more groups independently selected from oxo, halo, Ci Ce alkyl, cyano, N(Rd”)2, ORd”, C3-C12 heterocyclyl, and C3-C12 carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and Ci Ce alkyl;

[0594] each Rd" is, independently, hydrogen, Ci Ce alkyl, C2-C6 alkenyl, C2 Cealkynyl, Ci-Ce alkoxy, C3C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2Cealkynyl, Ci Ce alkoxy, C3 C12 carbocyclyl, and C3 C12 heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci Ce alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rdare taken together with the nitrogen to which they are attached to form a C2-C12 heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0595] each Re” is, independently, oxo, Ci Ce alkyl, C2-C6 alkenyl, C2-Cealkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, N(Rf”)2, CN, C(O)N(Rf')2, S(O)N(Rf” )2, PATENT

[0596] ATTORNEY DOCKET NO.: 51121-108WO2

[0597] S(O)2N(Rf”)2, ORf”, SRf, OC(O)Rf", OC(O)ORf, C(O)Rf”, C(O)ORf”, S(O)Rf, S(O)2Rf, OC(O)N(Rf”)2, N(Rf)C(O)ORf, N(Rf”)C(O)N(Rf')2, N(Rf")C(O)Rf”, N(Rf)S(O)Rf, N(Rf')S(O)2Rf”, N(Rf)S(O)N(Rf")2, or N(Rf")S(O)2N(Rf”)2, wherein any C1 C0 alkyl, C2Ce alkenyl, C2-C6alkynyl, Cs-Ci2carbocyclyl, C3-Ci2heterocyclyl, C2-Cg aryl, and C2-Cio heteroaryl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf")2, S(O)2N(Rf")2, OR', SRf", OC(O)Rf", C(O)Rf”, C(O)ORf, S(O)Rf", S(O)2Rf”, C(O)N(Rf)2, N(Rf")C(O)Rf”, N(Rf)S(O)Rf”, N(Rf”)S(O)2Rf”, C3-Ci2carbocycle, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0598] each Rf"is, independently, hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-C6alkynyl, C3-Ci2carbocyclyl, or C3-Ci2heterocyclyl, wherein any Ci-Ce alkyl, C2-Ce alkenyl, Cg-Cealkynyi, C3-Ci2carbocyclyl, and C3-Ci2heterocyclyl is optionally substituted with one or more groups independently selected from oxo, C3-Ci2carbocyclyl, C3-Ci2heterocyclyl, halo, NO2, N(Rs")2, CN, C(O)N(Rs')2, S(O)N(Rs ")2, S(O)2N(Rs')2, ORT, SR8”, OC(O)R9”, C(O)R9", C(O)OR9", S(O)R9”, S(O)2R8", C(O)N(R9")2, N(R9”)C(O)R8", N(R9”)S(O)R9", N(R9 )S(O)2R9 ", and Ci-Ce alkyl, which C3-Ci2carbocyclyl and Ci-Ce alkyl are optionally substituted with A1and / or one or more groups independently selected from oxo, halo, Ci-Ce alkyl, cyano, N(R9")2, ORa", C2-Ci2heterocyclyl, and C3-C1? carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and Ci-Ce alkyl;

[0599] each Rs” is, independently, hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Cealkynyl, Ci-Ce alkoxy, Cs-Ci2carbocyclyl, or Cs-Ci2heterocyclyl, wherein each Ci-Ce alkyl, C2-Ce alkenyl, C2-Cealkynyl, Ci-Ce alkoxy, C3-Ci2carbocyclyl, and Cs-Ci2heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Ce alkoxy, Cs-Ci2carbocyclyl, Cs-Ci2heterocyclyl, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg”are taken together with the nitrogen to which they are attached to form a C2Ci2heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and

[0600] each Rh"is, independently, hydrogen, C1-C4 alkyl, C2C4 alkenyl, C2-C4alkynyl, C3-Ci2heterocyclyl, or C2-Cs cycloalkyl, wherein each C1 C4 alkyl, C2-C4 alkenyl, C2C4alkynyl, C3-Ci2heterocyclyl and C2-Cs cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1 C3 alkoxy, and C1-C3 alkyl that is optionally substituted with A1and / or one or more groups independently selected from halo; and

[0601] wherein one and only one of R2af, R3af, or R4a?comprises A1.

[0602] In some embodiments, the CBP binding moiety having the structure of Formula IDA has the structure of Formula IIIF2: PATENT

[0603] ATTORNEY DOCKET NO.: 51121-108WO2

[0604]

[0605] Formula IIIF2,

[0606] or a pharmaceutically acceptable salt thereof, wherein

[0607] n is 0, 1, or 2,

[0608] m is 0, 1, or 2,

[0609] o is 0, 1, or 2, and

[0610] R1’ is C(O)OH, or carboxylic acid bioisostere.

[0611] In some embodiments, the CBP binding moiety having the structure of Formula IIIF3 has the structure of Formula III F3:

[0612]

[0613] Formula IIIF3.

[0614] or a pharmaceutically acceptable salt thereof.

[0615]

[0616] PATENT

[0617] ATTORNEY DOCKET NO.: 51121-108WO2

[0618]

[0619] PATENT

[0620] ATTORNEY DOCKET NO.: 51121-108WO2

[0621]

[0622] PATENT

[0623] ATTORNEY DOCKET NO.: 51121-108WO2

[0624]

[0625] In some embodiments, the carboxylic acid bioisostere is Ci heteroaryl, C2 heteroaryl, C3 heteroaryl, C3heterocycle, C4heterocycle, C(O)N(RC')2, C(O)N(RC')OH, N(R°’’)S(O)2RC’, N(RC- )C(O)N(R°”)2, S(O)2RC’, or P(O)2RC”. PATENT

[0626] ATTORNEY DOCKET NO.: 51121-108WO2

[0627] IIn some embodiments, the CBP binding moiety has the structure:

[0628]

[0629] PATENT

[0630] ATTORNEY DOCKET NO.: 51121-108WO2

[0631]

[0632] PATENT

[0633] ATTORNEY DOCKET NO.: 51121-108WO2

[0634]

[0635]

[0636] , PATENT

[0637] ATTORNEY DOCKET NO.: 51121-108WO2

[0638]

[0639] PATENT

[0640] ATTORNEY DOCKET NO.: 51121-108WO2

[0641]

[0642] PATENT

[0643] ATTORNEY DOCKET NO.: 51121-108WO2

[0644]

[0645] PATENT

[0646] ATTORNEY DOCKET NO.: 51121-108WO2

[0647] IIn some embodiments, the CBP binding moiety has the structure:

[0648]

[0649]

[0650] PATENT

[0651] ATTORNEY DOCKET NO.: 51121-108WO2

[0652]

[0653] PATENT

[0654] ATTORNEY DOCKET NO.: 51121-108WO2

[0655]

[0656] PATENT

[0657] ATTORNEY DOCKET NO.: 51121-108WO2

[0658]

[0659] PATENT

[0660] ATTORNEY DOCKET NO.: 51121-108WO2

[0661]

[0662] PATENT

[0663] ATTORNEY DOCKET NO.: 51121-108WO2

[0664]

[0665] PATENT

[0666] ATTORNEY DOCKET NO.: 51121-108WO2

[0667]

[0668]

[0669] PATENT

[0670] ATTORNEY DOCKET NO.: 51121-108WO2

[0671]

[0672] PATENT

[0673] ATTORNEY DOCKET NO.: 51121-108WO2

[0674]

[0675] PATENT

[0676] ATTORNEY DOCKET NO.: 51121-108WO2

[0677]

[0678] PATENT

[0679] ATTORNEY DOCKET NO.: 51121-108WO2

[0680]

[0681] In some embodiments, C is carbonyl. PATENT

[0682] ATTORNEY DOCKET NO.: 51121-108WO2

[0683]

[0684] In some embodiments, the structure of Formula

[0685]

[0686] In some embodiments, the CBP binding moiety has the structure of Formula IIIG:

[0687]

[0688] Formula IIIG

[0689] wherein:

[0690] R1g’ is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, or C2-Ci2 heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycie, and C2-C12 heterocycle of R1is optionally substituted with one or more groups of Rb;

[0691] R4g’is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, C2-C5 heterocycle, C(O)N(Rh')2, S(O)N(Rh)2, S(O)2N(Rb)2, C(O)Rh, C(O)ORb’, S(O)Rh, or S(O)2Rh’, wherein any C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, and C2-C5 heterocycle is optionally substituted with one or more substituent groups independently selected from F, Ci, Br, I, C3-C5 carbocycle, C(O)N(R ’)2, S(O)N(Rh’)2,

[0692]

[0693] N(R0’)S(O)2N(RC')2, wherein any Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, Ce-Cio aryl, and C2-C12 heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(RC’)2, CN, C(O)N(RC’)2, S(O)N(R°’)2, S(O)2N(RC)2, ORC’, SRC’, OC(O)R°, C(O)RC’, S(O)RC’, S(O)2R°’, C(O)N(Rc')2, N(Rc’)C(O)Rc’, N(RC')S(O)RC’, N(RC')S(O)2RC’ and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0694] each Rc' is, independently, hydrogen, C1-C6alkyl, C2-C6 alkenyl, C2 C6 alkynyl, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein any Ci-Ce alkyl, C2 C6 alkenyl, C2-C6 alkynyl, C3 C12 carbocyclyl, and C3 C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd’)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd’, SRd, PATENT

[0695] ATTORNEY DOCKET NO.: 51121-108WO2

[0696] OC(O)Rd, C(O)Rd, C(O)ORd, S(O)Rd, S(O)2Rd, C(O)N(Rd')2, N(Rd')C(O)R'd, N(Rd)S(O)Rd, N(Rd')S(O)2Rdand Ci-Ce alkyl, which C3-C12 carbocyclyl and Ci-Ce alkyl are optionally substituted with one or more groups independently selected from oxo, halo, Ci-Ce alkyl, cyano, N(Rd')2, ORd, C3-Ci2heterocyclyl, and C3-C12 carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and Ci-Ce alkyl;

[0697] each Rdis, independently, hydrogen, C1-C6 alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-Ci2heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, Ci-Ce alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rdare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0698] each Rhis, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo;

[0699]

[0700] R14®’ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, C1-C3 alkoxy, or CN; and

[0701] RN2is C1-C3 alkyl or H.

[0702] In some embodiments, R1®’ is Methyl.

[0703] In some embodiments,

[0704]

[0705] In some embodiments, R1gis 3-12 membered heterocycle, e.g.,

[0706]

[0707] In some embodiments, R4g' is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazolyl or isoxazolyl.

[0708] In some embodiments, R4g' has the structure:

[0709] In some embodime

[0710]

[0711] PATENT

[0712] ATTORNEY DOCKET NO.: 51121-108WO2

[0713]

[0714] In some embodiments, R14gis optionally substituted C1-C3 alkyl.

[0715] In some embodiments, R14gis CHF2, CF3, CHCl2, CH3.

[0716] In some embodiments, R14gis optionally substituted C1-C3 alkoxy.

[0717] In some embodiments, R14gis OCH3.

[0718] In some embodiments, R14g’is halo.

[0719] In some embodiments, R14g’is F or Cl.

[0720] In some embodiments, R14g’is CN.

[0721] In some embodiments, RN2is H.

[0722] In some embodiments, RN2is C1-C3 alkyl.

[0723] In some embodiments, C1-C3 alkyl is methyl.

[0724] In some embodiments, the degradation moiety is a ubiquitin ligase binding moiety.

[0725] IIn some embodiments, the CBP binding moiety has the structure:

[0726]

[0727] PATENT

[0728] ATTORNEY DOCKET NO.: 51121-108WO2

[0729]

[0730] PATENT

[0731] ATTORNEY DOCKET NO.: 51121-108WO2

[0732]

[0733] PATENT

[0734] ATTORNEY DOCKET NO.: 51121-108WO2

[0735]

[0736] PATENT

[0737] ATTORNEY DOCKET NO.: 51121-108WO2

[0738]

[0739] PATENT

[0740] ATTORNEY DOCKET NO.: 51121-108WO2

[0741]

[0742] In some embodiments, the ubiquitin ligase binding moiety has the structure of Formula A:

[0743]

[0744] wherein

[0745] X1ais CH2, O, S, or NR1y, PATENT

[0746] ATTORNEY DOCKET NO.: 51121-108WO2

[0747] R1yis H, optionally substituted Ci-Cs alkyl, or optionally substituted C1-C8 heteroalkyl;

[0748] R4y

[0749]

[0750] X2ais C=O, CH2, or -" w ; R3yand R4yare, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted Ci-Ce heteroalkyl; m is 0, 1, 2, 3, or 4; and

[0751] each R2yis, independently, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C1-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio ary I, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino, or a pharmaceutically acceptable salt thereof.

[0752] In some embodiments, the ubiquitin ligase binding moiety has the structure:

[0753]

[0754] or is a derivative or an analog thereof, or a pharmaceutically acceptable salt thereof.

[0755] In some embodiments, the degradation moiety (B) comprises the structure of Formula V:

[0756]

[0757] Formula V,

[0758] wherein

[0759] RB1ais H, A2, C(O)A2, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;

[0760] RB2ais A2, -C(O)-A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl wherein alkyl, heteroalkyl, carbocyclyl or aryl is optionally substituted with A2and / or one or more groups RJ2;

[0761] RB3ais, independently, A2, C(O)A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl;

[0762] RB4ais, independently, H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl;

[0763] RB5ais, independently, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;

[0764] RB6ais H, C1 C12 alkyl, C2-C12 alkenyl, C2 C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1 C12 alkyl, C212 alkenyl, C2-C12 alkynyl, 3-12 membered PATENT

[0765] ATTORNEY DOCKET NO.: 51121-108WO2

[0766] carbocycle, and 3-12 membered heterocycle of RB5ais optionally substituted with A2and / or one or more groups Re; or

[0767] RB5and RB6ataken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A2and / or one or more groups Re;

[0768] each Reis, independently, oxo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, NH2, or CN, wherein any Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, and C2-C10 heteroaryl is optionally substituted with A2and / or one or more groups independently selected from oxo, halo, NO2, NH2, CN, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0769] each RJ2is, independently, hydrogen, Ci-Cs alkyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl, wherein each Ci-Cs alkyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from halo, amino, hydroxyl, Ci-Ce alkoxy, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, or Ci-Ce alkyl that is optionally substituted with A2and / or one or more groups independently selected from oxo and halo; and

[0770] wherein one and only one of RB1a, RB2a, RB3a, RB5a, and RJ2is A2or C(O)A2.

[0771] In some embodiments, the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-A):

[0772]

[0773] Formula V-A,

[0774] wherein

[0775] RB1ais H, A2, C(O)A2, optionally substituted C1-C0 alkyl, or optionally substituted C1-C0 heteroalkyl;

[0776] RB2ais A2, -C(O)-A2, optionally substituted Ci-Cs alkyl, optionally substituted Ci-Cs heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Cs-C o aryl wherein alkyl, heteroalkyl, carbocyclyl or aryl is optionally substituted with A2and / or one or more groups RJ2;

[0777] RB3ais, independently, A2, C(O)A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroaikyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl;

[0778] RB4ais, independently, H, optionally substituted C1-C0 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl;

[0779] RB5ais, independently, H, optionally substituted C1-C0 alkyl, or optionally substituted Ci-Ce heteroaikyl;

[0780] RBSais H, Ci~Ci2alkyl, C2-Ci2alkenyl, C2-Ci2alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered PATENT

[0781] ATTORNEY DOCKET NO.: 51121-108WO2

[0782] carbocycle, and 3-12 membered heterocycle of RB5ais optionally substituted with A2and / or one or more groups Re; or

[0783] RB5and RB6ataken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A2and / or one or more groups Re;

[0784] each Reis, independently, oxo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, NH2, or CN, wherein any CvCealkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, and C2-C10 heteroaryl is optionally substituted with A2and / or one or more groups independently selected from oxo, halo, NO2, NH2, CN, and Ci-Ce alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0785] each RJ2is, independently, hydrogen, Ci-Csalkyi, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl, wherein each alkyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from halo, amino, hydroxyl, C Cs alkoxy, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, or Ci-Ce alkyl that is optionally substituted with A2and / or one or more groups independently selected from oxo and halo; and

[0786] wherein one and only one of RB1a, RB2a, RB3a, RB5a, and RJ2is A2or C(O)A2.

[0787] In some embodiments, the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-B):

[0788]

[0789] Formula V-B,

[0790] wherein

[0791] RB1ais H, A2, C(O)A2, optionally substituted C1-C0 alkyl, or optionally substituted C1-C0 heteroalkyl;

[0792] RB2ais A2, -C(O)-A2, optionally substituted Ci-Cs alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Cs-C o aryl wherein alkyl, heteroalkyl, carbocyclyl or aryl is optionally substituted with A2and / or one or more groups RJ2;

[0793] RB3ais, independently, A2, C(O)A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroaikyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl;

[0794] RB4ais, independently, H, optionally substituted C1-C0 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl;

[0795] RB5ais, independently, H, optionally substituted C1-C0 alkyl, or optionally substituted Ci-Ce heteroaikyl;

[0796] RBSais H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered PATENT

[0797] ATTORNEY DOCKET NO.: 51121-108WO2

[0798] carbocycle, and 3-12 membered heterocycle of RB5ais optionally substituted with A2and / or one or more groups Re; or

[0799] RB5and RB6ataken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A2and / or one or more groups Re;

[0800] each Reis, independently, oxo, Ci-Cs alkyl, C2-C6 alkenyl, C2-Csalkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, NH2, or CN, wherein any Ci-Cs alkyl, C2-C6 alkenyl, C2-Csalkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, and C2-C10 heteroaryl is optionally substituted with A2and / or one or more groups independently selected from oxo, halo, NO2, NH2, CN, and Ci-Cs alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

[0801] each RJ2is, independently, hydrogen, Ci-Cs alkyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl, wherein each Ci-Cs alkyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from halo, amino, hydroxyl, Ci-Cs alkoxy, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, or Ci-Cs alkyl that is optionally substituted with A2and / or one or more groups independently selected from oxo and halo; and

[0802]

[0803] wherein each RB6is, independently, halogen, optionally substituted Ci-Cs alkyl, optionally substituted Ci-Cs heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C0 heteroalkenyl, optionally substituted C2-C6 alkynyl, hydroxy, thiol;

[0804] RBSis, independently, H, or optionally substituted C -Cs alkyl;

[0805] RB10is, independently, H, or optionally substituted Ci-Cs alkyl, and

[0806] v2 is 0, 1, 2, 3, or 4.

[0807] In some embodiments,

[0808]

[0809] In some embodiments,

[0810]

[0811] In some embodiments,

[0812]

[0813] PATENT

[0814] ATTORNEY DOCKET NO.: 51121-108WO2

[0815]

[0816] In some embodiments,

[0817]

[0818] In some

[0819]

[0820] In some

[0821]

[0822] wherein

[0823] each RB6is, independently, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci- Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio ary I, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, hydroxy, thiol; PATENT

[0824] ATTORNEY DOCKET NO.: 51121-108WO2

[0825] R311is optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C o aryl, optionally substituted C2-C9 heteroaryl;

[0826] R3Sis, independently, H, or optionally substituted C -Cs alkyl;

[0827] R310is, independently, H, or optionally substituted Ci-Ce alkyi, and

[0828] v2 is 0, 1, 2, 3, or 4.

[0829] In some embodiments,

[0830]

[0831] In some embodiments,

[0832]

[0833] In some

[0834]

[0835] In some

[0836]

[0837] In some

[0838]

[0839] In some

[0840]

[0841] In some

[0842]

[0843] wherein v2 is 0, 1, 2, 3, or 4;

[0844] each R36is, independently, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci- Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, PATENT

[0845] ATTORNEY DOCKET NO.: 51121-108WO2

[0846] optionally substituted Ce-C o aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino;

[0847] each of R37and R38is, independently, H, halogen, optionally substituted Ci-Ce alkyi, or optionally substituted C6-C10 aryl; and

[0848] R39and R3 0are, independently, H, or optionally substituted Ci-Ce alkyl.

[0849] In some embodiments,

[0850]

[0851] wherein v2 is 0, 1, 2, 3, or 4;

[0852] each R36is, independently, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C1- Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino;

[0853] each of R37and R38is, independently, H, halogen, optionally substituted C1-C0 alkyl, or optionally substituted C6-C10 aryl; and

[0854] R3Sand R310are, independently, H, or optionally substituted Ci-Ce alkyl.

[0855] In some embodiments, R36ais.

[0856]

[0857] In some embodiments, the degradation moiety of formula V has the structure:

[0858]

[0859] PATENT

[0860] ATTORNEY DOCKET NO.: 51121-108WO2

[0861]

[0862] PATENT

[0863] ATTORNEY DOCKET NO.: 51121-108WO2

[0864]

[0865] derivative or analog thereof.

[0866] In some embodiments, the degradation moiety (B) comprises the structure of Formula IVab:

[0867]

[0868] wherein

[0869] Xaa is CH, CRB6, or N;

[0870] RB1aa is H, A2, C(O)-A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C o aryl, wherein the alkyl, heteroalkyl, carbocyclyi, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl;

[0871] c(O)-A2, optionally substituted C1-C0 alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C o aryl, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl;

[0872] RB4aa is H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl;

[0873] R34aa’is H, halo, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl; R35aais H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;

[0874] 2 is 0, 1, 2, 3, or 4;

[0875] each R36aais, independently, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, optionally substituted C2-C9 heteroaryl, optionally substituted Co-Ce alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, hydroxy, thiol; and R39aais H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, or A2; wherein one and only one of R31aa, RB3aa, or R39aacomprises A2or C(O)-A2,

[0876] or a pharmaceutically acceptable salt thereof. PATENT

[0877] ATTORNEY DOCKET NO.: 51121-108WO2

[0878] In some embodiments, the structure of Formula IVab is:

[0879]

[0880] In some embodiments, RB6aais optionally substituted C2-C9 heteroaryl.

[0881]

[0882] In some embodiments, the structure of Formula IVab is

[0883]

[0884] thereof.

[0885] In some embodiments, the structure of Formula IVab is

[0886]

[0887] PATENT

[0888] ATTORNEY DOCKET NO.: 51121-108WO2

[0889] In some embodiments, the structure of Formula IVab is

[0890]

[0891] derivative or analog thereof.

[0892] In some embodiments, the structure of Formula IVab is

[0893]

[0894] In some embodiments, the degradation moiety comprises the structure of Formula IVac:

[0895]

[0896] Formula IVac.

[0897] wherein

[0898] Xbc is CH, CR113, or N;

[0899] Xcc is CH, CR11a, or N;

[0900] Xdc is CH, CR113, or N;

[0901] Xec is CH, CR113, or N;

[0902] optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Cs heteroalkyl; RB2ac is H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;

[0903] RB3ac is H, A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Cs heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C10 heterocyclyl, optionally substituted Ce-C-io aryl wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl;

[0904] RBS’ac jsH; or RB3aoand RB3’acof Formula IVac taken together with the carbon to which they are attached form an optionally substituted 3-12 membered carbocycle or 3-12 membered heterocycle; PATENT

[0905] ATTORNEY DOCKET NO.: 51121-108WO2

[0906] RB4a° |S|_| optionally substituted Ci-Ce alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl;

[0907] RB4acis H ha|0optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl; RB5ac isR optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl; v2ac is 0, 1, 2, 3, or 4;

[0908] each RB6acis, independently, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C o aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and

[0909] RB9a°ancj RBioaca|-eindependently, H, optionally substituted Ci-Ce aikyl, optionally substituted Ci-Ce heteroalkyl, or A2, or RB9acand RB10acof Formula I Vac taken together with the carbon to which they are attached form an optionaliy substituted 3-12 membered carbocycie;

[0910] each R11aois independently, H, or halo;

[0911] wherein one and only one of RB1acRB3ac, BSSCorBioac comprises A2,

[0912] or a pharmaceutically acceptable salt thereof.

[0913] In some embodiments, Xbc is CH, Xcc is CH, and Xdc is CH, and Xec is CH.

[0914] In some embodiments, Xbc is CH, Xcc is N, and Xdc is CH, and Xec is CH.

[0915] In some embodiments, Xbc is N, and Xcc is N, Xdc is CH, and Xec is CH.

[0916] In some embodiments, Xbc is CH, and Xcc is CH, Xdc is CH, and Xec is CH.

[0917] In some embodiments, Xbc is N, and Xcc is CH, Xdc is CH, and Xec is CH.

[0918] In some embodiments, Xbc is CH, Xcc is N, Xdc is CH, and Xec is N.

[0919] In some embodiments, Xbc is CH, Xcc is N, Xdc is N, and Xec is CH.

[0920] In some embodiments, Xbc is CH, Xcc is CH, and Xdc is CH, and Xec is CR11ac.

[0921] In some embodiments, Xbc is CH, Xcc is CH, and Xdc is CH, and Xec is CF.

[0922] In some embodiments, RB1acis A2.

[0923] In some embodiments, RB3acis optionally substituted Ci-Ce alkyl.

[0924]

[0925] In some embodiments, RB3acis optionally substituted C2-C10 heterocyclyl.

[0926] In some embodiments,

[0927]

[0928] PATENT

[0929] ATTORNEY DOCKET NO.: 51121-108WO2

[0930] In some embodiments, RB3acand RB3acof Formula IVac taken together with the carbon to which they are attached form an optionally substituted 3-12 membered carbocycle or optionally substituted 3-12 membered heterocycle.

[0931] In some embodiments, RB3acand RB3acof Formula IVac taken together with the carbon to which

[0932] they are attached form

[0933] In some embod

[0934]

[0935] ,

[0936] In some embodiments, RB4’acis H.

[0937] In some embodiments, RB4 acis F.

[0938] In some embodiments, RB9acis optionally substituted Ci-Ce alkyl.

[0939] In some embodiments,

[0940]

[0941] In some embodiments, RB9acis optionally substituted Ci-Ce heteroalkyl.

[0942] In some embodiments,

[0943]

[0944] In some embodiments, RB9acand RB10aoof Formula IVac taken together with the carbon to which they are attached form an optionally substituted 3-12 membered carbocycle.

[0945] In some embodiments, RB9acand RB10aoof Formula IVac taken together with the carbon to which

[0946]

[0947] In some embodiments, RBSacis optionally substituted C2-C9 heteroaryl.

[0948]

[0949] PATENT

[0950] ATTORNEY DOCKET NO.: 51121-108WO2

[0951]

[0952] PATENT

[0953] ATTORNEY DOCKET NO.: 51121-108WO2

[0954]

[0955] PATENT

[0956] ATTORNEY DOCKET NO.: 51121-108WO2

[0957]

[0958] PATENT

[0959] ATTORNEY DOCKET NO.: 51121-108WO2

[0960]

[0961] PATENT

[0962] ATTORNEY DOCKET NO.: 51121-108WO2

[0963]

[0964] PATENT

[0965] ATTORNEY DOCKET NO.: 51121-108WO2

[0966]

[0967] derivative or analog thereof.

[0968] In some embodiments, the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-C):

[0969]

[0970] Formula V-C,

[0971] wherein PATENT

[0972] ATTORNEY DOCKET NO.: 51121-108WO2

[0973] RB1is H, A2, -C(O)-A2, optionally substituted Ci-e alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C o aryl, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C-M alkyl;

[0974] R33is A2, -C(O)-A2, optionally substituted Ci-e alkyl, optionally substituted C -e heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C o aryl, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C-M alkyl;

[0975] R34is, independently, H, optionally substituted C1-C0 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-Cio aryl, optionally substituted C -Ce alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ci-Ce alkyl, or optionally substituted C6-C10 aryl;

[0976] R35is, independently, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;

[0977] v2 is, independently, 0, 1, 2, 3, or 4;

[0978] each RB6is, independently, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino;

[0979] R39is, independently, H, A2, or optionally substituted Ci-Ce alkyl; and

[0980] each RJ2is, independently, hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 carbocyclyl, and optionally substituted C3-C12 heterocyclyl, wherein each Ci-Ce alkyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from amino, hydroxyl, thiol, Ci-Ce alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, or Ci-Ce alkyl that is optionally substituted with A2and / or one or more groups independently selected from oxo and halo; and

[0981] wherein one of RB1, R33and R39is A2or C(O)A2,

[0982] or a pharmaceutically acceptable salt thereof.

[0983] In some embodiments, R39is H.

[0984] In some embodiments, R39is optionally substituted Ci-Ce alkyl.

[0985] In some embodiments, RBSis methyl.

[0986] In some embodiments, RB4is H.

[0987] In some embodiments, R35is H.

[0988] In some embodiments, RB1is A2.

[0989] In some embodiments, RB1is C(O)A2.

[0990] In some embodiments, RB3is optionally substituted Ci-Ce alkyl.

[0991]

[0992] In some embodiments, R36is optionally substituted C2-C9 heteroaryl. PATENT

[0993] ATTORNEY DOCKET NO.: 51121-108WO2

[0994]

[0995] In some embodiments, the degradation moiety (B) has the structure:

[0996]

[0997] PATENT

[0998] ATTORNEY DOCKET NO.: 51121-108WO2

[0999]

[1000]

[1001] derivative or analog thereof.

[1002] In some embodiments, RB6is halogen or optionally substituted C2-C6 alkynyl.

[1003] In some embodiments, RB6is optionally substituted O-Cs heteroalkyl.

[1004] In some embodiments, optionally substituted Ci-Ce heteroalkyl is methoxy.

[1005] In some embodiments, the degradation moiety (B) has the structure:

[1006] Formula

[1007]

[1008] PATENT

[1009] ATTORNEY DOCKET NO.: 51121-108WO2

[1010]

[1011] Formula V-D,

[1012] wherein

[1013] R31is H, A2, -C(O)-A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl;

[1014] R32is, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[1015] R33is A2, -C(O)-A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl;

[1016] R34is, independently, H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-Cio aryl, optionally substituted Ci-Ce alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ci-Ce alkyl, or optionally substituted C6-C10 aryl;

[1017] R35is, independently, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;

[1018] v2 is, independently, 0, 1, 2, 3, or 4;

[1019] each RB6is, independently, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and each of R37and R38is, independently, H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C10 aryl,

[1020] each RJ2is, independently, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 carbocyclyl, and optionally substituted C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from amino, hydroxyl, thiol, C1-C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, or C1-C6 alkyl that is optionally substituted with A2and / or one or more groups independently selected from oxo and halo; and

[1021] RB9and RB10are, independently, H, or optionally substituted C1-C6 alkyl,

[1022] wherein one of RB1and R33is A2,

[1023] or a pharmaceutically acceptable salt thereof.

[1024] In some embodiments, RB1is H.

[1025] In some embodiments, RB1is A2. PATENT

[1026] ATTORNEY DOCKET NO.: 51121-108WO2

[1027] In some embodiments, RB2is H.

[1028] In some embodiments,

[1029]

[1030] In some embodiments,

[1031]

[1032] In some embodiments, RB4is H.

[1033] In some embodiments, RB5is H.

[1034] In some embodiments, RB6is H.

[1035] In some embodiments, RB7is H, or optionally substituted Ci-Ce alkyl. In some embodiments, RB7is methyl.

[1036] In some embodiments, RB8is H.

[1037] In some embodiments, RB9is H, or optionally substituted Ci-Ce alkyl. In some embodiments, RB9is H.

[1038] In some embodiments, RB9is methyl.

[1039] In some embodiments, RB10is H, or optionally substituted C1-C6 alkyl. In some embodiments, RB10is H.

[1040] In some embodiments, RB10is methyl.

[1041] In some embodiments, the degradation moiety (B) has the structure:

[1042]

[1043] PATENT

[1044] ATTORNEY DOCKET NO.: 51121-108WO2

[1045]

[1046] In some embodiments, the degradation moiety has the structure:

[1047]

[1048] In some embodiments, the degradation moiety comprises the structure of Formula V-E:

[1049]

[1050] Formula V-E

[1051] RC1is, independently, optionally substituted Ci-Cs alkyl;

[1052] RC2is, independently, A2, or optionally substituted Ci-Ce alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C io aryl, or optionally substituted C2-C9 heteroaryl, that is substituted with A2and / or one or more groups RJ;

[1053] RC3is, independently, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; PATENT

[1054] ATTORNEY DOCKET NO.: 51121-108WO2

[1055] RC4is, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;

[1056] v2 is, independently, 0, 1, 2, 3, or 4;

[1057] each of RC5and RC6is, independently, H, or optionally substituted Ci-Ce alkyl;

[1058] each RC7is, independently, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C -Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino;

[1059] each of RG8and R09is, independently, H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted C6-C10 aryl; and

[1060] each RJis, independently, hydrogen, Ci-Cs alkyl, carbocyclyl, and heterocyclyl, wherein each Ci-Ce alkyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from amino, hydroxyl, Ci-Ce alkoxy, carbocyclyl, heterocyclyl, or Ci-Ce alkyl that is optionally substituted with A2and / or one or more groups independently selected from oxo and halo;

[1061] or a pharmaceutically acceptable salt thereof.

[1062] In some embodiments,

[1063]

[1064] In some embodiments, RC2is optionally substituted C2-C9 heteroaryl that is substituted with A2. In some embodiments, RC3is H.

[1065] In some embodiments, RC4is H.

[1066] In some embodiments, v2 is 0.

[1067] In some embodiments, each of RC5and RC6is, independently, H or methyl.

[1068] In some embodiments, each of RC8and RC9is, independently, H or methyl.

[1069] In some embodiments, the degradation moiety has the structure:

[1070]

[1071] analog thereof. PATENT

[1072] ATTORNEY DOCKET NO.: 51121-108WO2

[1073] In some embodiments, the degradation moiety of Formula (V) comprises the structure of Formula V-FF:

[1074]

[1075] Formula V-FF,

[1076] wherein

[1077] RB1is H, A2, -C(O)-A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-4 alkyl;

[1078] RB3is, A2, -C(O)-A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-4 alkyl;

[1079] RB4is, independently, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl;

[1080] RB5is, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl or arylalkyl;

[1081] each RJ2is, independently, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 carbocyclyl, and optionally substituted C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from amino, hydroxyl, thiol, C1-C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, or C1-C6 alkyl that is optionally substituted with A2and / or one or more groups independently selected from oxo and halo; and

[1082] wherein one of RB1and RB3is A2or C(O)A2,

[1083] or a pharmaceutically acceptable salt thereof.

[1084] In some embodiments, RB4is H.

[1085] In some embodiments, RB5is H.

[1086] In some embodiments, RB1is A2.

[1087] In some embodiments, RB1is C(O)A2.

[1088] In some embodiments, RB3is optionally substituted C1-C6 alkyl.

[1089] In some embodiments,

[1090]

[1091] PATENT

[1092] ATTORNEY DOCKET NO.: 51121-108WO2

[1093] In some embodiments, the degradation moiety (B) has the structure:

[1094]

[1095] PATENT

[1096] ATTORNEY DOCKET NO.: 51121-108WO2

[1097] In some embodiments, the degradation moiety (B) has the structure:

[1098]

[1099] PATENT

[1100] ATTORNEY DOCKET NO.: 51121-108WO2

[1101] In some embodiments, the degradation moiety (B) has the structure:

[1102]

[1103] In some embodiments, the degradation moiety (B) has the structure:

[1104]

[1105] PATENT

[1106] ATTORNEY DOCKET NO.: 51121-108WO2

[1107] In some embodiments, the degradation moiety (B) has the structure:

[1108]

[1109] In some embodiments, the degradation moiety (B) has the structure:

[1110]

[1111] derivative or analog thereof.

[1112] In some embodiments, the degradation moiety (B) has the structure:

[1113]

[1114] derivative or analog thereof. PATENT

[1115] ATTORNEY DOCKET NO.: 51121-108WO2

[1116] In some embodiments, the degradation moiety (B) has the structure:

[1117]

[1118] analog thereof.

[1119] In some embodiments, RB6is halogen or optionally substituted C2-C6 alkynyl.

[1120] In some embodiments, RB6is optionally substituted Ci-Ce heteroalkyl.

[1121] In some embodiments, optionally substituted Ci-Cs heteroalkyl is methoxy.

[1122] In some embodiments, the degradation moiety (B) has the structure:

[1123]

[1124] In some embodiments, the degradation moiety (B) has the structure:

[1125]

[1126] derivative or analog thereof.

[1127] In some embodiments, the degradation moiety comprises the structure of Formula IVaa:

[1128]

[1129] Formula IVaa, PATENT

[1130] ATTORNEY DOCKET NO.: 51121-108WO2

[1131] wherein

[1132] RB11is A2, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C o aryl, or optionally substituted C2-C9 heteroaryl; wherein the carbocyciyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with A2;

[1133] R33is A2, -C(O)-A2, optionally substituted C1-C0 alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C o aryl, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl;

[1134] R34is H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl;

[1135] R35is H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;

[1136] v2 is 0, 1, 2, 3, or 4;

[1137] each R36is, independently, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, optionally substituted C2-C9 heteroaryl, optionally substituted Co-Ce alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, hydroxy, thiol; and R39is H, optionally substituted Ci-Ce alkyl, or A2;

[1138] wherein one and only one of R39, RB11and R33comprises A2or -C(O)-A2,

[1139] or a pharmaceutically acceptable salt thereof.

[1140] In some embodiments, RB11is optionally substituted C2-C9 heteroaryl.

[1141]

[1142] In some embodiments, R36is optionally substituted C2-C9 heteroaryl.

[1143]

[1144] PATENT

[1145] ATTORNEY DOCKET NO.: 51121-108WO2

[1146] In some embodiments, the degradation moiety (B) has the structure:

[1147]

[1148] derivative or analog thereof.

[1149] In some embodiments, the degradation moiety (B) has the structure:

[1150]

[1151] analog thereof. PATENT

[1152] ATTORNEY DOCKET NO.: 51121-108WO2

[1153] In some embodiments, RB6is halogen.

[1154] In some embodiments, the degradation moiety (B) has the structure:

[1155]

[1156] In some embodiments, the degradation moiety (B) has the structure:

[1157]

[1158] derivative or analog thereof.

[1159] In some embodiments, the degradation moiety comprises the structure of Formula IV:

[1160]

[1161] PATENT

[1162] ATTORNEY DOCKET NO.: 51121-108WO2

[1163] Formula IV,

[1164] wherein

[1165] RB1is H, A2, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;

[1166] RB2is H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;

[1167] RB3is A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Cs-Cio aryl wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl;;

[1168] R34is H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl;

[1169] RB5is H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;

[1170] v2 is 0, 1, 2, 3, or 4;

[1171] each RB6is, independently, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C1Q carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and each of RB7and R38is, independently, H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted C6-C10 aryl; and

[1172] RB9and RB10are, independently, H, optionally substituted Ci-Cs alkyl, or A2;

[1173] wherein one and only one of RB1, RB3, RB9or RB10comprises A2,

[1174] or a pharmaceutically acceptable salt thereof.

[1175] In some embodiments, the degradation moiety (B) has the structure:

[1176]

[1177] In some embodiments, RB1is H.

[1178] In some embodiments, RB1is A2.

[1179] In some embodiments, RB2is H.

[1180] In some embodiments, RB3is optionally substituted Ci-Cs alkyl or optionally substituted Ci-Ce heteroalkyl wherein any Ci-Ce alkyl, and Ci-Cs heteroalkyl is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, carbocycle, and Ci-salkyl that is optionally substituted with one or more groups independently selected from oxo and halo.

[1181] In some embodiments,

[1182]

[1183] PATENT

[1184] ATTORNEY DOCKET NO.: 51121-108WO2

[1185] In some embodiments,

[1186]

[1187] In some embodiments, RB3is methyl.

[1188] In some embodiments, RB4is H.

[1189] In some embodiments, RB5is H.

[1190] In some embodiments, RB6is H.

[1191] In some embodiments, RB7is H, or optionally substituted Ci-Ce alkyl.

[1192] In some embodiments, RB7is H or methyl.

[1193] In some embodiments, RB8is H or methyl.

[1194] In some embodiments, the degradation moiety (B) has the structure:

[1195]

[1196] PATENT

[1197] ATTORNEY DOCKET NO.: 51121-108WO2

[1198]

[1199] derivative or analog thereof.

[1200] In some embodiments, RB9is H, or optionally substituted Ci-Ce alkyl.

[1201] In some embodiments, RB9is H.

[1202] In some embodiments, RB9is methyl.

[1203] In some embodiments, RB10is H, or optionally substituted Ci-Ce alkyl.

[1204] In some embodiments, RB10is H.

[1205] In some embodiments, RB10is methyl.

[1206] In some embodiments, the degradation moiety (B) has the structure:

[1207]

[1208] analog thereof.

[1209] In some embodiments, the degradation moiety (B) has the structure:

[1210]

[1211] PATENT

[1212] ATTORNEY DOCKET NO.: 51121-108WO2

[1213]

[1214] analog thereof.

[1215] In some embodiments, the degradation moiety comprises the structure of Formula V: PATENT

[1216] ATTORNEY DOCKET NO.: 51121-108WO2

[1217]

[1218] Formula V

[1219] RC1is optionally substituted Ci-Ce alkyl

[1220] RC2is A2, or optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heteroaryl, wherein the C1-6 alkyl, C1-6 heteroalkyl, C3-10 carbocyclyl, C6-10 aryl, C2-9 heteroaryl, is optionally substituted with A2and / or one or more groups RJ;

[1221] RC3is H, optionally substituted C1-6 alkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C6-10 aryl,;

[1222] RC4is H, optionally substituted C1-6 alkyl, or optionally substituted C1-6 heteroalkyl;

[1223] v2 is 0, 1, 2, 3, or 4;

[1224] each of RC5and RC6is, independently, H, optionally substituted C1-6 alkyl, or A2;

[1225] each RC7is, independently, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heteroaryl, optionally substituted C2-6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and

[1226] each of RC8and RC9is, independently, H, halogen, optionally substituted C1-6 alkyl, or optionally substituted Ce-io aryl; and

[1227] each RJis, independently, hydrogen, C1-6 alkyl, carbocyclyl, and heterocyclyl, wherein each C1-6 alkyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from amino, hydroxyl, C1-6 alkoxy, carbocyclyl, heterocyclyl, or C1-6 alkyl that is optionally substituted with A2and / or one or more groups independently selected from oxo and halo;

[1228] wherein one and only one of RC2, RC5, RC6, or RJcomprises A2,

[1229] or a pharmaceutically acceptable salt thereof.

[1230] In some embodiments, the structure of Formula V is

[1231]

[1232] PATENT

[1233] ATTORNEY DOCKET NO.: 51121-108WO2

[1234] In some embodiments, RC2is optionally substituted C2-C9 heteroaryl that is substituted with A2. In some embodiments, RC3is H.

[1235] In some embodiments, RC4is H.

[1236] In some embodiments, v2 is 0.

[1237] In some embodiments, each of RC5and RC5and RC6is, independently, H or methyl.

[1238] In some embodiments, each of RC8and RC9is, independently, H or methyl.

[1239] In some embodiments, the degradation moiety (B) has the structure:

[1240]

[1241] PATENT

[1242] ATTORNEY DOCKET NO.: 51121-108WO2

[1243]

[1244] analog thereof.

[1245] In some embodiments, the degradation moiety (B) has the structure:

[1246]

[1247] PATENT

[1248] ATTORNEY DOCKET NO.: 51121-108WO2

[1249] In some embodiments, the degradation moiety (B) has the structure:

[1250]

[1251] derivative or analog thereof.

[1252] In some embodiments, the degradation moiety comprises the structure of Formula IVc:

[1253]

[1254] Formula IVc,

[1255] wherein

[1256] RE2is H, A2, -C(O)-A2, -C(O)-RJ2, optionally substituted Ci-Cs alkyl, or optionally substituted Ci-Ci heteroalkyl;

[1257] RE3is A2, -C(O)-A2, optionally substituted C1-C6 alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-Cio aryl, or optionally substituted C2-C10 heteroaryl, wherein alkyl, heteroalkyl, carbocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups RJ2;

[1258] RE4is H, optionally substituted 0-6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce- o aryl;

[1259] RE5is A2, H, optionally substituted Ci-Cs alkyl, or optionally substituted Ci-Cs heteroalkyl; wherein one of RE2, RE3and RE5is A2or -C(O)-A2, and

[1260] each RJ2is, independently, hydrogen, C Ce alkyl, carbocyclyl, and heterocyclyl, wherein each Ci Ce alkyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from halo, amino, hydroxyl, Ci-Ce alkoxy, carbocyclyl, heterocyclyl, or Ci-Ce alkyl that is optionally substituted with A2and / or one or more groups independently selected from oxo and halo; wherein one and only one of RE2, RE3, RE5, or RJ2comprises A1,

[1261] or a pharmaceutically acceptable salt thereof.

[1262] In some embodiments, the structure of Formula

[1263]

[1264] PATENT

[1265] ATTORNEY DOCKET NO.: 51121-108WO2

[1266] In some embodiments, the degradation moiety (B) has the structure:

[1267]

[1268] PATENT

[1269] ATTORNEY DOCKET NO.: 51121-108WO2

[1270]

[1271] In some embodiments, the compound is any one of compounds in Table 1. PATENT

[1272] ATTORNEY DOCKET NO.: 51121-108WO2

[1273] Table 1. Compounds of the invention 1-536

[1274]

[1275] PATENT

[1276] ATTORNEY DOCKET NO.: 51121-108WO2

[1277]

[1278] PATENT

[1279] ATTORNEY DOCKET NO.: 51121-108WO2

[1280]

[1281] PATENT

[1282] ATTORNEY DOCKET NO.: 51121-108WO2

[1283]

[1284] PATENT

[1285] ATTORNEY DOCKET NO.: 51121-108WO2

[1286]

[1287] PATENT

[1288] ATTORNEY DOCKET NO.: 51121-108WO2

[1289]

[1290] PATENT

[1291] ATTORNEY DOCKET NO.: 51121-108WO2

[1292]

[1293] PATENT

[1294] ATTORNEY DOCKET NO.: 51121-108WO2

[1295]

[1296] PATENT

[1297] ATTORNEY DOCKET NO.: 51121-108WO2

[1298]

[1299] PATENT

[1300] ATTORNEY DOCKET NO.: 51121-108WO2

[1301]

[1302] PATENT

[1303] ATTORNEY DOCKET NO.: 51121-108WO2

[1304]

[1305] PATENT

[1306] ATTORNEY DOCKET NO.: 51121-108WO2

[1307]

[1308] PATENT

[1309] ATTORNEY DOCKET NO.: 51121-108WO2

[1310]

[1311] PATENT

[1312] ATTORNEY DOCKET NO.: 51121-108WO2

[1313]

[1314] PATENT

[1315] ATTORNEY DOCKET NO.: 51121-108WO2

[1316]

[1317] PATENT

[1318] ATTORNEY DOCKET NO.: 51121-108WO2

[1319]

[1320] PATENT

[1321] ATTORNEY DOCKET NO.: 51121-108WO2

[1322]

[1323] PATENT

[1324] ATTORNEY DOCKET NO.: 51121-108WO2

[1325]

[1326] PATENT

[1327] ATTORNEY DOCKET NO.: 51121-108WO2

[1328]

[1329] PATENT

[1330] ATTORNEY DOCKET NO.: 51121-108WO2

[1331]

[1332] PATENT

[1333] ATTORNEY DOCKET NO.: 51121-108WO2

[1334]

[1335] PATENT

[1336] ATTORNEY DOCKET NO.: 51121-108WO2

[1337]

[1338] PATENT

[1339] ATTORNEY DOCKET NO.: 51121-108WO2

[1340]

[1341] PATENT

[1342] ATTORNEY DOCKET NO.: 51121-108WO2

[1343]

[1344] PATENT

[1345] ATTORNEY DOCKET NO.: 51121-108WO2

[1346]

[1347] PATENT

[1348] ATTORNEY DOCKET NO.: 51121-108WO2

[1349]

[1350] PATENT

[1351] ATTORNEY DOCKET NO.: 51121-108WO2

[1352]

[1353] PATENT

[1354] ATTORNEY DOCKET NO.: 51121-108WO2

[1355]

[1356] PATENT

[1357] ATTORNEY DOCKET NO.: 51121-108WO2

[1358]

[1359] PATENT

[1360] ATTORNEY DOCKET NO.: 51121-108WO2

[1361]

[1362] PATENT

[1363] ATTORNEY DOCKET NO.: 51121-108WO2

[1364]

[1365] PATENT

[1366] ATTORNEY DOCKET NO.: 51121-108WO2

[1367]

[1368] PATENT

[1369] ATTORNEY DOCKET NO.: 51121-108WO2

[1370]

[1371] PATENT

[1372] ATTORNEY DOCKET NO.: 51121-108WO2

[1373]

[1374] PATENT

[1375] ATTORNEY DOCKET NO.: 51121-108WO2

[1376]

[1377] PATENT

[1378] ATTORNEY DOCKET NO.: 51121-108WO2

[1379]

[1380] PATENT

[1381] ATTORNEY DOCKET NO.: 51121-108WO2

[1382]

[1383] PATENT

[1384] ATTORNEY DOCKET NO.: 51121-108WO2

[1385]

[1386] PATENT

[1387] ATTORNEY DOCKET NO.: 51121-108WO2

[1388]

[1389] PATENT

[1390] ATTORNEY DOCKET NO.: 51121-108WO2

[1391]

[1392] PATENT

[1393] ATTORNEY DOCKET NO.: 51121-108WO2

[1394]

[1395] PATENT

[1396] ATTORNEY DOCKET NO.: 51121-108WO2

[1397]

[1398] PATENT

[1399] ATTORNEY DOCKET NO.: 51121-108WO2

[1400]

[1401] PATENT

[1402] ATTORNEY DOCKET NO.: 51121-108WO2

[1403]

[1404] PATENT

[1405] ATTORNEY DOCKET NO.: 51121-108WO2

[1406]

[1407] PATENT

[1408] ATTORNEY DOCKET NO.: 51121-108WO2

[1409]

[1410] PATENT

[1411] ATTORNEY DOCKET NO.: 51121-108WO2

[1412]

[1413] PATENT

[1414] ATTORNEY DOCKET NO.: 51121-108WO2

[1415]

[1416] PATENT

[1417] ATTORNEY DOCKET NO.: 51121-108WO2

[1418]

[1419] PATENT

[1420] ATTORNEY DOCKET NO.: 51121-108WO2

[1421]

[1422] PATENT

[1423] ATTORNEY DOCKET NO.: 51121-108WO2

[1424]

[1425] PATENT

[1426] ATTORNEY DOCKET NO.: 51121-108WO2

[1427]

[1428] PATENT

[1429] ATTORNEY DOCKET NO.: 51121-108WO2

[1430]

[1431] PATENT

[1432] ATTORNEY DOCKET NO.: 51121-108WO2

[1433]

[1434] PATENT

[1435] ATTORNEY DOCKET NO.: 51121-108WO2

[1436]

[1437] PATENT

[1438] ATTORNEY DOCKET NO.: 51121-108WO2

[1439]

[1440] PATENT

[1441] ATTORNEY DOCKET NO.: 51121-108WO2

[1442]

[1443] PATENT

[1444] ATTORNEY DOCKET NO.: 51121-108WO2

[1445]

[1446] PATENT

[1447] ATTORNEY DOCKET NO.: 51121-108WO2

[1448]

[1449] PATENT

[1450] ATTORNEY DOCKET NO.: 51121-108WO2

[1451]

[1452] PATENT

[1453] ATTORNEY DOCKET NO.: 51121-108WO2

[1454]

[1455] PATENT

[1456] ATTORNEY DOCKET NO.: 51121-108WO2

[1457]

[1458] PATENT

[1459] ATTORNEY DOCKET NO.: 51121-108WO2

[1460]

[1461] PATENT

[1462] ATTORNEY DOCKET NO.: 51121-108WO2

[1463]

[1464] PATENT

[1465] ATTORNEY DOCKET NO.: 51121-108WO2

[1466]

[1467] PATENT

[1468] ATTORNEY DOCKET NO.: 51121-108WO2

[1469]

[1470] PATENT

[1471] ATTORNEY DOCKET NO.: 51121-108WO2

[1472]

[1473] PATENT

[1474] ATTORNEY DOCKET NO.: 51121-108WO2

[1475]

[1476] PATENT

[1477] ATTORNEY DOCKET NO.: 51121-108WO2

[1478]

[1479] PATENT

[1480] ATTORNEY DOCKET NO.: 51121-108WO2

[1481]

[1482] PATENT

[1483] ATTORNEY DOCKET NO.: 51121-108WO2

[1484]

[1485] PATENT

[1486] ATTORNEY DOCKET NO.: 51121-108WO2

[1487]

[1488] PATENT

[1489] ATTORNEY DOCKET NO.: 51121-108WO2

[1490]

[1491] PATENT

[1492] ATTORNEY DOCKET NO.: 51121-108WO2

[1493]

[1494] PATENT

[1495] ATTORNEY DOCKET NO.: 51121-108WO2

[1496]

[1497] PATENT

[1498] ATTORNEY DOCKET NO.: 51121-108WO2

[1499]

[1500] PATENT

[1501] ATTORNEY DOCKET NO.: 51121-108WO2

[1502]

[1503] PATENT

[1504] ATTORNEY DOCKET NO.: 51121-108WO2

[1505]

[1506] PATENT

[1507] ATTORNEY DOCKET NO.: 51121-108WO2

[1508]

[1509] PATENT

[1510] ATTORNEY DOCKET NO.: 51121-108WO2

[1511]

[1512] PATENT

[1513] ATTORNEY DOCKET NO.: 51121-108WO2

[1514]

[1515] PATENT

[1516] ATTORNEY DOCKET NO.: 51121-108WO2

[1517]

[1518] PATENT

[1519] ATTORNEY DOCKET NO.: 51121-108WO2

[1520]

[1521] PATENT

[1522] ATTORNEY DOCKET NO.: 51121-108WO2

[1523]

[1524] PATENT

[1525] ATTORNEY DOCKET NO.: 51121-108WO2

[1526]

[1527] PATENT

[1528] ATTORNEY DOCKET NO.: 51121-108WO2

[1529]

[1530] PATENT

[1531] ATTORNEY DOCKET NO.: 51121-108WO2

[1532]

[1533] PATENT

[1534] ATTORNEY DOCKET NO.: 51121-108WO2

[1535]

[1536] PATENT

[1537] ATTORNEY DOCKET NO.: 51121-108WO2

[1538]

[1539] PATENT

[1540] ATTORNEY DOCKET NO.: 51121-108WO2

[1541]

[1542] PATENT

[1543] ATTORNEY DOCKET NO.: 51121-108WO2

[1544]

[1545] PATENT

[1546] ATTORNEY DOCKET NO.: 51121-108WO2

[1547]

[1548] PATENT

[1549] ATTORNEY DOCKET NO.: 51121-108WO2

[1550]

[1551] PATENT

[1552] ATTORNEY DOCKET NO.: 51121-108WO2

[1553]

[1554] PATENT

[1555] ATTORNEY DOCKET NO.: 51121-108WO2

[1556]

[1557] PATENT

[1558] ATTORNEY DOCKET NO.: 51121-108WO2

[1559]

[1560] PATENT

[1561] ATTORNEY DOCKET NO.: 51121-108WO2

[1562]

[1563] PATENT

[1564] ATTORNEY DOCKET NO.: 51121-108WO2

[1565]

[1566] PATENT

[1567] ATTORNEY DOCKET NO.: 51121-108WO2

[1568]

[1569] PATENT

[1570] ATTORNEY DOCKET NO.: 51121-108WO2

[1571]

[1572] PATENT

[1573] ATTORNEY DOCKET NO.: 51121-108WO2

[1574]

[1575] PATENT

[1576] ATTORNEY DOCKET NO.: 51121-108WO2

[1577]

[1578] PATENT

[1579] ATTORNEY DOCKET NO.: 51121-108WO2

[1580]

[1581] PATENT

[1582] ATTORNEY DOCKET NO.: 51121-108WO2

[1583]

[1584] PATENT

[1585] ATTORNEY DOCKET NO.: 51121-108WO2

[1586]

[1587] PATENT

[1588] ATTORNEY DOCKET NO.: 51121-108WO2

[1589]

[1590] PATENT

[1591] ATTORNEY DOCKET NO.: 51121-108WO2

[1592]

[1593] PATENT

[1594] ATTORNEY DOCKET NO.: 51121-108WO2

[1595]

[1596] PATENT

[1597] ATTORNEY DOCKET NO.: 51121-108WO2

[1598]

[1599] PATENT

[1600] ATTORNEY DOCKET NO.: 51121-108WO2

[1601]

[1602] PATENT

[1603] ATTORNEY DOCKET NO.: 51121-108WO2

[1604]

[1605] PATENT

[1606] ATTORNEY DOCKET NO.: 51121-108WO2

[1607]

[1608] PATENT

[1609] ATTORNEY DOCKET NO.: 51121-108WO2

[1610]

[1611] PATENT

[1612] ATTORNEY DOCKET NO.: 51121-108WO2

[1613]

[1614] PATENT

[1615] ATTORNEY DOCKET NO.: 51121-108WO2

[1616]

[1617] PATENT

[1618] ATTORNEY DOCKET NO.: 51121-108WO2

[1619]

[1620] PATENT

[1621] ATTORNEY DOCKET NO.: 51121-108WO2

[1622]

[1623] PATENT

[1624] ATTORNEY DOCKET NO.: 51121-108WO2

[1625]

[1626] PATENT

[1627] ATTORNEY DOCKET NO.: 51121-108WO2

[1628]

[1629] PATENT

[1630] ATTORNEY DOCKET NO.: 51121-108WO2

[1631]

[1632] PATENT

[1633] ATTORNEY DOCKET NO.: 51121-108WO2

[1634]

[1635] PATENT

[1636] ATTORNEY DOCKET NO.: 51121-108WO2

[1637]

[1638] PATENT

[1639] ATTORNEY DOCKET NO.: 51121-108WO2

[1640]

[1641] PATENT

[1642] ATTORNEY DOCKET NO.: 51121-108WO2

[1643]

[1644] PATENT

[1645] ATTORNEY DOCKET NO.: 51121-108WO2

[1646]

[1647] PATENT

[1648] ATTORNEY DOCKET NO.: 51121-108WO2

[1649]

[1650] PATENT

[1651] ATTORNEY DOCKET NO.: 51121-108WO2

[1652]

[1653] PATENT

[1654] ATTORNEY DOCKET NO.: 51121-108WO2

[1655]

[1656] PATENT

[1657] ATTORNEY DOCKET NO.: 51121-108WO2

[1658]

[1659] PATENT

[1660] ATTORNEY DOCKET NO.: 51121-108WO2

[1661]

[1662] PATENT

[1663] ATTORNEY DOCKET NO.: 51121-108WO2

[1664]

[1665] PATENT

[1666] ATTORNEY DOCKET NO.: 51121-108WO2

[1667]

[1668] PATENT

[1669] ATTORNEY DOCKET NO.: 51121-108WO2

[1670]

[1671] PATENT

[1672] ATTORNEY DOCKET NO.: 51121-108WO2

[1673]

[1674] PATENT

[1675] ATTORNEY DOCKET NO.: 51121-108WO2

[1676]

[1677] PATENT

[1678] ATTORNEY DOCKET NO.: 51121-108WO2

[1679]

[1680] PATENT

[1681] ATTORNEY DOCKET NO.: 51121-108WO2

[1682] In some embodiments, the compound is any one of compounds in Table 2.

[1683] Table 2. Compounds 1 A to 28A of the invention

[1684]

[1685] PATENT

[1686] ATTORNEY DOCKET NO.: 51121-108WO2

[1687]

[1688] PATENT

[1689] ATTORNEY DOCKET NO.: 51121-108WO2

[1690]

[1691] PATENT

[1692] ATTORNEY DOCKET NO.: 51121-108WO2

[1693]

[1694] PATENT

[1695] ATTORNEY DOCKET NO.: 51121-108WO2

[1696]

[1697] PATENT

[1698] ATTORNEY DOCKET NO.: 51121-108WO2

[1699]

[1700] In some embodiments, the compound is any one of compounds of Table 2a. PATENT

[1701] ATTORNEY DOCKET NO.: 51121-108WO2

[1702] Table 2a. Compounds of the invention 1b-149b

[1703]

[1704] PATENT

[1705] ATTORNEY DOCKET NO.: 51121-108WO2

[1706]

[1707] PATENT

[1708] ATTORNEY DOCKET NO.: 51121-108WO2

[1709]

[1710] PATENT

[1711] ATTORNEY DOCKET NO.: 51121-108WO2

[1712]

[1713] PATENT

[1714] ATTORNEY DOCKET NO.: 51121-108WO2

[1715]

[1716] PATENT

[1717] ATTORNEY DOCKET NO.: 51121-108WO2

[1718]

[1719] PATENT

[1720] ATTORNEY DOCKET NO.: 51121-108WO2

[1721]

[1722] PATENT

[1723] ATTORNEY DOCKET NO.: 51121-108WO2

[1724]

[1725] PATENT

[1726] ATTORNEY DOCKET NO.: 51121-108WO2

[1727]

[1728] PATENT

[1729] ATTORNEY DOCKET NO.: 51121-108WO2

[1730]

[1731] PATENT

[1732] ATTORNEY DOCKET NO.: 51121-108WO2

[1733]

[1734] PATENT

[1735] ATTORNEY DOCKET NO.: 51121-108WO2

[1736]

[1737] PATENT

[1738] ATTORNEY DOCKET NO.: 51121-108WO2

[1739]

[1740] PATENT

[1741] ATTORNEY DOCKET NO.: 51121-108WO2

[1742]

[1743] PATENT

[1744] ATTORNEY DOCKET NO.: 51121-108WO2

[1745]

[1746] PATENT

[1747] ATTORNEY DOCKET NO.: 51121-108WO2

[1748]

[1749] PATENT

[1750] ATTORNEY DOCKET NO.: 51121-108WO2

[1751]

[1752] PATENT

[1753] ATTORNEY DOCKET NO.: 51121-108WO2

[1754]

[1755] PATENT

[1756] ATTORNEY DOCKET NO.: 51121-108WO2

[1757]

[1758] PATENT

[1759] ATTORNEY DOCKET NO.: 51121-108WO2

[1760]

[1761] PATENT

[1762] ATTORNEY DOCKET NO.: 51121-108WO2

[1763]

[1764] PATENT

[1765] ATTORNEY DOCKET NO.: 51121-108WO2

[1766]

[1767] PATENT

[1768] ATTORNEY DOCKET NO.: 51121-108WO2

[1769]

[1770] PATENT

[1771] ATTORNEY DOCKET NO.: 51121-108WO2

[1772]

[1773] PATENT

[1774] ATTORNEY DOCKET NO.: 51121-108WO2

[1775]

[1776] PATENT

[1777] ATTORNEY DOCKET NO.: 51121-108WO2

[1778]

[1779] PATENT

[1780] ATTORNEY DOCKET NO.: 51121-108WO2

[1781]

[1782] PATENT

[1783] ATTORNEY DOCKET NO.: 51121-108WO2

[1784]

[1785] PATENT

[1786] ATTORNEY DOCKET NO.: 51121-108WO2

[1787]

[1788] PATENT

[1789] ATTORNEY DOCKET NO.: 51121-108WO2

[1790]

[1791] PATENT

[1792] ATTORNEY DOCKET NO.: 51121-108WO2

[1793]

[1794] PATENT

[1795] ATTORNEY DOCKET NO.: 51121-108WO2

[1796]

[1797] PATENT

[1798] ATTORNEY DOCKET NO.: 51121-108WO2

[1799]

[1800] PATENT

[1801] ATTORNEY DOCKET NO.: 51121-108WO2

[1802]

[1803] PATENT

[1804] ATTORNEY DOCKET NO.: 51121-108WO2

[1805]

[1806] PATENT

[1807] ATTORNEY DOCKET NO.: 51121-108WO2

[1808]

[1809] PATENT

[1810] ATTORNEY DOCKET NO.: 51121-108WO2

[1811]

[1812] PATENT

[1813] ATTORNEY DOCKET NO.: 51121-108WO2

[1814]

[1815] PATENT

[1816] ATTORNEY DOCKET NO.: 51121-108WO2

[1817]

[1818] PATENT

[1819] ATTORNEY DOCKET NO.: 51121-108WO2

[1820]

[1821] PATENT

[1822] ATTORNEY DOCKET NO.: 51121-108WO2

[1823]

[1824] PATENT

[1825] ATTORNEY DOCKET NO.: 51121-108WO2

[1826]

[1827] PATENT

[1828] ATTORNEY DOCKET NO.: 51121-108WO2

[1829]

[1830] PATENT

[1831] ATTORNEY DOCKET NO.: 51121-108WO2

[1832]

[1833] PATENT

[1834] ATTORNEY DOCKET NO.: 51121-108WO2

[1835]

[1836] PATENT

[1837] ATTORNEY DOCKET NO.: 51121-108WO2

[1838]

[1839] PATENT

[1840] ATTORNEY DOCKET NO.: 51121-108WO2

[1841]

[1842] PATENT

[1843] ATTORNEY DOCKET NO.: 51121-108WO2

[1844]

[1845] PATENT

[1846] ATTORNEY DOCKET NO.: 51121-108WO2

[1847]

[1848] PATENT

[1849] ATTORNEY DOCKET NO.: 51121-108WO2

[1850]

[1851] PATENT

[1852] ATTORNEY DOCKET NO.: 51121-108WO2

[1853]

[1854] PATENT

[1855] ATTORNEY DOCKET NO.: 51121-108WO2

[1856]

[1857] PATENT

[1858] ATTORNEY DOCKET NO.: 51121-108WO2

[1859]

[1860] PATENT

[1861] ATTORNEY DOCKET NO.: 51121-108WO2

[1862]

[1863] PATENT

[1864] ATTORNEY DOCKET NO.: 51121-108WO2

[1865]

[1866] PATENT

[1867] ATTORNEY DOCKET NO.: 51121-108WO2

[1868]

[1869] PATENT

[1870] ATTORNEY DOCKET NO.: 51121-108WO2

[1871]

[1872] PATENT

[1873] ATTORNEY DOCKET NO.: 51121-108WO2

[1874]

[1875] PATENT

[1876] ATTORNEY DOCKET NO.: 51121-108WO2

[1877]

[1878] PATENT

[1879] ATTORNEY DOCKET NO.: 51121-108WO2

[1880]

[1881] PATENT

[1882] ATTORNEY DOCKET NO.: 51121-108WO2

[1883]

[1884] PATENT

[1885] ATTORNEY DOCKET NO.: 51121-108WO2

[1886]

[1887] PATENT

[1888] ATTORNEY DOCKET NO.: 51121-108WO2

[1889]

[1890] PATENT

[1891] ATTORNEY DOCKET NO.: 51121-108WO2

[1892]

[1893] PATENT

[1894] ATTORNEY DOCKET NO.: 51121-108WO2

[1895]

[1896] PATENT

[1897] ATTORNEY DOCKET NO.: 51121-108WO2

[1898]

[1899] PATENT

[1900] ATTORNEY DOCKET NO.: 51121-108WO2

[1901]

[1902] PATENT

[1903] ATTORNEY DOCKET NO.: 51121-108WO2

[1904]

[1905] PATENT

[1906] ATTORNEY DOCKET NO.: 51121-108WO2

[1907]

[1908] PATENT

[1909] ATTORNEY DOCKET NO.: 51121-108WO2

[1910]

[1911] PATENT

[1912] ATTORNEY DOCKET NO.: 51121-108WO2

[1913]

[1914] PATENT

[1915] ATTORNEY DOCKET NO.: 51121-108WO2

[1916]

[1917] PATENT

[1918] ATTORNEY DOCKET NO.: 51121-108WO2

[1919]

[1920] In some embodiments, the compounds have the structure of any of the compounds in Table 1 b.

[1921] Table 1b Compounds of the Invention 150c-380c

[1922]

[1923] PATENT

[1924] ATTORNEY DOCKET NO.: 51121-108WO2

[1925]

[1926] PATENT

[1927] ATTORNEY DOCKET NO.: 51121-108WO2

[1928]

[1929] PATENT

[1930] ATTORNEY DOCKET NO.: 51121-108WO2

[1931]

[1932] PATENT

[1933] ATTORNEY DOCKET NO.: 51121-108WO2

[1934]

[1935] PATENT

[1936] ATTORNEY DOCKET NO.: 51121-108WO2

[1937]

[1938] PATENT

[1939] ATTORNEY DOCKET NO.: 51121-108WO2

[1940]

[1941] PATENT

[1942] ATTORNEY DOCKET NO.: 51121-108WO2

[1943]

[1944] PATENT

[1945] ATTORNEY DOCKET NO.: 51121-108WO2

[1946]

[1947] PATENT

[1948] ATTORNEY DOCKET NO.: 51121-108WO2

[1949]

[1950] PATENT

[1951] ATTORNEY DOCKET NO.: 51121-108WO2

[1952]

[1953] PATENT

[1954] ATTORNEY DOCKET NO.: 51121-108WO2

[1955]

[1956] PATENT

[1957] ATTORNEY DOCKET NO.: 51121-108WO2

[1958]

[1959] PATENT

[1960] ATTORNEY DOCKET NO.: 51121-108WO2

[1961]

[1962] PATENT

[1963] ATTORNEY DOCKET NO.: 51121-108WO2

[1964]

[1965] PATENT

[1966] ATTORNEY DOCKET NO.: 51121-108WO2

[1967]

[1968] PATENT

[1969] ATTORNEY DOCKET NO.: 51121-108WO2

[1970]

[1971] PATENT

[1972] ATTORNEY DOCKET NO.: 51121-108WO2

[1973]

[1974] PATENT

[1975] ATTORNEY DOCKET NO.: 51121-108WO2

[1976]

[1977] PATENT

[1978] ATTORNEY DOCKET NO.: 51121-108WO2

[1979]

[1980] PATENT

[1981] ATTORNEY DOCKET NO.: 51121-108WO2

[1982]

[1983] PATENT

[1984] ATTORNEY DOCKET NO.: 51121-108WO2

[1985]

[1986] PATENT

[1987] ATTORNEY DOCKET NO.: 51121-108WO2

[1988]

[1989] PATENT

[1990] ATTORNEY DOCKET NO.: 51121-108WO2

[1991]

[1992] PATENT

[1993] ATTORNEY DOCKET NO.: 51121-108WO2

[1994]

[1995] PATENT

[1996] ATTORNEY DOCKET NO.: 51121-108WO2

[1997]

[1998] PATENT

[1999] ATTORNEY DOCKET NO.: 51121-108WO2

[2000]

[2001] PATENT

[2002] ATTORNEY DOCKET NO.: 51121-108WO2

[2003]

[2004] PATENT

[2005] ATTORNEY DOCKET NO.: 51121-108WO2

[2006]

[2007] PATENT

[2008] ATTORNEY DOCKET NO.: 51121-108WO2

[2009]

[2010] PATENT

[2011] ATTORNEY DOCKET NO.: 51121-108WO2

[2012]

[2013] PATENT

[2014] ATTORNEY DOCKET NO.: 51121-108WO2

[2015]

[2016] PATENT

[2017] ATTORNEY DOCKET NO.: 51121-108WO2

[2018]

[2019] PATENT

[2020] ATTORNEY DOCKET NO.: 51121-108WO2

[2021]

[2022] PATENT

[2023] ATTORNEY DOCKET NO.: 51121-108WO2

[2024]

[2025] PATENT

[2026] ATTORNEY DOCKET NO.: 51121-108WO2

[2027]

[2028] PATENT

[2029] ATTORNEY DOCKET NO.: 51121-108WO2

[2030]

[2031] PATENT

[2032] ATTORNEY DOCKET NO.: 51121-108WO2

[2033]

[2034] PATENT

[2035] ATTORNEY DOCKET NO.: 51121-108WO2

[2036]

[2037] PATENT

[2038] ATTORNEY DOCKET NO.: 51121-108WO2

[2039]

[2040] PATENT

[2041] ATTORNEY DOCKET NO.: 51121-108WO2

[2042]

[2043] PATENT

[2044] ATTORNEY DOCKET NO.: 51121-108WO2

[2045]

[2046] PATENT

[2047] ATTORNEY DOCKET NO.: 51121-108WO2

[2048]

[2049] PATENT

[2050] ATTORNEY DOCKET NO.: 51121-108WO2

[2051]

[2052] PATENT

[2053] ATTORNEY DOCKET NO.: 51121-108WO2

[2054]

[2055] PATENT

[2056] ATTORNEY DOCKET NO.: 51121-108WO2

[2057]

[2058] PATENT

[2059] ATTORNEY DOCKET NO.: 51121-108WO2

[2060]

[2061] PATENT

[2062] ATTORNEY DOCKET NO.: 51121-108WO2

[2063]

[2064] PATENT

[2065] ATTORNEY DOCKET NO.: 51121-108WO2

[2066]

[2067] PATENT

[2068] ATTORNEY DOCKET NO.: 51121-108WO2

[2069]

[2070] PATENT

[2071] ATTORNEY DOCKET NO.: 51121-108WO2

[2072]

[2073] PATENT

[2074] ATTORNEY DOCKET NO.: 51121-108WO2

[2075]

[2076] PATENT

[2077] ATTORNEY DOCKET NO.: 51121-108WO2

[2078]

[2079] PATENT

[2080] ATTORNEY DOCKET NO.: 51121-108WO2

[2081]

[2082] PATENT

[2083] ATTORNEY DOCKET NO.: 51121-108WO2

[2084]

[2085] PATENT

[2086] ATTORNEY DOCKET NO.: 51121-108WO2

[2087]

[2088] PATENT

[2089] ATTORNEY DOCKET NO.: 51121-108WO2

[2090]

[2091] PATENT

[2092] ATTORNEY DOCKET NO.: 51121-108WO2

[2093]

[2094] PATENT

[2095] ATTORNEY DOCKET NO.: 51121-108WO2

[2096]

[2097] PATENT

[2098] ATTORNEY DOCKET NO.: 51121-108WO2

[2099]

[2100] PATENT

[2101] ATTORNEY DOCKET NO.: 51121-108WO2

[2102]

[2103] PATENT

[2104] ATTORNEY DOCKET NO.: 51121-108WO2

[2105]

[2106] PATENT

[2107] ATTORNEY DOCKET NO.: 51121-108WO2

[2108]

[2109] PATENT

[2110] ATTORNEY DOCKET NO.: 51121-108WO2

[2111]

[2112] PATENT

[2113] ATTORNEY DOCKET NO.: 51121-108WO2

[2114]

[2115] PATENT

[2116] ATTORNEY DOCKET NO.: 51121-108WO2

[2117]

[2118] PATENT

[2119] ATTORNEY DOCKET NO.: 51121-108WO2

[2120]

[2121] PATENT

[2122] ATTORNEY DOCKET NO.: 51121-108WO2

[2123]

[2124] PATENT

[2125] ATTORNEY DOCKET NO.: 51121-108WO2

[2126]

[2127] PATENT

[2128] ATTORNEY DOCKET NO.: 51121-108WO2

[2129]

[2130] PATENT

[2131] ATTORNEY DOCKET NO.: 51121-108WO2

[2132]

[2133] PATENT

[2134] ATTORNEY DOCKET NO.: 51121-108WO2

[2135]

[2136] PATENT

[2137] ATTORNEY DOCKET NO.: 51121-108WO2

[2138]

[2139] PATENT

[2140] ATTORNEY DOCKET NO.: 51121-108WO2

[2141]

[2142] PATENT

[2143] ATTORNEY DOCKET NO.: 51121-108WO2

[2144]

[2145] PATENT

[2146] ATTORNEY DOCKET NO.: 51121-108WO2

[2147]

[2148] PATENT

[2149] ATTORNEY DOCKET NO.: 51121-108WO2

[2150]

[2151] PATENT

[2152] ATTORNEY DOCKET NO.: 51121-108WO2

[2153]

[2154] In some embodiments, the compounds have the structure of any of the compounds in Table 1c.

[2155] Table 1c Compounds of the Invention 1d-58d

[2156]

[2157] PATENT

[2158] ATTORNEY DOCKET NO.: 51121-108WO2

[2159]

[2160] PATENT

[2161] ATTORNEY DOCKET NO.: 51121-108WO2

[2162]

[2163] PATENT

[2164] ATTORNEY DOCKET NO.: 51121-108WO2

[2165]

[2166] PATENT

[2167] ATTORNEY DOCKET NO.: 51121-108WO2

[2168]

[2169] PATENT

[2170] ATTORNEY DOCKET NO.: 51121-108WO2

[2171]

[2172] PATENT

[2173] ATTORNEY DOCKET NO.: 51121-108WO2

[2174]

[2175] PATENT

[2176] ATTORNEY DOCKET NO.: 51121-108WO2

[2177]

[2178] PATENT

[2179] ATTORNEY DOCKET NO.: 51121-108WO2

[2180]

[2181] PATENT

[2182] ATTORNEY DOCKET NO.: 51121-108WO2

[2183]

[2184] PATENT

[2185] ATTORNEY DOCKET NO.: 51121-108WO2

[2186]

[2187] PATENT

[2188] ATTORNEY DOCKET NO.: 51121-108WO2

[2189]

[2190] PATENT

[2191] ATTORNEY DOCKET NO.: 51121-108WO2

[2192]

[2193] PATENT

[2194] ATTORNEY DOCKET NO.: 51121-108WO2

[2195]

[2196] PATENT

[2197] ATTORNEY DOCKET NO.: 51121-108WO2

[2198]

[2199] PATENT

[2200] ATTORNEY DOCKET NO.: 51121-108WO2

[2201]

[2202] In another aspect, the disclosure features a pharmaceutical composition including any of the foregoing compounds, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.

[2203] Chemical Terms

[2204] For any of the following chemical definitions, a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety. As will be PATENT

[2205] ATTORNEY DOCKET NO.: 51121-108WO2

[2206] understood, other atoms, such as hydrogen atoms, or substituent groups, as described herein, may be present, as necessary, to satisfy the valences of the atoms. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. When used with the groups defined herein, a reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups. A reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring.

[2207] The term “acyl,” as used herein, represents a hydrogen or an alkyl group that is attached to a parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups include from 1 to 6, from 1 to 11, or from 1 to 21 carbons.

[2208] The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms).

[2209] An alkylene is a divalent alkyl group. The term “alkenyl,” as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

[2210] The term “alky ny I,” as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

[2211] The term “amino,” as used herein, represents -N(RN1)2, wherein each RN1 is, independently, H, OH, NO2, N(RN2)2, SO2ORN2, SO2RN2, SORN2, an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), wherein each of these recited RN1 groups can be optionally substituted; or two RN1 combine to form an alkylene or heteroalkylene, and wherein each RN2 is, independently, H, alkyl, or aryl. The amino groups of the compounds described herein can be an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(RN1)2).

[2212] The term “aryl,” as used herein, refers to an aromatic mono- or polycarbocyclic radical of 6 to 1 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.

[2213] The term “arylalkyl,” as used herein, represents an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-C6 alkyl C6-C10 aryl, C1-C10 alkyl C6-C10 aryl, or C1-C20 alkyl C6-C10 aryl), such as, benzyl and phenethyl. In some embodiments, the alkyl and the aryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups.

[2214] The term “azido,” as used herein, represents a -N3 group.

[2215] The term “bridged polycycloalkyl,” as used herein, refers to a bridged polycyclic group of 5 to 20 carbons, containing from 1 to 3 bridges.

[2216] The term “cyano,” as used herein, represents a -CN group.

[2217] The term “carbocyclyl,” as used herein, refers to a non-aromatic C3-C12 monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals. PATENT

[2218] ATTORNEY DOCKET NO.: 51121-108WO2

[2219] The term “cycloalkyl,” as used herein, refers to a saturated, non-aromatic, monovalent mono- or polycarbocyclic radical of 3 to 10, preferably 3 to 6 carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

[2220] The term “halogen,” as used herein, means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[2221] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups. An example of a heteroalkyl group is an “alkoxy”, which, as used herein, refers alkyl-O- (e.g., methoxy and ethoxy). A heteroalkylene is a divalent heteroalkyl group. The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroaikenyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkenyl groups. Examples of heteroaikenyl groups are an “alkenoxy” which, as used herein, refers alkenyl-O-. A heteroalkenylene is a divalent heteroalkenyl group. The term “heteroalkynyl,” as used herein, refers to an alkynyi group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkynyi groups. Examples of heteroalkynyl groups are an “alkynoxy” which, as used herein, refers alkynyl-O-. A heteroalkynylene is a divalent heteroalkynyl group.

[2222] The term “heteroaryl,” as used herein, refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing 1, 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.

[2223] The term “heteroarylalkyl,” as used herein, represents an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-C6 alkyl C2-C9 heteroaryl, C1-C10 alkyl C2-C9 heteroaryl, or C1-C20 alkyl C2-C9 heteroaryl). In some embodiments, the alkyl and the heteroaryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups.

[2224] The term “heterocyclyl,” as used herein, refers a mono- or polycyclic radical having 3 to 12 atoms having at least one ring containing 1, 2, 3, or 4 ring atoms selected from N, O or S, optionally wherein no ring is aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl.

[2225] The term “heterocyclylalkyl,” as used herein, represents an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-C6 alkyl C2-C9 heterocyclyl, C1-C10 alkyl C2-C9 heterocyclyl, or C1-C20 alkyl C2-C9 heterocyclyl). In some embodiments, the alkyl and the heterocyclyl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups. PATENT

[2226] ATTORNEY DOCKET NO.: 51121-108WO2

[2227] The term “hydroxyalkyl,” as used herein, represents alkyl group substituted with an -OH group. The term “hydroxyl,” as used herein, represents an -OH group.

[2228] The term “N-protecting group,” as used herein, represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 3rd Edition (John Wiley & Sons, New York, 1999). N-protecting groups include, but are not limited to, acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L, or D, L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl, and p-toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- 20 dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2, 2, 2, -trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and silyl groups, such as trimethylsilyl. Preferred N-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[2229] The term “nitro,” as used herein, represents an -NO2 group.

[2230] The term “thiol,” as used herein, represents an -SH group.

[2231] The alkyl, alkenyl, alky nyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. When substituted, there will generally be 1 to 4 substituents present, unless otherwise specified. Substituents include, for example: alkyl (e.g., unsubstituted and substituted, where the substituents include any group described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, oxo, or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted such as arylalkyl (e.g., substituted and unsubstituted benzyl)).

[2232] Compounds described herein can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbent or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs PATENT

[2233] ATTORNEY DOCKET NO.: 51121-108WO2

[2234] of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. The appropriate technique and / or method for separating an enantiomer of a compound described herein from a racemic mixture can be readily determined by those of skill in the art. "Racemate" or "racemic mixture" means a compound containing two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light. “Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on 25 opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds described herein may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide 35 of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure. Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by moie fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. Percent purity by mole fraction is the ratio of the PATENT

[2235] ATTORNEY DOCKET NO.: 51121-108WO2

[2236] moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer.

[2237] Similarly, percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound, or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s), or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms.

[2238] Compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium.

[2239] The compounds described herein may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds described herein, be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art.

[2240] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,180,32P,33P,35S,18F,36CI,123l and125l. Isotopically-labeled compounds (e.g., those labeled with3H and14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes can be useful fortheir ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by2H or3H, or one or more carbon atoms are replaced by13C- or14C-enriched carbon. Positron emitting isotopes such as15O,13N,11C, and18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.

[2241] Preparations of isotopically labelled compounds are known to those of skill in the art. For example, isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds of the present invention described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. PATENT

[2242] ATTORNEY DOCKET NO.: 51121-108WO2

[2243] Unless otherwise defined, 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 invention belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[2244] Definitions

[2245] In this application, unless otherwise clear from context, (i) the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; and (iii) the terms “including” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps.

[2246] As used herein, the terms “about” and “approximately” refer to a value that is within 10% above or below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM.

[2247] As used herein, any values provided in a range of values include both the upper and lower bounds, and any values contained within the upper and lower bounds.

[2248] As used herein, the term “administration” refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system.

[2249] Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal.

[2250] As used herein, the term “atherosclerosis” refers to a condition where plaque builds up in the walls of arteries, narrowing or blocking them. The plaque consists of cholesterol, fat, blood cells, calcium, and other substances in the blood. Atherosclerosis can affect many arteries in the body, including those in the heart, brain, arms, legs, pelvis, and kidneys.

[2251] As used herein, the term “Body Mass Index, (or BMI)” refers to a calculation that uses the height and weight of an individual to estimate the amount of the individual's body fat. Too much body fat (e.g. obesity) can lead to illnesses and other health problems. BMI is the measurement of choice for many physicians and researchers studying obesity. BMI is calculated using a mathematical formula that takes into account both height and weight of the individual. BMI equals a person's weight in kilograms divided by height in meters squared. (BMI=kg / m2). Subjects having a BMI less than 18.5 are considered to be underweight, while those with a BMI of between 18.5 and 25 are considered to be of normal weight, while a BMI of between 25 to 30 are generally considered overweight, while individuals with a BMI of 30 or more are typically considered obese. Morbid obesity refers to a subject having a BMI of 40 or greater.

[2252] As used herein, the term “cardiovascular risk factors” means risk for cardiovascular disease selected from the group consisting of: current tobacco use (any form of tobacco); use of at least 1 PATENT

[2253] ATTORNEY DOCKET NO.: 51121-108WO2

[2254] approved lipid modifying therapy to treat hypercholesterolemia or a documented untreated low-density lipoprotein cholesterol (LDL-C) >3.4 mmol / L (100 mg / dL) within the past 6 months; documented treated or untreated high-density lipoprotein cholesterol (HDL-C) <1.0 mmol / L (40 mg / dL) for men and <1.3 mmol / L (50 mg / dL) for women or triglycerides >2.3 mmol / L (150 mg / dL) within the past 6 months; use of at least 1 blood pressure medication to treat high blood pressure or untreated systolic blood pressure (SBP) >130mm Hg or diastolic blood pressure (DBP) >80 mmHg; measured waist circumference for a male 102 cm; for a female 88 cm.

[2255] As used herein, the term “CBP” refers to the CREB-binding protein in a human cell.

[2256] As used herein, the term “CBP-related disorder” refers to a disorder that is caused or affected by the level of activity of CBP.

[2257] As used herein, the term “cognitive disorders” refers to and intends diseases and conditions that are believed to involve or be associated with or do involve or are associated with progressive loss of structure and / or function of neurons, including death of neurons, and where a central feature of the disorder may be the impairment of cognition (e.g., memory, attention, perception and / or thinking). \ Examples of cognitive disorders include Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, schizophrenia, amyotrophic lateral sclerosis (ALS), autism, ADHD, mild cognitive impairment (MCI), stroke, traumatic brain injury (TBI) and age-associated memory impairment (AAMI).

[2258] As used herein, the term “chronic kidney disease” as used herein refers to the progressive loss of renal function over time, usually months or years. Chronic kidney disease (CKD) is diagnosed by a qualified caregiver using appropriate information, tests or markers known to those skilled in the art.

[2259] Chronic kidney disease implicitly includes kidney disease.

[2260] A “compound of the present disclosure” and similar terms as used herein, whether explicitly noted or not, refers to CBP degraders described herein, including compounds of Formula I and subformula thereof, and compounds of Table 1, Table 1a, Table 2 and Table 3, as well as salts (e.g., pharmaceutically acceptable salts), stereoisomers (including atropisomers), and tautomers thereof.

[2261] As used herein, a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated. In some embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally. PATENT

[2262] ATTORNEY DOCKET NO.: 51121-108WO2

[2263] As used herein, the term “comorbid" means that a subject is diagnosed with having 2 or more medical conditions, in some embodiments, the subject’s risk of hypertensive crisis is reduced by at least about 14%.

[2264] As used herein, the term “degradation moiety” refers to a moiety whose binding results in degradation of a protein, e.g., CBP. In one example, the moiety binds to a protease or a ubiquitin ligase that metabolizes the protein, e.g., CBP.

[2265] As used herein, the term “degrader” refers to a small molecule compound including a degradation moiety, wherein the compound interacts with a protein (e.g., CBP) in a way which results in degradation of the protein, e.g., binding of the compound results in at least 5% reduction of the level of the protein, e.g., in a cell or subject.

[2266] By “determining the level of a protein” refers to the detection of a protein, or an mRNA encoding the protein, by methods known in the art either directly or indirectly. “Directly determining” means performing a process (e.g., performing an assay or test on a sample or “analyzing a sample” as that term is defined herein) to obtain the physical entity or value. “Indirectly determining” refers to receiving the physical entity or value from another party or source (e.g., a third-party laboratory that directly acquired the physical entity or value). Methods to measure protein level generally include, but are not limited to, western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix -assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometry, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry, as well as assays based on a property of a protein including, but not limited to, enzymatic activity or interaction with other protein partners. Methods to measure mRNA levels are known in the art.

[2267] As used herein, the term “diabetic condition” includes prediabetes and diabetes. Type 1 diabetes (sometimes referred to as “insulin-dependent diabetes” or “juvenile onset diabetes”) is an autoimmune disease characterized by destruction of the pancreatic p cells that leads to a total or near total lack of insulin. Type 2 diabetes (sometimes referred to as “non-insulin dependent diabetes” or “adult-onset diabetes”), the body does not respond to insulin, though it is present.

[2268] As used herein, the term “diabetic kidney disease” or “diabetic nephropathy” refers to diabetes with the presence of proteinuria and / or impaired renal function (i.e., reduced glomerular filtration rate), and / or kidney disease caused by diabetes. For example, diabetic kidney disease, or diabetic nephropathy is a form of chronic kidney disease.

[2269] As used herein, the term “diabetes mellitus” refers to a disease caused by a relative or absolute lack of insulin leading to uncontrolled carbohydrate metabolism, commonly simplified to “diabetes,” though diabetes mellitus should not be confused with diabetes insipidus. As used herein, “diabetes” refers to diabetes mellitus, unless otherwise indicated.

[2270] Refractory diabetes refers to a condition where a subject has poor glycemic control despite receiving adequate treatment. Some signs of refractory diabetes include: persistent elevations of hemoglobin A1c (HbA1c) >8, Frequent insulin reactions, Ketosis, and Inability to maintain normal weight.

[2271] As used herein, the term “diabetic kidney disease” as used herein refers to a kidney disease caused by, exacerbated by, or coexisting with diabetes. Diabetic kidney disease is a form of chronic PATENT

[2272] ATTORNEY DOCKET NO.: 51121-108WO2

[2273] kidney disease that occurs in nearly 30% of diabetic subjects. Diabetic kidney disease is defined as diabetes with the presence of proteinuria and / or impaired renal function (i.e., reduced glomerular filtration rate) (de B, I et al. Temporal trends in the prevalence of the kidney kidney), disease in the United States. JAMA, 22 June 2011; 305 (24): 2532-2539).

[2274] As used herein, the term “dyslipidemia” refers to a metabolic disorder that occurs when there are abnormal levels of lipids in the blood, such as abnormally high or low cholesterol or triglyceride levels, preferably wherein any one or two or more of the total triglyceride (TG) level, the total cholesterol (TC) level, the VLDL cholesterol (VLDL-C) level, the LDL cholesterol (LDL-C) level, or the HDL cholesterol (HDL-C) level, in the blood deviate from a range of the normal level.

[2275] As used herein, the terms “effective amount,” “therapeutically effective amount,” and “a “sufficient amount” of an agent that reduces the level and / or activity of CBP (e.g., in a cell or a subject) described herein refer to a quantity sufficient to, when administered to the subject, including a human, effect beneficial or desired results, including clinical results, and, as such, an “effective amount” or synonym thereto depends on the context in which it is being applied. For example, in the context of treating cancer, it is an amount of the agent that reduces the level and / or activity of CBP sufficient to achieve a treatment response as compared to the response obtained without administration of the agent that reduces the level and / or activity of CBP. The amount of a given agent that reduces the level and / or activity of CBP described herein that will correspond to such an amount will vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, and / or weight) or host being treated, and the like, but can nevertheless be routinely determined by one of skill in the art. Also, as used herein, a “therapeutically effective amount” of an agent that reduces the level and / or activity of CBP of the present disclosure is an amount which results in a beneficial or desired result in a subject as compared to a control. As defined herein, a therapeutically effective amount of an agent that reduces the level and / or activity of CBP of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response.

[2276] As used herein, the term “EP300” refers to the EP300 protein in a human cell.

[2277] As used herein, the term “hypertensive crisis” means blood pressure is dangerously high and may threaten subject organs or life. Hypertensive crisis is typically blood pressure that is at least 180 / 120. High blood pressure is generally 130 / 80 systolic / diastolic pressure. As used herein, “refractory type 2 diabetes” refers to a subject unable to achieve their HbA1c goal using oral standard of care medications, such as metformin.

[2278] As used herein, the term “HbA1c goal” means the desired average HbA1c level to be achieved by the subject, as determined by the subject’s clinical treatment plan and measured using clinically accepted methods. -Current ADA guidelines suggest a reasonable HbA1 c treatment goal of less than or equal to 7% following current treatment options of diet, exercise, metformin, oral diabetes treatments, followed by basal insulin. However, many subjects fail to reach their HbA1c goals despite clinical treatment and are considered to have refractory type 2 diabetes. In some embodiments, the HbAlcgoal is 7% or less. In some embodiments, the HbA1c goal is 5.7% or less.

[2279] As used herein, the terms “improve” and “improving,” in reference to recovery from a disease or condition, e.g., a metabolic disorder, refer to an enhancement of recovery in one or more parameters PATENT

[2280] ATTORNEY DOCKET NO.: 51121-108WO2

[2281] measuring or quantifying the severity of the metabolic disorder relative to the recovery in these parameters in or prior to treatment with the compounds or compositions described herein. Alternatively, improvement may be measured with respect to a reference subject having the same diagnosis as the subject butthat did not receive treatment with a compound or composition of the disclosure. For metabolic disorders, such parameters may include metabolic parameters, e.g., HDL-C levels or HbA1c levels, and motor function, e.g., six-minute walk test of a subject. Methods for assessing metabolic parameters and motor function in a subject suffering from a metabolic disorder are known in the art and are further described herein.

[2282] As used herein, the term “increase HDL-C” means the measured HDL-C level increases from baseline. In some embodiments, increase HDL-C change is statistically significant increase. In some embodiments, increase HDL-C is greater than 2% increase from baseline. In some embodiments, increase HDL-C is greater than 5% increase from baseline. In some embodiments, the increase of HDL-C is greater than 7% increase from baseline. In some embodiments, the increase of HDL-C is greater than 10% increase from baseline.

[2283] By “level” is meant a level of a protein, or mRNA encoding the protein, as compared to a reference. The reference can be any useful reference, as defined herein. By a “decreased level” or an “increased level” of a protein is meant a decrease or increase in protein level, as compared to a reference (e.g., a decrease or an increase by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, as compared to a reference; a decrease or an increase by less than about 0.01-fold, about 0.02-fold, about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less; or an increase by more than about 1.2-fold, about 1.4-fold, about 1.5-fold, about 1.8-fold, about 2.0-fold, about 3.0-fold, about 3.5-fold, about 4.5-fold, about 5.0-fold, about 10-fold, about 15-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 100-fold, about 1000-fold, or more). A level of a protein may be expressed in mass / vol (e.g., g / dL, mg / mL, pg / mL, ng / mL) or percentage relative to total protein or mRNA in a sample.

[2284] As used herein, “metabolic syndrome” is used herein in the broadest sense. Metabolic syndrome includes the co-occurrence in an adult subject of several metabolic risk factors, including at least three of the following five traits: abdominal obesity, which can be, for example, a waist circumference in men of greater than or equal to 90 cm and in women greater than or equal to 80 cm; elevated serum triglycerides, which can be, for example, greater than or equal to 150 mg / dL, or drug treatment for elevated triglycerides; reduced serum HDL cholesterol level, which can be, for example, below 40 mg / dL in men and below 50 mg / dL in women, or drug treatment for low HDL cholesterol; hypertension, which can be, for example, systolic blood pressure greater than 130 mmHg and diastolic blood pressure greater than 85 mmHg, or drug treatment for hypertension; and elevated fasting plasma glucose, which can be, for example, greater than or equal to 100 mg / dL, drug treatment for elevated glucose, or previously diagnosed type 2 diabetes. See also Meigs, the Metabolic Syndrome (Insulin Resistance Syndrome or Syndrome X), http: / / www.uptodate.com / contents / the-metabolic-syndrome-insulin-resistance-syndrome-or-syndrome-x, the disclosure of which is hereby incorporated by reference herein. PATENT

[2285] ATTORNEY DOCKET NO.: 51121-108WO2

[2286] As used herein, "nonalcoholic steatohepatitis (NASH)" or "NASH" is defined as the presence of hepatic steatosis, hepatocyte swelling and liver inflammation. NASH may also include liver fibrosis in this basic definition of the disease.

[2287] As used herein, the term “non-obese” means a subject who is not obese by applicable standards. In some embodiments, the non-obese subject has body mass index is less than 30 BMI.

[2288] As used herein, the term “obesity" generally refers to a condition, temporary or chronic, which is defined by an excess amount body fat. The normal amount of body fat (expressed as percentage of body weight) is between about 25-30% in women and about 18-23% in men. Women with over 30% body fat and men with over 25% body fat are characterized as being obese.

[2289] The term “visceral obesity” is defined as a condition where the ratio of waist to hip is measured as 1.0 or more for men and 0.8 or more for women. Visceral obesity defines the risk for developing insulin resistance and prediabetes.

[2290] The term “abdominal obesity” is usually defined as a condition where the waist circumference is> 40 inches or> 102 cm for men and> 35 inches or> 94 cm for women.

[2291] As used herein, an “obesity-related disease or condition” includes, but is not limited to, coronary artery disease, hypertension, stroke, peripheral vascular disease, insulin resistance, glucose intolerance, diabetes mellitus, hyperglycemia, hyperlipidemia, hypercholesteremia, hypertriglyceridemia, hyperinsulinemia, atherosclerosis, cellular proliferation and endothelial dysfunction, diabetic dyslipidemia, lipodystrophy and metabolic syndrome, type II diabetes, diabetic complications including diabetic neuropathy, nephropathy, retinopathy or cataracts, heart failure, inflammation, thrombosis, congestive heart failure, asthmatic or pulmonary disease related to obesity, and cardiovascular disease related to obesity.

[2292] As used herein, the term “Percent (%) sequence identity” with respect to a reference polynucleotide or polypeptide sequence is defined as the percentage of nucleic acids or amino acids in a candidate sequence that are identical to the nucleic acids or amino acids in the reference polynucleotide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid or amino acid sequence identity can be achieved in various ways that are within the capabilities of one of skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, or Megalign software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For example, percent sequence identity values may be generated using the sequence comparison computer program BLAST. As an illustration, the percent sequence identity of a given nucleic acid or amino acid sequence, A, to, with, or against a given nucleic acid or amino acid sequence, B, (which can alternatively be phrased as a given nucleic acid or amino acid sequence, A that has a certain percent sequence identity to, with, or against a given nucleic acid or amino acid sequence, B) is calculated as follows:

[2293] 100 multiplied by (the fraction X / Y)

[2294] where X is the number of nucleotides or amino acids scored as identical matches by a sequence alignment program (e.g., BLAST) in that program’s alignment of A and B, and where Y is the total number of nucleic acids in B. It will be appreciated that where the length of nucleic acid or amino acid sequence A PATENT

[2295] ATTORNEY DOCKET NO.: 51121-108WO2

[2296] is not equal to the length of nucleic acid or amino acid sequence B, the percent sequence identity of A to B will not equal the percent sequence identity of B to A.

[2297] As used herein, the term “pharmaceutical composition,” represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup): for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.

[2298] As used herein, the term “pharmaceutically acceptable excipient,” refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a subject. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[2299] As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of the compound of any of the compounds described herein. For example, pharmaceutically acceptable salts of any of the compounds described herein include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting a free base group with a suitable organic acid.

[2300] By “reducing the activity of CBP” is meant decreasing the level of an activity related to a CBP, or a related downstream effect. A non-limiting example of decreasing the activity of CBP is decreasing the level of a CBP in a cell. The activity level of CBP may be measured using any method known in the art. In some embodiments, an agent which reduces the activity of CBP is a small molecule CBP degrader.

[2301] By “reducing the level of CBP” refers to decreasing the level of CBP in a cell or subject. The level of CBP may be measured using any method known in the art. PATENT

[2302] ATTORNEY DOCKET NO.: 51121-108WO2

[2303] By a “reference” refers to any useful reference used to compare protein or mRNA levels. The reference can be any sample, standard, standard curve, or level that is used for comparison purposes. The reference can be a normal reference sample or a reference standard or level. A “reference sample” can be, for example, a control, e.g., a predetermined negative control value such as a “normal control” or a prior sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not having a disease; a sample from a subject that is diagnosed with a disease, but not yet treated with a compound described herein; a sample from a subject that has been treated by a compound described herein; or a sample of a purified protein (e.g., any described herein) at a known normal concentration. By “reference standard or level” is meant a value or number derived from a reference sample. A “normal control value” is a pre-determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range (“between X and Y”), a high threshold (“no higher than X”), or a low threshold (“no lower than X”). A subject having a measured value within the normal control value for a particular biomarker is typically referred to as “within normal limits” for that biomarker. A normal reference standard or level can be a value or number derived from a normal subject not having a disease or disorder (e.g., cancer); a subject that has been treated with a compound described herein. In preferred embodiments, the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health. A standard curve of levels of a purified protein, e.g., any described herein, within the normal reference range can also be used as a reference.

[2304] As used herein, the term “subject” refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.

[2305] As used herein, the terms "treat," "treated," or "treating" mean both therapeutic treatment wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the subject; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[2306] As used herein, the terms “variant” and “derivative” are used interchangeably and refer to naturally-occurring, synthetic, and semi-synthetic analogues of a compound, peptide, protein, or other substance described herein. A variant or derivative of a compound, peptide, protein, or other substance described herein may retain or improve upon the biological activity of the original material. PATENT

[2307] ATTORNEY DOCKET NO.: 51121-108WO2

[2308] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

[2309] Brief Description of the Drawings

[2310] Figure 1 is a graph illustrating the effects of subcutaneous dosing of Compound 1b, and subcutaneous dosing of semaglutide on body weight in a DIO mouse model as described in Example 1.

[2311] Figure 2a is a graph illustrating the effects of subcutaneous dosing of Compound 1b, and subcutaneous dosing of semaglutide on food consumption in a DIO mouse model as described in Example 1.

[2312] Figure 2b is a graph illustrating the effects of subcutaneous dosing of Compound 1b, and subcutaneous dosing of semaglutide on water consumption in a DIO mouse model as described in Example 1.

[2313] Figure 3a and 3b are graphs illustrating the effects of subcutaneous dosing of Compound 1, and subcutaneous dosing of semaglutide on the concentration of glucose in a glucose tolerance test on Day 0 and Day 27, respectively, as described in Example 1.

[2314] Figure 3c and 3d are graphs illustrating the effects of subcutaneous dosing of Compound 1, and subcutaneous dosing of semaglutide on the concentration of glucose on Day 0 and Day 27, respectively, as described in Example 1.

[2315] Figure 4a is a graph illustrating the effects of subcutaneous dosing of Compound 1b, and subcutaneous dosing of semaglutide on the concentration of glucose in an insulin tolerance test (ITT) pre-insulin dose and at 0 min, 15 min, 30 min, 60 min, 120 min ad 150 min post-insulin dose, as described in Example 1.

[2316] Figure 4b is a graph illustrating the effects of subcutaneous dosing of Compound 1b, and subcutaneous dosing of semaglutide on the concentration of glucose in an insulin tolerance test (ITT), as described in Example 1.

[2317] Figure 5a, 5b and 5c are a series of graphs illustrating the effects of subcutaneous dosing of Compound 1 b, and subcutaneous dosing of semaglutide on the weight of fat tissue, mass of fat tissue, and lean mass, respectively, as described in Example 1.

[2318] Figure 6 is a graph illustrating the effects of subcutaneous dosing of Compound 1b, and subcutaneous dosing of semaglutide on the concentration of Leptin, as described in Example 1.

[2319] Figure 7a and 7b are a series of graphs illustrating the effects of subcutaneous dosing of Compound 1b, and subcutaneous dosing of semaglutide on the concentration in Muscle tissue of CBP and EP300, respectively, as described in Example 1.

[2320] Figure 8a and 8b are a series of graphs illustrating the effects of subcutaneous dosing of Compound 1b, and subcutaneous dosing of semaglutide on the concentration in liver tissue of CBP and EP300, respectively, as described in Example 1.

[2321] Figure 9 is a series of images illustrating the effects of subcutaneous dosing of Compound 1 b, and subcutaneous dosing of semaglutide on the size of the adipocyte cells as described in Example 1.

[2322] Figure 10a is a graph illustrating the daily body weight change in HFD mice treated with compounds, shown as a percentage relative to baseline (day 1) as described in Example 2.

[2323] Figure 10b is a graph illustrating the body weight changes in NC mice treated with compound 225c, showing no significant weight loss as described in Example 2.

[2324] Figure 10c is a graph illustrating the comparison of weight loss at the end of the study in HFD mice treated with compound 225c, 140b, semaglutide, and tirzepatide as described in Example 2. PATENT

[2325] ATTORNEY DOCKET NO.: 51121-108WO2

[2326] Figure 11a is a graph illustrating the daily food intake (g) in HFD mice treated with compound 225c, 140b, semaglutide, or tirzepatide as described in Example 2.

[2327] Figure 11b is a graph illustrating the food intake in NC mice treated with compound 225c, showing no significant changes as described in Example 2.

[2328] Figure 11c is a graph illustrating the average food intake daily (g) for all groups.

[2329] Figure 12a is a graph illustrating the daily water intake (g) in HFD mice treated with compound 225c, 140b, semaglutide, or tirzepatide as described in Example 2.

[2330] Figure 1 b is a graph illustrating the water intake in NC mice treated with compound 225c, showing no significant changes as described in Example 2.

[2331] Figure 12c is a graph illustrating the average daily water intake (g) for all groups as described in Example 2 as described in Example 2.

[2332] Figure 13a is a graph illustrating the quantification of CBP and EP300 protein levels in the mouse hypothalamus of mice treated with compound 225c or 140b in HFD and NC mice by Jess Western blotting as described in Example 2.

[2333] Figure 13b is a series of images illustrating the Hypothalamus Jess Western blot images showing CBP and EP300 expression as described in Example 2.

[2334] Figure 14a is a graph illustrating the Leptin levels measured by MDS assay, showing a decrease that correlates with the amount of weight loss as described in Example 2.

[2335] Figure 14b is a graph illustrating the Glucagon levels measured by MSD assay, showing no significant changes as described in Example 2.

[2336] Figure 14c is a graph illustrating the FGF-21 levels measured by MDS assay, showing a significant reduction after compound 225c and 140b treatment in both HFD and NC cohorts, while semaglutide and tirzepatide increased FGF-21 as described in Example 2.

[2337] Figure 15a is a graph illustrating the PYY levels following treatment with compounds 225c, 140b, semaglutide, or tirzepatidein HFD and NC mice by MSD assay as described in Example 2.

[2338] Figure 15b is a graph illustrating the Total GLP-1 (active + inactive) levels measured by MSD as described in Example 2.

[2339] Figure 15c is a graph illustrating the GLP-1 Active GLP-1 levels measured by MSD as described in Example 2.

[2340] Figure 15d is a graph illustrating the GLP-1 Inactive GLP levels measured by MSD as described in Example 2.

[2341] Detailed Description

[2342] The present invention features methods to treat diabetes, type 2 diabetes, type 2 diabetes mellitus, refractory type 2 diabetes, obesity, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, dyslipidemia, chronic kidney disease, atherosclerosis, diabetic kidney disease, a cognitive disorder, and / or metabolic syndrome e.g., in a subject in need thereof. Exemplary methods are described herein. PATENT

[2343] ATTORNEY DOCKET NO.: 51121-108WO2

[2344] CBP-Reducing Agents

[2345] Agents described herein that reduce the level and / or activity of CBP in a cell may be a small molecule compound. The agents reduce the level of an activity related to CBP, or a related downstream effect, or reduce the level of CBP in a cell or subject.

[2346] Small Molecule Compounds

[2347] In some embodiments of the invention, the agent that reduces the level and / or activity of CBP in a cell is a small molecule compound. In some embodiments, the small molecule compound is a structure of Formula I.

[2348] In some embodiments, the small molecule CBP degrader is a compound, or pharmaceutically acceptable salt thereof, having the structure of Formula I:

[2349] A-L-B

[2350] Formula I,

[2351] wherein

[2352] A is a CBP binding moiety;

[2353] B is a degradation moiety; and

[2354] L is a linker.

[2355] Pharmaceutical Uses

[2356] The compounds described herein are useful in the methods of the invention and, while not bound by theory, are believed to exert their desirable effects through their ability to modulate the level, status, and / or activity of CBP in a cell, or in a subject.

[2357] An aspect of the present invention relates to methods of treating disorders related to CBP in a subject in need thereof. In some embodiments, the compound is administered in an amount and for a time effective to result in one of (or more, e.g., two or more, three or more, four or more of): (a) raise HDL-C in a subject, (b) improve glycemic control in a subject, (c) reduce the risk of major adverse cardiovascular events in a subject, (d) improve weight management in a subject or (e) preventing or delaying cognitive decline in a subject.

[2358] In some embodiments, the disorder related to CBP is type 2 diabetes mellitus, obesity, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, dyslipidemia, chronic kidney disease, atherosclerosis, diabetic kidney disease, a cognitive disorder, and / or metabolic syndrome.

[2359] Treating diabetes can result in a reduction of the risk of myocardial infarction, stroke, microvascular events and mortality. Treating diabetes can result in the inhibition or slowing of the progression of related disorders, i.e., high blood pressure, coronary heart disease, obesity, diabetic kidney disease, cognitive disorders or metabolic syndrome.

[2360] Treating diabetes can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in the average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may also be measured, PATENT

[2361] ATTORNEY DOCKET NO.: 51121-108WO2

[2362] for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[2363] Treating diabetes can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[2364] Treating obesity can result in a reduction of the risk of type 2 diabetes, cardiometabolic diseases, hepatic disorders, cardiovascular disease, inflammatory diseases, premature aging, and some forms of cancer. Treating obesity can result in the inhibition or slowing of the progression of related disorders, i.e., type 2 diabetes, cardiometabolic diseases, hepatic disorders, cardiovascular disease, inflammatory diseases, premature aging, and some forms of cancer.

[2365] Treating obesity can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in the average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[2366] Treating obesity can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[2367] Treating non-alcoholic steatohepatitis (NASH) can result in a reduction of the risk of cirrhosis and liver failure. Treating non-alcoholic steatohepatitis (NASH) can result in the inhibition or slowing of the progression of related disorders, i.e., cirrhosis and liver failure.

[2368] Treating non-alcoholic steatohepatitis (NASH) can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in the average survival time of a population may be PATENT

[2369] ATTORNEY DOCKET NO.: 51121-108WO2

[2370] measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[2371] Treating non-alcoholic steatohepatitis (NASH) can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[2372] Treating dyslipidemia can result in a reduction of the risk of cardiovascular pathologies and mortality. Treating dyslipidemia can result in the inhibition or slowing of the progression of related disorders, i.e., obesity, type 2 diabetes mellitus and hypertension.

[2373] Treating dyslipidemia can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in the average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[2374] Treating dyslipidemia can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[2375] Treating chronic kidney disease can result in a reduction of the risk of kidney failure and mortality. Treating chronic kidney disease can result in the inhibition or slowing of the progression of related disorders, i.e., kidney failure.

[2376] Treating chronic kidney disease can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. PATENT

[2377] ATTORNEY DOCKET NO.: 51121-108WO2

[2378] For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in the average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[2379] Treating chronic kidney disease can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[2380] Treating atherosclerosis can result in a reduction of the risk of heart disease including myocardial infarction, stroke and surrounding arterial disease. Treating atherosclerosis can result in the inhibition or slowing of the progression of related disorders, i.e., heart disease including myocardial infarction, stroke and surrounding arterial disease.

[2381] Treating atherosclerosis can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in the average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[2382] Treating atherosclerosis can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[2383] Treating diabetic kidney disease can result in a reduction of the risk of kidney failure. Treating diabetic kidney disease can result in the inhibition or slowing of the progression of related disorders, i.e., kidney failure. PATENT

[2384] ATTORNEY DOCKET NO.: 51121-108WO2

[2385] Treating diabetic kidney disease can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in the average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may aiso be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable sait of a compound described herein.

[2386] Treating diabetic kidney disease can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a popuiation the average number of disease-reiated deaths per unit time following initiation of treatment with a pharmaceutically acceptable sait of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a popuiation the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable sait of a compound described herein.

[2387] Treating cognitive disorders can result in a reduction of the risk of attention deficit hyperactivity disorder (ADHD), traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), obsessive compulsive disorder (ODD), substance dependence disorder (SDD), depression (e.g., major depressive disorder), dementia, Alzheimer's disease, Parkinson's disease, autism, and schizophrenia. Treating cognitive disorders can result in the inhibition or slowing of the progression of related disorders, i.e., attention deficit hyperactivity disorder (ADHD), traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD), substance dependence disorder (SDD), depression (e.g., major depressive disorder), dementia, Alzheimer's disease, Parkinson's disease, autism, and schizophrenia.

[2388] Treating cognitive disorders can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in the average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[2389] Treating cognitive disorders can also result in a decrease in the mortality rate of a popuiation of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment PATENT

[2390] ATTORNEY DOCKET NO.: 51121-108WO2

[2391] with a pharmaceutically acceptable salt of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable sait of a compound described herein.

[2392] Treating metabolic syndrome can result in a reduction of the risk of heart disease, cardiovascular disease, stroke, cancer, asthma, hypertriglyceridemia, hypertension, glycometabolism disorders, blood coagulation disorders, obesity, atherosclerotic cardiovascular disease, fatty liver disease with steatosis, fibrosis, and cirrhosis, hepatocellular and intrahepatic cholangiocarcinoma, chronic kidney disease, polycystic ovary syndrome, sleep disordered breathing, including obstructive sleep apnea, hyperuricemia, gout, and diabetes. Treating metabolic syndrome can result in the inhibition or slowing of the progression of related disorders, i.e., heart disease, cardiovascular disease, stroke, cancer, asthma, hypertriglyceridemia, hypertension, glycometabolism disorders, blood coagulation disorders, obesity, atherosclerotic cardiovascular disease, fatty liver disease with steatosis, fibrosis, and cirrhosis, hepatocelluiar and intrahepatic cholangiocarcinoma, chronic kidney disease, polycystic ovary syndrome, sleep disordered breathing, including obstructive sleep apnea, hyperuricemia, gout, and diabetes.

[2393] Treating metabolic syndrome can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in the average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[2394] Treating metabolic syndrome can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[2395] Combination Therapies

[2396] A method of the invention can be used alone or in combination with an additional therapeutic agent, e.g., other agents that treat type 2 diabetes mellitus, obesity, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, dyslipidemia, chronic kidney disease, atherosclerosis, diabetic kidney disease, a cognitive disorder, and / or metabolic syndrome or symptoms associated therewith, or in combination with other types of therapies to treat type 2 diabetes mellitus, obesity, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, dyslipidemia, chronic kidney disease, atherosclerosis, diabetic PATENT

[2397] ATTORNEY DOCKET NO.: 51121-108WO2

[2398] kidney disease, a cognitive disorder, and / or metabolic syndrome. In combination treatments, the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65: S3-S6 (2005)). In this case, dosages of the compounds when combined should provide a therapeutic effect.

[2399] In some embodiments, the second therapeutic agent is a type of diabetes medicine (e.g., SGLT2 inhibitor, glucagon-like peptide 1 receptor agonist or glucose-dependent insulinotropic polypeptide receptor agonist, or other chemical compound useful in the treatment of diabetes). In some embodiments, the diabetes medicine is metformin. In some embodiments, the diabetes medicine is an SGLT2 inhibitor. In some embodiments the subject is administered one or more of the second therapeutic agents.

[2400] In some embodiments, the second therapeutic agent is a type of non-drug treatment. For example, the second therapeutic agent is a lifestyle modification and / or dietary intervention prior to, during, or subsequent to administration of the compounds or compositions. The lifestyle modification can include, but is not limited to increase in physical activity (e.g., exercise), decrease in smoking, or participation in behavioral therapy. Dietary interventions can include participation in low calorie eating regiments, very low-calorie eating regiments, portion-controlled meals, avoidance of sugar / sweetened beverages.

[2401] In any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially, in either order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after the second therapeutic agent.

[2402] Pharmaceutical Compositions

[2403] The pharmaceutical compositions described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.

[2404] The compounds described herein may be used in the form of the free base, in the form of salts. All forms are within the methods described herein. In accordance with the methods of the invention, the described compounds or salts thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.

[2405] The compounds described herein may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.

[2406] Dosages

[2407] The dosage of the compounds described herein, and / or compositions including a compound described herein, can vary depending on many factors, such as the pharmacodynamic properties of the PATENT

[2408] ATTORNEY DOCKET NO.: 51121-108WO2

[2409] compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response, in general, satisfactory results may be obtained when the compounds described herein are administered to a human at a daily dosage of, for example, between 0.05 mg and 3000 mg (measured as the solid form).

[2410] Alternatively, the dosage amount can be calculated using the body weight of the patient. For example, the dose of a compound, or pharmaceutical composition thereof, administered to a patient may range from 0.1-50 mg / kg.

[2411] Kits

[2412] The invention also features kits including (a) a pharmaceutical composition including an agent that reduces the level and / or activity of CREB-binding protein in a cell or subject described herein, and (b) a package insert with instructions to perform any of the methods described herein. In some embodiments, the kit includes (a) a pharmaceutical composition including an agent that reduces the level and / or activity of CREB-binding protein in a cell or subject described herein, (b) an additional therapeutic agent, and (c) a package insert with instructions to perform any of the methods described herein.

[2413] Obesity

[2414] The compounds and compositions described herein are useful for treating obesity Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have a negative effect on health, resulting in increased health problems Obesity may be caused by a combination of excessive food intake, lack of physical activity, emotional issues, and genetic susceptibility as well as endocrine disorders, certain medications, or psychiatric illness. Individuals with obesity have an increased risk of many physical and mental conditions, and obesity has thus been found to reduce life expectancy. Nonlimiting examples of conditions associated with obesity include metabolic syndrome, type 2 diabetes, high blood pressure, high blood cholesterol, cardiovascular diseases, obstructive sleep apnea, certain types of cancer, osteoarthritis, asthma, hypertension, infertility, birth defects, polycystic ovarian syndrome, depression, gout, osteoarthritis, migraines, dementia, myocardial infarction, congestive heart failure, multiple sclerosis, and carpal tunnel syndrome. Obesity may further be characterized by high triglyceride levels in blood plasma and hyperglycemia, in which an excessive amount of glucose circulates in blood plasma. Accordingly, treatment with compositions of the present invention has been shown to not only promote weight loss, but also to normalize high blood glucose and high triglyceride plasma levels in obese or overweight subjects. Furthermore, since about 90% of obese subjects are also diabetic, the treatment methods of the present invention also encompass the population of obese subjects who are also diabetic.

[2415] Diabetes

[2416] The compounds and compositions described herein may be useful for treating or preventing the development of diabetes. Diabetes can be any metabolic disease in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin PATENT

[2417] ATTORNEY DOCKET NO.: 51121-108WO2

[2418] that is produced. Accordingly, treatment with compositions of the present invention has been shown to normalize high blood glucose levels in diabetic subjects. There are two major forms of diabetes: Type 1 diabetes (also referred to as insulin-dependent diabetes or IDDM) and Type 2 diabetes (also referred to as noninsulin dependent diabetes or NIDDM). Type 1 diabetes is the result of an absolute deficiency of insulin, the hormone that regulates glucose utilization. Type 1 diabetes has two forms: Immune-Mediated Diabetes Mellitus, which results from a cellular mediated autoimmune destruction of the p cells of the pancreas; and Idiopathic Diabetes Mellitus, which refers to forms of the disease that have no known etiologies. Type 2 diabetes is a disease characterized by insulin resistance accompanied by relative, rather than absolute, insulin deficiency. Premature development of atherosclerosis and increased rate of cardiovascular and peripheral vascular diseases are characteristic features of subjects with diabetes. Non-limiting examples of diabetes includes, type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes, congenital diabetes, cystic fibrosis-related diabetes, steroid diabetes, latent autoimmune diabetes of adults, and monogenic diabetes. Complications associated with diabetes include but are not limited to hypoglycemia, diabetic ketoacidosis, nonketotic hyperosmolar coma, cardiovascular disease, chronic renal failure, diabetic nephropathy, diabetic neuropathy, diabetes-related foot problems (e.g., diabetic foot ulcers), and diabetic retinopathy.

[2419] Diabetes mellitus, commonly called diabetes, refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose, referred to as hyperglycemia. Diabetes mellitus is a serious metabolic disease that is defined by the presence of chronically elevated levels of blood glucose (hyperglycemia). This state of hyperglycemia is the result of a relative or absolute lack of activity of the peptide hormone, insulin. Insulin is produced and secreted by the p cells of the pancreas. Insulin is reported to promote glucose utilization, protein synthesis, and the formation and storage of carbohydrate energy as glycogen. Glucose is stored in the body as glycogen, a form of polymerized glucose, which can be converted back into glucose to meet metabolism requirements. Under normal conditions, insulin is secreted at both a basal rate and at enhanced rates following glucose stimulation, all to maintain metabolic homeostasis by the conversion of glucose into glycogen. There remains a need for new treatment paradigms for atherosclerosis and prevention of CVD events, metabolic syndrome, acute endotoxemia and sepsis, and insulin-related disorders.

[2420] Subjects referred herein as “diabetic” may have diabetes or associated conditions. Nonlimiting examples of conditions associated with diabetes include Type 1 diabetes, Type 2 diabetes, gestational diabetes mellitus (GDM), maturity onset of diabetes of the young (MODY), pancreatitis, polycystic ovarian disease, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, Syndrome X, dysmetabolic syndrome and related diseases, diabetic complications (including retinopathy, neuropathy, nephropathy) and sexual dysfunction. The conditions, diseases, and maladies collectively referenced to as “Syndrome X” or Dysmetabolic Syndrome (as detailed in Johanson, J. Clin. Endocrinol. Metab., 1997, 82, 727-734, and other publications) include hyperglycemia and / or prediabetic insulin resistance syndrome, and is characterized by an initial insulin resistant state generating hyperinsulinemia, dyslipidemia, and impaired glucose PATENT

[2421] ATTORNEY DOCKET NO.: 51121-108WO2

[2422] tolerance, which can progress to Type II diabetes, characterized by hyperglycemia, which can progress to diabetic complications or NAFLD.

[2423] Fatty Liver Disorders

[2424] This disclosure provides compositions and methods for treating fatty liver disorders which may include but are not limited to non-alcoholic steatohepatitis (NASH), non-alcoholic associated fatty liver disease, secondary NAFLD, steatosis, progressive fibrosis, liver failure and cirrhosis. Non-alcoholic fatty liver disease (NAFLD) is a chronic liver condition that occurs when fat builds up in the liver, but it's not caused by heavy drinking. Non-alcoholic steatohepatitis (NASH) is an advanced form of non-alcoholic fatty liver disease (NAFLD). Non-limiting examples of conditions associated with non-alcoholic steatohepatitis (NASH), and non-alcoholic associated fatty liver disease (NAFLD) are cirrhosis and liver failure.

[2425] Dyslipidemia

[2426] This disclosure provides compositions and methods for treating dyslipidemia. Dyslipidemia is a metabolic disorder that occurs when there are abnormal levels of lipids in the blood, such as abnormally high or low cholesterol or triglyceride levels, preferably wherein any one or two or more of the total triglyceride (TG) level, the total cholesterol (TC) level, the VLDL cholesterol (VLDL-C) level, the LDL cholesterol (LDL-C) level, or the HDL cholesterol (HDL-C) level, in the blood deviate from a range of the normal level.

[2427] Dyslipidemia is a class of diseases that includes hyperlipidemia. Fredrickson’s Type I dyslipidemia (sometimes referred to as Buerger-Gruetz syndrome, primary hyperlipoproteinaemia, or familial hyperchylomicronemia) is characterized by elevated cholesterol levels, subjects with Fredrickson's Type Ila dyslipidemia (also known as familial hypercholesterolemia) exhibit elevated LDL levels. Those with Fredrickson's Type lib dyslipidemia (familial combined hyperlipoproteinemia (FCH) or secondary combined hyperlipoproteinemia) show increased LDL and VLDL levels. Fredrickson's Type III dyslipidemia (sometimes called beta disease or dysbetalipoproteinemia) features elevated intermediate density lipoproteins (“IDL”), while Fredrickson's Type IV dyslipidemics (sometimes called “pure hypertrig lyceridemics”) have elevated VLDL levels. Subjects with Fredrickson's Type V dyslipidemia have increased VLDL and chylomicron levels. Nonlimiting examples of conditions associated with dyslipidemia are obesity, type 2 diabetes meliitus and hypertension.

[2428] Chronic kidney disease

[2429] This disclosure provides compositions and methods for treating chronic kidney disease. Chronic kidney disease is a gradual and progressive loss of the ability of the kidneys to excrete wastes, concentrate urine, and conserve electrolytes. Chronic kidney disease or failure is defined as having glomerular filtration rate less than 60 ml / min for three months or more. Unlike acute kidney failure with its abrupt but reversible of kidney function, the kidney functions in chronic kidney disease progress and deteriorate irreversibly towards end stage renal disease (ESRD). Subjects suffering from ESRD cannot PATENT

[2430] ATTORNEY DOCKET NO.: 51121-108WO2

[2431] survive without diaiysis or kidney transplantation. Nonlimiting examples of conditions associated with chronic kidney disease is kidney failure.

[2432] Atherosclerosis

[2433] This disclosure provides compositions and methods for treating atherosclerosis. Atherosclerosis is a chronic disease that causes thickening of the innermost layer (intima) of the aorta or middle artery. This reduces blood flow and can cause ischemia and tissue destruction in organs supplied by affected blood vessels. Atherosclerosis is a major cause of heart disease including myocardial infarction, stroke and surrounding arterial disease. Atherosclerosis can affect many arteries in the body, including those in the heart, brain, arms, legs, pelvis, and kidneys. When arteries narrow, it reduces the supply of oxygenrich blood to vital organs, which can lead to serious health problems. Atherosclerosis can cause blood clots to form or plaque to splinter, which can completely block arteries and lead to a heart attack or stroke. Nonlimiting examples of conditions associated with atherosclerosis is heart disease, myocardial infarction, stroke and surrounding arterial disease.

[2434] Diabetic kidney disease

[2435] This disclosure provides compositions and methods for treating diabetic kidney disease. Diabetic kidney disease is a form of chronic kidney disease that occurs in nearly 30% of diabetic subjects. The high blood sugar associated with diabetes also causes damage to the kidney through many different and complicated pathways. Most of this damage is directed toward the blood vessels that filter the blood to make urine.

[2436] Diabetic kidney disease is defined as diabetes with the presence of proteinuria and / or impaired renal function (i.e., reduced glomerular filtration rate) (de B, I et al. Temporal trends in the prevalence of the kidney kidney), disease in the United States. JAMA, 22 June 2011; 305 (24): 2532-2539).

[2437] Hypertension, or high blood pressure, is a complication of diabetes that is believed to contribute most directly to diabetic nephropathy. Hypertension is believed to be both a cause of diabetic nephropathy, as well as a result of the damage that is created by the disease. As kidney disease progresses, physical changes in the kidneys often lead to increased blood pressure. Uncontrolled hypertension can make the progress toward stage five diabetic nephropathy occur more rapidly. Nonlimiting examples of conditions associated with diabetic kidney disease is kidney failure.

[2438] Cognitive disorder

[2439] This disclosure provides compositions and methods for treating cognitive disorders. Cognitive disorders are diseases and conditions that are believed to involve or be associated with or do involve or are associated with progressive loss of structure and / or function of neurons, including death of neurons, and where a central feature of the disorder may be the impairment of cognition (e.g., memory, attention, perception and / or thinking). Examples of cognitive disorders include Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, schizophrenia, amyotrophic lateral sclerosis (ALS), autism, ADHD, mild cognitive impairment (MCI), stroke, traumatic brain injury (TBI) and age-associated memory impairment (AAMI).

[2440] Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) have been associated with reduced performance on multiple domains of cognitive function and with evidence of abnormal structural and PATENT

[2441] ATTORNEY DOCKET NO.: 51121-108WO2

[2442] functional brain magnetic resonance imaging (MRI). Cognitive deficits may occur at the very earliest stages of diabetes and are further exacerbated by the metabolic syndrome. The duration of diabetes and glycemic control may have an impact on the type and severity of cognitive impairment, but as yet we cannot predict who is at greatest risk of developing cognitive impairment. The patho-physiology of cognitive impairment is muitifactorial, although dysfunction in each interconnecting pathway ultimately leads to discordance in metabolic signaling. The pathophysiology includes defects in insulin signaling, autonomic function, neurolnflammatory pathways, mitochondrial (Mt) metabolism, the sirtuin-peroxisome proliferator-activated receptor-gamma co-activator 1a (SIRT-PGC-1a) axis, and Tau signaling. Nonlimiting examples of conditions associated with cognitive disorders is attention deficit hyperactivity disorder (ADHD), traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD), substance dependence disorder (SDD), depression (e.g., major depressive disorder), dementia, Alzheimer's disease, Parkinson's disease, autism, and schizophrenia.

[2443] Metabolic syndrome

[2444] This disclosure provides compositions and methods for treating metabolic syndrome. Metabolic syndrome is a complex state characterized by a series of risk factors that contribute to thrombosis, hypertension, dyslipidemia, and inflammation. Insulin resistance and obesity are major pathogenic mechanisms underlying the metabolic syndrome. Metabolic syndrome includes the co-occurrence in an adult subject of several metabolic risk factors, including any of the following traits: abdominal obesity, which can be, for example, a waist circumference in men of greater than or equal to 90 cm and in women greater than or equal to 80 cm; elevated serum triglycerides, which can be, for example, greater than or equal to 150 mg / dL, or drug treatment for elevated triglycerides; reduced serum HDL cholesterol level, which can be, for example, below 40 mg / dL in men and below 50 mg / dL in women, or drug treatment for low HDL cholesterol; hypertension, which can be, for example, systolic blood pressure greater than 130 mmHg and diastolic blood pressure greater than 85 mmHg, or drug treatment for hypertension; and elevated fasting plasma glucose, which can be, for example, greater than or equal to 100 mg / dL, drug treatment for elevated glucose, or previously diagnosed type 2 diabetes.

[2445] Metabolic Syndrome and Related Disorders may also include insulin resistance, obesity, glucose intolerance, dyslipidemia with elevated triglycerides, Low HDL-cholesterol, microalbuminuria, predominance of small dense LDL-cholesterol particles, hypertension, endothelial dysfunction, oxidative stress, inflammation, and related disorders of polycystic ovarian syndrome, fatty liver disease (NASH), and gout, including Nonlimiting examples of conditions associated with metabolic syndrome are heart disease, cardiovascular disease, stroke, cancer, asthma, hypertriglyceridemia, hypertension, glycometabolism disorders, blood coagulation disorders, obesity, atherosclerotic cardiovascular disease, fatty liver disease with steatosis, fibrosis, and cirrhosis, hepatocellular and intrahepatic cholangiocarcinoma, chronic kidney disease, polycystic ovary syndrome, sleep disordered breathing, including obstructive sleep apnea, hyperuricemia, gout, and diabetes

[2446] Subject Population

[2447] The subjects to be treated with the compositions of the invention can include, for example, subjects who are considered borderline diabetic (e.g., prediabetic, blood sugar level between 100-125 in fasting plasma glucose test, blood sugar level between 140-199 in oral glucose tolerance test, PATENT

[2448] ATTORNEY DOCKET NO.: 51121-108WO2

[2449] hemoglobin A1C of 5.7 to 6.4%), borderline overweight, diabetic, overweight, obese, or subjects who have a desire to maintain a healthy weight, prevent weight gain, or promote weight loss as well as subjects with both obesity and type 2 diabetes. In addition to the previously described associated disease risk (e.g., type 2 diabetes, and obesity), obese subjects may be categorized as having a BMI exceeding normal, e.g. greater than about 30 kg / m2(e.g., about 29, 31, 32, 33, 34, or 35 kg / m2) and a higher than normal waist circumference, e.g., a waste circumference of greater than about 102 cm for a male (e.g., about 100, 101, 102, 103, 104, or 105 cm) or about 88 cm (e.g., about 86, 87, 89, 90, 91, or 92 cm) for a female. Additional physical conditions associated with obesity may include shortness of breath, feelings of tiredness, sore joints or muscles, skin problems, varicose veins, and irregular menstrual cycles. In some embodiments, obese subjects are identified by high plasma levels of triglycerides or the condition of hypertriglyceridemia, e.g., levels greater than about 150 mg / dL (e.g., about 148, 149, 151, 152, or 153 mg / dL). Obese subjects may further have higher than normal levels of plasma glucose when fasting, e.g., greater than about 100 mg / dL (e.g., about 98, 99, 101, 102, or 103 mg / dL). Further nonlimiting symptoms of obesity may include reduced HDL cholesterol, e.g., less than about 40 mg / dL (e.g., about 37, 38, 39, 41, or 42 mg / dL), and raised blood pressure, e.g., systolic blood pressure greater than about 130 mm Hg (e.g., about 127, 128, 129, 131, or 132 mm Hg). Furthermore, obese subjects may have previously been prescribed the treatment involving lifestyle modification, e.g., an increase in physical activity, and / or a dietary intervention, e.g., a low calorie or very low-calorie diet, without improvements in the symptoms or condition of obesity.

[2450] Subjects who have a desire to maintain a healthy weight, prevent weight gain, or promote weight loss may be subjects who were previously obese and have undergone operative medical procedures (e.g., gastric bypass, laparoscopic adjustable gastric binding, biliopancreatic diversion, vertical banded gastroplasty) to reduce weight. Subjects who have a desire to maintain a healthy weight, prevent weight gain, or promote weight loss may also be healthy subjects considered within the scope of the invention (e.g., subjects who are not obese, overweight, prediabetic, or diabetic).

[2451] In some embodiments, the subjects to be treated with the compositions of the invention are also involved in lifestyle modifications and / or dietary interventions prior to, during, or subsequent to administration of the composition. The lifestyle modification can include, but is not limited to increase in physical activity (e.g., exercise), decrease in smoking, or participation in behavioral therapy. Dietary interventions can include participation in low calorie eating regiments, very low-calorie eating regiments, portion-controlled meals, avoidance of sugar / sweetened beverages.

[2452] Nonlimiting symptoms of diabetes (e.g., type 2 diabetes) include increased hunger and thirst, unexpected weight loss, decreased energy, decreased insulin sensitivity, an improvement in body mass index, and decreased renal function. In some embodiments, subjects with diabetes may be identified as individuals with elevated plasma glucose levels. Plasma glucose levels may be determined after fasting conditions with no food or liquids for a predetermined period. After fasting conditions and determination of plasma glucose levels, a subject with prediabetes (e.g., a subject with blood glucose levels higher than normal, but not high enough for diagnosis as diabetes) may have a blood glucose range of about 100 to about 125 mg / dL plasma glucose and a subject with type 2 diabetes may have a blood glucose range of greater than about 126 mg / dL plasma glucose (e.g., about 124, 125, 127, 128, 129, or 130 mg / dL).

[2453] Alternatively, conditions of diabetes and prediabetes may be determined by administration of a standard PATENT

[2454] ATTORNEY DOCKET NO.: 51121-108WO2

[2455] amount of glucose, wherein the physician collects a blood sample before and approximately two to four hours after the subject ingests the glucose to determine glucose tolerance. Subjects with prediabetes may then have a blood glucose range of about 140 to about 199 mg / dL plasma glucose and a subject with type 2 diabetes may have a blood glucose range of greater than about 200 mg / dL plasma glucose (e.g., about 195, 196, 197, 198, 199, 121, or 122 mg / dL).

[2456] Examples

[2457] Example 1: Treatment of Mice with CBP degrader

[2458] Animals: Male C57BL / 6J background mice were subjected to either a normal diet or high fat diet (DIO). Prior to dosing, the mice will be fasted for 16 hours and their base fast blood glucose levels will be measured.

[2459] Compound 1b Preparation: The 10 mpkdose was prepapred by mixing 2 mg of Compound 1b in 0.986 mL 20% Captisol (w / v) in 50% Kreb-Ringer Buffer to form a uniform suspension and prepared freshly. The 1 mpkdose was prepapred by mixing 0.2 mg of Compound 1b in 1.8 mL20% Captisol (w / v) in 50% Kreb-Ringer Buffer to form a uniform suspension and prepared freshly.

[2460] Semaglutide: 1 mg Semaglutide in 6.068 mL PBS buffer was transferred to 7 vials and stored at -80°C was prepared weekly. 0.8mL of the solution was mixed with 7.2mL PBS.

[2461] Treatment: Compound 1 b was administered subcutaneously at 10 mpk QD along with a normal diet, at 1 mpk QD along with a normal diet, and Compound 1b was administered subcutaneously at 10 mpk QD along with a DIO diet, and at 1 mpk QD along with a DIO diet, and vehicle was administered in mice having a normal diet and in mice having a DIO diet (Table 3). In addition, standard of care treatments of semaglutide (20nmo / kg QD) in 10 DIO mice for comparision to Compound 1b (Table 3). Mice were monitored daily for weight loss and were euthanized if they showed signs of distress (e.g., 10% BWL or hind limb paralysis).

[2462] Table 3 Group and Treatments

[2463]

[2464] Fasting Blood glucose detection: On Day 1 and Day 27, the mice will be fasted overnight (16 h) and fasting blood glucose will be measured via tail vein by using Accu-Chek guide prior dose and at terminal. PATENT

[2465] ATTORNEY DOCKET NO.: 51121-108WO2

[2466] Insulin Tolerance test: On Day 25, the mice will be fasted 4 h before dosing and insulin solution (0.75 lU / Kg IP; 10 mL / kG) will be administered 15 min post dose. The blood glucose will be measured at 15, 30, 60, 120 and 150 minutes post insulin dosing by using Accu-Chek Performa System. If the animals exhibit severe hypoglycemia (glucose levels below 45 and decreased consciousness), intraperitoneal injection of 0.5 gr / kg glucose will be administered for rescue.

[2467] Oral Glucose Tolerance Test: On Day 1 (prior to treatment) and on Day 27, the mice will be fasted 16 h before dosing and 2g / kg glucose will be administered 15 min post dose. The blood glucose will be measured at 0, 15, 30, 60, 120 minutes post glucose dosing by using Accu-Chek Performa System.

[2468] Body Fat / Lean rate: On Day 28, the mice will be measured for body fat / lean rate by UltraFocus DXA, n=5 at 6 h and n=5 at 24 h post last dose.

[2469] PK Analysis: At 12 h and 24 h post last dose, blood samples from groups 3-7 will be collected at 2 h and 6 h (n=5) into EDTA-K2 coated centrifuge tubes. The samples were immediately centrifuged at 4°C, 4000 ref for 5 minutes and then plasma was transferred into new sample tubes for PK analysis, including 4 dosing samples.

[2470] Blood Chemistry Analysis: At 12 h and 24 h post last dose, blood samples will be collected via cardiac puncture. Blood will be collected into centrifuge tubes without anticoagulant. Following at least 30 minutes at room temperature to allow clot formation, serum will be separated by centrifugation at 12000 ref for 15 minutes for blood biochemistry parameters analysis. The blood biochemistry parameters are shown in Table 4.

[2471] Table 4 Blood Biochemistry Parameter

[2472]

[2473] Terminal Blood Collection: At 6 h and 24 h post last dose, blood samples will be collected ) into EDTA-K2 coated centrifuge tubes. The samples were immediately centrifuged at 4°C, 4000 ref for 5 PATENT

[2474] ATTORNEY DOCKET NO.: 51121-108WO2

[2475] minutes and then plasma was transferred into new sample tubes for Elisa analysis, including adiponectin, leptin and insulin.

[2476] Tissue Collection: On Day 29, tissue collection will occur. Liver tissue will be collected from the liver left lobe into 10%NBF for pathology analysis. The remaining will be snap freeze for Western Blotting. Fat tissue collected by recording the eight of the Inguinal fat tissue and Epipdidymal adipose tissue, then the left Inguinal fat tissue will be collected into 10%NBF for pathology (H& E) analysis, the right Inguinal fat tissue will snap freeze and store at -80°C. Gastrocnemius Muscle, WAT (Epipdidymal fat) and BAT (Scapular fat) was collected by snap freeze for RNA-seq or WB by Jess (store samples at -80°C). Pancreas Tissue was collected into 10%NBF for pathology analysis.

[2477] IHC Analysis: On Day 29, the left Inguinal fat tissue will be collected into 10%NBF for UCP-1 IHC staining and analysis. The pancreas tissues was stained for beta-cells (insulin) and alpha cells (glucagon).

[2478] Histopathology Analysis: On Day 29, the liver left lobe will be collected into 10%NBF for H& E analysis. The left Inguinal fat tissue will be collected into 10%NBF for H& E analysis. The pancreas tissue will be collected into 10%NBF for H& E analysis.

[2479] Western Blot Analysis: The same lobe of liver tissues and muscles from all mice will be collected for WB analysis, including CBP, EP300 and Vinculin.

[2480] Results: Mice dosed with Compound 1 b at 1 mpk showed no change in body weight as compared to vehicle and Mice dosed with Compound 1 b at 1 mpk showed less body weight change than mice dosed with semaglutide (Figure 1). Mice dosed with Compound 1b showed no effects on food or water consumption as compared to semaglutide which showed a decrease in food and water consumption in the initial days (Figure 2a and 2b).

[2481] In the Oral Glucose Tolerance Test, Compound 1b showed a faster return to baseline glucose levels and lower AUG values indicates better glucose tolerance (more efficient processing of glucose) in mice than semaglutide (Figure 3a-3d. In the insulin tolerance test, Compound 1b showed a faster drop in blood glucose and lower AUG values indicates higher insulin sensitivity (better response to insulin) in mice than semaglutide (Figur4a and 4b).

[2482] In the DIO model, semaglutide can induce lean mass loss of about 5-15%, whereas Compound 1b at 1 mpk showed no lean mass loss (Figure 5c). In the DIO model, compound 1b showed more decrease in Leptin than Semaglutide. In the DIO model, Compound 1 b showed that selective CBP degradation in muscle and liver tissue (Figure 7a-7b and 8a-8b) Compound 1 b at 10 mpk and Semaglutide showed similar reduction in adipocyte size (Figure 9).

[2483] Example 2: Treatment of Mice with CBP degrader

[2484] Animals: 88 male C57BL / 6J background mice were subjected to either a normal chow diet (groups 8-11, ”NC) or high fat diet (groups 1-7, "HFD”).

[2485] Vehicle 1 is 20% Captisol (w / v) in 50% Kreb-Ringer Buffer.

[2486] Vehicle 2 is PBS.

[2487] Compound 225c Preparation: The 10 mpk dose was prepapred by mixing 20 mg of Compound 225c in 9.970 mL 20% Captisol (w / v) in 50% Kreb-Ringer Buffer to form a uniform suspension and prepared freshly. The 3 mpk dose was prepapred by mixing 2 mL of 10 mpk stock in 4.667 mL 20% Captisol (w / v) in 50% Kreb-Ringer Buffer to form a uniform suspension and prepared freshly. The 1 mpk PATENT

[2488] ATTORNEY DOCKET NO.: 51121-108WO2

[2489] dose was prepapred by mixing 1.0 mL of 3 mpk stock in 2.0 mL 20% Captisol (w / v) in 50% Kreb-Ringer Buffer to form a uniform suspension and prepared freshly.

[2490] Compound 140b Preparation: The 10 mpk dose was prepapred by mixing 20 mg of Compound 140b in 9.910 mL 20% Captisol (w / v) in 50% Kreb-Ringer Buffer to form a uniform suspension and prepared freshly.

[2491] Semaglutide: 1 mg Semaglutide in 9.708 mL PBS buffer was transferred to 7 vials and stored at -80°C, prepared weekly (25 nmol / mL stock solutions). When ready to use, 0.2mL of the solution was mixed with 12.3 mL PBS to get 0.4 nmol / mL solution.

[2492] Tirzepatide: 1 mg Tirzepatide in 41.446 mL PBS buffer was transferred to 7 vials and stored at -80°C, prepared weekly (5 nmol / mL stock solutions). When ready to use, 0.1 mL ...

Claims

PATENTATTORNEY DOCKET NO.: 51121-108WO2What is claimed is:Claims1. A method of treating diabetes, type 2 diabetes, type 2 diabetes mellitus, obesity, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, dyslipidemia, chronic kidney disease, atherosclerosis, diabetic kidney disease, a cognitive disorder, and / or metabolic syndrome in a subject, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

2. A method of treating diabetes in a subject, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

3. A method to induce remission or regression of diabetes, in a subject in need thereof, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

4. A method of treating high blood pressure, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

5. A method for raising HDL-C in a subject in need thereof, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

6. The method of any one of claims 1 to 5, wherein the subject has diabetes.

7. The method of claim 6, wherein the diabetes is type 2 diabetes mellitus.

8. The method of claim 6, wherein the diabetes is refractory.

9. The method of any one of claims 1 to 8, wherein the subject has had diabetes for at least 8 years.

10. The method of any one of claims 1 to 9, wherein the subject has an HbA1c goal of less than 7%.

11. The method of any one of claims 1 to 9, wherein the subject has an HbA1 c goal of equal to or less than 5.7%.

12. The method of any one of claims 1 to 9, wherein the subject has an HbA1c goal of greater than 10%.

13. The method of any one of claims 1 to 9, wherein the subject has an HbA1 c goal of greater thanPATENTATTORNEY DOCKET NO.: 51121-108WO214. The method of any one of claims 1 to 13, wherein the subject age is at least 46 years.

15. The method of claim 14, wherein the subject age is at least 60 years old.

16. The method of any one of claims 1 to 15, wherein the subject is taking an SGLT2 inhibitor.

17. The method of any one of claims 1 to 16, wherein the subject is taking metformin.

18. The method of any one of claims 1 to 17, wherein the subject is not administered a basal insulin.

19. The method of any one of claims 17 to 18, wherein the subject failed to reach their HbA1 c goal while taking metformin and an SGLT2 inhibitor.

20. The method of any one of claim 1 to 19, wherein the subject is not obese.

21. The method of any one of claims 1 to 20, wherein the subject has comorbid high blood pressure.

22. The method of any one of claim 1 to 21, wherein the subject has comorbid low HDL-C.

23. The method of any one of claims 1 to 22, wherein the subject has comorbid obesity.

24. The method of any one of claims 1 to 23, wherein the subject has at least two cardiovascular risk factors.

25. The method of any one of claims 1 to 23, wherein the subject has no cardiovascular risk factors.

26. The method of any one of claim 1 to 24, wherein the subject has comorbid high blood pressure.

27. A method of improving glycemic control in a subject with type 2 diabetes mellitus, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

28. A method of reducing the risk of major adverse cardiovascular events in a subject with type 2 diabetes mellitus, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

29. A method of treating obesity in a subject, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

30. A method for chronic weight management in a subject, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.PATENTATTORNEY DOCKET NO.: 51121-108WO231. A method of improving weight management in a subject, the method comprises administering to the subject an effective amount of an agent that reduces the level and / or activity of CREB-binding protein.

32. The method of any one of claim 1 to 31, wherein the subject has an initial body mass index of 30 kg / m2 or greater or 27 kg / m2 in the presence of at least one weight-related comorbid condition.

33. The method of claim 32, wherein at least one weight-related comorbid condition is hypertension, type 2 diabetes mellitus, or dyslipidemia.

34. The method of any one of claim 1 to 33, wherein the agent that reduces the level and / or activity of CREB-binding protein is administered as an adjunct to diet and exercise.

35. The method of claim of any one of claim 1 to 33, wherein the agent that reduces the level and / or activity of CREB-binding protein is administered as an adjunct to a reduced-calorie diet and increased physical activity.

36. The method of claim of any one of claim 1 to 35, wherein the agent that reduces the level and / or activity of CREB-binding protein is administered in combination with a glucagon-like peptide 1 receptor agonist, or a glucagon-like peptide 1 receptor agonist and glucose-dependent insulinotropic polypeptide receptor agonist.

37. A method of treating, preventing or delaying development of a cognitive disorder in a subject, comprises administering an effective amount of an agent that reduces the level and / or activity of CREB-binding protein, or a pharmaceutically acceptable salt thereof, to the subject once weekly.

38. The method as claimed by claim 37, wherein the cognitive disorder is selected from the group consisting of MCI and dementia.

39. A method of preventing or delaying cognitive decline in a subject, comprises administering an effective amount of an agent that reduces the level and / or activity of CREB-binding protein, or a pharmaceutically acceptable salt thereof, to the subject once weekly.

40. The method of any one of claim 36 to 39, wherein the subject has type 2 diabetes mellitus.

41. A method of improving glycemic control and preventing or delaying cognitive decline in a subject in a subject with type 2 diabetes mellitus, comprises administering an effective amount of an agent that reduces the level and / or activity of CREB-binding protein or a pharmaceutically acceptable salt thereof, to the subject once weekly.PATENTATTORNEY DOCKET NO.: 51121-108WO242. The method of any one of claim 1 to 41, wherein the method results in a reduction in the risk of the subject experiencing cognitive decline.

43. The method of any one of claim 1 to 42, wherein the agent that reduces the level and / or activity of agent that reduces the level and / or activity of CREB-binding protein is a small molecule compound.

44. The method of claim 43, wherein the small molecule compound is a compound of Formula I.

45. The method of claim 44, wherein the small molecule compound has the structure of any one of compounds of Table 1.

46. The method of claim 44, wherein the small molecule compound has the structure of any one of compounds of Table 2.

47. The method of claim 44, wherein the small molecule compound has the structure of any one of compounds of Table 1a.

48. The method of claim 44, wherein the small molecule compound has the structure of any one of compounds of Table 1b.

49. The method of claim 44, wherein the small molecule compound has the structure of any one of compounds of Table 1c.

Images