Alpha-v-beta-8 integrin inhibitors and uses thereof

Abstract

The present disclosure relates to compounds of Formula (A) and Formula (I), for example: (I) or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, L1, L2, L3, Y, and Q are as described herein. Compounds of formula (A) and formula (I) and pharmaceutical compositions thereof are inhibitors of at least one or more of avPs, avPi and avPe integrin. Also disclosed are methods of treating fibrosis, such as non-alcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF), and non-specific interstitial pneumonia (NSIP), as well as cancer, comprising administering the compounds and pharmaceutical compositions thereof.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 435,496, filed December 27, 2022, U.S. Provisional Patent Application No. 63 / 585,565, filed September 26, 2023, and U.S. Provisional Patent Application No. 63 / 593,454, filed October 26, 2023. The contents of these applications are hereby incorporated by reference in their entirety. TECHNICAL FIELD

[0003] The present disclosure generally relates to therapeutic agents that are inhibitors of α V β8 integrin. The therapeutic agents can be used to treat or prevent the treatment of fibrosis, such as idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP). The therapeutic agents can also be used to treat cancer. BACKGROUND

[0004] Fibrosis is a pathological feature of many diseases that results from a dysfunction in the body’s natural ability to repair damaged tissue. If left untreated, fibrosis causes scarring in vital organs, causing damage that cannot be repaired and eventually leading to organ failure.

[0005] Patients with nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis to nonalcoholic steatohepatitis (NASH) and then to fibrosis. While liver fibrosis is reversible in its early stages, progressive liver fibrosis can lead to cirrhosis.

[0006] Kidney fibrosis, characterized by glomerulosclerosis and tubulointerstitial fibrosis, is a common end-stage manifestation of many chronic kidney diseases (CKD). Regardless of the initial cause, progressive CKD often leads to extensive tissue scarring, causing destruction of the kidney parenchyma and end-stage renal failure, a devastating condition that requires dialysis or a kidney transplant.

[0007] Scleroderma encompasses a complex and heterogeneous group of conditions characterized primarily by fibrosis, vascular alterations, and autoimmunity. The conditions in the scleroderma spectrum share the common feature of fibrosis, which causes the skin to become hard or thick. For some patients, this hardening occurs only in limited areas, but for others, it can spread to other major organs.

[0008] Following myocardial infarction, cardiac structural remodeling is associated with an inflammatory response, leading to the formation of scar tissue at the site of the infarction. This scar formation is the result of the deposition of fibrotic tissue, which can lead to decreased cardiac function and disruption of electrical activity within the heart.

[0009] Crohn's disease is a chronic disease of unknown cause that tends to progress even with medical or surgical treatment. Intestinal fibrosis is one of the most common complications of Crohn's disease, which leads to stricture formation in the small intestine and colon.

[0010] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic disease of unknown cause that occurs in adults and is limited to the lungs. In IPF, lung tissue becomes thickened, stiff, and scarred. As pulmonary fibrosis progresses, it becomes more difficult for the lungs to transport oxygen into the blood, and organs do not receive the oxygen needed to function properly. IPF currently affects about 200,000 people in the United States and causes 40,000 deaths per year. Patients diagnosed with IPF experience progressive shortness of breath and eventually complete respiratory failure.

[0011] Primary biliary cholangitis (PBC), also known as primary biliary cirrhosis, is a chronic liver disease that leads to damage and fibrosis of the liver. It is caused by a slow, progressive destruction of the small bile ducts of the liver, leading to the buildup of bile and other toxins in the liver, a condition known as cholestasis. Over time, this leads to scarring and fibrosis in the liver and bile ducts.

[0012] Non-specific interstitial pneumonia (NSIP) is a rare condition that affects the tissue that surrounds and separates the tiny air sacs of the lungs. These air sacs are called alveoli, where the exchange of oxygen and carbon dioxide between the lungs and the bloodstream takes place. Interstitial pneumonia is a disease in which the meshwork walls of the alveoli become inflamed. The pleura, a thin covering that protects and cushions the lungs and individual lobes of the lung, can also become inflamed. NSIP has two main forms, cellular and fibrotic. The cellular form is defined primarily by inflammation of the cells of the interstitium. The fibrotic form is defined by thickening and scarring of the lung tissue. This scarring is called fibrosis and is irreversible. When lung tissue becomes thickened or scarred, it cannot function effectively. Respiratory efficiency is reduced, and oxygen levels in the blood are lower. (Kim et al., Proc. Am. Thorac. Soc. (2006) 3:285-292; Lynch, D., Radiology (2001) 221:583-584; Kinder et al., Am. J. Respir. Crit. Care Med. (2007) 176:691-697)

[0013] Biliary atresia (BA) is a fibroobliterative cholangiopathy that affects approximately 1:5,000 to 1:18,000 infants, causing inflammation that leads to end-stage liver disease. If left without surgical intervention, patients typically die before the age of two. To restore biliary drainage, a cholangioenterostomy can be performed. However, even with restoration of biliary drainage, almost all patients develop liver fibrosis and require a liver transplant to survive (see Mohanty et al., “Rotavirus Reassortant-Induced Murine Model of Liver Fibrosis Parallels Human Biliary Atresia,” Hepatology 71:1316 (2020)).

[0014] Ocular fibrosis encompasses a variety of eye conditions. For example, TGF signaling in epithelial cells has been shown to cause epithelial-mesenchymal transition (EMT), leading to fibrosis with similarities to cataract formation. Examples include anterior subcapsular cataract (ASC) and posterior capsular opacification (PCO), which can occur after cataract surgery. Studies have shown that TGF -induced EMT is involved in the wound healing response of lens epithelial cells and can induce expression of various extracellular matrix proteins associated with fibrosis and integrins, leading to the production of alpha-smooth muscle actin (a-SMA)-expressing myofibroblasts and lens fibrocytes that cause vision impairment.

[0015] There are few available treatment processes, as there are currently no market options that have demonstrated an impact on long-term patient survival or symptomology. There remains a need for treatment of fibrotic diseases.

[0016] α V The a8 integrin is expressed in epithelial cells, binds to the latency-associated peptide of transforming growth factor-β1 (TGFβ1), and mediates TGFβ1 activation. Its expression levels are significantly increased after lung and bile duct cell injury and plays a key in vivo role in tissue fibrosis. Increased levels are also associated with increased mortality in IPF and NSIP patients.

[0017] Primary sclerosing cholangitis (PSC) involves inflammation of the bile ducts and fibrosis that occludes the bile ducts. The obstruction to the flow of bile to the intestine can lead to cirrhosis of the liver and subsequent complications, such as liver failure and liver cancer. Expression of avb6 is elevated in the livers and bile ducts of PSC patients. SUMMARY

[0018] Disclosed herein are amino acid compounds that are inhibitors of a8 integrin, compositions containing these compounds, and methods of treating diseases mediated by a8 integrin, such as fibrotic diseases or cancer. V β8 integrin inhibitors, compositions containing these compounds, and methods of treating diseases mediated by a8 integrin, such as fibrotic diseases or cancer. V β8 integrin inhibitors, compositions containing these compounds, and methods of treating diseases mediated by a8 integrin, such as fibrotic diseases or cancer.

[0019] In one aspect, there is provided a compound of Formula (A) as detailed herein, or any variation thereof, or a salt (e.g., a pharmaceutically acceptable salt thereof).

[0020] In one aspect, there is provided a compound of Formula (I) as detailed herein, or any variation thereof, or a salt (e.g., a pharmaceutically acceptable salt thereof).

[0021] Further provided is a pharmaceutical composition comprising a compound of Formula (A) as detailed herein, or any variation thereof, or a salt (e.g., a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier or excipient.

[0022] Further provided is a pharmaceutical composition comprising a compound of Formula (I) as detailed herein, or any variation thereof, or a salt (e.g., a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier or excipient.

[0023] Also provided is a pharmaceutical composition comprising a compound of Formula (A) as detailed herein, or any variation thereof, or a salt (e.g., a pharmaceutically acceptable salt thereof), a checkpoint inhibitor, and a pharmaceutically acceptable carrier or excipient.

[0024] Also provided is a pharmaceutical composition comprising a compound of Formula (I) as detailed herein, or any variation thereof, or a salt (e.g., a pharmaceutically acceptable salt thereof), a checkpoint inhibitor, and a pharmaceutically acceptable carrier or excipient.

[0025] In another aspect, there is provided a method of treating a fibrotic disease or condition in a subject (e.g., a human) in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (A) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method of treating a fibrotic disease or condition in a subject (e.g., a human) in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the fibrotic disease or condition is lung, liver, kidney, heart, skin, or gastrointestinal fibrosis. In other embodiments, the fibrotic disease or condition is idiopathic pulmonary fibrosis, interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), fibrosis induced by alcoholic liver disease, Agar-Ell syndrome, primary sclerosing cholangitis, primary biliary cholangitis (also known as primary biliary cirrhosis), interstitial lung disease associated with systemic sclerosis, scleroderma (also known as systemic sclerosis), diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, biliary atresia, and Crohn’s disease.

[0026] In another aspect, there is provided a method of delaying the onset and / or progression of a fibrotic disease or condition in an individual (such as a human) at risk of developing a fibrotic disease or condition, comprising administering to the individual a therapeutically effective amount of a compound of Formula (A) as described herein, or any variation thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method of delaying the onset and / or progression of a fibrotic disease or condition in an individual (such as a human) at risk of developing a fibrotic disease or condition, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I) as described herein, or any variation thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is pulmonary, liver, kidney, cardiac, skin, or gastrointestinal fibrosis. In other embodiments, the fibrotic disease or condition is idiopathic pulmonary fibrosis, interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), fibrosis induced by alcoholic liver disease, Agar-Ell syndrome, primary sclerosing cholangitis, primary biliary cholangitis (also known as primary biliary cirrhosis), interstitial lung disease associated with systemic sclerosis, scleroderma (also known as systemic sclerosis), diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, biliary atresia, and Crohn’s disease.

[0027] Also provided are compounds of Formula (A) as described herein, or any variation thereof, or a pharmaceutical composition thereof, for use in the treatment of a fibrotic disease.

[0028] Also provided are compounds of Formula (I) as described herein, or any variation thereof, or a pharmaceutical composition thereof, for use in the treatment of a fibrotic disease.

[0029] Also provided is the use of a compound of Formula (A) as described herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.

[0030] Also provided is the use of a compound of Formula (I) as described herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.

[0031] Further provided is the use of a compound of Formula (A) as described herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of a disease mediated by cells expressing α V β1 and / or α V β8. Further provided is the use of a compound of Formula (I) as described herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of a disease mediated by cells expressing α V β1 and / or α VUse of β8 cells in cell-mediated diseases. In some embodiments, the cells are associated with the intrahepatic biliary system. In some embodiments, the cells are associated with the extrahepatic biliary system. In some embodiments, the cells are associated with both the intrahepatic and extrahepatic biliary systems.

[0032] Further, kits are provided that comprise compounds of formula (A) detailed herein, or any variations thereof, or pharmaceutically acceptable salts thereof. Kits are also provided that comprise compounds of formula (I) detailed herein, or any variations thereof, or pharmaceutically acceptable salts thereof. In some embodiments, the kit comprises instructions for use according to the methods described herein, such as methods for treating an individual with fibrotic disease. In some embodiments, the kit comprises instructions for use according to the methods described herein, such as methods for treating an individual with cancer.

[0033] Kits are also provided that contain compounds of formula (A) detailed herein, or any variations thereof, or pharmaceutically acceptable salts thereof, and checkpoint inhibitors. Kits are also provided that contain compounds of formula (I) detailed herein, or any variations thereof, or pharmaceutically acceptable salts thereof, and checkpoint inhibitors. In some embodiments, the kits include instructions for use according to the methods described herein, such as methods for treating an individual with fibrotic disease. In some embodiments, the kits include instructions for use according to the methods described herein, such as methods for treating an individual with cancer.

[0034] Further, it provides information on suppressing α in individuals. V Methods of administration of β8 integrin include administering a compound of formula (A) detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof.

[0035] Further, it provides information on suppressing α in individuals. V Methods of administration of β8 integrin include administering a compound of formula (I) detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof.

[0036] It also provides methods for inhibiting α in individuals who require it. V β1, α V β6 or α V Methods involving one or more of β8 integrins, including administering to the individual a compound of formula (A) detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0037] It also provides methods for inhibiting α in individuals who require it. V β1, α V β6 or α VMethods of inhibiting one or more of the β8 integrins, comprising administering to the individual a compound of Formula (I) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0038] Further provided are methods of inhibiting TGFβ activation in a cell, comprising administering to the cell a compound of Formula (A) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0039] Further provided are methods of inhibiting TGFβ activation in a cell, comprising administering to the cell a compound of Formula (I) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0040] Also provided is the use of a compound of Formula (A) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.

[0041] Also provided is the use of a compound of Formula (I) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.

[0042] Also provided is the use of a compound of Formula (A) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease mediated by cells expressing one or more of: V β1; α V β6; and α V β8. Also provided is the use of a compound of Formula (I) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease mediated by cells expressing one or more of: V β1; α V β6; and α V β8. For example, in some embodiments, the disease is mediated by cells expressing α V β1. In some embodiments, the disease is mediated by cells expressing α V β6. In some embodiments, the disease is mediated by cells expressing α V β8. In some embodiments, the disease is mediated by cells expressing α V β1 and α V β6. In some embodiments, the disease is mediated by cells expressing α V β1 and α V β8. In some embodiments, the fibrotic disease is mediated by cells expressing α V β6 and α VCell-mediated by cells expressing one or more of: a V β1, a V β6, and a V β8.

[0043] In another aspect, there is provided a method of treating cancer in an individual in need thereof, comprising administering to the individual a compound of Formula (A) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the method further comprises administering to the individual a checkpoint inhibitor.

[0044] In another aspect, there is provided a method of treating cancer in an individual in need thereof, comprising administering to the individual a compound of Formula (I) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the method further comprises administering to the individual a checkpoint inhibitor.

[0045] Also provided is the use of a compound of Formula (A) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of cancer.

[0046] Also provided is the use of a compound of Formula (I) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of cancer.

[0047] Also provided is the use of a compound of Formula (A) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a checkpoint inhibitor, together in the manufacture of a medicament for the treatment of a disease mediated by cells expressing one or more of: a V β1; a V β6; and a V β8. Also provided is the use of a compound of Formula (A) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a checkpoint inhibitor, together in the manufacture of a medicament for the treatment of cancer.

[0048] Also provided is the use of a compound of Formula (I) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a checkpoint inhibitor, together in the manufacture of a medicament for the treatment of a disease mediated by cells expressing one or more of: a V β1; a V β6; and a V β8. Also provided is the use of a compound of Formula (I) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a checkpoint inhibitor, together in the manufacture of a medicament for the treatment of cancer.

[0049] Further, methods for treating subjects in need are provided. In some embodiments, the method includes providing the subject. In some embodiments, the subject includes at least one tissue requiring treatment. In some embodiments, the at least one tissue is characterized by at least one value being elevated compared to a healthy value for the tissue in a healthy state. In some embodiments, the tissue includes α... V Elevated levels of β1 integrin activity and / or expression. In some embodiments, the tissue includes α V Elevated levels of β6 integrin activity and / or expression. In some embodiments, the tissue includes α V Elevated levels of β8 integrin activity and / or expression. In some embodiments, the tissue includes an elevated pSMAD / SMAD ratio. In some embodiments, the tissue includes an elevated level of new collagen formation or accumulation. In some embodiments, the tissue includes an elevated level of total collagen. In some embodiments, the tissue includes an elevated level of type I collagen gene Col1a1 expression. In some embodiments, the tissue includes an elevated level of perforin. In some embodiments, the tissue includes an elevated level of granzyme B. In some embodiments, the tissue includes an elevated level of interferon-γ. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of formula (A) detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I) detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0050] Also provided are methods of characterizing the anti-cancer activity of a small molecule inhibitor in a subject. In some embodiments, the method comprises providing a first live cell sample from the subject. In some embodiments, the first live cell sample is characterized by the presence of at least one integrin capable of activating transforming growth factor beta (TGF-beta) from a latency-associated peptide TGF-beta. In some embodiments, the method comprises determining a first value in the first live cell sample. In some embodiments, the first value is a pSMAD2 / SMAD2 ratio. In some embodiments, the first value is a pSMAD3 / SMAD3 ratio. In some embodiments, the first value is a perforin level. In some embodiments, the first value is a granzyme B level. In some embodiments, the first value is an interferon gamma level. In some embodiments, the method comprises administering the small molecule to the subject. In some embodiments, the method comprises providing a second live cell sample from the subject. In some embodiments, the second live cell sample is taken from the same tissue in the subject as the first live cell sample. In some embodiments, the method comprises determining a second value in the second live cell sample. In some embodiments, the second value corresponds to the first value of pSMAD2 / SMAD2 ratio, pSMAD3 / SMAD3 ratio, perforin level, granzyme B level, or interferon gamma level. In some embodiments, the anti-cancer activity of the small molecule in the subject is characterized by comparing the second value to the first value.

[0051] In another aspect, methods of making a compound of Formula (A), or any variation thereof, are provided. Also provided are compound intermediates useful in the synthesis of a compound of Formula (A), or any variation thereof.

[0052] In another aspect, methods of making a compound of Formula (I), or any variation thereof, are provided. Also provided are compound intermediates useful in the synthesis of a compound of Formula (I), or any variation thereof.

[0053] In another aspect, a compound of Formula (A), or any variation thereof, made by the methods disclosed herein is provided.

[0054] In another aspect, a compound of Formula (I), or any variation thereof, made by the methods disclosed herein is provided.

[0055] It is to be understood that several aspects and variations described herein also include aspects and variations that "consist of" and / or "consist essentially of." BRIEF DESCRIPTION OF DRAWINGS

[0056] Figure 1is a graphic illustrating several aspects of integrin-mediated TGF-β activation in tumor adaptive immunity.

[0057] Figure 2A is a graphic illustrating a preliminary experiment performed in mice.

[0058] Figure 2B is a graphic showing that EMT6 cell proliferation is not affected by anti-α V β8 or IgG control in vitro.

[0059] Figure 3A is a graphic showing tumor volume over time for the short group of the study of Example B3.

[0060] Figure 3B is a graphic showing tumor volume over time for the long group of the study of Example B3.

[0061] Figure 4A is a graphic showing tumor volume versus time for the 1stgroup of mice.

[0062] Figure 4B is a graphic showing tumor volume versus time for the 2ndgroup of mice.

[0063] Figure 4C is a graphic showing tumor volume versus time for the 3rdgroup of mice.

[0064] Figure 4D is a graphic showing tumor volume versus time for the 4thgroup of mice.

[0065] Figure 4E is a graphic showing tumor volume versus time for the 5thgroup of mice.

[0066] Figure 5 is a graphic showing percent survival over time for 5 weeks, showing that the combination of anti-PD1 and anti-α V β8 antibodies significantly improved long-term survival in the 4thgroup.

[0067] Figure 6A is a graphic showing that inhibition of α V β8 significantly reduced SMAD3 phosphorylation in the 3rdand 4thgroups, consistent with a significant reduction in TGFβ signaling inside tumor cells.

[0068] Figure 6B is a graphic showing that inhibition of α V β8 significantly reduced integrin α V β1 expression in myofibroblasts.

[0069] Figure 7A is a bar graph showing granzyme B expression assessed by immunohistochemical staining with anti-granzyme B antibody in EMT6 tumors treated with anti-αV Significant enhancement in Group 3 and Group 4 of β8 antibodies.

[0070] Figure 7B is a graph showing CD8+ cytotoxic T cells in the presence of anti-α V Increased in Group 3 of β8 antibodies, and in Group 4 of β8 antibodies when combined with anti-PD-1 and anti-α V Graph showing significant increase in Group 4 of β8 antibodies.

[0071] Figure 8A is a graph showing α V β8 inhibition results in cytotoxic T cell activation 14 days after perforin (PRF1) treatment.

[0072] Figure 8B is a graph showing α V β8 inhibition results in cytotoxic T cell activation 14 days after granzyme B (GZMB) treatment.

[0073] Figure 8C is a graph showing α V β8 inhibition results in cytotoxic T cell activation 14 days after interferon gamma (IFNg) treatment.

[0074] Figure 8D is a graph showing α V β8 inhibition results in cytotoxic T cell activation 14 days after Fas ligand (FASL) treatment.

[0075] Figure 9A is a graph showing upregulation of CD8 T cells by α V β8 inhibition.

[0076] Figure 9B is a graph showing upregulation of NK cells by α V β8 inhibition.

[0077] Figure 9C is a graph showing upregulation of cytotoxic T cells by α V β8 inhibition.

[0078] Figure 10A shows tumor antibody concentration (left axis) and pSMAD3 / SMAD3 ratio (right axis) indicating treatment with anti-α V β8 antibodies in combination with anti-PD-1 antibodies has a clear dose response relationship.

[0079] Figure 10B shows anti-α VThe clear dose response relationship of the β8 antibody in combination with anti-PD-1 antibody versus Granzyme B (pg / mL, left axis) and Interferon gamma (IFNy, pg / mL, right axis).

[0080] Figure 11 The anti-α V Results of the β8 antibody in combination with anti-PD1, anti-PDL1 or anti-CTLA-4 resulted in similar T cell activation.

[0081] Figure 12A is a graphical representation of experiments performed in mice.

[0082] Figure 12B is a table showing the compounds and doses used for each group.

[0083] Figure 13 is a graph showing the change in tumor volume over time for mice bearing EMT6 tumors in the study of Example B6. Treatment with Compound 39 + anti-mPD-1 significantly (*p<0.05, one-way ANOVA) reduced tumor growth of EMT6 tumors by day 21 of treatment compared to vehicle. Tumors were monitored for an additional 7 days until day 28. Bars: ± standard error of the mean.

[0084] Figure 14A is a bar graph comparing CD8 + T cell density in EMT6 tumors for different dosing regimens in the study of Example B6. Treatment with Compound 39 + anti-mPD-1 significantly increased the number of CD8 + T cells in tumors. Bars: ± standard deviation; n=10 in each group; ns: not significant. ****=p<0.0001 (by one-way ANOVA)

[0085] Figure 14B shows CD8 staining of EMT6 tumors receiving different dosing regimens in the study of Example B6. Treatment with Compound 39 + anti-mPD-1 significantly increased the number of CD8 + T cells in tumors.

[0086] Figure 14C shows CD8 staining of EMT6 tumors receiving different dosing regimens in the study of Example B6. CD8 + T cells were arranged at the periphery of tumors treated with vehicle or vehicle + anti-mPD-1, but were numerous and inside tumors treated with Compound 39 + anti-mPD-1.

[0087] Figure 15AThis is a graph showing the change in tumor volume over time in mice with EMT6 tumors in the study of Example B6. Treatment with compound 39 + anti-mPD-1 significantly attenuated EMT6 tumor growth (*p<0.05 by two-way ANOVA compared to mediator + Rat IgG2A). Bars in the growth curves: mean ± standard error. N (number of mice) = 9 in the mediator + anti-mPD-1 group and n = 10 in the compound 39 + anti-mPD-1 group.

[0088] Figure 15B This is a comparative study of CD8 in EMT6 tumors using different dosing regimens in Example B6. + Bar chart of T cell density. Compound 39+ anti-mPD-1 treatment reduced CD8... + Significantly greater T cell infiltration. Bars on the histogram: ± standard deviation; according to Student's t-test (unpaired, two-tailed), **** = p < 0.0001. N (number of mice) = 9 mice in the mediator + anti-mPD-1 group and 10 mice in the compound 39 + anti-mPD-1 group.

[0089] Figure 15C This is a comparative study of granzyme B in EMT6 tumors using different dosing regimens in Example B6. + Bar chart of cell density. Compound 39 + anti-mPD-1 treatment increased the number of granzyme B positive cells. Bars on the histogram: ± standard deviation; Student's t-test (unpaired, two-tailed), *p = 0.0291 for granzyme B. N (number of mice) = 9 in the vector + anti-mPD-1 group and 10 in the compound 39 + anti-mPD-1 group.

[0090] Figure 15D This is a comparative study of FoxP3 in EMT6 tumors using different dosing regimens in Example B6. + Bar chart of cell density. Compound 39+ anti-mPD-1 treatment did not induce Treg cells (=FoxP3). + Differences were observed in cell infiltration. Bars on the histogram: ± standard deviation; ns: not significant (by Student's t-test). N (number of mice) = 9 mice in the mediator + anti-mPD-1 group, and n = 10 mice in the compound 39 + anti-mPD-1 group.

[0091] Figure 15E This is a comparative study of PD-L1 in EMT6 tumors using different dosing regimens in Example B6. +Histogram of cell density. Compound 39 + anti-mPD-1 treatment resulted in increased PD-L1 expression compared to vehicle + anti-mPD-1 treatment. Bars on histogram: ± standard deviation; *p = 0.0169 for PD-L1 by Student's t-test (unpaired, two-tailed). N (number of mice) = 9 in vehicle + anti-mPD-1 group, n = 10 in compound 39 + anti-mPD-1 group.

[0092] Figure 16A is a graph showing tumor volume over time in mice bearing Pan02 tumors in the study of Example B6. Compound 39 + anti-mPD-1 combination treatment was more effective at reducing tumor growth and volume compared to anti-a V β8 treatment + anti-mPD-1. Error bars in growth curves: ± standard error of the mean, n = 10 mice in each group, **** = p < 0.0001 (one-way ANOVA), and ns: not significant.

[0093] Figure 16B is a histogram comparing CD8 + T cell density in Pan02 tumors between different dosing regimens in the study of Example B6. Compound 39 + anti-mPD-1 treatment (right bar) resulted in a significant increase in CD8 + T cell infiltration compared to vehicle + anti-mPD-1 treatment (left bar). n = 10 mice in each group, bars on histogram: ± standard deviation, **** = p < 0.0001 (Student's t-test), and ns: not significant.

[0094] Figure 16C is a histogram comparing Granzyme B + cell density in Pan02 tumors between different dosing regimens in the study of Example B6. Compound 39 + anti-mPD-1 treatment (right bar) resulted in a significant increase in Granzyme B release compared to vehicle + anti-mPD-1 treatment (left bar). n = 10 mice in each group, bars on histogram: ± standard deviation, **** = p < 0.0001 (Student's t-test), and ns: not significant.

[0095] Figure 16D is a histogram comparing PD-L1 + cell density in Pan02 tumors between different dosing regimens in the study of Example B6. Compound 39 + anti-mPD-1 treatment (right bar) resulted in a significant increase in PD-L1 expression compared to vehicle + anti-mPD-1 treatment (left bar). n = 10 mice in each group, bars on histogram: ± standard deviation, **** = p < 0.0001 (one-way ANOVA), and ns: not significant.

[0096] Figure 16E FoxP3 in Pan02 tumors between different dosing regimens in the study comparing Example B6 + Cell density. Compound 39 + anti-mPD-1 treatment (right column) did not result in differences in T reg Cell (marked by FoxP3 + Cell marker) compared to vehicle + anti-mPD-1 treatment (left column). n = 10 mice per group, bars on histograms: ± standard deviation, **** = p < 0.0001 (one-way ANOVA), and ns: not significant.

[0097] Figure 17A is a graph showing tumor volume over time in mice bearing CT26 tumors in the study of Example B6. Compound 39 + anti-mPD-1 combination treatment significantly reduced tumor growth and volume compared to anti-mPD-1 + vehicle treatment in CT26 tumor-bearing mice. Error bars in growth curves: ± standard error of the mean. *** = p < 0.001 (two-way ANOVA). n = 10 mice per group.

[0098] Figure 17B is a bar graph showing CD8 + T cell density in CT26 tumors for different dosing regimens in the study comparing Example B6. Compound 39 + anti-mPD-1 treatment (right column) resulted in a significant increase in CD8 + T cell infiltration compared to vehicle + anti-mPD-1 treatment (left column). Bars on histograms: ± standard deviation; * = p < 0.05 (Student’s t-test). n = 10 mice per group.

[0099] Figure 17C is a representative immunohistochemistry (IHC) image showing CD8 + Cells in CT26 tumors receiving different dosing regimens in the study of Example B6.

[0100] Figure 18A is a graph showing tumor volume over time in mice bearing A20 tumors in the study of Example B6.

[0101] Figure 18B is a graph showing tumor volume over time in mice bearing RM-1 tumors in the study of Example B6.

[0102] Figure 18C is a graph showing tumor volume over time in mice bearing B16F10 tumors in the study of Example B6.

[0103] Figure 18D is a bar graph showing CD8+ Histogram of T cell density. n = 10 mice per group. Ns = not significant (using Student's t-test).

[0104] Figure 18E CD8 staining of A20 tumors receiving different dosing regimens in the study of Example B6 is shown.

[0105] Figure 18F is a comparison of CD8 + Histogram of T cell density. n = 10 mice per group. Ns = not significant (using Student's t-test).

[0106] Figure 18G CD8 staining of RM-1 tumors receiving different dosing regimens in the study of Example B6 is shown.

[0107] Figure 18H is a comparison of CD8 + Histogram of T cell density. n = 10 mice per group. Ns = not significant (using Student's t-test).

[0108] Figure 18I CD8 staining of B16F10 tumors receiving different dosing regimens in the study of Example B6 is shown.

[0109] Figure 19 A summary of the study design for the study of Example B10 is shown.

[0110] Figure 20A A schematic of the treatment regimen for the study of Example B11 is shown.

[0111] Figure 20B Tumor weights of KPC tumors in mice treated with Compound 39 alone or in combination with anti-PD-1 Ab are shown. Error bars ± S.D. and p-values derived by one-way ANOVA.

[0112] Figure 20C Tumor weights of KPC tumors in mice treated with ADWA-11 alone or in combination with anti-PD-1 are shown. Error bars ± S.D. and p-values derived by one-way ANOVA.

[0113] Figure 21A Graphs measuring the average percentage of CD8+ cells in each ROI in the invasive margin in mice treated with Compound 39 alone or in combination with anti-PD-1 Ab are shown. Bars ± SEM and p-values derived by one-way ANOVA.

[0114] Figure 21BGraphical representation of the mean percentage of CD8+ cells in each region of origin (ROI) of internal KPC tumors treated with compound 39 alone or in combination with anti-PD-1Ab. Columns ± SEM and p-values ​​derived by one-way ANOVA.

[0115] Figure 21C Graphical representation of the mean percentage of CD8+ cells in each ROI within an invasive margin treated alone or in combination with anti-PD-1. Columns ± SEM and p-values ​​derived by one-way ANOVA.

[0116] Figure 21D Graphical representation of the mean percentage of CD8+ cells in each region of origin (ROI) of internal KPC tumors treated with ADWA-11 alone or in combination with anti-PD-1. Columns ± SEM and p-values ​​derived by one-way ANOVA.

[0117] Figure 21E Graphical representation of the mean percentage of CD4+ cells in each ROI at the edge of an invasive site treated alone or in combination with anti-PD-1Ab. Column ± SEM and p-values ​​derived by one-way ANOVA.

[0118] Figure 21F Graphical representation of the mean percentage of CD4+ cells in each region of origin (ROI) of internal KPC tumors treated with compound 39 alone or in combination with anti-PD-1Ab. Columns ± SEM and p-values ​​derived by one-way ANOVA.

[0119] Figure 22A Paraffin-fixed KPC tumor sections stained with Pico Sirius Red (PSR) are shown for the mediator (left) and for the KPC tumor treated with compound 39 (right).

[0120] Figure 22B Show depiction of the medium and use Figure 22A A bar chart of the total birefringence of KPC tumors treated with compound 39. Columns ± SEM and p-values ​​obtained by Student's t-test, * = 0.05.

[0121] Figure 23A A schematic diagram depicting the treatment protocol used in a KPC tumor mouse study for survival research related to Example B11.

[0122] Figure 23B First Kaplan-Meier survival curves for indicated treatment in mice bearing KPC tumors are plotted. P-values ​​obtained by log-rank analysis are *p = 0.015, **p = 0.0059, and ***p = < 0.0001.

[0123] Figure 23CSecond Kaplan Meier survival curves depicting indicated treatments in KPC tumor-bearing mice. P values derived from log-rank analysis, *p=0.015, **p=0.0059, and ***p=<0.0001.

[0124] Figure 24A Schematic depicting treatment regimen in TKCC-10 mice for the study related to Example B12.

[0125] Figure 24B Graph depicting final tumor weights showing TKCC-10 PDX mice treated with Gemcitabine / Abraxane (G / A), Compound 39, and Compound 39 + G / A. P values derived from one-way ANOVA.

[0126] Figure 24C Graph depicting final tumor weights showing TKCC-10 PDX mice treated with Gemcitabine / Abraxane (G / A), ADWA-11, and ADWA-11 + G / A. P values derived from one-way ANOVA.

[0127] Figure 25A Image depicting lung metastases in vehicle-treated TKCC-10 PDX mice.

[0128] Figure 25B Image depicting lung metastases in Compound 39-treated TKCC-10 PDX mice.

[0129] Figure 25C Image depicting lung metastases in Compound 39 + Gemcitabine / Abraxane (G / A)-treated TKCC-10 PDX mice.

[0130] Figure 25D Graph depicting quantification of total lung metastases in TKCC-10 tumor-bearing mice treated with Gemcitabine / Abraxane (G / A), Compound 39, and Compound 39 + G / A for the study related to Example B12. P values derived from one-way ANOVA.

[0131] Figure 25E Graph depicting quantification of total lung metastases in TKCC-10 tumor-bearing mice treated with Gemcitabine / Abraxane (G / A), ADWA-11, and ADWA-11 + G / A for the study related to Example B12. P values derived from one-way ANOVA.

[0132] Figure 26ASchematic depicting treatment regimen in TKCC-05PDAC PDX model for studies related to Example B12.

[0133] Figure 26B Graph depicting quantification of tumor weight in mice treated with Compound 39, Reference Compound B, and ADWA-11 Ab for studies related to Example B12. P values by one-way ANOVA.

[0134] Figure 26C Graph depicting quantification of tumor weight in mice treated with Gemcitabine / Albumin-bound Paclitaxel (G / A), Compound 39 + G / A, Reference Compound B + G / A, and ADWA-11 + G / A for studies related to Example B12. P values by one-way ANOVA.

[0135] Figure 27A Graph depicting tumor growth curves for TKCC-08PDAC PDX (subcutaneous) model treated as indicated for studies related to Example B12.

[0136] Figure 27B Graph depicting quantification of tumor weight in mice treated as indicated for studies related to Example B12. P values by one-way ANOVA, *p = 0.05, and ***p = 0.001.

[0137] Figure 28A First image (left) of pSMAD3 and second image (right) of fibrosis / EMT marker aSMA at 0 hours post-cataract surgery (PCS) for Example B5-1.

[0138] Figure 28B First image (left) of pSMAD3 and second image (right) of fibrosis / EMT marker aSMA at 5 days post-cataract surgery (PCS) for Example B5-1 in relation to Reference Compound A control.

[0139] Figure 28C First image (left) of pSMAD3 and second image (right) of fibrosis / EMT marker aSMA at 5 days post-cataract surgery (PCS) for Example B5-1 in relation to 3 mg / mL Reference Compound A.

[0140] Figure 28D First image (left) of pSMAD3 and second image (right) of fibrosis / EMT marker aSMA at 5 days post-cataract surgery (PCS) for Example B5-1 in relation to 30 mg / mL Reference Compound A.

[0141] Figure 28E First image (left) and second image (right) depicting pSMAD3 (left) and fibrosis / EMT marker aSMA (right) associated with 300 mg / mL reference Compound A 5 days post cataract surgery (PCS) for Example B5-1.

[0142] Figure 28F First image (left) and second image (right) depicting pSMAD3 (left) and fibrosis / EMT marker aSMA (right) associated with Compound C control 5 days post cataract surgery (PCS) for Example B5-1.

[0143] Figure 28G First image (left) and second image (right) depicting pSMAD3 (left) and fibrosis / EMT marker aSMA (right) associated with Compound C 5 days post cataract surgery (PCS) for Example B5-1.

[0144] Figure 28H First image (left) and second image (right) depicting pSMAD3 (left) and fibrosis / EMT marker aSMA (right) associated with Compound D 5 days post cataract surgery (PCS) for Example B5-1.

[0145] Figure 28I Graph depicting the mean fluorescence intensity (MFI) measured for pSMAD3 5 days post cataract surgery (PCS) for various amounts of Compound A, Compound C, and Compound D in Example B5-1.

[0146] Figure 28J Graph depicting the mean fluorescence intensity (MFI) measured for aSMA 5 days post cataract surgery (PCS) for various amounts of Compound A, Compound C, and Compound D in Example B5-1.

[0147] Figure 29A First image (left) and second image (right) depicting fibrosis marker tenascin C (left) and fibrosis / EMT marker aSMA (right) 0 hours post cataract surgery (PCS) for Example B5-1.

[0148] Figure 29B First image (left) and second image (right) depicting fibrosis marker tenascin C (left) and fibrosis / EMT marker aSMA (right) associated with reference Compound A control 5 days post cataract surgery (PCS) for Example B5-1.

[0149] Figure 29C First image (left) and second image (right) depicting fibrosis marker tenascin C (left) and fibrosis / EMT marker aSMA (right) associated with 3 mg / mL reference Compound A 5 days post cataract surgery (PCS) for Example B5-1.

[0150] Figure 29D Depiction of first image (left) of fibrosis marker Tenascin C and second image (right) of fibrosis / EMT marker aSMA associated with 30 mg / mL reference Compound A for Example B5-1 at 5 days post cataract surgery (PCS).

[0151] Figure 29E Depiction of first image (left) of fibrosis marker Tenascin C and second image (right) of fibrosis / EMT marker aSMA associated with 300 mg / mL reference Compound A for Example B5-1 at 5 days post cataract surgery (PCS).

[0152] Figure 29F Depiction of first image (left) of fibrosis marker Tenascin C and second image (right) of fibrosis / EMT marker aSMA associated with Compound C control for Example B5-1 at 5 days post cataract surgery (PCS).

[0153] Figure 29G Depiction of first image (left) of fibrosis marker Tenascin C and second image (right) of fibrosis / EMT marker aSMA associated with Compound C for Example B5-1 at 5 days post cataract surgery (PCS).

[0154] Figure 29H Depiction of first image (left) of fibrosis marker Tenascin C and second image (right) of fibrosis / EMT marker aSMA associated with Compound D for Example B5-1 at 5 days post cataract surgery (PCS).

[0155] Figure 29I Depiction of graph of mean fluorescence intensity (MFI) of Tenascin C measured for various amounts of Compound A, Compound C, and Compound D for Example B5-1 at 5 days post cataract surgery (PCS).

[0156] Figure 30A Depiction of first image (left) of fibrosis marker Fibronectin and second image (right) of fibrosis / EMT marker aSMA for Example B5-1 at 0 hours post cataract surgery (PCS).

[0157] Figure 30B Depiction of first image (left) of fibrosis marker Fibronectin and second image (right) of fibrosis / EMT marker aSMA associated with reference Compound A control for Example B5-1 at 5 days post cataract surgery (PCS).

[0158] Figure 30CFirst image (left) and second image (right) depicting fibrosis marker fibronectin and fibrosis / EMT marker aSMA associated with 3 mg / mL reference compound A 5 days post cataract surgery (PCS) for Example B5-1.

[0159] Figure 30D First image (left) and second image (right) depicting fibrosis marker fibronectin and fibrosis / EMT marker aSMA associated with 30 mg / mL reference compound A 5 days post cataract surgery (PCS) for Example B5-1.

[0160] Figure 30E First image (left) and second image (right) depicting fibrosis marker fibronectin and fibrosis / EMT marker aSMA associated with 300 mg / mL reference compound A 5 days post cataract surgery (PCS) for Example B5-1.

[0161] Figure 30F First image (left) and second image (right) depicting fibrosis marker fibronectin and fibrosis / EMT marker aSMA associated with compound C control 5 days post cataract surgery (PCS) for Example B5-1.

[0162] Figure 30G First image (left) and second image (right) depicting fibrosis marker fibronectin and fibrosis / EMT marker aSMA associated with compound C 5 days post cataract surgery (PCS) for Example B5-1.

[0163] Figure 30H First image (left) and second image (right) depicting fibrosis marker fibronectin and fibrosis / EMT marker aSMA associated with compound D 5 days post cataract surgery (PCS) for Example B5-1.

[0164] Figure 30I Graph depicting the average fluorescence intensity (MFI) of fibronectin measured 5 days post cataract surgery (PCS) for various amounts of compound A, compound C, and compound D in Example B5-1.

[0165] Figure 30J Graph depicting the number of nuclei per slice measured 5 days post cataract surgery (PCS) for various amounts of compound A, compound C, and compound D in Example B5-1.

[0166] Figure 31 Graph depicting the inhibition of tumor growth in EMT6 tumors by vehicle and compound 39 associated with Example B6.

[0167] Figure 32AImages of CD8 T cells associated with tumors for Compound 39 related to Example B6 + T cells.

[0168] Figure 32B Images of CD8 T cells associated with tumors for Compound 39 related to Example B6 + T cells.

[0169] Figure 32C Images showing CD8 T cells / mm2of tissue for Vehicle and Compound 39 related to Example B6 + T cells / mm 2 of tissue.

[0170] Figure 33 Images showing decreased TGFp activity for Compound 39 compared to Vehicle.

[0171] Figure 34A Images showing increased expression of IFNy regulated gene Granzyme B for Compound 39 compared to Vehicle.

[0172] Figure 34B Images showing increased expression of IFNy regulated gene IFNy for Compound 39 compared to Vehicle.

[0173] Figure 34C Images showing increased expression of IFNy regulated gene CXCL9 for Compound 39 compared to Vehicle.

[0174] Figure 34D Images showing increased expression of IFNy regulated gene PDL1 for Compound 39 compared to Vehicle.

[0175] Figure 35 Survival curves depicting the probability of survival over a 30 day period for Vehicle, Vehicle + anti-mPD-1, and Compound 39 + anti-mPD-1.

[0176] Figure 36 Images depicting the EMT-6 syngeneic model for Vehicle, anti-PD1 + Vehicle, Compound 39, and anti-PD1 + a V p8 SMI show tumor volume over a thirty day period.

[0177] Figure 37 Images depicting for Vehicle, anti-mPD-1, a V p8 small molecule inhibitor (SMI), and anti-mPD-1 + a V p8 SMI show CD8 + T cells / mm 2**p < 0.01 by one-way ANOVA, and ****p < 0.0001 by one-way ANOVA.

[0178] Figure 38 For vehicle, anti-mPD-1 + vehicle, a V β8 small molecule inhibitor (SMI) and anti-mPD-1 + a V β8 SMI depicts I-O for various enzymes.

[0179] Figure 39 For vehicle and Compound 39 depicts graphs showing tumor volume in EMT6 tumors over a 15 day period.

[0180] Figure 40A Depicts graphs showing plasma biomarker response of CXCL9 after 14 days of monotherapy with Compound 39.

[0181] Figure 40B Depicts graphs showing plasma biomarker response of VEGF a after 14 days of monotherapy with Compound 39.

[0182] Figure 41 Depicts graphs showing inhibition of tumor growth in Pan02 tumors by Rat IgG2a + vehicle, anti-mPD-1 + vehicle, and anti-mPD-1 + Compound 39 over a 30 day period.

[0183] Figure 42 Depicts graphs comparing pSMAD3 / SMAD3 between vehicle + Rat IgG2a, anti-mPD-1 + vehicle, and anti-mPD-1 + Compound 39.

[0184] Figure 43 Depicts graphs comparing the size of CD8 + T cells / mm 2 of tumors between vehicle, anti-mPD-1, and anti-mPD-1 + Compound 39.

[0185] Figure 44 For IgG + vehicle, anti-mPD-1 + vehicle, and Compound 39 + anti-mPD-1 depicts graphs showing tumor volume in EMT6 syngeneic model up to 15 days post-treatment.

[0186] Figure 45A Depicts percentage of total non-granulocytes associated with healthy group, vehicle + IgG group, vehicle + a-mPD-1 group, and a-mPD-1 + Compound 39 group.

[0187] Figure 45BPercentages of total T cells associated with the healthy group, vehicle + IgG group, vehicle + a-mPD-1 group, and a-mPD-1 + Compound 39 group are depicted.

[0188] Figure 45C Percentages of total CD8 T cells associated with the healthy group, vehicle + IgG group, vehicle + a-mPD-1 group, and a-mPD-1 + Compound 39 group are depicted. +

[0189] Figure 45D Percentages of non-granulocytes associated with the healthy group, vehicle + IgG group, vehicle + a-mPD-1 group, and a-mPD-1 + Compound 39 group are depicted.

[0190] Figure 45E Percentages of CD4 T cells associated with the healthy group, vehicle + IgG group, vehicle + a-mPD-1 group, and a-mPD-1 + Compound 39 group are depicted. +

[0191] Figure 45F Percentages of tissue-homing Treg cells associated with the healthy group, vehicle + IgG group, vehicle + a-mPD-1 group, and a-mPD-1 + Compound 39 group are depicted.

[0192] Figure 46 Graphs depicting tumor weight in the immunocompetent KPC model for each group are depicted. Statistical evaluation by one-way ANOVA.

[0193] Figure 47 Survival curves in the immunocompetent KPC model for each group over 70 days are depicted. **p<0.01 by one-way ANOVA with Tukey, and ****p<0.0001 by one-way ANOVA with Tukey.

[0194] Figure 48 IFN-g gene signature (top panel) and TGFp gene signature (bottom panel) for vehicle + aPD1 and Compound 39 + a-PD1 are depicted.

[0195] Figure 49 Schematic depicting the association of Compound 39 with ICI responsiveness.

[0196] Figure 50A Images associated with IHC detection of a V betal in lung adenocarcinoma are depicted.

[0197] Figure 50B Images associated with IHC detection of a V betal in prostate cancer are depicted.

[0198] ​​Figure 50C Graph depicting IHC detection of a V b1 in various cancers.

[0199] Figure 51 Graph depicting a V b1 protein expression in fibroblast cells (CAF) associated with various cancers.

[0200] Figure 52 Graph depicting the percent of adherent cells (fraction) of Compound 39 in fibroblast cells (CAF) associated with lung adenocarcinoma cancer from Figure 51

[0201] Graph depicting two Picrosirius staining for vehicle + anti-mPD-1 (top panel) and Compound 39 + anti-mPD-1 (bottom panel). Figure 53A

[0202] Graph depicting the fibrosis composite score for vehicle + anti-PD-1, anti-a V b8 + anti-PD-1, and Compound 39 + anti-mPD-1. Figure 53B

[0203] Graph depicting changes associated with ACTA2 for vehicle + anti-PD-1, anti-a V b8 + anti-PD-1, and Compound 39 + anti-mPD-1. Figure 54A

[0204] Graph depicting changes associated with SERPINE1 for vehicle + anti-PD-1, anti-a V b8 + anti-PD-1, and Compound 39 + anti-mPD-1. Figure 54B

[0205] Graph depicting changes associated with CTHRC1 for vehicle + anti-PD-1, anti-a V b8 + anti-PD-1, and Compound 39 + anti-mPD-1. Figure 54C

[0206] Graph depicting changes associated with SMAD7 for vehicle + anti-PD-1, anti-a V b8 + anti-PD-1, and Compound 39 + anti-mPD-1. Figure 54D

[0207] Graph depicting changes associated with high birefringence (percent) for vehicle and Compound 39. Statistical evaluation by one-way ANOVA with Tukey. Figure 55A

[0208] Figure 55B ​Graph depicting the low birefringence (percent) associated with vehicle and compound 39. Statistical evaluation by one-way ANOVA with Tukey.

[0209] Figure 55C Graph depicting the medium birefringence (percent) associated with vehicle and compound 39. Statistical evaluation by one-way ANOVA with Tukey.

[0210] Figure 56 Graph depicting the tumor weight in the orthotopic immunodeficient PDX-10 model for vehicle, gemcitabine / albumin-bound paclitaxel (G / A), compound 39, and compound 39 + G / A, where *p < 0.05 by one-way ANOVA with Tukey, **p < 0.01 by one-way ANOVA with Tukey, and ****p < 0.0001 by one-way ANOVA with Tukey.

[0211] Figure 57 Graph depicting the average number of lung metastases in the orthotopic immunodeficient PDX-10 model for vehicle, gemcitabine / albumin-bound paclitaxel (G / A), compound 39, and compound 39 + G / A, where *p < 0.05 by one-way ANOVA with Tukey.

[0212] Figure 58 Graph depicting the average number of lung metastases in the PDX-05 orthotopic model for each group in the 30-day study.

[0213] Figure 59 Graph depicting the average number of liver metastases in the PDX-05 orthotopic model for each group in the 30-day study.

[0214] Figure 60 Graph depicting the average number of lung metastases in the PDX-05 orthotopic model for each group in the 60-day study.

[0215] Figure 61 Graph depicting the average number of liver metastases in the PDX-05 orthotopic model for each group in the 60-day study.

[0216] Figure 62 Graph depicting the number of mice that developed lung metastases for each group.

[0217] Figure 63 Graph depicting the number of mice that developed liver metastases for each group.

[0218] Figure 64 Graph depicting a schematic of the Phase 1 clinical overview: a two-part study to evaluate safety, tolerability, pharmacokinetics, and preliminary evidence of anti-tumor activity.

[0219] Figure 65 Schematic depicting the clinical biomarker plan.

[0220] Figure 66 Schematic depicting the Bayesian Optimal Interval (BOIN) dose escalation and decision criteria for Example B10.

[0221] Figure 67 Schematic depicting PDA model of FOLFIRINOX resistance.

[0222] Figure 68A Graph depicting tumor volume (percent) for PDA model showing for vehicle 102 and for FOLFIRINOX 104 over a period of 120 days.

[0223] Figure 68B Graph depicting tumor volume (percent) for PDA model showing for vehicle 102 and for FOLFIRINOX 104 over a period of 40 days.

[0224] Figure 69A Graph depicting tumor volume (percent) for PDA model showing for vehicle 106, FOLFIRINOX (FNX) 108, Compound 39 110, and Compound 39 + FX 112 over a period of 25 days.

[0225] Figure 69B Graph depicting tumor volume (grams) for vehicle 106, FOLFIRINOX (FNX) 108, Compound 39 110, and Compound 39 + FX 112 related to PDX-10. Figure 69A

[0226] Figure 70 Schematic depicting the Universal Epithelial-Mesenchymal Transition (EMT) signature for PDX-08.

[0227] Figure 71 Schematic depicting the Universal Epithelial-Mesenchymal Transition (EMT) signature for PDX-10.

[0228] Figure 72 Graph depicting the amount of protein (ng / mg) showing for a V betal and a V beta8 in the PDX-10 orthotopic model.

[0229] Figure 73 ​A plot depicting the number of mice with lung metastasis (percent) in the PDX-10 orthotopic model for vehicle 114, Compound 39 116, gemcitabine / albumin-bound paclitaxel (G / A) 118, Compound 39 + G / A 120, IgG2a control 122, ADWA-11 Ab 124, and ADWA-11 + G / A 126.

[0230] Figure 74 A plot depicting the average number of lung metastasis in the PDX-10 orthotopic model for vehicle 114, Compound 39 116, gemcitabine / albumin-bound paclitaxel (G / A) 118, Compound 39 + G / A 120, IgG2a control 122, ADWA-11 Ab 124, and ADWA-11 + G / A 126.

[0231] Figure 75 A plot depicting the average number of lung metastasis in the PDX-10 orthotopic model for vehicle 114, Compound 39 116, gemcitabine / albumin-bound paclitaxel (G / A) 118, Compound 39 + G / A 120, IgG2a control 122, ADWA-11 Ab 124, and ADWA-11 + G / A 126.

[0232] Figure 76 A plot depicting the average number of lung metastasis in the PDX-10 orthotopic model for vehicle 114, Compound 39 116, gemcitabine / albumin-bound paclitaxel (G / A) 118, Compound 39 + G / A 120, IgG2a control 122, ADWA-11 Ab 124, and ADWA-11 + G / A 126.

[0233] Figure 77 A plot depicting the average number of lung metastasis in the PDX-10 orthotopic model for vehicle 114, Compound 39 116, gemcitabine / albumin-bound paclitaxel (G / A) 118, Compound 39 + G / A 120, IgG2a control 122, ADWA-11 Ab 124, and ADWA-11 + G / A 126.

[0234] Figure 78A A plot depicting the average number of lung metastasis in the PDX-10 orthotopic model for vehicle 114, Compound 39 116, gemcitabine / albumin-bound paclitaxel (G / A) 118, Compound 39 + G / A 120, IgG2a control 122, ADWA-11 Ab 124, and ADWA-11 + G / A 126.

[0235] Figure 78B A plot depicting the average number of lung metastasis in the PDX-10 orthotopic model for vehicle 114, Compound 39 116, gemcitabine / albumin-bound paclitaxel (G / A) 118, Compound 39 + G / A 120, IgG2a control 122, ADWA-11 Ab 124, and ADWA-11 + G / A 126.

[0236] Figure 79 The illustration shows tumor weight (g) for the following: mediator 128, compound 39 130, anti-PD-1Ab 132, and compound 39+ anti-PD-1Ab 134.

[0237] Figure 80 The illustration shows tumor weight (g) for the following: IgG2a control 136, ADWA-11Ab 138, anti-PD-1Ab 140, and ADWA-11+ anti-PD-1Ab 142.

[0238] Figure 81 Depicting and displaying the uniform manifold approximation and projection (UMAP) of ducts for various tumors.

[0239] Figure 82 A graphic depicting universal epithelial-mesenchymal transition (EMT) tags for various tumors (tumor A, tumor C, tumor E, tumor B, tumor G, tumor F, and tumor D) that have received the mediator and compound 39.

[0240] Figure 83 A graph depicting the differential expression of tumor A.

[0241] Figure 84 A graph depicting the differential expression of tumor C.

[0242] Figure 85 A graph depicting the differential expression of tumor E.

[0243] Figure 86 A graph depicting the differential expression of tumor F.

[0244] Figure 87 A schematic diagram relating to the PDX-05 in-situ model.

[0245] Figure 88 The depiction shows the effect of α in the PDX-05 in-situ model. V β1 and α V A graph showing the amount of β8 protein (ng / mg).

[0246] Figure 89 A graph depicting tumor weight (g) in the PDX-05 in situ model for mediator 144, compounds 39 and 146, reference compound 148, ADWA-11Ab 150, gemcitabine / albumin-bound paclitaxel (G / A) 152, compound 39+G / A 154, reference compound+G / A 156, and ADWA-11+G / A 158.

[0247] Figure 90Plot depicting the number of mice (percent) with lung metastasis in the PDX-05 orthotopic model for vehicle 144, Compound 39 146, Reference Compound 148, ADWA-11Ab 150, Gemcitabine / Albumin-bound Paclitaxel (G / A) 152, Compound 39 + G / A 154, Reference Compound + G / A 156, and ADWA-11 + G / A 158.

[0248] Figure 91 Schematic depicting the Universal Epithelial-Mesenchymal Transition (EMT) signature of PDX-05.

[0249] Figure 92 Plot depicting the pSMDA3 / SMAD3 ratio in the PDX-05 orthotopic model for IgG, ADWA-11, Gemcitabine / Albumin-bound Paclitaxel (G / A), Compound 39 + G / A, Reference Compound + G / A, and ADWA-11 + G / A.

[0250] Figure 93 Plot depicting the average number of liver metastases in the PDX-05 orthotopic model for vehicle 160, Compound 39 162, Reference Compound 164, ADWA-11Ab 166, Gemcitabine / Albumin-bound Paclitaxel (G / A) 168, Compound 39 + G / A 170, Reference Compound + G / A 172, and ADWA-11 + G / A 174.

[0251] Figure 94 Plot depicting the average number of liver micrometastases in the PDX-05 orthotopic model for vehicle 160, Compound 39 162, Reference Compound 164, ADWA-11Ab 166, Gemcitabine / Albumin-bound Paclitaxel (G / A) 168, Compound 39 + G / A 170, Reference Compound + G / A 172, and ADWA-11 + G / A 174.

[0252] Figure 95 Plot depicting the average number of lung metastases in the PDX-05 orthotopic model for vehicle 160, Compound 39 162, Reference Compound 164, ADWA-11Ab 166, Gemcitabine / Albumin-bound Paclitaxel (G / A) 168, Compound 39 + G / A 170, Reference Compound + G / A 172, and ADWA-11 + G / A 174.

[0253] Figure 96Graphical depiction showing the average number of lung micrometastases in PDX-05 orthotopic models for vehicle 160, Compound 39 162, Reference Compound 164, ADWA-11 Ab 166, Gemcitabine / Albumin-bound Paclitaxel (G / A) 168, Compound 39 + G / A 170, Reference Compound + G / A 172, and ADWA-11 + G / A 174.

[0254] Figure 97 Various images depicting Sirius Red (PSR) stained liver metastases in PDX-05 orthotopic models for vehicle, Compound 39, Gemcitabine / Albumin-bound Paclitaxel (G / A), Compound 39 + G / A, Reference Compound, ADWA-11, Reference Compound + G / A, and ADWA-11 + G / A.

[0255] Figure 98 Various images depicting Sirius Red (PSR) stained lung metastases in PDX-05 orthotopic models for vehicle, Compound 39, Gemcitabine / Albumin-bound Paclitaxel (G / A), Compound 39 + G / A, Reference Compound, ADWA-11, Reference Compound + G / A, and ADWA-11 + G / A.

[0256] Figure 99 Schematic depicting Compound 39 (top panel) and molecules that bind to a V β8 (bottom panel).

[0257] Figure 100 Graphical depiction showing the relative IC 50 efficacy of Compound 39 compared to indicated integrin indications.

[0258] Figure 101 Depiction of images of OCT-embedded human tissue cores showing a V β1 expression detected by IHC.

[0259] Figure 102 Graphical depiction showing a V β1 protein expression on CAFs isolated from indicated cancers compared to normal human lung fibroblasts (NHLF) as determined by an electrochemiluminescence mesoscale discovery assay.

[0260] Figure 103 Graphical depiction related to a cell adhesion assay depicting the percentage of adherent cells related to lung adenocarcinoma (LUAD) cancer-associated fibroblasts (CAFs) for various concentrations of Compound 39 (log nM).

[0261] Figure 104AGraph depicting cell adhesion assay depicting the percentage of adherent cells related to cancer-associated fibroblasts (CAFs) related to lung squamous cell carcinoma (LUSC) for various concentrations of compound 39 (log nM).

[0262] Figure 104B Graph depicting cell adhesion assay depicting the percentage of adherent cells related to cancer-associated fibroblasts (CAFs) related to pancreatic stellate cancer for various concentrations of compound 39 (log nM).

[0263] Figure 105 Image depicting the adhesion of cancer-associated fibroblasts (CAFs) on LAP-coated plates in the presence or absence of compound 39.

[0264] Figure 106 Schematic depicting the process (left) related to fresh collected human breast tumor tissue treated ex vivo with compound 39 for a period of time, showing aSMA + Graph of immunofluorescence analysis of cells (middle) and representative images of aSMA and DAPI stained tissue (right).

[0265] Figure 107 Graph depicting compound 39 in combination with anti-mPD-1 reduces the expression of fibrosis markers in EMT6 tumors.

[0266] Figure 108 Graph depicting shows the expression of connective tissue growth factor (CTGF) for vehicle + anti-mPD-1, anti-a V β8 + anti-mPD-1, and compound 39 + anti-mPD-1. Error bars show ± S.D. *p=0.05, **p=0.01, ***p=0.001, and ****p=0.0001 calculated by one-way Anova.

[0267] Figure 109 Graph depicting shows the expression of periostin (POSTN) for vehicle + anti-mPD-1, anti-a V β8 + anti-mPD-1, and compound 39 + anti-mPD-1. Error bars show ± S.D. *p=0.05, **p=0.01, ***p=0.001, and ****p=0.0001 calculated by one-way Anova.

[0268] Figure 110 Graph depicting shows the expression of periostin (POSTN) for vehicle + anti-mPD-1, anti-a VExpression of plasminogen activator inhibitor-1 (SERPINE1) gene by β8 + anti-mPD-1 and Compound 39 + anti-mPD-1. Error bars show ± S.D. *p=0.05, **p=0.01, ***p=0.001, and ****p=0.0001 calculated by one-way Anova.

[0269] Figure 111 Images associated with sirius red staining are depicted for vehicle + anti-mPD-1 (top panel) and vehicle + Compound 39 (bottom panel).

[0270] Figure 112 For vehicle + anti-mPD-1, anti-α V β8 + anti-mPD-1 and Compound 39 + anti-mPD-1 depict graphs associated with fibrosis score. Error bars show ± S.D. *p=0.05, **p=0.01, ***p=0.001, and ****p=0.0001 calculated by one-way Anova. DETAILED DESCRIPTION

[0271] Provided herein, inter alia, are compounds of Formula (A) and variations thereof, pharmaceutical compositions comprising compounds of Formula (A), and methods of using such compounds and compositions to treat fibrotic diseases. Also provided are compounds and pharmaceutical compositions comprising salts of compounds of Formula (A).

[0272] Provided herein, inter alia, are compounds of Formula (I) and variations thereof, pharmaceutical compositions comprising compounds of Formula (I), and methods of using such compounds and compositions to treat fibrotic diseases. Also provided are compounds and pharmaceutical compositions comprising salts of compounds of Formula (I).

[0273] Unless defined otherwise, all technical and scientific terms used herein are to be given the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0274] DEFINITIONS

[0275] For use herein, the use of the terms "a" and "an" and "the" and "at least one" and "one or more" are intended to be equivalent to "one, two, three, or more," unless otherwise indicated.

[0276] Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, reference to "about X" encompasses

[0277] Unless otherwise indicated, "alkyl" as used herein means and includes both "unsubstituted alkyl" and "substituted alkyl" having the indicated number of carbon atoms (i.e., C1-C 10This refers to a saturated straight-chain (i.e., unbranched) or branched monovalent hydrocarbon chain, or a combination thereof, having one to ten carbon atoms. Specific alkyl groups have 1 to 20 carbon atoms (“C1-C2”). 20 Alkyl groups, having 1 to 10 carbon atoms ("C1-C1") 10 Alkyl groups, having 6 to 10 carbon atoms ("C6-C") 10 Alkyl groups are groups having 1 to 6 carbon atoms (“C1-C6 alkyl”), 2 to 6 carbon atoms (“C2-C6 alkyl”), or 1 to 4 carbon atoms (“C1-C4 alkyl”). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc.

[0278] As used herein, "alkylene" refers to residues that are identical to alkyl but have a divalent oxidation state. Specific alkylene groups have 1 to 20 carbon atoms ("C1-C2"). 20 Alkylenes ("C1-C1") have 1 to 10 carbon atoms. 10 Alkylenes ("C6-C10") have 6 to 10 carbon atoms. 10 Alkylenes (“C1-C6 alkylenes”), having 1 to 6 carbon atoms (“C1-C5 alkylenes”), 1 to 4 carbon atoms (“C1-C4 alkylenes”), or 1 to 3 carbon atoms (“C1-C3 alkylenes”). Examples of alkylenes include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), and butylene (-CH2(C4)-). Groups such as H2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), pentylene (-CH2(CH2)3CH2-), hexylene (-CH2(CH2)4CH2-), heptamethylene (-CH2(CH2)5CH2-), and octylene (-CH2(CH2)6CH2-) are used. It should be understood that when an alkylene group is substituted (e.g., substituted with a cycloalkyl group), the substituent is not one of the divalent sites. For example, propylene substitution with a cyclopropyl group yields... But I can't get it. The wavy line represents a bivalent site.

[0279] Unless otherwise stated, as used herein, "alkenyl" means and includes having at least one alkene unsaturated site (i.e., having at least one C=C portion) and having a specified number of carbon atoms (i.e., C2-C). 10Alkenes are unsaturated straight-chain (i.e., unbranched) or branched monovalent hydrocarbon chains, or combinations thereof, with two to ten carbon atoms. Alkenes can have "cis" or "trans" configurations, or "E" or "Z" configurations. Certain alkenes have 2 to 20 carbon atoms ("C2-C2"). 20 Alkenyl groups, having 6 to 10 carbon atoms ("C6-C") 10 Alkenes are groups having 2 to 8 carbon atoms (“C2-C8 alkenes”), 2 to 6 carbon atoms (“C2-C6 alkenes”), or 2 to 4 carbon atoms (“C2-C4 alkenes”). Examples of alkenes include, but are not limited to, groups such as ethenyl, propyl-1-enyl, propyl-2-enyl (or allyl), 2-methylpropyl-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-dienyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, etc.

[0280] As used in this article, "alkenyl" refers to a residue that is identical to an alkenyl group but has a divalent oxidation state. Specific alkenyl groups have 2 to 20 carbon atoms ("C2-C2"). 20 ("alkenyl"), having 2 to 10 carbon atoms ("C2-C") 10 ("alkenyl"), having 6 to 10 carbon atoms ("C6-C") 10 "Idelenyl" refers to a group having 2 to 6 carbon atoms ("C2-C6 idelenyl"), 2 to 4 carbon atoms ("C2-C4 idelenyl"), or 2 to 3 carbon atoms ("C2-C3 idelenyl"). Examples of idelenyl groups include, but are not limited to, groups such as ethenylene (-CH=CH-), propenyl (-CH=CHCH2-), 1,4-but-1-idelenyl (-CH=CH-CH2CH2-), 1,4-but-2-idelenyl (-CH2CH=CHCH2-), and 1,6-hex-1-idelenyl (-CH=CH-(CH2)3CH2-).

[0281] Unless otherwise stated, as used herein, "alkynyl" means and includes having at least one alkynyl unsaturated site (i.e., having at least one part of the formula C≡C) and having a specified number of carbon atoms (i.e., C2-C). 10 This refers to an unsaturated straight-chain (i.e., unbranched) or branched monovalent hydrocarbon chain, or a combination thereof, with two to ten carbon atoms. A specific alkynyl group has 2 to 20 carbon atoms (“C2-C2”). 20 (Alkyne group), having 6 to 10 carbon atoms ("C6-C") 10The alkynyl group includes groups having 2 to 8 carbon atoms ("C2-C8 alkynyl"), 2 to 6 carbon atoms ("C2-C6 alkynyl"), or 2 to 4 carbon atoms ("C2-C4 alkynyl"). Examples of alkynyl groups include, but are not limited to, groups such as ethynyl, propynyl, propynyl (or propynyl), butynyl, butynyl, butynyl, butynyl, and so on.

[0282] As used in this article, "ethynyl group" refers to a residue that is identical to an ethynyl group but has a divalent oxidation state. Specific ethynyl groups have 2 to 20 carbon atoms ("C2-C2"). 20 "Iso-ynyl", having 2 to 10 carbon atoms ("C2-C") 10 "Hydynyl", having 6 to 10 carbon atoms ("C6-C") 10 The group consists of 2 to 6 carbon atoms ("C2-C6 ethynyl"), 2 to 4 carbon atoms ("C2-C4 ethynyl"), or 2 to 3 carbon atoms ("C2-C3 ethynyl"). Examples of ethynyl groups include, but are not limited to, groups such as ethynylene (-C≡C-) and propynylene (-C≡CCH2-).

[0283] Unless otherwise stated, as used herein, "cycloalkyl" refers to and includes alkyl groups having a specified number of carbon atoms (i.e., C3-C4). 10 A cycloalkyl group is a saturated cyclic monovalent hydrocarbon structure (meaning three to ten carbon atoms). A cycloalkyl group can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl group containing more than one ring can be fused, spirocyclic, bridged, or a combination thereof. A particular cycloalkyl group has 3 to 12 ring carbon atoms. Preferred cycloalkyl groups are cyclic hydrocarbons having 3 to 8 ring carbon atoms (“C3-C8 cycloalkyl”), 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”), or 3 to 4 ring carbon atoms (“C3-C4 cycloalkyl”). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, etc.

[0284] As used herein, "cycloalkylene" refers to residues that are identical to cycloalkyl but have a divalent charge. A cycloalkylene ring can consist of one or more rings, which can be fused, spirocyclic, bridged, or combinations thereof. A particular cycloalkylene ring has 3 to 12 ring carbon atoms. Preferred cycloalkylene rings are cyclic hydrocarbons having 3 to 8 ring carbon atoms ("C3-C8 cycloalkylene"), 3 to 6 carbon atoms ("C3-C6 cycloalkylene"), or 3 to 4 ring carbon atoms ("C3-C4 cycloalkylene"). Examples of cycloalkylene rings include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, etc. A cycloalkylene ring can be linked to the rest of the structure via the same ring carbon atom (e.g., 1,1-cyclopropylene) or different ring carbon atoms (e.g., 1,2-cyclopropylene). When a cycloalkyl group is linked to the rest of the structure via two different ring carbon atoms, the linking bonds can be cis or trans (e.g., cis-1,2-cyclopropyl or trans-1,2-cyclopropyl). If no linking point is specified, the portion may include any chemically possible link. For example, cyclopropyl may represent 1,1-cyclopropyl or 1,2-cyclopropyl (e.g., cis-1,2-cyclopropyl, trans-1,2-cyclopropyl, or mixtures thereof) or mixtures thereof.

[0285] Unless otherwise stated, "cycloalkenyl" means and includes having at least one alkene unsaturated site (i.e., having at least one C=C portion) and having a specified number of carbon atoms (i.e., C3-C). 10 Cycloalkenyl refers to an unsaturated cyclic non-aromatic monovalent hydrocarbon structure with three to ten carbon atoms. A cycloalkenyl group can consist of a single ring, such as cyclohexenyl, or multiple rings, such as norbornyl. Preferred cycloalkenyl groups are unsaturated cyclic hydrocarbons having 3 to 8 ring carbon atoms (“C3-C8 cycloalkenyl”). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornyl.

[0286] As used in this article, "cycloalkenyl" refers to a residue that is the same as cycloalkenyl but has a divalent form.

[0287] As used herein, “aryl” or “Ar” refers to an unsaturated aromatic carbocyclic group having a monocyclic (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracene) that are carbocyclic and may or may not be aromatic, provided that at least one ring in the multiple fused ring structure is aromatic. A particular aryl group has 6 to 14 cyclic carbon atoms (“C6-C…”). 14 aryl groups ("aryl"). An aryl group having one or more rings (at least one of which is non-aromatic) may be attached to the parent structure at an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl group having one or more rings (at least one of which is non-aromatic) is attached to the parent structure at an aromatic ring position.

[0288] As used herein, "arylene" refers to the same as aryl but having a divalent residue. Particular arylene groups have 6 to 14 ring carbon atoms ("C6-C14 arylene"). 14 As used herein, "heteroarylene" refers to the same as heteroaryl but having a divalent residue.

[0289] As used herein, "heteroaryl" refers to an unsaturated aromatic cyclic group having 1 to 14 ring carbon atoms and at least one ring heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen, and sulfur. Heteroaryl groups can have a single ring (e.g., pyridinyl, furanyl) or multiple condensed rings (e.g., indolizinyl, benzothiophenyl), which can be carbocyclic or can contain one or more ring heteroatoms, and which can or can not be aromatic, so long as at least one ring in the multiple condensed ring structure is aromatic and contains at least one ring heteroatom. Particular heteroaryl groups are 5- to 14-membered rings having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered rings having 1 to 8 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-, 6-, or 7-membered rings having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, a particular heteroaryl group is a monocyclic aromatic 5-, 6-, or 7-membered ring having 1 to 6 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, a particular heteroaryl group is a polycyclic aromatic ring having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heteroaryl groups having more than one ring (at least one of which is non-aromatic) can be attached to the parent structure at an aromatic ring position or at a non-aromatic ring position. In one variation, a heteroaryl group having more than one ring (at least one of which is non-aromatic) is attached to the parent structure at an aromatic ring position. Heteroaryl groups can be attached to the parent structure at a ring carbon atom or at a ring heteroatom.

[0290] As used herein, "heteroarylene" refers to the same as heteroaryl but having a divalent residue.

[0291] As used herein, "heterocyclo," "heterocyclic," or "heterocyclyl" refers to a saturated or unsaturated non-aromatic cyclic group having from 1 to 14 ring carbon atoms and from 1 to 6 ring heteroatoms (such as nitrogen, sulfur, or oxygen, among others). Heterocyclyl groups can have a single ring (e.g., pyrrolidinyl) or multiple condensed rings (e.g., decahydroisoquinolin-l-yl), which condensed rings can or can not be aromatic and can be carbocyclic or contain one or more ring heteroatoms, but excluding heteroaryl rings. Heterocyclic rings containing more than one ring can be fused, bridged, or spirocyclic or any combination thereof. In a condensed ring system, one or more of the condensed rings can be cycloalkyl or aryl, but excluding heteroaryl. Heterocyclyl groups can be optionally independently substituted with one or more substituents described herein. Particular heterocyclyl groups are 3- to 14-membered rings having from 1 to 13 ring carbon atoms and from 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 12-membered rings having from 1 to 11 ring carbon atoms and from 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 10-membered rings having from 1 to 9 ring carbon atoms and from 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 8-membered rings having from 1 to 7 ring carbon atoms and from 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 3- to 6-membered rings having from 1 to 5 ring carbon atoms and from 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, heterocyclyl groups include single ring 3-, 4-, 5-, 6-, or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 ring carbon atoms and from 1 to 2, 1 to 3, or 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, heterocyclyl groups include polycyclic non-aromatic rings having from 1 to 12 ring carbon atoms and from 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0292] As used herein, "heterocycloalkylene" refers to the same as heterocyclyl but having a divalent residue.

[0293] "Halo" or "halogen" refers to an element of atomic number 9 to 85 of the group 17 series. Preferred halo groups include fluoro, chloro, bromo, and iodo groups. Where a residue is substituted with one or more halogens, it can be referred to using the prefix "halo", e.g., haloaryl, haloalkyl, and the like refer to aryl and alkyl groups substituted with one or more halo groups, which in the case of two or more halo groups can but need not be the same halogen. Where a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl, and the like refer to aryl and alkyl groups substituted with two ("di") or three ("tri") halo groups, which can but need not be the same halogen; thus, 4-chloro-3-fluorophenyl falls within the scope of dihaloaryl. Alkyl groups in which each hydrogen is replaced by a halo group are referred to as "perhaloalkyl". A preferred haloalkyl (e.g., perhaloalkyl) is trifluoromethyl (-CF3). Similarly, "perhaloalkoxy" refers to an alkoxy group in which each H in the alkyl portion of the alkoxy group is replaced by a halogen. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

[0294] "Carbonyl" refers to the group C=0.

[0295] "Thiocarbonyl" refers to the group C=S.

[0296] "Oxo" refers to the moiety =0.

[0297] "D" refers to deuterium ( 2 H).

[0298] "Boc" refers to tert-butoxycarbonyl.

[0299] "Cbz" refers to carboxybenzyl.

[0300] "HATU" refers to 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate.

[0301] "BOP" refers to Benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate.

[0302] "PyBOP" refers to Benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.

[0303] Unless otherwise indicated, "optionally substituted" means that the group can be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents listed for that group, where the substituents can be the same or different. In some embodiments, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In some embodiments, an optionally substituted group is unsubstituted.

[0304] "Individual" or "subject" as used herein, unless otherwise indicated, is intended to mean a mammal, including, but not limited to, a primate, human, bovine, equine, feline, canine, or rodent. In one variation, the individual or subject is a human.

[0305] As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. For the purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: reducing one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, delaying the onset or recurrence of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, remission (whether partial or total), decreasing the dose of one or more other medications required to treat the disease, enhancing effects of another medication, delaying the progression of the disease, increasing the quality of life, and / or increasing the length of survival. "Treatment" also encompasses alleviating pathological consequences of fibrosis. The methods herein encompass any one or more of these treatment aspects.

[0306] As used herein, the term "effective amount" is intended to mean the amount of a compound herein that is effective for a given treatment. As understood in the art, an effective amount can be one or more doses, i.e., a single dose or multiple doses can be needed to achieve the desired therapeutic endpoint. An effective amount can be considered in the context of administering one or more therapeutic agents (e.g., a compound or a pharmaceutically acceptable salt thereof), and a single agent can be considered to be given in an effective amount if, in conjunction with one or more other agents, a desired or beneficial result can be or is achieved. Suitable doses of any co-administered compounds can optionally be reduced as a result of the combined action (e.g., additive or synergistic effect) of the compounds.

[0307] "Therapeutically effective amount" refers to the amount of a compound or salt thereof that is sufficient to effectuate a desired therapeutic result.

[0308] As used herein, “unit dosage form” refers to physically discrete units suitable as unitary dosages for human or animal subjects, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Unit dosage forms can contain monotherapy or combination therapy.

[0309] As used herein, the term “controlled release” refers to a formulation or portion thereof containing a drug, wherein the release of the drug is not immediate, i.e., with a “controlled release” formulation, administration does not result in immediate release of the drug into the absorption pool. The term encompasses depot formulations designed to gradually release the drug compound over an extended period of time. Controlled release formulations can include a number of drug delivery systems, often involving mixing the drug compound with a carrier, polymer, or other compound having the desired release properties (e.g., pH-dependent or non-pH-dependent solubility, varying degrees of water solubility, etc.), and formulating the mixture according to the desired delivery route (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, etc.).

[0310] As used herein, the term “composition” or “pharmaceutical composition” refers to the combination of an active agent with a non-active or active excipient or carrier, such that the composition is particularly suitable for in vivo or ex vivo diagnostic or therapeutic use. Pharmaceutical compositions can be prepared by known methods of pharmacy. Suitable compositions, excipients, or carriers can be found in, e.g., Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21stedition (2005), which is incorporated herein by reference in its entirety.

[0311] As used herein, by “pharmaceutically acceptable” or “pharmacologically acceptable” is meant a substance that is not biologically or otherwise undesirable, e.g., the material can be incorporated into a pharmaceutical composition administered to a patient without any deleterious biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients preferably meet the required standards of toxicological and manufacturing testing, and / or are included in the U.S. Food and Drug Administration’s guidelines for inactive ingredients.

[0312] A "pharmaceutically acceptable salt" is a salt that retains at least some biological activity of the free (non-salt) compound and is suitable for use as a pharmaceutical or medicament on an individual. See, e.g., Handbook of Pharmaceutical Salts Properties, Selection, and Use, International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), which is hereby incorporated by reference in its entirety. Such salts include, for example: (1) acid addition salts formed with inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids, e.g., acetic acid, oxalic acid, propionic acid, malic acid, maleic acid, tartaric acid, and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, and the like. Acceptable inorganic bases that can be used to prepare salts include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Pharmaceutically acceptable salts can be prepared in situ during the manufacturing process, or by reacting the purified compound in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.

[0313] The term "excipient" as used herein means an inert or inactive substance that can be used in the production of a medicament or pharmaceutical product, such as a tablet containing a compound as an active ingredient. See, e.g., Handbook of Pharmaceutical Excipients. 6thEd., Pharmaceutical Press (2008), which is hereby incorporated by reference in its entirety. The term "excipient" can encompass a variety of substances, including but not limited to any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solution for parenteral administration, substance for chewable tablets, sweetener or flavoring agent, suspending / gelling agent, or wet granulation agent. Binders include, e.g., carbomer, povidone, xanthan gum, and the like; coatings include, e.g., cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coating, and the like; compression / encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc = "direct compressible"), honey dc, lactose (anhydrous or monohydrate; optionally combined with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, and the like; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, and the like; cream or lotion includes, e.g., maltodextrin, carrageenan, and the like; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, and the like; substances for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally combined with aspartame or cellulose), and the like; suspending / gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, and the like; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, and the like; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, and the like.

[0314] "Substantially pure" is intended to be a composition containing no more than 10% impurities, such as a composition comprising less than about 9%, 7%, 5%, 3%, 1%, 0.5% impurities, unless otherwise specified.

[0315] The term "comprising" or variations such as "comprise", "comprises" or "comprised" shall not be understood as being restrictive, but rather as meaning that additional steps, elements, features or components can be added. It will be understood that aspects and embodiments described herein as "comprising" include aspects and embodiments "consisting of and aspects and embodiments "consisting essentially of the steps, elements, features or components specifically recited, in addition to any steps, elements, features or components not specifically recited.

[0316] When a composition is described as "consisting essentially of' the recited components, it contains the recited components and can contain additional components that do not materially affect the disease or condition being treated. However, the composition does not contain any additional components that materially affect the disease or condition being treated other than those recited; or, if the composition does contain additional components that materially affect the disease or condition being treated other than those recited, the composition contains these additional components in a concentration or amount that does not materially affect the disease or condition being treated. When a method is described as "consisting essentially of' the recited steps, it contains the recited steps and can contain additional steps that do not materially affect the disease or condition being treated, but it does not contain any additional steps that materially affect the disease or condition being treated other than those recited; or, if the method does contain additional steps that materially affect the disease or condition being treated other than those recited, the method contains these additional steps in a manner that does not materially affect the disease or condition being treated.

[0317] As used herein, where a given structure exists in enantiomeric and / or diastereomeric forms, "flat bond" indicates that all stereoisomeric forms of the depicted structure can be present, e.g., Compound 1 in Table 1 below.

[0318]

[0319] Compound

[0320] In one aspect, provided is a compound of Formula (A):

[0321]

[0322] or a pharmaceutically acceptable salt thereof, wherein:

[0323] R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted with one or more R 1a 1b is 1,2,3,4-tetrahydro-l,8-naphthyridin-2-yl optionally substituted with one or more R 1c is 6-aminopyridin-2-yl optionally substituted with one or more R 1d is (pyridin-2-yl)amino optionally substituted with one or more R

[0324] R 2 is H or Ci-C6alkyl;

[0325] R 3 is H or Ci-C6alkyl;

[0326] or R 2 and R 3 together with the carbon atom to which they are attached form an optionally substituted 5- or 6-membered ring; 2a ​substituted C3-C6cycloalkyl or 3- to 6-membered heterocyclyl;

[0327] R 4 is phenyl, 5- to 6-membered heteroaryl, 6-membered heterocyclyl, or C1-C6haloalkyl;

[0328] wherein the 5- to 6-membered heteroaryl contains at least one nitrogen atom and is optionally fused to phenyl;

[0329] wherein the 6-membered heterocyclyl contains at least one nitrogen atom and is optionally fused to phenyl;

[0330] wherein the phenyl and 5- to 6-membered heteroaryl are optionally substituted with one or more R 4a ; and

[0331] wherein the 6-membered heterocyclyl is optionally substituted with one or more groups selected from R 4a and oxo;

[0332] or R 2 , R 3 and R 4 together form a 5-membered heteroaryl containing two nitrogen atoms and substituted with phenyl, wherein the phenyl is optionally substituted with one or more R 4a ;

[0333] each R 4a is independently halo, CN, C1-C6alkyl, C1-C6haloalkyl, -(C1-C6alkylene)-O-(C1-C6alkyl), C3-C6cycloalkyl, -OH, -O-(C1-C6alkyl), -O-(C1-C6haloalkyl), -S(O)2(C1-C6alkyl), or -C(=O)-NH2;

[0334] or R 4a and R 2 together with the atoms to which they are attached form a 6-membered heterocyclyl, wherein the heterocyclyl contains one oxygen atom;

[0335] Q is H or C1-C8alkyl;

[0336] L 1 is C2-C4alkylene optionally substituted with one or more L 1a ;

[0337] L 2 is a bond or C1-C3alkylene optionally substituted with one or more L 2a ;

[0338] L 3 is C2-C4alkylene optionally substituted with one or more L 3a ;

[0339] Y is a key;

[0340] R 1a R 1b R 1c R 1d R 2a L 1a L 2a and L 3a Each independently selected from R A ;

[0341] Two Rs on the same carbon atom 1a The groups can be chosen to combine with the carbon atoms they are attached to to form C3-C6 cycloalkyl groups;

[0342] Two Rs on the same carbon atom 1b The groups can be chosen to combine with the carbon atoms they are attached to to form C3-C6 cycloalkyl groups;

[0343] Each R A Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3 to 12-membered heterocyclic, C6-C 14 Aryl, 5- to 10-membered heteroaryl, -CN, -OR 5 -SR 5 -NR 6 R 7 -NO2, -C = NH (OR 5 -C(O)R 5 -OC(O)R 5 -C(O)OR 5 -C(O)NR 6 R 7 -NR 5 C(O)R 6 -NR 5 C(O)OR 6 -NR 5 C(O)NR 6 R 7 -S(O)R 5 -S(O)2R 5 -NR 5 S(O)R 6 -NR 5 S(O)2R 6 -S(O)NR 6 R 7 -S(O)2NR 6 R 7 or -P(O)(OR 5 (OR) 6 ), where RA C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, C6-C 14 aryl, and 5- to 10-membered heteroaryl are each independently and optionally substituted by one or more R Aa substituents;

[0344] each R Aa is independently deuterium, halogen, oxo, -OR 8 , -NR 8 R 9 , -C(O)R 8 , -C(O)OR 8 , -NR 8 C(O)OR 10 , -CN, -S(O)R 8 , -S(O)2R 8 , -P(O)(OR 8 )(OR 9 ), C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-C 14 aryl, or C1-C6alkyl, wherein R Aa of the 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-C 14 aryl, and C1-C6alkyl are each independently and optionally substituted by one or more R Ab substituents;

[0345] each R Ab is independently deuterium, oxo, -OH, -O( 2 H), halogen, or C1-C6alkyl optionally substituted with one or more of deuterium, halogen, -OH, -O( 2 H), or oxo;

[0346] each R 5 is independently hydrogen, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein R 5 of the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl are each independently and optionally substituted by one or more R 5a substituents;

[0347] each R 5a is independently halogen, deuterium, oxo, -CN, -OR 10 , -NR 11 R 12 , -P(O)(OR11 (OR) 12 ), 3 to 12-membered heterocyclic groups or optionally coated with deuterium, halogen, -OH, -O ( 2 C1-C6 alkyl groups substituted with one or more of the H or oxo groups;

[0348] Each R 6 Independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl or 3- to 6-membered heterocyclic, wherein R 6 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 The aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclic groups are independently and optionally substituted by one or more of the following: deuterium, halogen, oxo, -CN, -OR. 10 -NR 11 R 12 Or optionally, deuterium, halogen, -OH, -O ( 2 C1-C6 alkyl groups substituted with one or more of the H or oxo groups;

[0349] Each R 7 Independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl or 3- to 6-membered heterocyclic, wherein R 7 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 The aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclic groups are independently and optionally substituted by one or more of the following: deuterium, halogen, oxo, -CN, -OR. 10 -NR 11 R 12 Or optionally, deuterium, halogen, -OH, -O ( 2 C1-C6 alkyl groups substituted with one or more of the H or oxo groups;

[0350] Or R 6 and R 7 Together with the atoms they are attached to, they form 3 to 10-membered heterocyclic groups that may be substituted with one or more of the following: deuterium, halogen, oxo, -OR 10 -NR 11 R 12 Alternatively, it can be selected from deuterium, halogen, oxo, -OH, or -O ( 2 One or more of the C1-C6 alkyl groups substituted in H);

[0351] Each R8 independently hydrogen, deuterium; C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, or oxo; C2-C6 alkenyl optionally substituted with one or more of deuterium, halogen, or oxo; or C2-C6 alkynyl optionally substituted with one or more of deuterium, halogen, or oxo;

[0352] each R 9 independently hydrogen, deuterium; C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, or oxo; C2-C6 alkenyl optionally substituted with one or more of deuterium, halogen, or oxo; or C2-C6 alkynyl optionally substituted with one or more of deuterium, halogen, or oxo;

[0353] each R 10 independently hydrogen, deuterium; C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, or oxo; C2-C6 alkenyl optionally substituted with one or more of deuterium, halogen, or oxo; or C2-C6 alkynyl optionally substituted with one or more of deuterium, halogen, or oxo;

[0354] each R 11 independently hydrogen, deuterium; C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, or oxo; C2-C6 alkenyl optionally substituted with one or more of deuterium, halogen, or oxo; or C2-C6 alkynyl optionally substituted with one or more of deuterium, halogen, or oxo; and

[0355] each R 12 independently hydrogen, deuterium; C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, or oxo; C2-C6 alkenyl optionally substituted with one or more of deuterium, halogen, or oxo; or C2-C6 alkynyl optionally substituted with one or more of deuterium, halogen, or oxo;

[0356] or R 11 and R 12 are taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted with one or more of deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted with one or more of deuterium, oxo, or halogen.

[0357] In one aspect, provided is a compound of Formula (I):

[0358]

[0359] or a pharmaceutically acceptable salt thereof, wherein:

[0360] R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted with one or more R 1a substituted with one or more R1b substituted 1,2,3,4-tetrahydro-l,8-naphthyridin-2-yl, optionally substituted with R 1c substituted 6-aminopyridin-2-yl or optionally substituted with one or more R 1d substituted (pyridin-2-yl)amino;

[0361] R 2 is H or Ci-C6alkyl;

[0362] R 3 is H or Ci-C6alkyl;

[0363] or R 2 and R 3 together with the carbon atom to which they are attached form C3-C6cycloalkyl or 3- to 6-membered heterocyclyl;

[0364] R 4 is phenyl, 5- to 6-membered heteroaryl or 6-membered heterocyclyl;

[0365] wherein the 5- to 6-membered heteroaryl contains at least one nitrogen atom and is optionally fused to phenyl;

[0366] wherein the 6-membered heterocyclyl contains at least one nitrogen atom and is optionally fused to phenyl;

[0367] wherein the phenyl and 5- to 6-membered heteroaryl are optionally substituted with one or more R 4a ; and

[0368] wherein the 6-membered heterocyclyl is optionally substituted with one or more groups selected from R 4a and oxo;

[0369] each R 4a is independently halo, CN, Ci-C6alkyl, Ci-C6haloalkyl, -(Ci-C6alkylene)-0-(Ci-C6alkyl), C3-C6cycloalkyl, -0-(Ci-C6alkyl), -0-(Ci-C6haloalkyl), or -S(0)2(Ci-C6alkyl);

[0370] or R 4a and R 2 together with the atoms to which they are attached form a 6-membered heterocyclyl, wherein the heterocyclyl contains one oxygen atom;

[0371] Q is H or Ci-C8alkyl;

[0372] L 1 is C2-C4alkylene optionally substituted with one or more L 1a ; and

[0373] L 2Is a key or optional to be one or more L 2a Substituted C1-C3 alkylene groups;

[0374] L 3 It is arbitrarily controlled by one or more L 3a Substituted C2-C4 alkylene groups;

[0375] Y is a key;

[0376] R 1a R 1b R 1c R 1d L 1a L 2a and L 3a Each independently selected from R A ;

[0377] Two Rs on the same carbon atom 1a The groups can be chosen to combine with the carbon atoms they are attached to to form C3-C6 cycloalkyl groups;

[0378] Two Rs on the same carbon atom 1b The groups can be chosen to combine with the carbon atoms they are attached to to form C3-C6 cycloalkyl groups;

[0379] Each R A Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3 to 12-membered heterocyclic, C6-C 14 Aryl, 5- to 10-membered heteroaryl, -CN, -OR 5 -SR 5 -NR 6 R 7 -NO2, -C = NH (OR 5 -C(O)R 5 -OC(O)R 5 -C(O)OR 5 -C(O)NR 6 R 7 -NR 5 C(O)R 6 -NR 5 C(O)OR 6 -NR 5 C(O)NR 6 R 7 -S(O)R 5 -S(O)2R 5 -NR 5 S(O)R 6 -NR 5 S(O)2R 6-S(O)NR 6 R 7 -S(O)2NR 6 R 7 or -P(O)(OR 5 (OR) 6 ), where R A The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, C6-C 14 aryl and 5 to 10-membered heteroaryl groups are independently and optionally constituting one or more R Aa replace;

[0380] Each R Aa Independently deuterium, halogen, oxo, -OR 8 -NR 8 R 9 -C(O)R 8 -C(O)OR 8 -NR 8 C(O)OR 10 -CN, -S(O)R 8 -S(O)2R 8 -P(O)(OR) 8 (OR) 9 ), C3-C8 cycloalkyl, 3 to 12-membered heterocyclic, 5 to 10-membered heteroaryl, C6-C 14 aryl or C1-C6 alkyl, wherein R Aa 3- to 12-membered heterocyclic groups, 5- to 10-membered heteroaryl groups, C6-C 14 The aryl and C1-C6 alkyl groups are independently and optionally influenced by one or more R groups. Ab replace;

[0381] Each R Ab Independently deuterium, oxo, -OH, -O( 2 H), halogen or optionally deuterium, halogen, -OH, -O ( 2 C1-C6 alkyl groups substituted with one or more of the H or oxo groups;

[0382] Each R 5 Independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic, wherein R 5 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic groups are each independently and optionally constituting one or more R groups. 5asubstituted;

[0383] each R 5a is independently halogen, deuterium, oxo, -CN, -OR 10 , -NR 11 R 12 , -P(O)(OR 11 )(OR 12 ), 3- to 12-membered heterocyclyl, or C1-C6alkyl optionally substituted with one or more of deuterium, halogen, -OH, -O( 2 H), or oxo;

[0384] each R 6 is independently hydrogen, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C 6 aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R 14 are each independently optionally substituted with one or more of deuterium, halogen, oxo, -CN, -OR 10 , -NR 11 R 12 , or C1-C6alkyl optionally substituted with one or more of deuterium, halogen, -OH, -O( 2 H), or oxo;

[0385] each R 7 is independently hydrogen, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C 7 aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R 14 are each independently optionally substituted with one or more of deuterium, halogen, oxo, -CN, -OR 10 , -NR 11 R 12 , or C1-C6alkyl optionally substituted with one or more of deuterium, halogen, -OH, -O( 2 H), or oxo;

[0386] or R 6 and R 7 , together with the atom to which they are attached, form a 3- to 10-membered heterocyclyl optionally substituted with one or more of deuterium, halogen, oxo, -OR 10, -NR 11 R 12 or C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, oxo, -OH, or -O( 2 H);

[0387] each R 8 is independently hydrogen, deuterium; C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, or oxo; C2-C6 alkenyl optionally substituted with one or more of deuterium, halogen, or oxo; or C2-C6 alkynyl optionally substituted with one or more of deuterium, halogen, or oxo;

[0388] each R 9 is independently hydrogen, deuterium; C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, or oxo; C2-C6 alkenyl optionally substituted with one or more of deuterium, halogen, or oxo; or C2-C6 alkynyl optionally substituted with one or more of deuterium, halogen, or oxo;

[0389] each R 10 is independently hydrogen, deuterium; C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, or oxo; C2-C6 alkenyl optionally substituted with one or more of deuterium, halogen, or oxo; or C2-C6 alkynyl optionally substituted with one or more of deuterium, halogen, or oxo;

[0390] each R 11 is independently hydrogen, deuterium; C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, or oxo; C2-C6 alkenyl optionally substituted with one or more of deuterium, halogen, or oxo; or C2-C6 alkynyl optionally substituted with one or more of deuterium, halogen, or oxo; and

[0391] each R 12 is independently hydrogen, deuterium; C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, or oxo; C2-C6 alkenyl optionally substituted with one or more of deuterium, halogen, or oxo; or C2-C6 alkynyl optionally substituted with one or more of deuterium, halogen, or oxo;

[0392] or R 11 and R 12 , taken together with the atoms to which they are attached, form a 3-6 membered heterocyclyl optionally substituted with one or more of deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted with one or more of deuterium, oxo, or halogen.

[0393] In one variation, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided wherein R 2 )R 3 is -CO2Q.4 The carbon of the moiety is in the "S" configuration. In another variation, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the carbon of the moiety is in the "R" configuration. 2 (R 3 )R 4 The carbon of the moiety is in the "R" configuration. Mixtures of compounds of Formula (I) are also contemplated, including racemic or non-racemic mixtures of a given compound, as well as mixtures of two or more different chemical formulas.

[0394] In the description herein, it is to be understood that each description, variation, embodiment, or aspect of one moiety can be combined with each description, variation, embodiment, or aspect of the other moieties, just as if each and every combination were specifically and individually listed. For example, each description, variation, embodiment, or aspect of R 4 provided can be combined with each description, variation, embodiment, or aspect of R 1 , R 2 , R 3 , L 1 , L 2 , L 3 , Y, and / or Q, just as if each and every combination were specifically and individually listed. It is also to be understood that all descriptions, variations, embodiments, or aspects of Formula (I) or Formula (A) are equally applicable to the other chemical formulas detailed herein, where applicable, and are described as if each and every description, variation, embodiment, or aspect were separately and individually listed for all chemical formulas. For example, all descriptions, variations, embodiments, or aspects of Formula (I) or Formula (A) are equally applicable to any of Formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), and (IV) detailed herein, where applicable, and are described as if each and every description, variation, embodiment, or aspect were separately and individually listed for all chemical formulas.

[0395] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, L 1 is unsubstituted C2-C4alkylene. In a particular variation, L 1 is -CH2-CH2-, -CH2-CH2-CH2-, or -CH2-CH2-CH2-CH2-. In a particular variation, L1 It is -CH2CH2-.

[0396] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 2 It is a key.

[0397] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 2 It is an unsubstituted C1-C3 alkylene group. In certain variations, L 2 It is -CH2CH2-.

[0398] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 3 It is an unsubstituted C2-C4 alkylene group. In certain variations, L 3 It is -CH2CH2-. In certain variations, L 3 It is –CH2CH2CH2CH2-.

[0399] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, -L 1 -OL 2 -YL 3 -Combined to form

[0400] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R A R Aa R Ab R 5 R 5a R 6 R 7 R 8 R 9 R 10 R 11 Or R 12 At least one of them is deuterium.

[0401] In some embodiments, the compound of formula (I) has formula (II-a):

[0402]

[0403] Or a pharmaceutically acceptable salt thereof, wherein R 4 As defined for formula (I). In some embodiments of the compound of formula (II-a), R 4 It is arbitrarily controlled by one or more R 4a Substituted phenyl. In some embodiments of compounds of formula (II-a), R 4is a 5- to 6-membered heteroaryl containing at least one nitrogen atom, wherein the 5- to 6-membered heteroaryl is optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-a), R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom, wherein the 5- to 6-membered heteroaryl is optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-a), R 4 is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl is optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-a), R 4 is pyridyl optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-a), R 4 is pyrimidinyl optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-a), R 4 is a 6-membered heterocyclyl containing at least one nitrogen atom, optionally fused with phenyl, wherein the 6-membered heterocyclyl is optionally substituted with one or more groups selected from R 4a and oxo.

[0404] In some embodiments, the compound of Formula (I) has Formula (II-b):

[0405]

[0406] or a pharmaceutically acceptable salt thereof, wherein R 4 is as defined for Formula (I). In some embodiments of the compound of Formula (II-b), R 4 is phenyl optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-b), R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom, wherein the 5- to 6-membered heteroaryl is optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-b), R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom, wherein the 5- to 6-membered heteroaryl is optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-b), R 4 is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl is optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-b), R 4 is pyridyl optionally substituted with one or more R4a Substituted pyridinyl group. In some embodiments of compounds of formula (II-b), R 4 It is arbitrarily controlled by one or more R 4a Substituted pyrimidinyl group. In some embodiments of compounds of formula (II-b), R 4 It is a 6-membered heterocyclic group containing at least one nitrogen atom and optionally fused with a phenyl group, wherein the 6-membered heterocyclic group is optionally composed of one or more atoms selected from R 4a Substitution with oxidized groups.

[0407] In some embodiments, the compound of formula (I) has formula (II-c):

[0408]

[0409] Or a pharmaceutically acceptable salt thereof, wherein R 4 As defined for formula (I). In some embodiments of compounds of formula (II-c), R 4 It is arbitrarily controlled by one or more R 4a Substituted phenyl. In some embodiments of compounds of formula (II-c), R 4 It is a 5- to 6-membered heteroaryl group containing at least one nitrogen atom and optionally fused with a phenyl group, wherein the 5- to 6-membered heteroaryl group is optionally fused with one or more R groups. 4a Substitution. In some embodiments of compounds of formula (II-c), R 4 It is a 5- to 6-membered heteroaryl group containing at least one nitrogen atom, wherein the 5- to 6-membered heteroaryl group is optionally surrounded by one or more R 4a Substitution. In some embodiments of compounds of formula (II-c), R 4 It is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl group is optionally surrounded by one or more R groups. 4a Substitution. In some embodiments of compounds of formula (II-c), R 4 It is arbitrarily controlled by one or more R 4a Substituted pyridinyl group. In some embodiments of compounds of formula (II-c), R 4 It is arbitrarily controlled by one or more R 4a Substituted pyrimidinyl group. In some embodiments of compounds of formula (II-c), R 4 It is a 6-membered heterocyclic group containing at least one nitrogen atom and optionally fused with a phenyl group, wherein the 6-membered heterocyclic group is optionally composed of one or more atoms selected from R 4a Substitution with oxidized groups.

[0410] In some embodiments, the compound of formula (I) has formula (II-d):

[0411]

[0412] or a pharmaceutically acceptable salt thereof, wherein R 4 is as defined for formula (I). In some embodiments of the compound of formula (II-d), R 4 is phenyl optionally substituted with one or more R 4a In some embodiments of the compound of formula (II-d), R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom and optionally fused to phenyl, wherein the 5- to 6-membered heteroaryl is optionally substituted with one or more R 4a In some embodiments of the compound of formula (II-d), R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom, wherein the 5- to 6-membered heteroaryl is optionally substituted with one or more R 4a In some embodiments of the compound of formula (II-d), R 4 is pyridinyl or pyrimidinyl, wherein the pyridinyl or pyrimidinyl is optionally substituted with one or more R 4a In some embodiments of the compound of formula (II-d), R 4 is pyridinyl optionally substituted with one or more R 4a In some embodiments of the compound of formula (II-d), R 4 is pyrimidinyl optionally substituted with one or more R 4a In some embodiments of the compound of formula (II-d), R 4 is a 6-membered heterocyclyl containing at least one nitrogen atom and optionally fused to phenyl, wherein the 6-membered heterocyclyl is optionally substituted with one or more groups selected from R 4a and oxo.

[0413] In some embodiments, the compound of formula (I) has formula (II-e):

[0414]

[0415] or a pharmaceutically acceptable salt thereof, wherein R 4 is as defined for formula (I). In some embodiments of the compound of formula (II-e), R 4 is phenyl optionally substituted with one or more R 4a In some embodiments of the compound of formula (II-e), R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom and optionally fused to phenyl, wherein the 5- to 6-membered heteroaryl is optionally substituted with one or more R 4a In some embodiments of the compound of formula (II-e), R 4is a 5- to 6-membered heteroaryl containing at least one nitrogen atom, wherein the 5- to 6-membered heteroaryl is optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-e), R 4 is pyridyl or pyrimidyl, wherein the pyridyl or pyrimidyl is optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-e), R 4 is pyridyl optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-e), R 4 is pyrimidyl optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-e), R 4 is a 6-membered heterocyclyl containing at least one nitrogen atom and optionally fused with phenyl, wherein the 6-membered heterocyclyl is optionally substituted with one or more groups selected from R 4a and oxo.

[0416] In some embodiments, the compound of Formula (I) has Formula (II-f):

[0417]

[0418] or a pharmaceutically acceptable salt thereof, wherein R 4 is as defined for Formula (I). In some embodiments of the compound of Formula (II-f), R 4 is phenyl optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-f), R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom and optionally fused with phenyl, wherein the 5- to 6-membered heteroaryl is optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-f), R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom, wherein the 5- to 6-membered heteroaryl is optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-f), R 4 is pyridyl or pyrimidyl, wherein the pyridyl or pyrimidyl is optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-f), R 4 is pyridyl optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-f), R 4 is pyrimidyl optionally substituted with one or more R 4asubstituted with one or more R 4 is a 6-membered heterocyclyl containing at least one nitrogen atom and optionally fused with phenyl, wherein the 6-membered heterocyclyl is optionally substituted with one or more groups selected from R 4a and oxo.

[0419] In some embodiments, the compound of Formula (I) has Formula (II-g):

[0420]

[0421] or a pharmaceutically acceptable salt thereof, wherein R 4 is as defined for Formula (I). In some embodiments of the compound of Formula (II-g), R 4 is phenyl optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-g), R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom and optionally fused with phenyl, wherein the 5- to 6-membered heteroaryl is optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-g), R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom and optionally fused with phenyl, wherein the 5- to 6-membered heteroaryl is optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-g), R 4 is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl is optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-g), R 4 is pyridyl optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-g), R 4 is pyrimidinyl optionally substituted with one or more R 4a In some embodiments of the compound of Formula (II-g), R 4 is a 6-membered heterocyclyl containing at least one nitrogen atom and optionally fused with phenyl, wherein the 6-membered heterocyclyl is optionally substituted with one or more groups selected from R 4a and oxo.

[0422] In some embodiments, the compound of Formula (I) has Formula (III-a):

[0423]

[0424] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 and R4a As defined for formula (I). In some embodiments of the compounds of formula (III-a), R 2 and R 3 together with the carbon atom to which they are attached form C3-C6cycloalkyl or 3- to 6-membered heterocyclyl; in some embodiments of the compounds of formula (III-a), R 2 and R 3 together with the carbon atom to which they are attached form C3-C6cycloalkyl. In some embodiments of the compounds of formula (III-a), R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl. In some embodiments of the compounds of formula (III-a), R 2 and R 3 together with the carbon atom to which they are attached form cyclobutyl. In some embodiments of the compounds of formula (III-a), R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl. In some embodiments of the compounds of formula (III-a), R 2 and R 3 together with the carbon atom to which they are attached form 3- to 6-membered heterocyclyl. In some embodiments of the compounds of formula (III-a), R 2 and R 3 together with the carbon atom to which they are attached form 4- to 6-membered heterocyclyl. In some embodiments of the compounds of formula (III-a), R 2 and R 3 together with the carbon atom to which they are attached form oxetane or pyran. In some embodiments of the compounds of formula (III-a), R 2 and R 3 together with the carbon atom to which they are attached form oxetane or pyran. In some embodiments of the compounds of formula (III-a), R 2 and R 3 together with the carbon atom to which they are attached form In some embodiments of the compounds of formula (III-a), R 2 and R 3 together with the carbon atom to which they are attached form In some embodiments of the compounds of formula (III-a), R 2 and R 3 together with the carbon atom to which they are attached form

[0425] In some embodiments, the compound of formula (I) has formula (III-b-1): In some embodiments, the compound of formula (I) has formula (III-b-1):

[0426]

[0427] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , and R 4a are as defined for formula (I). In some embodiments of the compound of formula (III-b-1), R 2 and R 3 , taken together with the carbon atom to which they are attached, form C3-C6cycloalkyl or 3- to 6-membered heterocyclyl; in some embodiments of the compound of formula (III-b-1), R 2 and R 3 , taken together with the carbon atom to which they are attached, form C3-C6cycloalkyl. In some embodiments of the compound of formula (III-b-1), R 2 and R 3 , taken together with the carbon atom to which they are attached, form cyclopropyl or cyclobutyl. In some embodiments of the compound of formula (III-b-1), R 2 and R 3 , taken together with the carbon atom to which they are attached, form cyclobutyl. In some embodiments of the compound of formula (III-b-1), R 2 and R 3 , taken together with the carbon atom to which they are attached, form cyclopropyl. In some embodiments of the compound of formula (III-b-1), R 2 and R 3 , taken together with the carbon atom to which they are attached, form 3- to 6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-1), R 2 and R 3 , taken together with the carbon atom to which they are attached, form 4- to 6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-1), R 2 and R 3 , taken together with the carbon atom to which they are attached, form oxetane or pyran. In some embodiments of the compound of formula (III-b-1), R 2 and R 3 , taken together with the carbon atom to which they are attached, form oxetane or pyran. In some embodiments of the compound of formula (III-b-1), R 2 and R 3 , taken together with the carbon atom to which they are attached, form In some embodiments of the compound of formula (III-b-1), R 2 and R 3 , taken together with the carbon atom to which they are attached, form In some embodiments of the compound of formula (III-b-1), R2 and R 3 and the carbon atom to which they are attached combine to form

[0428] In some embodiments, the compound of Formula (I) is of Formula (III-b-2):

[0429]

[0430] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 and R 4a are as defined for Formula (I). In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 combine with the carbon atom to which they are attached to form C3-C6cycloalkyl or 3- to 6-membered heterocyclyl; in some embodiments of the compound of Formula (III-b-2), R 2 and R 3 combine with the carbon atom to which they are attached to form C3-C6cycloalkyl. In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 combine with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl. In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 combine with the carbon atom to which they are attached to form cyclobutyl. In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 combine with the carbon atom to which they are attached to form cyclopropyl. In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 combine with the carbon atom to which they are attached to form 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 combine with the carbon atom to which they are attached to form 4- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 combine with the carbon atom to which they are attached to form oxetane or pyran. In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 combine with the carbon atom to which they are attached to form oxetane or pyran. In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 combine with the carbon atom to which they are attached to form In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 taken together with the carbon atom to which they are attached form In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 taken together with the carbon atom to which they are attached form

[0431] In some embodiments, the compound of Formula (I) is of Formula (III-b-3):

[0432]

[0433] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 and R 4a are as defined for Formula (I). In some embodiments of the compound of Formula (III-b-3), R 2 and R 3 taken together with the carbon atom to which they are attached form C3-C6cycloalkyl or 3- to 6-membered heterocyclyl; in some embodiments of the compound of Formula (III-b-3), R 2 and R 3 taken together with the carbon atom to which they are attached form C3-C6cycloalkyl. In some embodiments of the compound of Formula (III-b-3), R 2 and R 3 taken together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl. In some embodiments of the compound of Formula (III-b-3), R 2 and R 3 taken together with the carbon atom to which they are attached form cyclobutyl. In some embodiments of the compound of Formula (III-b-3), R 2 and R 3 taken together with the carbon atom to which they are attached form cyclopropyl. In some embodiments of the compound of Formula (III-b-3), R 2 and R 3 taken together with the carbon atom to which they are attached form 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-3), R 2 and R 3 taken together with the carbon atom to which they are attached form 4- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-3), R 2 and R 3 taken together with the carbon atom to which they are attached form oxetane or pyran. In some embodiments of the compound of Formula (III-b-3), R2 and R 3 and the carbon atom to which they are attached combine to form oxetane or pyran. In some embodiments of the compound of Formula (III-b-3), R 2 and R 3 and the carbon atom to which they are attached combine to form In some embodiments of the compound of Formula (III-b-3), R 2 and R 3 and the carbon atom to which they are attached combine to form In some embodiments of the compound of Formula (III-b-3), R 2 and R 3 and the carbon atom to which they are attached combine to form

[0434] In some embodiments, the compound of Formula (I) is of Formula (III-b-4):

[0435]

[0436] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 and R 4a are as defined for Formula (I). In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 and the carbon atom to which they are attached combine to form C3-C6cycloalkyl or 3- to 6-membered heterocyclyl; in some embodiments of the compound of Formula (III-b-4), R 2 and R 3 and the carbon atom to which they are attached combine to form C3-C6cycloalkyl. In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 and the carbon atom to which they are attached combine to form cyclopropyl or cyclobutyl. In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 and the carbon atom to which they are attached combine to form cyclobutyl. In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 and the carbon atom to which they are attached combine to form cyclopropyl. In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 and the carbon atom to which they are attached combine to form 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-4), R 2 and R 3form a 4- to 6-membered heterocyclyl with the carbon atom to which they are attached. In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 form an oxetane or pyran with the carbon atom to which they are attached. In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 form an oxetane or pyran with the carbon atom to which they are attached. In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 form a In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 form a In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 form a

[0437] In some embodiments, the compound of Formula (I) is of Formula (III-b-5):

[0438]

[0439] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 and R 4a are as defined for Formula (I). In some embodiments of the compound of Formula (III-b-5), R 2 and R 3 form a C3-C6cycloalkyl or 3- to 6-membered heterocyclyl with the carbon atom to which they are attached; in some embodiments of the compound of Formula (III-b-5), R 2 and R 3 form a C3-C6cycloalkyl with the carbon atom to which they are attached. In some embodiments of the compound of Formula (III-b-5), R 2 and R 3 form a cyclopropyl or cyclobutyl with the carbon atom to which they are attached. In some embodiments of the compound of Formula (III-b-5), R 2 and R 3 form a cyclobutyl with the carbon atom to which they are attached. In some embodiments of the compound of Formula (III-b-5), R 2 and R 3Together with the carbon atoms they are attached to, they form cyclopropyl groups. In some embodiments of compounds of formula (III-b-5), R 2 and R 3 Together with the carbon atoms they are attached to, they form 3 to 6-membered heterocyclic groups. In some embodiments of compounds of formula (III-b-5), R 2 and R 3 Together with the carbon atoms they are attached to, they form 4- to 6-membered heterocyclic groups. In some embodiments of compounds of formula (III-b-5), R 2 and R 3 Together with the carbon atoms they are attached to, they form oxetanes or pyrans. In some embodiments of compounds of formula (III-b-5), R 2 and R 3 Together with the carbon atoms they are attached to, they form oxetanes or pyrans. In some embodiments of compounds of formula (III-b-5), R 2 and R 3 Together with the carbon atoms they are attached to form In some embodiments of the compound of formula (III-b-5), R 2 and R 3 Together with the carbon atoms they are attached to form In some embodiments of the compound of formula (III-b-5), R 2 and R 3 Together with the carbon atoms they are attached to form

[0440] In some embodiments, the compound of formula (I) has formula (III-b-6):

[0441]

[0442] Or a pharmaceutically acceptable salt thereof, wherein R 2 R 3 and R 4a As defined for formula (I). In some embodiments of the compound of formula (III-b-6), R 2 and R 3 Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl or 3- to 6-membered heterocyclic groups; in some embodiments of compounds of formula (III-b-6), R 2 and R 3 Together with the carbon atoms they are attached to, they form C3-C6 cycloalkyl groups. In some embodiments of compounds of formula (III-b-6), R 2 and R 3Together with the carbon atoms they are attached to, they form cyclopropyl or cyclobutyl groups. In some embodiments of compounds of formula (III-b-6), R 2 and R 3 Together with the carbon atoms they are attached to, they form cyclobutyl groups. In some embodiments of compounds of formula (III-b-6), R 2 and R 3 Together with the carbon atoms they are attached to, they form cyclopropyl groups. In some embodiments of compounds of formula (III-b-6), R 2 and R 3 Together with the carbon atoms they are attached to, they form 3 to 6-membered heterocyclic groups. In some embodiments of compounds of formula (III-b-6), R 2 and R 3 Together with the carbon atoms they are attached to, they form 4- to 6-membered heterocyclic groups. In some embodiments of compounds of formula (III-b-6), R 2 and R 3 Together with the carbon atoms they are attached to, they form oxetanes or pyrans. In some embodiments of compounds of formula (III-b-6), R 2 and R 3 Together with the carbon atoms they are attached to, they form oxetanes or pyrans. In some embodiments of compounds of formula (III-b-6), R 2 and R 3 Together with the carbon atoms they are attached to form In some embodiments of the compound of formula (III-b-6), R 2 and R 3 Together with the carbon atoms they are attached to form In some embodiments of the compound of formula (III-b-6), R 2 and R 3 Together with the carbon atoms they are attached to form

[0443] In some embodiments, the compound of formula (I) has formula (III-b-7):

[0444]

[0445] Or a pharmaceutically acceptable salt thereof, wherein R 2 R 3 and R 4a As defined for formula (I). In some embodiments of the compound of formula (III-b-7), R 2 and R 3Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl or 3- to 6-membered heterocyclic groups; in some embodiments of compounds of formula (III-b-7), R 2 and R 3 Together with the carbon atoms they are attached to, they form C3-C6 cycloalkyl groups. In some embodiments of compounds of formula (III-b-7), R 2 and R 3 Together with the carbon atoms they are attached to, they form cyclopropyl or cyclobutyl groups. In some embodiments of compounds of formula (III-b-7), R 2 and R 3 Together with the carbon atoms they are attached to, they form cyclobutyl groups. In some embodiments of compounds of formula (III-b-7), R 2 and R 3 Together with the carbon atoms they are attached to, they form cyclopropyl groups. In some embodiments of compounds of formula (III-b-7), R 2 and R 3 Together with the carbon atoms they are attached to, they form 3 to 6-membered heterocyclic groups. In some embodiments of compounds of formula (III-b-7), R 2 and R 3 Together with the carbon atoms they are attached to, they form 4- to 6-membered heterocyclic groups. In some embodiments of compounds of formula (III-b-7), R 2 and R 3 Together with the carbon atoms they are attached to, they form oxetanes or pyrans. In some embodiments of compounds of formula (III-b-7), R 2 and R 3 Together with the carbon atoms they are attached to, they form oxetanes or pyrans. In some embodiments of compounds of formula (III-b-7), R 2 and R 3 Together with the carbon atoms they are attached to form In some embodiments of the compound of formula (III-b-7), R 2 and R 3 Together with the carbon atoms they are attached to form In some embodiments of the compound of formula (III-b-7), R 2 and R 3 Together with the carbon atoms they are attached to form

[0446] In some embodiments, the compound of formula (I) has formula (III-b-8):

[0447]

[0448] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , and R 4a are as defined for formula (I). In some embodiments of the compound of formula (III-b-8), R 2 and R 3 , taken together with the carbon atom to which they are attached, form C3-C6cycloalkyl or 3- to 6-membered heterocyclyl; in some embodiments of the compound of formula (III-b-8), R 2 and R 3 , taken together with the carbon atom to which they are attached, form C3-C6cycloalkyl. In some embodiments of the compound of formula (III-b-8), R 2 and R 3 , taken together with the carbon atom to which they are attached, form cyclopropyl or cyclobutyl. In some embodiments of the compound of formula (III-b-8), R 2 and R 3 , taken together with the carbon atom to which they are attached, form cyclobutyl. In some embodiments of the compound of formula (III-b-8), R 2 and R 3 , taken together with the carbon atom to which they are attached, form cyclopropyl. In some embodiments of the compound of formula (III-b-8), R 2 and R 3 , taken together with the carbon atom to which they are attached, form 3- to 6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-8), R 2 and R 3 , taken together with the carbon atom to which they are attached, form 4- to 6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-8), R 2 and R 3 , taken together with the carbon atom to which they are attached, form oxetane or pyran. In some embodiments of the compound of formula (III-b-8), R 2 and R 3 , taken together with the carbon atom to which they are attached, form oxetane or pyran. In some embodiments of the compound of formula (III-b-8), R 2 and R 3 , taken together with the carbon atom to which they are attached, form In some embodiments of the compound of formula (III-b-8), R 2 and R 3 , taken together with the carbon atom to which they are attached, form In some embodiments of the compound of formula (III-b-8), R 2 and R 3 , taken together with the carbon atom to which they are attached, form

[0449] In some embodiments, the compound of Formula (I) is of Formula (III-b-9):

[0450]

[0451] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , and R 4a are as defined for Formula (I). In some embodiments of the compound of Formula (III-b-9), R 2 and R 3 are taken together with the carbon atom to which they are attached to form C3-C6cycloalkyl or 3- to 6-membered heterocyclyl; in some embodiments of the compound of Formula (III-b-9), R 2 and R 3 are taken together with the carbon atom to which they are attached to form C3-C6cycloalkyl. In some embodiments of the compound of Formula (III-b-9), R 2 and R 3 are taken together with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl. In some embodiments of the compound of Formula (III-b-9), R 2 and R 3 are taken together with the carbon atom to which they are attached to form cyclobutyl. In some embodiments of the compound of Formula (III-b-9), R 2 and R 3 are taken together with the carbon atom to which they are attached to form cyclopropyl. In some embodiments of the compound of Formula (III-b-9), R 2 and R 3 are taken together with the carbon atom to which they are attached to form 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-9), R 2 and R 3 are taken together with the carbon atom to which they are attached to form 4- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-9), R 2 and R 3 are taken together with the carbon atom to which they are attached to form oxetane or pyran. In some embodiments of the compound of Formula (III-b-9), R 2 and R 3 are taken together with the carbon atom to which they are attached to form oxetane or pyran. In some embodiments of the compound of Formula (III-b-9), R 2 and R 3 are taken together with the carbon atom to which they are attached to form In some embodiments of the compound of Formula (III-b-9), R 2 and R3 together with the carbon atom to which they are attached form In some embodiments of the compound of formula (III-b-9), R 2 and R 3 together with the carbon atom to which they are attached form

[0452] In some embodiments, the compound of formula (I) is of formula (IV):

[0453]

[0454] or a pharmaceutically acceptable salt thereof, wherein R 3 is as defined for formula (I).

[0455] In some embodiments, the compound of formula (I) is

[0456]

[0457] In another embodiment also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted with one or more R 1a is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted with one or more R 1b is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted with one or more R 1c is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted with one or more R 1d is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted with one or more R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted with one or more R 1a is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted with one or more R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted with one or more R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted with one or more R 1a is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted with one or more R 1a together with the carbon atom to which they are attached form C3-C6cycloalkyl (e.g., cyclopropyl). In one aspect of the foregoing embodiments, R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted with one or more R 1b is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted with one or more R 1is unsubstituted 1,2,3,4-tetrahydro-l,8-naphthyridin-2-yl. In one aspect of the foregoing embodiments, R 1 is 1,2,3,4-tetrahydro-l,8-naphthyridin-2-yl substituted with two R 1b groups on the same carbon atom, wherein the two R 1b groups, taken together with the carbon atom to which they are attached, form C3-C6cycloalkyl (e.g., cyclopropyl).

[0458] In another embodiment there is also provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are independently H or C1-C6alkyl. In one aspect of the foregoing embodiments, R 2 and R 3 are the same. In one aspect of the foregoing embodiments, R 2 and R 3 are different. In one aspect of the foregoing embodiments, R 2 and R 3 are both H. In one aspect of the foregoing embodiments, R 2 is H and R 3 is C1-C6alkyl. In one aspect of the foregoing embodiments, R 2 is H and R 3 is C1-C3alkyl. In one aspect of the foregoing embodiments, R 2 is H and R 3 is -CH3. In one aspect of the foregoing embodiments, R 2 and R 3 are independently C1-C6alkyl. In one aspect of the foregoing embodiments, R 2 and R 3 are independently C1-C3alkyl. In one aspect of the foregoing embodiments, R 2 and R 3 are independently methyl, ethyl, n-propyl or i-propyl. In one aspect of the foregoing embodiments, R 2 and R 3 are both -CH3.

[0459] In another embodiment there is also provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , taken together with the carbon atom to which they are attached, form C3-C6cycloalkyl. In one aspect of the foregoing embodiments, R 2 and R 3 , taken together with the carbon atom to which they are attached, form C3-C4cycloalkyl. In one aspect of the foregoing embodiments, R 2 and R 3together with the carbon atom to which they are attached form cyclopropyl. In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atom to which they are attached form cyclobutyl.

[0460] In another embodiment there is also provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered heterocyclyl. In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered heterocyclyl, wherein the heterocyclyl contains at least one oxygen atom. In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl. In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl contains at least one oxygen atom. In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atom to which they are attached form oxetanyl. In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atom to which they are attached form tetrahydropyranyl. In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atom to which they are attached form In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atom to which they are attached form In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atom to which they are attached form

[0461] In another embodiment there is also provided a compound of formula (A) or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 together with the carbon atom to which they are attached form C3-C6cycloalkyl substituted with R 2a In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atom to which they are attached form C3-C6cycloalkyl substituted with deuterium or C1-C6alkyl optionally substituted with halogen. In one aspect of the foregoing embodiment, R2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl substituted with R 2a In one aspect of the foregoing embodiments, R 2 and R 3 together with the carbon atom to which they are attached form

[0462] In another embodiment, there is also provided a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered heterocyclyl substituted with R 2a In one aspect of the foregoing embodiments, R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered heterocyclyl substituted with deuterium or C1-C6 alkyl optionally substituted with halo. In one aspect of the foregoing embodiments, R 2 and R 3 together with the carbon atom to which they are attached form a piperidine substituted with R 2a In one aspect of the foregoing embodiments, R 2 and R 3 together with the carbon atom to which they are attached form

[0463] In another embodiment, there is also provided a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl optionally substituted with one or more R 4a In one aspect of the foregoing embodiments, R 4 is unsubstituted phenyl. In one aspect of the foregoing embodiments, R 4 is phenyl substituted with 1-5 R 4a groups, wherein each R 4a is independently selected from halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -OH, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), -S(O)2(C1-C6 alkyl), or -C(=O)-NH2.

[0464] In another embodiment, there is also provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl optionally substituted with one or more R 4a In one aspect of the foregoing embodiments, R 4 is unsubstituted phenyl. In one aspect of the foregoing embodiments, R 4 is phenyl substituted with 1-5 R4a phenyl substituted with 1-5 R 4a are independently selected from halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), and -S(O)2(C1-C6 alkyl). In one aspect of the foregoing embodiments, R 4 is phenyl substituted with 1-5 R 4a are independently selected from F, Cl, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), and -S(O)2(C1-C3 alkyl). In one aspect of the foregoing embodiments, R 4a is phenyl substituted with 1-5 R 4 are independently selected from halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), and -S(O)2(C1-C3 alkyl). In one aspect of the foregoing embodiments, R 4a is phenyl substituted with 1-5 R 4a are independently selected from halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), and -S(O)2(C1-C3 alkyl). In one aspect of the foregoing embodiments, R 4 is phenyl substituted with 1-5 R 4a are independently selected from halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), and -S(O)2(C1-C3 alkyl). In one aspect of the foregoing embodiments, R 4a is phenyl substituted with 1-5 R 4 are independently selected from halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), and -S(O)2(C1-C3 alkyl). In one aspect of the foregoing embodiments, R 4a is phenyl substituted with 1-5 R 4a are independently selected from halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), and -S(O)2(C1-C3 alkyl). In one aspect of the foregoing embodiments, R 4 is phenyl substituted with 1-5 R 4a are independently selected from halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), and -S(O)2(C1-C3 alkyl). In one aspect of the foregoing embodiments, R 4a is phenyl substituted with 1-5 R 4 are independently selected from halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), and -S(O)2(C1-C3 alkyl). In one aspect of the foregoing embodiments, R 4a is phenyl substituted with 1-5 R 4a are independently selected from halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), and -S(O)2(C1-C3 alkyl). In one aspect of the foregoing embodiments, R 4 is phenyl substituted with 1-5 R 4a are independently selected from halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), and -S(O)2(C1-C3 alkyl). In one aspect of the foregoing embodiments, R 4a is phenyl substituted with 1-5 R 4 are independently selected from halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), and -S(O)2(C1-C3 alkyl). In one aspect of the foregoing embodiments, R 4a is phenyl substituted with 1-5 R 4ahalo, CN, -O-(Ci-C6alkyl), and -O-(Ci-C6haloalkyl). In a further aspect of the foregoing embodiments, R 4 is phenyl substituted with 2-5 R 4a groups, wherein at least two of the R 4a groups are halo (e.g., fluoro or chloro). In a further aspect of the foregoing embodiments, R 4 is phenyl substituted with 2-5 R 4a groups, wherein at least one of the R 4a groups is halo (e.g., fluoro or chloro), and at least one of the R 4a groups is CN. In a further aspect of the foregoing embodiments, R 4 is phenyl substituted with 2-5 R 4a groups, wherein at least one of the R 4a groups is halo (e.g., fluoro or chloro), and at least one of the R 4a groups is -O-(Ci-C3alkyl) (e.g., -O-CH3). In a further aspect of the foregoing embodiments, R 4 is phenyl substituted with 2-5 R 4a groups, wherein at least one of the R 4a groups is halo (e.g., fluoro or chloro), and at least one of the R 4a groups is -O-(Ci-C3haloalkyl) (e.g., -O-CHF2). In a further aspect of the foregoing embodiments, R 4 is phenyl substituted with 2-5 R 4a groups, wherein at least one of the R 4a groups is CN, and at least one of the R 4a groups is -O-(Ci-C3alkyl) (e.g., -O-CH3).

[0465] In another embodiment, there is also provided a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom, wherein the 5- to 6-membered heteroaryl is optionally fused to phenyl, and wherein the 5- to 6-membered heteroaryl is optionally substituted with one or more R 4a groups. In a further aspect of the foregoing embodiments, R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom, and is optionally substituted with one or more R 4a groups. In a further aspect of the foregoing embodiments, R 4 is a 5-membered heteroaryl containing two nitrogen atoms (e.g., R 4 is pyrazolyl, imidazolyl, or thiazolyl), and is optionally substituted with one or more R4a In another aspect of the foregoing embodiments, R 4 is 6-membered heteroaryl, wherein the 6-membered heteroaryl contains one nitrogen atom, and is optionally substituted with one or more R 4a In another aspect of the foregoing embodiments, R 4 is pyridyl optionally substituted with one or more R 4a In another aspect of the foregoing embodiments, R 4 is 6-membered heteroaryl, wherein the 6-membered heteroaryl contains two nitrogen atoms (e.g., R 4 is pyrimidinyl or pyrazinyl), and is optionally substituted with one or more R 4a In another aspect of the foregoing embodiments, R 4 is pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, or pyrazinyl, each substituted with 1-4 R 4a groups, wherein the R 4a groups are independently selected from halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -OH, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), -S(O)2(C1-C6 alkyl), or -C(=O)-NH2.

[0466] In another embodiment, there is also provided a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein R 4 is 6-membered heterocyclyl containing at least one nitrogen atom, wherein the 6-membered heterocyclyl is optionally fused to phenyl, and wherein the 6-membered heterocyclyl is optionally substituted with one or more R 4a or oxo. In another aspect of the foregoing embodiments, R 4 is 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains one nitrogen atom, and is optionally substituted with one or more R 4a or oxo. In another aspect of the foregoing embodiments, R 4 is 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains two nitrogen atoms, and is optionally substituted with one or more R 4a or oxo. In another aspect of the foregoing embodiments, R 4 is 6-membered heterocyclyl optionally fused to phenyl, wherein the 6-membered heterocyclyl contains one nitrogen atom, is substituted with one oxo group, and is optionally substituted with one or more R 4a In another aspect of the foregoing embodiments, R 4 is substituted with 1-4 R 4a or oxo groups, wherein the R 4aR is independently selected from halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -OH, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), -S(O)2(C1-C6 alkyl), or -C(=O)-NH2. In another aspect of the foregoing embodiments, R 4 is optionally fused to phenyl and optionally substituted with one or more R 4a substituents. In another aspect of the foregoing embodiments, R is optionally fused to phenyl and optionally substituted with one or more R 4 substituents. In another aspect of the foregoing embodiments, R is optionally fused to phenyl and optionally substituted with one or more R 4 substituents. In another aspect of the foregoing embodiments, R is optionally fused to phenyl and optionally substituted with one or more R 4 substituents. In another aspect of the foregoing embodiments, R

[0467] In another embodiment, there is also provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom, wherein the 5- to 6-membered heteroaryl is optionally fused to phenyl, and wherein the 5- to 6-membered heteroaryl is optionally substituted with one or more R 4a substituents. In another aspect of the foregoing embodiments, R 4 is a 6-membered heteroaryl fused to phenyl (e.g., pyrimidinyl). In another aspect of the foregoing embodiments, R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom, and optionally substituted with one or more R 4a substituents. In another aspect of the foregoing embodiments, R 4 is a 5-membered heteroaryl containing two nitrogen atoms (e.g., R 4 is pyrazolyl, imidazolyl, or thiazolyl), and optionally substituted with one or more R 4a substituents. In another aspect of the foregoing embodiments, R 4 is a 6-membered heteroaryl containing one nitrogen atom, and optionally substituted with one or more R 4a substituents. In another aspect of the foregoing embodiments, R 4 is pyridyl optionally substituted with one or more R 4a substituents. In another aspect of the foregoing embodiments, R 4 is a 6-membered heteroaryl containing two nitrogen atoms (e.g., R 4 is pyrimidinyl or pyrazinyl), and optionally substituted with one or more R 4a substituents. In another aspect of the foregoing embodiments, R 4is each unsubstituted pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl, or pyrazinyl. In another aspect of the foregoing embodiments, R 4 is each pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl, or pyrazinyl substituted with 1-4 R 4a groups, wherein the R 4a groups are independently selected from halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -O-(C1-C6 alkyl), and -O-(C1-C6 haloalkyl). In another aspect of the foregoing embodiments, R 4 is each pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl, or pyrazinyl substituted with 1-4 R 4a groups, wherein the R 4a groups are independently selected from F, Cl, CN, -CH3, -CF3, -CHF2, -CH2F, -CH2-O-CH3, cyclopropyl, -O-CH3, and -O-CHF2. In one aspect of the foregoing embodiments, R 4 is each pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl, or pyrazinyl substituted with 1-4 R 4a groups, wherein the R 4a groups are independently selected from F, Cl, CN, -CH3, -CF3, -CHF2, -CH2F, -CH2-O-CH3, cyclopropyl, -O-CH3, and -O-CHF2. In one aspect of the foregoing embodiments, R 4 is substituted with 1-4 R 4a groups, wherein at least one R 4a group is F or Cl. In one aspect of the foregoing embodiments, R 4 is substituted with 1-4 R 4a groups, wherein at least one R 4a group is CN. In one aspect of the foregoing embodiments, R 4 is substituted with 1-4 R 4a groups, wherein at least one R 4a group is C1-C3 alkyl. In one aspect of the foregoing embodiments, R 4 is substituted with 1-4 R 4a groups, wherein at least one R 4a group is C1-C3 haloalkyl. In one aspect of the foregoing embodiments, R 4 is substituted with 1-4 R 4a groups, wherein at least one R 4aThe group is -0-(Ci-C3alkyl). In one aspect of the foregoing embodiments, R 4 substituted with 1-4 R 4a groups, wherein at least one R 4a group is cyclopropyl. In one aspect of the foregoing embodiments, R 4 substituted with 1-4 R 4a groups, wherein at least one R 4a group is -0-(Ci-C3alkyl). In one aspect of the foregoing embodiments, R 4 substituted with 1-4 R 4a groups, wherein at least one R 4a group is -0-(Ci-C3haloalkyl). In one aspect of the foregoing embodiments, R 4 substituted with 2-4 R 4a groups, wherein at least one R 4a group is F, and wherein at least one R 4a group is Cl. In one aspect of the foregoing embodiments, R 4 substituted with 2-4 R 4a groups, wherein at least one R 4a group is F, and wherein at least one R 4a group is Ci-C3alkyl. In one aspect of the foregoing embodiments, R 4 substituted with 2-4 R 4a groups, wherein at least one R 4a group is Cl, and wherein at least one R 4a group is Ci-C3alkyl. In one aspect of the foregoing embodiments, R 4 substituted with 2-4 R 4a groups, wherein at least one R 4a group is Cl, and wherein at least one R 4a group is -0-(Ci-C3alkyl). In one aspect of the foregoing embodiments, R 4 substituted with 2-4 R 4a groups, wherein at least two R 4a groups are Cl.

[0468] In another embodiment there is also provided a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein R 4 is pyridyl substituted with 1-4 R 4a groups, wherein the R 4aR is selected from halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -OH, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), -S(O)2(C1-C6 alkyl), or -C(=O)-NH2.

[0469] In another embodiment there is also provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 is pyridyl substituted with 1-4 R 4a groups, wherein the R 4a groups are independently selected from halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl). In one aspect of the foregoing embodiment, R 4 is pyridyl substituted with 1-4 R 4a groups, wherein the R 4a groups are independently selected from F, Cl, CN, -CH3, -CF3, -CHF2, -CH2F, -CH2-O-CH3, cyclopropyl, -O-CH3, and -O-CHF2. In one aspect of the foregoing embodiment, R 4 is pyridyl substituted with 2-4 R 4a groups, wherein the R 4a groups are independently selected from halo (e.g., F or Cl), C1-C3 alkyl (e.g., -CH3), and -O-(C1-C3 alkyl) (e.g., -O-CH3). In one aspect of the foregoing embodiment, R 4 is pyridyl substituted with 2-4 R 4a groups, wherein at least two of the R 4a groups are halo (e.g., fluoro or chloro). In one aspect of the foregoing embodiment, R 4 is pyridyl substituted with 2-4 R 4a groups, wherein at least one of the R 4a groups is halo (e.g., fluoro or chloro), and the R 4 groups are independently selected from halo (e.g., F or Cl), C1-C3 alkyl (e.g., -CH3), and -O-(C1-C3 alkyl) (e.g., -O-CH3). In one aspect of the foregoing embodiment, R 4a is pyridyl substituted with 2-4 R 4a groups, wherein at least one of the R 4aAt least one of the groups is C1-C3 alkyl (e.g., -CH3). In one aspect of the foregoing embodiment, R 4 is pyridyl substituted with 2-4 R 4a groups, wherein at least one of the R 4a groups is halo (e.g., fluoro or chloro), and at least one of the R 4a groups is -0-(Ci-C3 alkyl) (e.g., -O-CH3).

[0470] In another embodiment there is also provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 is 5-membered heteroaryl, wherein the 5-membered heteroaryl contains at least one nitrogen atom, and is optionally substituted with one or more R 4a groups. In one aspect of the foregoing embodiment, R 4 is 5-membered heteroaryl containing at least one nitrogen atom and at least one additional heteroatom selected from oxygen and sulfur (e.g., R 4 is thiazolyl), and is optionally substituted with one or more R 4a groups. In one aspect of the foregoing embodiment, R 4 is 5-membered heteroaryl, wherein the 5-membered heteroaryl contains one nitrogen atom, and is optionally substituted with one or more R 4a groups. In one aspect of the foregoing embodiment, R 4 is 5-membered heteroaryl, wherein the 5-membered heteroaryl contains two nitrogen atoms (e.g., R 4 is pyrazolyl or imidazolyl), and is optionally substituted with one or more R 4a groups. In one aspect of the foregoing embodiment, R 4 is unsubstituted 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl). In one aspect of the foregoing embodiment, R 4 is 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted with 1-3 R 4a groups, wherein the R 4a groups are independently selected from halo, CN, C1-C6 alkyl, and C1-C6 haloalkyl. In one aspect of the foregoing embodiment, R 4 is 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted with 1-3 R 4a groups, wherein the R 4a groups are independently selected from F, Cl, CN, C1-C3 alkyl (e.g., -CH3), and C1-C3 haloalkyl (e.g., -CF3). In one aspect of the foregoing embodiment, R 4 is 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted with 2-3 R 4a groups, wherein the R 4aR is independently selected from halo (e.g., F or CI), CN, Ci-C3alkyl (e.g., -CH3), and Ci-C3haloalkyl (e.g., -CF3). In one aspect of the foregoing embodiments, R 4 is a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted with 2-3 R 4a groups, wherein at least two of the R 4a groups are halo (e.g., chloro). In one aspect of the foregoing embodiments, R 4 is a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted with 2-3 R 4a groups, wherein at least one of the R 4a groups is halo (e.g., chloro), and at least one of the R 4a groups is Ci-C3alkyl (e.g., -CH3). In one aspect of the foregoing embodiments, R 4 is a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted with 2-3 R 4a groups, wherein at least one of the R 4a groups is CN, and at least one of the R 4a groups is Ci-C3alkyl (e.g., -CH3). In one aspect of the foregoing embodiments, R 4 is a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted with 2-3 R 4a groups, wherein at least one of the R 4a groups is Ci-C3alkyl (e.g., -CH3), and at least one of the R 4a groups is Ci-C3haloalkyl (e.g., -CF3).

[0471] In another embodiment, compounds of Formula (I), or pharmaceutically acceptable salts thereof, are also provided wherein R 4 is a 6-membered heteroaryl, wherein the 6-membered heteroaryl contains two nitrogen atoms (e.g., R 4 is pyrimidinyl or pyrazinyl), and is optionally substituted with one or more R 4a groups. In one aspect of the foregoing embodiments, R 4 is an unsubstituted 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl). In one aspect of the foregoing embodiments, R 4 is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted with 1-3 R 4a groups, wherein the R 4a groups are independently selected from halo, Ci-C6alkyl, Ci-C6haloalkyl, and -0-(Ci-C6alkyl). In one aspect of the foregoing embodiments, R 4 is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted with 1-3 R4a a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted with 1-3 R 4a groups independently selected from halo, C1-C3 alkyl, C1-C3 haloalkyl, and -O-(C1-C3 alkyl). In one aspect of the foregoing embodiments, R 4 is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted with 1-3 R 4a groups independently selected from Cl, CH3, -CF3, -CHF2, and -O-CH3. In one aspect of the foregoing embodiments, R 4a is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted with 2-3 R 4 groups independently selected from halo (e.g., Cl), C1-C6 alkyl (e.g., -CH3), and -O-(C1-C6 alkyl) (e.g., -O-CH3). In one aspect of the foregoing embodiments, R 4a is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted with 2-3 R 4a groups, at least one of which is halo (e.g., chloro), and at least one of which is C1-C3 alkyl (e.g., -CH3). In one aspect of the foregoing embodiments, R 4 is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted with 2-3 R 4a groups, at least one of which is halo (e.g., chloro), and at least one of which is -O-(C1-C3 alkyl) (e.g., -O-CH3). In one aspect of the foregoing embodiments, R 4a is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted with 2-3 R 4a groups, at least two of which are C1-C3 alkyl (e.g., -CH3). In one aspect of the foregoing embodiments, R 4 is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted with 2-3 R 4a groups, at least one of which is C1-C3 alkyl (e.g., -CH3), and at least one of which is -O-(C1-C3 alkyl) (e.g., -O-CH3). In one aspect of the foregoing embodiments, R 4a is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted with 2-3 R 4a groups, at least one of which is C1-C3 alkyl (e.g., -CH3), and at least one of which is -O-(C1-C3 alkyl) (e.g., -O-CH3). In one aspect of the foregoing embodiments, R 4 is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted with 2-3 R 4a groups, at least two of which are C1-C3 alkyl (e.g., -CH3). In one aspect of the foregoing embodiments, R 4a is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted with 2-3 R 4 groups, at least one of which is C1-C3 alkyl (e.g., -CH3), and at least one of which is -O-(C1-C3 alkyl) (e.g., -O-CH3). In one aspect of the foregoing embodiments, R 4a is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted with 2-3 R 4a groups, at least one of which is C1-C3 alkyl (e.g., -CH3), and at least one of which is -O-(C1-C3 alkyl) (e.g., -O-CH3). In one aspect of the foregoing embodiments, R 4a is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted with 2-3 R

[0472] In another embodiment there is also provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 is a 6-membered heterocyclyl group, wherein the 6-membered heterocyclyl group contains at least one nitrogen atom, is optionally fused to phenyl, and is optionally substituted with one or more groups selected from R 4a (e.g., CI) and oxo. In one aspect of the foregoing embodiment, R 4 is a 6-membered heterocyclyl group containing one nitrogen atom, wherein the 6-membered heterocyclyl group is fused to phenyl, and is substituted with oxo. In one aspect of the foregoing embodiment, R 4 is a 6-membered heterocyclyl group, wherein the 6-membered heterocyclyl group contains one nitrogen atom, and is optionally substituted with one or more groups selected from R 4a (e.g., CI) and oxo. In one aspect of the foregoing embodiment, R 4 is a 6-membered heterocyclyl group, wherein the 6-membered heterocyclyl group contains two nitrogen atoms, and is optionally substituted with one or more groups selected from R 4a (e.g., CI) and oxo. In one aspect of the foregoing embodiment, R 4 is substituted with CI and oxo. In one aspect of the foregoing embodiment, R 4 is a 6-membered heterocyclyl group, wherein the 6-membered heterocyclyl group contains one nitrogen atom, and is substituted with CI and oxo. In one aspect of the foregoing embodiment, R 4 is a 6-membered heterocyclyl group, wherein the 6-membered heterocyclyl group contains two nitrogen atoms, and is substituted with CI and oxo.

[0473] In another embodiment there is also provided a compound of Formula (A), or a pharmaceutically acceptable salt thereof, wherein R 4 is C1-C6 haloalkyl. In one aspect of the foregoing embodiment, R 4 is C1-C6 fluoroalkyl. In one aspect of the foregoing embodiment, R 4 is C1 haloalkyl. In one aspect of the foregoing embodiment, R 4 is C1-C6 fluoroalkyl. In one aspect of the foregoing embodiment, R 4

[0474] In another embodiment there is also provided a compound of Formula (A), or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 and R 4 are taken together to form a 5-membered heteroaryl group containing two nitrogen atoms and substituted with phenyl, wherein the phenyl is optionally substituted with one or more R 4a . In one aspect of the foregoing embodiment, R 2 , R 3 ​and R 4 combined to form

[0475] In another embodiment there is also provided a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein each R 4a is independently selected from halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -OH, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), -S(O)2(C1-C6 alkyl), or -C(=O)-NH2.

[0476] In another embodiment there is also provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R 4a is independently selected from halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), and -S(O)2(C1-C6 alkyl). In one aspect of the foregoing embodiment, each R 4a is independently selected from halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), and -S(O)2(C1-C3 alkyl). In one aspect of the foregoing embodiment, each R 4a is independently selected from F, Cl, CN, -CH3, -CH2F, -CHF2, -CF3, -CH2-O-CH3, cyclopropyl, -OCH3, -OCHF2, and -S(O)2CH3.

[0477] In some embodiments, R 4a is halo. In some embodiments, R 4a is F or Cl. In some embodiments, R 4a is F. In some embodiments, R 4a is Cl.

[0478] In some embodiments, R 4a is CN.

[0479] In some embodiments, R 4a is C1-C6 alkyl. In some embodiments, R 4a is C1-C3 alkyl. In some embodiments, R 4a is methyl, ethyl, n-propyl, or i-propyl. In some embodiments, R 4ais methyl, ethyl, or isopropyl. In some embodiments, R 4a is -CH3.

[0480] In some embodiments, R 4a is C1-C6haloalkyl. In some embodiments, R 4a is C1-C3haloalkyl. In some embodiments, the halogen atoms are all fluorine atoms. In some embodiments, the halogen atoms are all chlorine atoms. In some embodiments, the halogen atoms are a combination of fluorine atoms and chlorine atoms. In some embodiments, R 4a is -CF3, -CC13, -CF2C1, -CFCl2, -CHF2, -CH2F, -CHC12, -CH2C1, or -CHFC1. In some embodiments, R 4a is -CF3, -CHF2, -CH2F. In some embodiments, R 4a is -CF3. In some embodiments, R 4a is -CHF2. In some embodiments, R 4a is -CH2F.

[0481] In some embodiments, R 4a is -(C1-C6alkylene)-O-(C1-C6alkyl). In some embodiments, R 4a is -(C1-C3alkylene)-O-(C1-C3alkyl). In some embodiments, R 4a is -CH2-O-CH3, -CH2-O-CH2CH3, -CH2-O-CH2CH2CH3, or -CH2-O-CH(CH3)2. In some embodiments, R 4a is -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH2CH2-O-CH2CH2CH3, or -CH2CH2-O-CH(CH3)2. In some embodiments, R 4a is -CH2CH2CH2-O-CH3, -CH2CH2CH2-O-CH2CH3, -CH2CH2CH2-O-CH2CH2CH3, or -CH2CH2CH2-O-CH(CH3)2. In some embodiments, R 4a is -CH2-O-CH3.

[0482] In some embodiments, R 4a is C3-C6cycloalkyl. In some embodiments, R 4a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 4a is cyclopropyl.

[0483] In some embodiments, R 4a is -0-(Ci-C6alkyl). In some embodiments, R 4a is -0-(Ci-C3alkyl). In some embodiments, R 4a is -0-CH3, -0-CH2CH3, -0-CH2CH2CH3, or -0-CH(CH3)2. In some embodiments, R 4a is -0-CH3.

[0484] In some embodiments, R 4a is -0-(Ci-C6haloalkyl). In some embodiments, R 4a is -0-(Ci-C3haloalkyl). In some embodiments, the halogen atoms are all fluorine atoms. In some embodiments, the halogen atoms are all chlorine atoms. In some embodiments, the halogen atoms are a combination of fluorine atoms and chlorine atoms. In some embodiments, R 4a is -0-CF3, -0-CC13, -0-CF2C1, -0-CFC12, -0-CHF2, -0-CH2F, -0-CHC12, -0-CH2C1, or -0-CHFC1. In some embodiments, R 4a is -0-CHF2.

[0485] In some embodiments, R 4a is -S(0)2(Ci-C6alkyl). In some embodiments, R 4a is -S(0)2(Ci-C4alkyl). In some embodiments, R 4a is -S(0)2CH3.

[0486] In some embodiments, R 4a is -OH. In some embodiments, R 4a is -C(=0)-NH2.

[0487] In another embodiment, there is also provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4a and R 2 taken together with the atoms to which they are attached form a 6-membered heterocyclyl. In some embodiments, R 4a and R 2 taken together with the atoms to which they are attached form a 6-membered heterocyclyl, wherein the heterocyclyl contains one oxygen atom. In some embodiments, R 4 is phenyl, R 4a and R 2 taken together with the atoms to which they are attached form a 6-membered heterocyclyl, wherein the heterocyclyl contains one oxygen atom. In some embodiments, R 2 , R3 and R 4 taken together with the carbon atom to which they are attached form In some embodiments, R 2 , R 3 and R 4 taken together with the carbon atom to which they are attached form In some embodiments, R 2 , R 3 and R 4 taken together with the carbon atom to which they are attached form

[0488] Also provided are compounds of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from:

[0489] Also provided are compounds of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from:

[0490]

[0491] Also provided are compounds of Formula (A) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from

[0492] In another embodiment also provided are compounds of Formula (I) or a pharmaceutically acceptable salt thereof, wherein Q is H or C1-C8 alkyl. In one aspect of the foregoing embodiment, Q is H. In one aspect of the foregoing embodiment, Q is C1-C6 alkyl. In one aspect of the foregoing embodiment, Q is methyl, ethyl, n-propyl or isopropyl, n-butyl, t-butyl, isobutyl or sec-butyl. In one aspect of the foregoing embodiment, Q is methyl.

[0493] In one aspect are provided compounds of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound has any one or more of the following characteristics:

[0494] (I) R 1 is

[0495] (II) -L 1 -O-L 2 -Y-L 3 taken together form

[0496] ​(III) Q is H or Ci-C6alkyl (e.g., -CH3or -CH2CH3);

[0497] (IV) R 2 and R 3 :

[0498] (i) are both H;

[0499] (ii) are both -CH3; or

[0500] (iii) taken together with the carbon atom to which they are attached form a cyclopropyl group; and

[0501] (V) R 4 is:

[0502] (i) phenyl substituted with 0-5 R 4a groups;

[0503] (ii) 5-membered heteroaryl containing at least one nitrogen atom (e.g., pyrazolyl or imidazolyl) and substituted with 0-4 R 4a groups;

[0504] (iii) 6-membered heteroaryl containing at least one nitrogen atom (e.g., pyridinyl, pyrimidinyl, or pyrazinyl) and substituted with 0-4 R 4a groups; or

[0505] (iv) 6-membered heterocyclyl containing at least one nitrogen atom (e.g., ) and substituted with 0-4 groups selected from R 4a and oxo.

[0506] In one variation of this aspect, (I), (II), (III), and (IV) (i) apply. In another variation, (I), (II), (III), and (IV) (ii) apply. In another variation, (I), (II), (III), and (IV) (iii) apply.

[0507] In the variations of the preceding paragraph, it is to be understood that each combination of variables is described. For example, it is to be understood that each variation of feature (IV) can be combined with each variation of feature (V), just as if each variation of features (IV) and (V) were specifically and individually listed. Thus, it is to be understood that the following combinations are described: (IV)(i)+(V)(i); (IV)(i)+(V)(ii); (IV)(i)+(V)(iii); (IV)(i)+(V)(iv); (IV)(ii)+(V)(i); (IV)(ii)+(V)(ii); (IV)(ii)+(V)(iii); (IV)(ii)+(V)(iv); (IV)(iii)+(V)(i); (IV)(iii)+(V)(ii); (IV)(iii)+(V)(iii); and (IV)(iii)+(V)(iv).

[0508] In some embodiments, R 1 is R 2 and R 3 are independently H or methyl, or R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl group; R 4 is phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, 2-oxopyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydropyridazinyl, or quinazolinyl; wherein the phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, 2-oxopyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or quinazolinyl is optionally substituted with one or more R 4a groups; and wherein the dihydropyridyl, dihydropyrimidinyl, or dihydropyridazinyl is optionally substituted with one or more groups selected from R 4a and oxo; each R 4a is independently halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), or -S(O)2(C1-C3 alkyl); Q is H; and -L 1 -O-L 2 -Y-L 3 together form

[0509] In some embodiments, R 1 is R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl group; R 4is phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, 2-oxopyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridyl, dihydropyrimidyl, dihydropyridazinyl, or quinazolinyl; wherein the phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, 2-oxopyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or quinazolinyl is optionally substituted with one or more R 4a groups; and wherein the dihydropyridyl, dihydropyrimidyl, or dihydropyridazinyl is optionally substituted with one or more groups selected from R 4a and oxo; each R 4a is independently halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), or -S(O)2(C1-C3 alkyl); Q is H; and -L 1 -O-L 2 -Y-L 3 - taken together form

[0510] In some embodiments, R 1 is R 2 and R 3 , taken together with the carbon atom to which they are attached, form cyclopropyl; R 4 is phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, 2-oxopyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridyl, dihydropyrimidyl, dihydropyridazinyl, or quinazolinyl; wherein the phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, 2-oxopyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or quinazolinyl is optionally substituted with one or more R 4a groups; and wherein the dihydropyridyl, dihydropyrimidyl, or dihydropyridazinyl is optionally substituted with one or more groups selected from R 4a and oxo; each R 4a is independently halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), or -S(O)2(C1-C3 alkyl); Q is H; and -L 1 -O-L 2 -Y-L 3 - taken together form

[0511] When a moiety is considered, it is understood that the moiety can be attached to the remainder of the structure at any available position. For example, a 3-chloro-6-methoxypyridinyl group can be attached to the remainder of the structure at the 2-, 4-, or 5-position (as in 3-chloro-6-methoxypyridin-2-yl, 3-chloro-6-methoxypyridin-4-yl, or 3-chloro-6-methoxypyridin-5-yl, respectively). The R 4 groups described herein are shown attached at a particular position (e.g., pyridin-2-yl or pyrimidin-5-yl), but they can also be attached via any other available valence (e.g., pyridin-3-yl or pyrimidin-4-yl, respectively).

[0512] Any embodiment of a compound of Formula (I) provided herein, or a stereoisomer or tautomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, as applicable, is applicable to any other chemical formula detailed herein, as if each and every embodiment were specifically and individually listed. In particular, any embodiment of a compound of Formula (I) provided herein, or a stereoisomer or tautomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, as applicable, is applicable to a compound of Formula (A), or a stereoisomer or tautomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, as if each and every embodiment of Formula (A) were specifically and individually listed. Thus, it is understood and described that each embodiment of a compound of Formula (I) provided herein, or a stereoisomer or tautomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, as applicable, as it relates to R 1 , R 2 , R 3 , R 4、 R 5 , R 6 , R 7 , R 8、 R 9 , R 10 , R 11 , R 12 , Q, L 1 , L 2 , L 3 , Y, R 1a , R 1b , R 1c , R 1d , R 2a , R 4a , R 5a , L 1a , L 2a , L 3a , R A , R Aa , R Abembodiments, as if each individual embodiment were specifically and individually written herein. Also understood and described are that all such embodiments can be used in any of the pharmaceutical compositions, methods, kits, uses, or other aspects detailed herein.

[0513] Representative compounds are listed in Table 1.

[0514] Table 1

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522] In some embodiments, provided is a compound selected from the compounds described in Table 1, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a salt of a compound selected from the compounds described in Table 1, or a stereoisomer thereof. The disclosure also encompasses “planar” forms of all of the compounds described in Table 1, including planar forms of any of the specific stereoisomeric forms in the table.

[0523] In some embodiments, provided is a compound selected from the compounds 1-82 described in Table 1, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a salt of a compound selected from the compounds 1-82 described in Table 1, or a stereoisomer thereof. The disclosure also encompasses “planar” forms of the compounds 1-82 described in Table 1, including planar forms of any of the specific stereoisomeric forms of the compounds 1-82 in the table.

[0524] In some embodiments, a compound provided is selected from compounds 83-104 described in Table 1, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a salt of a compound selected from compounds 83-104 described in Table 1, or a stereoisomer thereof. The disclosure also encompasses “planar” forms of compounds 83-104 described in Table 1, including planar forms of any particular stereoisomeric form of compounds 83-104 in the table.

[0525] In one variation, a compound detailed herein is selected from:

[0526] N-(2-methyl-2-phenylpropionyl)-O-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserine;

[0527] N-(2-phenylpropionyl)-O-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)homoserine;

[0528] N-(2-(2,3-difluoro-6-methoxyphenyl)-2-methylpropionyl)-O-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)homoserine;

[0529] N-(2-(2-(difluoromethoxy)-6-fluorophenyl)-2-methylpropionyl)-O-(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)homoserine;

[0530] N-(l-(2-chlorophenyl)cyclopropane-l-carbonyl)-O-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)homoserine;

[0531] N-(l-(2,6-dichlorophenyl)cyclopropane-l-carbonyl)-O-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)homoserine;

[0532] N-(2-(2-chlorophenyl)-2-methylpropionyl)-O-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)homoserine;

[0533] N-(l-(2-fluorophenyl)cyclopropane-l-carbonyl)-O-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)homoserine;

[0534] N-(l-phenylcyclopropane-l-carbonyl)-O-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserine;

[0535] N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0536] N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0537] N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0538] N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0539] N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0540] N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0541] N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0542] N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0543] N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0544] N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0545] N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0546] N-(1-(5-cyanopyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0547] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0548] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0549] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0550] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0551] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0552] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0553] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0554] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0555] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0556] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0557] N-(1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine;

[0558] N-(1-(3-chloro-5-methoxypyridin-4-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine;

[0559] N-(1-(2-methoxypyridin-3-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine;

[0560] N-(1-(3-chloro-5-methylpyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine;

[0561] N-(1-(2-cyano-6-fluorophenyl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine;

[0562] N-(1-(3-(difluoromethoxy)pyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine;

[0563] N-(1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine;

[0564] N-(1-(3-(difluoromethyl)pyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine;

[0565] N-(1-(4,6-dimethylpyrimidin-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine;

[0566] N-(1-(3-methylpyrazin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine;

[0567] N-(1-(2-cyano-4-fluorophenyl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine;

[0568] N-(1-(4-chloro-2-methoxy-pyridin-3-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine;

[0569] N-(1-(2-cyanophenyl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0570] N-(1-(2-(methylsulfonyl)phenyl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)homoserine;

[0571] N-(1-(3-fluoro-5-methyl-pyridin-4-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine;

[0572] 0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(4-(trifluoromethyl)pyrimidin-5- yl)cyclopropane-1-carbonyl)homoserine;

[0573] N-(1-(5-chloropyrimidin-4-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0574] N-(1-(3-methoxypyrazin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0575] N-(1-(4-chloro-1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine;

[0576] N-(1-(3-(fluoromethyl)pyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)homoserine;

[0577] N-(1-(3-(methoxymethyl)pyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)homoserine;

[0578] N-(1-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0579] N-(1-(3-chloro-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0580] N-(1-(2-cyano-6-methoxyphenyl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0581] N-(1-(2-(difluoromethyl)pyridin-3-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0582] N-(1-(3-cyclopropylpyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0583] N-(1-(4-(difluoromethyl)pyrimidin-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0584] N-(1-(4-chloro-2,6-dimethylpyrimidin-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0585] N-(1-(4-methoxy-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0586] N-(1-(4-chloro-6-methoxypyrimidin-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0587] N-(1-(4-chloro-6-oxo-1,6-dihydropyrimidin-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0588] N-(1-(5-(difluoromethyl)-1H-imidazol-1-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)homoserine;

[0589] N-(1-(6-chloro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)homoserine;

[0590] N-(1-(3-chloro-6-oxo-1,6-dihydropyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)homoserine;

[0591] O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-N-(1-(3-(trifluoromethyl)pyrazin-2-yl)cyclopropane-1-carbonyl)homoserine;

[0592] N-(1-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)homoserine;

[0593] N-(1-(3,5-dichloro-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)homoserine;

[0594] O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-N-(1-(2-(trifluoromethyl)-1H-imidazol-1-yl)cyclopropane-1-carbonyl)homoserine;

[0595] N-(1-(4-chloro-1H-pyrazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)homoserine;

[0596] N-(1-(5-chloro-3-methyl-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)homoserine;

[0597] N-(1-(5-chloro-2-methylpyrimidin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)homoserine;

[0598] N-(1-(5-chloro-1H-pyrazol-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)homoserine;

[0599] N-(1 -(4-cyano-1 -methyl- 1 H-pyrazol-3-yl)cyclopropane- 1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro- 1,8-naphthyridin-2-yl)butyl)homoserine;

[0600] N-(1 -(5-chlorothiazol-4-yl)cyclopropane- 1 -carbonyl)-0-(4-(5,6,7,8-tetrahydro- 1,8- naphthyridin-2-yl)butyl)homoserine,

[0601] N-(1 -(1 -methyl-4-(trifluoromethyl)- 1 H-pyrazol-3-yl)cyclopropane- 1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro- 1,8-naphthyridin-2-yl)butyl)homoserine;

[0602] N-(1 -(4-cyano- 1 H-pyrazol-3-yl)cyclopropane- 1 -carbonyl)-0-(4-(5,6,7,8-tetrahydro- 1,8- naphthyridin-2-yl)butyl)homoserine;

[0603] N-(1 -(4-chloro- 1 H-imidazol-5-yl)cyclopropane- 1 -carbonyl)-0-(4-(5,6,7,8-tetrahydro- 1,8- naphthyridin-2-yl)butyl)homoserine;

[0604] N-(1 -(4-chloro- 1 -methyl- 1 H-imidazol-5-yl)cyclopropane- 1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro- 1,8-naphthyridin-2-yl)butyl)homoserine;

[0605] N-(2-phenylacetyl)-0-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)homoserine; and

[0606] N-(1 -(5-chlorothiazol-4-yl)cyclopropane- 1 -carbonyl)-0-(4-(5,6,7,8-tetrahydro- 1,8- naphthyridin-2-yl)butyl)homoserine,

[0607] or a pharmaceutically acceptable salt thereof.

[0608] In one variation, the compounds detailed herein are selected from:

[0609] N-(3-(difluoromethyl)tetrahydrofuran-3-carbonyl)-0-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2- yl)butyl)-L-homoserine;

[0610] 0-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-N-( 1 -(trifluoromethyl)cyclohexane- 1 - carbonyl)-L-homoserine;

[0611] N-(4-(3-chlorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0612] O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(4-(3-(trifluoromethyl) phenyl)tetrahydro-2H-pyran-4-carbonyl)-L-homoserine;

[0613] N-(4-(3-chlorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0614] N-(4-(3-chlorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0615] N-(4-(3-chlorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0616] N-(1 -(2-oxoquinolin-1 (2H)-yl)cyclopropane-1 -carbonyl)-O-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0617] N-(1 -(6-cyclopropyl-2-oxopyridin-1 (2H)-yl)cyclopropane-1 -carbonyl)-O-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0618] N-(1 -(6-cyclopropyl-2-oxopyridin-1 (2H)-yl)cyclopropane-1 -carbonyl)-O-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0619] N-(1 -(6-cyclopropyl-2-oxopyridin-1 (2H)-yl)cyclopropane-1 -carbonyl)-O-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0620] N-(1 -(6-cyclopropyl-2-oxopyridin-1 (2H)-yl)cyclopropane-1 -carbonyl)-O-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0621] N-(1-(2-carbamoyl-6-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-L-homoserine;

[0622] O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-N-(1-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)piperidin-4-carbonyl)-L-homoserine;

[0623] N-(1-phenyl-1H-pyrazole-3-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-L-homoserine;

[0624] N-(1-phenyl-1H-pyrazole-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-L-homoserine;

[0625] N-(1-phenyl-1H-pyrazole-5-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-L-homoserine;

[0626] O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-N-(4-(trifluoromethyl)tetrahydro-2H-pyran-4-carbonyl)-L-homoserine;

[0627] N-(1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)homoserine;

[0628] N-(1-(4-hydroxy-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-L-homoserine;

[0629] N-(1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-L-homoserine methyl ester;

[0630] N-(1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl-2,2,3,3-d4)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-L-homoserine;

[0631] Or its pharmaceutically acceptable salt.

[0632] In various embodiments, the compound is selected from the compounds of the enumerated embodiments (e.g., Compounds 1-82), or a pharmaceutically acceptable salt thereof. For example, the compound can be selected from:

[0633] N-(2-methyl-2-phenylpropionyl)-O-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserine;

[0634] N-(2-methyl-2-phenylpropionyl)-O-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)-L-homoserine;

[0635] N-((S)-2-phenylpropionyl)-O-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)-L- homoserine;

[0636] N-(2-(2,3-difluoro-6-methoxyphenyl)-2-methylpropionyl)-O-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0637] N-(2-(2-(difluoromethoxy)-6-fluorophenyl)-2-methylpropionyl)-O-(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0638] N-(l-(2-chlorophenyl)cyclopropane-l-carbonyl)-O-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0639] N-(l-(2,6-dichlorophenyl)cyclopropane-l-carbonyl)-O-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0640] N-(2-(2-chlorophenyl)-2-methylpropionyl)-O-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl)butyl)-L-homoserine;

[0641] N-(l-(2-fluorophenyl)cyclopropane-l-carbonyl)-O-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0642] N-(l-phenylcyclopropane-l-carbonyl)-O-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)-L-homoserine;

[0643] N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0644] N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0645] N-(1-(2-methylpyridin-3-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0646] N-(1-(3-chloro-5-fluoropyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0647] N-(1-(3-chloropyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0648] N-(1-(4-methylpyridin-3-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0649] 0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(o-tolyl)cyclopropane-1- carbonyl)-L-homoserine;

[0650] N-(1-(6-methoxypyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0651] N-(1-(4-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0652] N-(1-(6-methylpyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0653] N-(1-(2,5-difluoropyridin-3-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0654] N-(1-(5-cyanopyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0655] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0656] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0657] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0658] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0659] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0660] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0661] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0662] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0663] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0664] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0665] N-(1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0666] N-(1-(3-chloro-5-methoxypyridin-4-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0667] N-(1-(2-methoxypyridin-3-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0668] N-(1-(3-chloro-5-methylpyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0669] N-(1-(2-cyano-6-fluorophenyl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0670] N-(1-(3-(difluoromethoxy)pyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0671] N-(1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0672] N-(1-(3-(difluoromethyl)pyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0673] N-(1-(4,6-dimethylpyrimidin-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0674] N-(1-(3-methylpyrazin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0675] N-(1-(2-cyanophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0676] N-(1-(4-chloro-2-methoxy-pyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0677] N-(1-(2-cyanophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0678] N-(1-(2-(methylsulfonyl)phenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0679] N-(1-(3-fluoro-5-methylpyridin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0680] O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(4-(trifluoromethyl)pyrimidin-5- yl)cyclopropane-1-carbonyl)-L-homoserine;

[0681] N-(1-(5-chloropyrimidin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0682] N-(1-(3-methoxypyrazin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0683] N-(1-(4-chloro-1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0684] N-(1-(3-(fluoromethyl)pyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0685] N-( 1 -( 1 -methyl- lH-pyrazol-5 -yl)cyclopropane- 1 -carbonyl)-O-(4-(5,6,7, 8-tetrahydro- 1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0686] N-( 1 -( 1 -methyl- lH-pyrazol-5 -yl)cyclopropane- 1 -carbonyl)-O-(4-(5,6,7, 8-tetrahydro- 1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0687] N-( 1 -( 1 -methyl- lH-pyrazol-5 -yl)cyclopropane- 1 -carbonyl)-O-(4-(5,6,7, 8-tetrahydro- 1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0688] N-( 1 -( 1 -methyl- lH-pyrazol-5 -yl)cyclopropane- 1 -carbonyl)-O-(4-(5,6,7, 8-tetrahydro- 1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0689] N-( 1 -( 1 -methyl- lH-pyrazol-5 -yl)cyclopropane- 1 -carbonyl)-O-(4-(5,6,7, 8-tetrahydro- 1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0690] N-( 1 -( 1 -methyl- lH-pyrazol-5 -yl)cyclopropane- 1 -carbonyl)-O-(4-(5,6,7, 8-tetrahydro- 1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0691] N-( 1 -( 1 -methyl- lH-pyrazol-5 -yl)cyclopropane- 1 -carbonyl)-O-(4-(5,6,7, 8-tetrahydro- 1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0692] N-( 1 -( 1 -methyl- lH-pyrazol-5 -yl)cyclopropane- 1 -carbonyl)-O-(4-(5,6,7, 8-tetrahydro- 1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0693] N-( 1 -( 1 -methyl- lH-pyrazol-5 -yl)cyclopropane- 1 -carbonyl)-O-(4-(5,6,7, 8-tetrahydro- 1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0694] N-( 1 -( 1 -methyl- lH-pyrazol-5 -yl)cyclopropane- 1 -carbonyl)-O-(4-(5,6,7, 8-tetrahydro- 1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0695] N-(1-(4-chloro-6-oxo-1,6-dihydropyrimidin-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0696] N-(1-(5-(difluoromethyl)-1H-imidazol-1-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0697] N-(1-(6-chloro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0698] N-(1-(3-chloro-6-oxo-1,6-dihydropyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0699] 0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(3-(trifluoromethyl)pyrazin-2-yl)cyclopropane-1-carbonyl)-L-homoserine;

[0700] N-(1-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0701] N-(1-(3,5-dichloro-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0702] 0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(2-(trifluoromethyl)-1H-imidazol-1-yl)cyclopropane-1-carbonyl)-L-homoserine;

[0703] N-(1-(4-chloro-1H-pyrazol-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0704] N-(1-(5-chloro-3-methyl-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0705] N-(1 -(5-chloro-2-methylpyrimidin-4-yl)cyclopropane-1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0706] N-(1 -(5-chloro-2-methylpyrimidin-4-yl)cyclopropane-1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0707] N-(1 -(5-chloro-2-methylpyrimidin-4-yl)cyclopropane-1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0708] N-(1 -(5-chloro-2-methylpyrimidin-4-yl)cyclopropane-1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0709] N-(1 -(5-chloro-2-methylpyrimidin-4-yl)cyclopropane-1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0710] N-(1 -(5-chloro-2-methylpyrimidin-4-yl)cyclopropane-1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0711] N-(1 -(5-chloro-2-methylpyrimidin-4-yl)cyclopropane-1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0712] N-(1 -(5-chloro-2-methylpyrimidin-4-yl)cyclopropane-1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0713] N-(2-phenylacetyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L- homoserine; and

[0714] N-(1 -(5-chloro-2-methylpyrimidin-4-yl)cyclopropane-1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine,

[0715] or a pharmaceutically acceptable salt thereof.

[0716] In various embodiments, the compound is selected from the compounds of the recited embodiments (e.g., compounds 83-104), or a pharmaceutically acceptable salt thereof. For example, the compound can be selected from:

[0717] N-(3-(difluoromethyl)tetrahydrofuran-3-carbonyl)-O-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0718] O-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)-N-(l-(trifluoromethyl)cyclohexane- 1 -carbonyl)- L-homoserine;

[0719] N-(4-(4-fluorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0720] O-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)-N-(4-(3-(trifluoromethyl)phenyl)tetrahydro- 2H-pyran-4-carbonyl)-L-homoserine;

[0721] N-(4-(3-methoxyphenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0722] N-(4-(3-fluorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0723] N-(4-(3-chlorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0724] N-(l-(2-oxoquinolin-l(2H)-yl)cyclopropane-l-carbonyl)-O-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0725] N-(l-(6-cyclopropyl-2-oxopyridin-l(2H)-yl)cyclopropane-l-carbonyl)-O-(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0726] N-(1-(6-methoxy-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0727] N-(1-(6-fluoro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0728] N-(1-(6-bromo-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0729] N-(1-(2-carbamoyl-6-fluorophenyl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0730] 0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(2,2,2-trifluoroethyl)-4- (trifluoromethyl)piperidine-4-carbonyl)-L-homoserine;

[0731] N-(1-phenyl-1H-pyrazole-3-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)butyl)-L-homoserine;

[0732] N-(1-phenyl-1H-pyrazole-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)butyl)-L-homoserine;

[0733] N-(1-phenyl-1H-pyrazole-5-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)butyl)-L-homoserine;

[0734] 0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(4-(trifluoromethyl)tetrahydro- 2H-pyran-4-carbonyl)-L-homoserine;

[0735] N-(1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine;

[0736] N-(1-(4-hydroxy-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0737] N-(1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0738] N-(1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl-2,2,3,3-d4)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0739] or a pharmaceutically acceptable salt thereof.

[0740] In one variation, the compounds detailed herein are selected from:

[0741] N-((S)-2-phenylpropanoyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L- homoserine;

[0742] N-(1-(2-chlorophenyl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0743] N-(1-(2,6-dichlorophenyl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0744] N-(1-(2-fluorophenyl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0745] N-(1-(2-methylpyridin-3-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0746] N-(1-(3-chloro-5-fluoropyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0747] N-(1-(3-chloropyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0748] N-(1-(4-methylpyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0749] O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(o-tolyl)cyclopropane-1- carbonyl)-L-homoserine;

[0750] N-(1-(6-methoxypyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0751] N-(1-(4-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0752] N-(1-(2,5-difluoropyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0753] N-(1-(3,5-dichloropyridin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0754] O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(3-(trifluoromethyl)pyridin-2- yl)cyclopropane-1-carbonyl)-L-homoserine;

[0755] N-(1-(3-chloro-6-methoxypyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0756] N-(1-(5-fluoro-2-methylpyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0757] N-(1-(3-methylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0758] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0759] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0760] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0761] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0762] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0763] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0764] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0765] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0766] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0767] N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0768] N-(1-(2-cyano-4-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0769] N-(1-(3-fluoro-5-methylpyridin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0770] O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(4-(trifluoromethyl)pyrimidin-5- yl)cyclopropane-1-carbonyl)-L-homoserine;

[0771] N-(1-(5-chloropyrimidin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0772] N-(1-(4-chloro-1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0773] N-(1-(3-(fluoromethyl)pyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0774] N-(1-(2-cyano-6-methoxyphenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0775] N-(1-(4-(difluoromethyl)pyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0776] N-(1-(4-chloro-2,6-dimethylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0777] N-(1-(4-methoxy-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0778] N-(1-(4-chloro-6-methoxy pyrimidin-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0779] N-(1-(6-chloro-2-oxo pyridin-1(2H)-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0780] N-(1-(3-chloro-6-oxo-1,6-dihydropyridin-2-yl)cyclopropane-1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0781] 0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(3-(trifluoromethyl)pyrazin- 2-yl)cyclopropane-1-carbonyl)-L-homoserine;

[0782] N-(1-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0783] N-(1-(3,5-dichloro-1 H-pyrazol-1-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0784] 0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(2-(trifluoromethyl)-1 H- imidazol-1-yl)cyclopropane-1-carbonyl)-L-homoserine;

[0785] N-(1-(4-chloro-1 H-pyrazol-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0786] N-(1-(5-chloro-3-methyl-1 H-pyrazol-1-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0787] N-(1-(5-chloro-2-methyl pyrimidin-4-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0788] N-(1-(5-chloro-1H-pyrazol-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-L-homoserine;

[0789] N-(1-(4-cyano-1-methyl-1H-pyrazol-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-L-homoserine;

[0790] N-(1-(5-chloro-3-oxo-2,3-dihydropyridazin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-L-homoserine;

[0791] N-(1-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-L-homoserine;

[0792] N-(1-(4-cyano-1H-pyrazol-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-L-homoserine;

[0793] N-(1-(4-chloro-1H-imidazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-L-homoserine;

[0794] N-(1-(4-chloro-1-methyl-1H-imidazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-L-homoserine;

[0795] N-(1-(5-chlorothiazol-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-L-homoserine; and

[0796] Or its pharmaceutically acceptable salt.

[0797] In one variant, the compounds detailed in this article are selected from:

[0798] N-(2-methyl-2-phenylpropionyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)-L-homoserine;

[0799] N-(2-(2,3-difluoro-6-methoxyphenyl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0800] N-(2-(2-(difluoromethoxy)-6-fluorophenyl)-2-methylpropanoyl)-O-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0801] N-(2-(2-chlorophenyl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0802] N-(1 -phenylcyclopropane-1 -carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)butyl)-L-homoserine;

[0803] N-(1 -(pyrazin-2-yl)cyclopropane-1 -carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0804] N-(1 -(pyrimidin-2-yl)cyclopropane-1 -carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0805] N-(1 -(6-methylpyridin-2-yl)cyclopropane-1 -carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0806] N-(1 -(pyrimidin-5-yl)cyclopropane-1 -carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0807] N-(2-(2-chloro-5-fluoropyridin-3-yl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0808] N-(1 -(5-cyanopyridin-3-yl)cyclopropane-1 -carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0809] N-(1 -(3-methoxypyridin-2-yl)cyclopropane-1 -carbonyl)-O-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0810] N-(1-(2-methoxy-pyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0811] N-(1-(4,6-dimethyl-pyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0812] N-(1-(4-chloro-2-methoxy-pyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0813] N-(1-(2-cyano-phenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)butyl)-L-homoserine;

[0814] N-(1-(2-(methylsulfonyl)-phenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0815] N-(1-(3-methoxy-pyrazin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0816] N-(1-(3-(methoxymethyl)-pyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0817] N-(1-(1-methyl-1 H-pyrazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0818] N-(1-(3-chloro-1 H-pyrazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0819] N-(1-(2-(difluoromethyl)-pyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0820] N-(1-(3-cyclopropylpyridin-2-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0821] N-(1-(4-chloro-6-oxo-1,6-dihydropyrimidin-5-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0822] N-(1-(5-(difluoromethyl)-1H-imidazol-1-yl)cyclopropane-1-carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; and

[0823] N-(2-phenylacetyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0824] or a pharmaceutically acceptable salt thereof.

[0825] In one variation, the compounds detailed herein are selected from:

[0826] N-(3-(difluoromethyl)tetrahydrofuran-3-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0827] 0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(trifluoromethyl)cyclohexane-1- carbonyl)-L-homoserine;

[0828] N-(4-(4-fluorophenyl)tetrahydro-2H-pyran-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0829] 0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(4-(3-(trifluoromethyl)phenyl) tetrahydro-2H-pyran-4-carbonyl)-L-homoserine;

[0830] N-(4-(3-methoxyphenyl)tetrahydro-2H-pyran-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0831] N-(4-(3-fluorophenyl)tetrahydro-2H-pyran-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)-L-homoserine;

[0832] N-(4-(3-chlorophenyl)tetrahydro-2H-pyran-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0833] N-(1 -(2-oxoquinolin-1 (2H)-yl)cyclopropane-1 -carbonyl)-0-(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0834] N-(1 -(6-cyclopropyl-2-oxopyridin-1 (2H)-yl)cyclopropane-1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0835] N-(1 -(6-methoxy-2-oxopyridin-1 (2H)-yl)cyclopropane-1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0836] N-(1 -(6-fluoro-2-oxopyridin-1 (2H)-yl)cyclopropane-1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0837] N-(1 -(6-bromo-2-oxopyridin-1 (2H)-yl)cyclopropane-1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0838] N-(1 -(2-carbamoyl-6-fluorophenyl)cyclopropane-1 -carbonyl)-0-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0839] 0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1 -(2,2,2-trifluoroethyl)-4- (trifluoromethyl)piperidine-4-carbonyl)-L-homoserine;

[0840] N-(1 -phenyl-1 H-pyrazole-3-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)butyl)-L-homoserine;

[0841] N-(1 -phenyl-1 H-pyrazole-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)butyl)-L-homoserine;

[0842] N-(1-phenyl-1H-pyrazole-5-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)butyl)-L-homoserine;

[0843] O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(4-(trifluoromethyl)tetrahydro- 2H-pyran-4-carbonyl)-L-homoserine;

[0844] N-(1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine;

[0845] N-(1-(4-hydroxy-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0846] N-(1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine methyl ester;

[0847] N-(1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl-2,2,3,3-d4)-O-(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0848] or a pharmaceutically acceptable salt thereof.

[0849] In some embodiments of the materials described herein, alkyl esters of the free acid material are also contemplated, such as C1-C8alkyl esters or C1-C4alkyl esters. In such embodiments, alkyl esters of the free acid (e.g., homoserine esters) are contemplated, such as methyl esters, ethyl esters, n-propyl esters, isopropyl esters, n-butyl esters, sec-butyl esters, isobutyl esters, and t-butyl esters, as well as various configurational isomers of higher alkyl groups, such as C5-C8alkyl esters.

[0850] In some embodiments, a composition, such as a pharmaceutical composition, is provided, wherein the composition comprises a compound selected from one or more of the compounds described in Table 1 or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises a compound selected from a salt of one or more of the compounds described in Table 1. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0851] In some embodiments, all salts of the compounds mentioned herein are contemplated, such as pharmaceutically acceptable salts. In some embodiments, any or all stereochemical forms of the compounds are contemplated, including any enantiomeric or diastereomeric forms, as well as any tautomeric or other forms. Except where otherwise explicitly indicated in a chemical structure or name, the structure or name is intended to encompass all possible stereochemical isomers of the described compound. In some embodiments, all forms of the compounds are included, such as crystalline or non-crystalline forms. In some embodiments, prodrugs, solvates, and metabolites of the compounds are contemplated. Compositions comprising a compound of Formula (A) or Formula (I) are also contemplated, such as compositions of substantially pure compounds, including particular stereochemical forms thereof. In some embodiments, compositions comprising mixtures of compounds of Formula (A) or Formula (I) in any ratio are also contemplated, including mixtures of two or more stereochemical forms of a compound of Formula (A) or Formula (I) in any ratio, such as racemic, non-racemic, enantiomerically enriched, and scalemic mixtures of compounds. In some embodiments where one or more tertiary amine moieties are present in the compound, N-oxides are also provided and described.

[0852] Further provided is a pharmaceutical composition comprising a compound of Formula (A) as detailed herein, or any variation thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient.

[0853] Further provided is a pharmaceutical composition comprising a compound of Formula (I) as detailed herein, or any variation thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient.

[0854] Also provided is a pharmaceutical composition comprising a compound of Formula (A) as detailed herein, or any variation thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), a checkpoint inhibitor, and a pharmaceutically acceptable carrier or excipient.

[0855] Also provided is a pharmaceutical composition comprising a compound of Formula (I) as detailed herein, or any variation thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), a checkpoint inhibitor, and a pharmaceutically acceptable carrier or excipient.

[0856] In various embodiments, the checkpoint inhibitor inhibits one or more of PD-1, PD-L1, and CTLA-4. For example, in some embodiments, the checkpoint inhibitor inhibits PD-1. In some embodiments, the checkpoint inhibitor inhibits PD-L1. In some embodiments, the checkpoint inhibitor inhibits CTLA-4.

[0857] As used herein, a“PD-1” checkpoint inhibitor can include, for example: pembrolizumab (also known as MK-3475, Keytruda, or Keyvoda), which targets, for example, melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma; nivolumab, which targets, for example, melanoma, squamous cell lung cancer, renal cell carcinoma, and Hodgkin’s lymphoma; cemiplimab, which targets, for example, cutaneous squamous cell carcinoma (CSCC); spartalizumab, which targets, for example, solid tumors and lymphomas; camrelizumab, which targets, for example, Hodgkin’s lymphoma; sintilimab, which targets, for example, non-small cell lung cancer; toripalimab, which targets, for example, solid tumors and hematologic cancers; tislelizumab; domvanalimab; INCMGA00012 (MGA012); AMP-224; and AMP-514.

[0858] As used herein, a“PD-L1” checkpoint inhibitor can include, for example: atezolizumab (Tecentriq), which targets, for example, urothelial carcinoma and non-small cell lung cancer; avelumab (Bavencio), which targets, for example, metastatic Merkel cell carcinoma and gastric cancer; durvalumab (Imfinzi), which targets, for example, urothelial carcinoma and non-small cell lung cancer, for example, non-small cell lung cancer that is not resectable after chemoradiation; KN035; CK-301; and BMS-986189.

[0859] As used herein, a“CTLA4” checkpoint inhibitor can include, for example: ipilimumab, which targets, for example, melanoma, lung cancer, and pancreatic cancer; and tremelimumab, which targets, for example, melanoma, mesothelioma, and non-small cell lung cancer.

[0860] Other checkpoint inhibitors can include dual acting compounds, for example: AUNP12, which is a dual PD-1 / PD-L1 inhibitor; and CA-170, which is a PD-L1 and VISTA antagonist.

[0861] Accordingly, in various embodiments, the checkpoint inhibitor comprises at least one of: pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, toripalimab, tislelizumab, domvanalimab, INCMGA00012, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab.

[0862] Further provided is the use of a compound of Formula (A) or Formula (I) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating a disease mediated by cells expressing one or more of: V β1; αV β6; and alpha V β8.

[0863] In various embodiments, further provided are uses of a compound of Formula (A) or Formula (I) as detailed herein, or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating a disease mediated by cells expressing one or more of the following: alpha V β1; alpha V β6; and alpha V β8. In some embodiments, the checkpoint inhibitor inhibits one or more of the following: PD-1, PD-L1, and CTLA-4. For example, in some embodiments, the checkpoint inhibitor inhibits PD-1. In some embodiments, the checkpoint inhibitor inhibits PD-L1. In some embodiments, the checkpoint inhibitor inhibits CTLA-4. For example, in some embodiments, the checkpoint inhibitor comprises at least one of the following: pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, INCMGA00012, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab. In some embodiments, the pembrolizumab is administered at about 200 mg every three weeks or about 400 mg every six weeks. In some embodiments, the pembrolizumab is administered as an injection (about 25 mg / mL) via infusion.

[0864] Also provided are methods of treating a subject in need thereof. In some embodiments, the method comprises providing the subject. In some embodiments, the subject has at least one tissue in need of treatment. In some embodiments, the at least one tissue is characterized by at least one value that is elevated compared to a healthy value for the tissue in a healthy state. In some embodiments, the tissue has an elevated value of alpha V β1 integrin activity and / or expression. In some embodiments, the tissue has an elevated value of alpha V β6 integrin activity and / or expression. In some embodiments, the tissue has an elevated value of alpha Vβ8 integrin activity and / or expression has an elevated value. In some embodiments, the pSMAD / SMAD ratio of the tissue has an elevated value. In some embodiments, the neocollagen formation or accumulation of the tissue has an elevated value. In some embodiments, the total collagen of the tissue has an elevated value. In some embodiments, the Col1a1 expression of the tissue has an elevated value. In some embodiments, the perforin of the tissue has an elevated value. In some embodiments, the granzyme B of the tissue has an elevated value. In some embodiments, the interferon gamma of the tissue has an elevated value. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (A) or Formula (I) as detailed herein or any variation thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the method comprises administering a therapeutically effective amount of a compound that reduces the at least one value.

[0865] In several embodiments, administering a therapeutically effective amount of the compound reduces the at least one value. For example, in some embodiments, the at least one value is measured after at least one administration of the compound to the subject to determine a post-administration value. In some embodiments, at least one administration of the compound is therapeutically effective if the post-administration value is reduced as compared to the at least one value. In some embodiments, at least one administration of the compound is therapeutically effective if the post-administration value is about the same as a healthy value.

[0866] In some embodiments, the method comprises reducing the activity and / or expression, e.g., of certain integrins. For example, in some embodiments, the method comprises reducing the activity and / or expression of α V β1. In some embodiments, the method comprises reducing the activity and / or expression of α V β8. In some embodiments, the method comprises reducing the activity and / or expression of α V β1 and α V β8. In some embodiments, the method comprises reducing the activity and / or expression of α V β6 and α V β8. In some embodiments, the method comprises reducing the activity and / or expression of α V β1, α V β6 and α V β8. In some embodiments, the reduction of the activity and / or expression of each integrin is selective as compared to at least one other α V containing integrin in the subject.

[0867] In several embodiments, the subject has an elevated value of at least one of the following: αV reduced activity of β1 integrin. In some embodiments, the subject has reduced activity of α V reduced activity of β6 integrin. In some embodiments, the subject has reduced activity of α V reduced activity of β8 integrin.

[0868] In various embodiments, the at least one tissue in the subject comprises lung tissue. In some embodiments, the at least one tissue in the subject comprises liver tissue. In some embodiments, the at least one tissue in the subject comprises skin tissue. In some embodiments, the at least one tissue in the subject comprises heart tissue. In some embodiments, the at least one tissue in the subject comprises kidney tissue. In some embodiments, the at least one tissue in the subject comprises gastrointestinal tissue. In some embodiments, the at least one tissue in the subject comprises gallbladder tissue. In some embodiments, the at least one tissue in the subject comprises bile duct tissue. In some embodiments, the at least one tissue in the subject comprises intrahepatic biliary system tissue. In some embodiments, the at least one tissue in the subject comprises extrahepatic biliary system tissue. In some embodiments, the at least one tissue in the subject comprises intrahepatic biliary system tissue and extrahepatic biliary system tissue.

[0869] In some embodiments, the at least one tissue in the subject comprises brain tissue. In some embodiments, the at least one tissue in the subject comprises lymph node tissue. In some embodiments, the at least one tissue in the subject comprises stomach tissue. In some embodiments, the at least one tissue in the subject comprises urethral tissue. In some embodiments, the at least one tissue in the subject comprises bladder tissue. In some embodiments, the at least one tissue in the subject comprises prostate tissue. In some embodiments, the at least one tissue in the subject comprises pancreatic tissue. In some embodiments, the at least one tissue in the subject comprises mesothelial tissue. In some embodiments, the at least one tissue in the subject comprises breast tissue.

[0870] In various embodiments, the tissue has an elevated pSMAD2 / SMAD2 value compared to a healthy state of the tissue. In some embodiments, the tissue has an elevated pSMAD3 / SMAD3 value compared to a healthy state of the tissue.

[0871] In various embodiments, the tissue comprises an ocular tissue. In some embodiments, the ocular tissue expresses a TGF-β receptor selected from the group consisting of α V β1, αV one, two, or three integrins of β6 and α V one, two, or three integrins of β8.

[0872] In some embodiments, the subject has a cancer. In some embodiments, the subject has a cancer selected from melanoma, colon cancer, breast cancer, prostate cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, lymphoma (such as Hodgkin’s lymphoma), cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, and mesothelioma. In some embodiments, the subject has Hodgkin’s lymphoma. In some embodiments, the subject has a solid tumor. In some embodiments, the subject has melanoma. In some embodiments, the subject has colon cancer. In some embodiments, the subject has breast cancer. In some embodiments, the subject has prostate cancer. In some embodiments, the subject has non-small cell lung cancer. In some embodiments, the subject has head and neck squamous cell carcinoma. In some embodiments, the subject has squamous cell lung cancer. In some embodiments, the subject has renal cell carcinoma. In some embodiments, the subject has a lymphoma, such as Hodgkin’s lymphoma. In some embodiments, the subject has cutaneous squamous cell carcinoma (CSCC). In some embodiments, the subject has urothelial carcinoma. In some embodiments, the subject has metastatic Merkel cell carcinoma. In some embodiments, the subject has gastric cancer. In some embodiments, the subject has lung cancer. In some embodiments, the subject has pancreatic cancer. In some embodiments, the subject has pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the subject has mesothelioma.

[0873] In some embodiments, the subject has a solid tumor. In some embodiments, the subject has a cancer selected from breast cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, CSCC, urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, and mesothelioma. In some embodiments, the subject has pancreatic cancer. In some embodiments, the subject has pancreatic ductal adenocarcinoma (PDAC).

[0874] In some embodiments, the subject has pulmonary fibrosis. In some embodiments, the subject has liver fibrosis. In some embodiments, the subject has skin fibrosis. In some embodiments, the subject has cardiac fibrosis. In some embodiments, the subject has renal fibrosis. In some embodiments, the subject has gastrointestinal fibrosis. In some embodiments, the subject has primary sclerosing cholangitis. In some embodiments, the subject has biliary fibrosis. In some embodiments, the subject has biliary atresia.

[0875] Also provided are methods of characterizing the anti-cancer activity of a small molecule inhibitor in a subject. In some embodiments, the method comprises providing a first live cell sample from the subject. In some embodiments, the first live cell sample is characterized by the presence of at least one integrin capable of activating transforming growth factor beta (TGF-b) from a latency associated peptide. In some embodiments, the method comprises determining a first value in the first live cell sample. In some embodiments, the first value is a pSMAD2 / SMAD2 ratio. In some embodiments, the first value is a pSMAD3 / SMAD3 ratio. In some embodiments, the first value is a perforin level. In some embodiments, the first value is a granzyme B level. In some embodiments, the first value is an interferon gamma level. In some embodiments, the method comprises administering the small molecule to the subject. In some embodiments, the method comprises providing a second live cell sample from the subject. In some embodiments, the second live cell sample is taken from the same tissue in the subject as the first live cell sample. In some embodiments, the method comprises determining a second value in the second live cell sample. In some embodiments, the second value corresponds to the first value of a pSMAD2 / SMAD2 ratio, a pSMAD3 / SMAD3 ratio, a perforin level, a granzyme B level, or an interferon gamma level. In some embodiments, the anti-cancer activity of the small molecule in the subject is characterized by comparing the second value to the first value.

[0876] In some embodiments, each live cell sample comprises a plurality of cancer cells derived from a tissue of the subject. In some embodiments, each live cell sample comprises a plurality of cancer cells derived from a blood cell of the subject. In some embodiments, at least one tissue in the subject comprises skin. In some embodiments, at least one tissue in the subject comprises lung. In some embodiments, at least one tissue in the subject comprises brain. In some embodiments, at least one tissue in the subject comprises lymph node. In some embodiments, at least one tissue in the subject comprises stomach. In some embodiments, at least one tissue in the subject comprises urethra. In some embodiments, at least one tissue in the subject comprises kidney. In some embodiments, at least one tissue in the subject comprises bladder. In some embodiments, at least one tissue in the subject comprises prostate. In some embodiments, at least one tissue in the subject comprises liver. In some embodiments, at least one tissue in the subject comprises pancreas. In some embodiments, at least one tissue in the subject comprises mesothelium. In some embodiments, at least one tissue in the subject comprises breast.

[0877] In several embodiments, the at least one integrin comprises an alpha V In some embodiments, the at least one integrin is an alpha V beta 1. In some embodiments, the at least one integrin is an alpha V beta 6. In some embodiments, the at least one integrin is an alpha V beta 8. In some embodiments, the at least one integrin comprises an alpha V beta 1 and an alpha V beta 6. In some embodiments, the at least one integrin comprises an alpha V beta 6 and an alpha V beta 8. In some embodiments, the at least one integrin comprises an alpha V beta 1, an alpha V beta 6, and an alpha V beta 8. In some embodiments, the first and second values are pSMAD2 / SMAD2 ratio or pSMAD3 / SMAD3 ratio.

[0878] In various embodiments, administering the small molecule to the subject comprises administering a compound of Formula (A) or Formula (I) or a salt thereof or a pharmaceutical composition thereof as described in any aspect described herein. In some embodiments, the method further comprises administering to the subject a checkpoint inhibitor. In some embodiments, characterizing the anti-cancer activity of the small molecule in the subject comprises comparing the second value to the first value. In some embodiments, the method comprises characterizing the anti-cancer activity of the small molecule with the checkpoint inhibitor.

[0879] In some embodiments, the subject has breast cancer. In some embodiments, the subject is administered an effective amount of Compound 39. In some embodiments, the subject is administered an effective amount of Compound 39 in a solution. In some embodiments, the solution comprises ethanol, propylene glycol, and PBS. In some embodiments, the solution comprises about 5% to about 15% v / v of ethanol, about 65% to about 75% w / v of propylene glycol, and about 15% to about 25% v / v of PBS. In some embodiments, the solution comprises about 10% v / v of ethanol, about 70% w / v of propylene glycol, and about 20% v / v of PBS. In some embodiments, the subject is administered an effective amount of Compound 39 at a dose for a duration. In some embodiments, the dose is about 135 to about 150 mg / kg of the subject’s body weight. In some embodiments, the dose is about 144 mg / kg of the subject’s body weight. In some embodiments, the duration is about 20 days, about 25 days, or about 30 days. In some embodiments, the duration is about 28 days. In some embodiments, the subject is administered at least one of mAb, anti-mPD-1, and anti-a V In some embodiments, the subject is administered at least one of mAb, anti-mPD-1, and anti-a V In some embodiments, the subject is administered at least one of mAb, anti-mPD-1, and anti-a V In some embodiments, the subject is administered at least one of mAb, anti-mPD-1, and anti-a V In some embodiments, administering Compound 39 + anti-mPD-1 to the subject reduces tumor volume in the subject having breast cancer. In some embodiments, administering Compound 39 + anti-a V In some embodiments, administering Compound 39 to the subject having breast cancer reduces tumor growth.

[0880] In some embodiments, the subject has pancreatic cancer. In some embodiments, the subject is administered an effective amount of Compound 39. In some embodiments, the subject is administered an effective amount of Compound 39 in a solution. In some embodiments, the solution comprises ethanol, propylene glycol, and PBS. In some embodiments, the solution comprises about 5% to about 15% v / v ethanol, about 65% to about 75% w / v propylene glycol, and about 15% to about 25% v / v PBS. In some embodiments, the solution comprises about 10% v / v ethanol, about 70% w / v propylene glycol, and about 20% v / v PBS. In some embodiments, the subject is administered an effective amount of Compound 39 in a dose over a duration. In some embodiments, the dose is about 135 to about 150 mg / kg of the subject’s body weight. In some embodiments, the dose is about 144 mg / kg of the subject’s body weight. In some embodiments, the duration is about 20 days, about 25 days, or about 30 days. In some embodiments, the duration is about 28 days. In some embodiments, the subject is administered at least one of mAb, anti-mPD-1, and anti-a V In some embodiments, the subject is administered at least one of mAb, anti-mPD-1, and anti-a V In some embodiments, the subject is administered at least one of mAb, anti-mPD-1, and anti-a V In some embodiments, the subject is administered at least one of mAb, anti-mPD-1, and anti-a V In some embodiments, the subject is administered at least one of mAb, anti-mPD-1, and anti-a

[0881] In some embodiments, the subject has colon cancer. In some embodiments, the subject is administered an effective amount of Compound 39. In some embodiments, the subject is administered an effective amount of Compound 39 in a solution. In some embodiments, the solution comprises ethanol, propylene glycol, and PBS. In some embodiments, the solution comprises about 5% to about 15% v / v of ethanol, about 65% to about 75% w / v of propylene glycol, and about 15% to about 25% v / v of PBS. In some embodiments, the solution comprises about 10% v / v of ethanol, about 70% w / v of propylene glycol, and about 20% v / v of PBS. In some embodiments, the subject is administered an effective amount of Compound 39 in a dose over a duration. In some embodiments, the dose is about 135 to about 150 mg / kg of the subject’s body weight. In some embodiments, the dose is about 144 mg / kg of the subject’s body weight. In some embodiments, the duration is about 20 days, about 25 days, or about 30 days. In some embodiments, the duration is about 28 days. In some embodiments, the subject is administered at least one of mAb, anti-mPD-1, and anti-a V In some embodiments, the subject is administered at least one of mAb, anti-mPD-1, and anti-a V In some embodiments, the subject is administered at least one of mAb, anti-mPD-1, and anti-a V In some embodiments, the subject is administered at least one of mAb, anti-mPD-1, and anti-a V In some embodiments, the subject is administered at least one of mAb, anti-mPD-1, and anti-a

[0882] In some embodiments, the subject has pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the subject having PDAC is administered a compound of Formula (A) or Formula (I) via a certain route of administration at a certain frequency of administration. In some embodiments, the compound of Formula (A) or Formula (I) is Compound 39. In some embodiments, the route of administration is oral gavage route of administration. In some embodiments, the route of administration is oral gavage route of administration at a certain level of administration and amount of administration. In some embodiments, the level of administration is about 300 mg / kg BID and the amount of administration is between about 5 to about 10 mL / kg. In some embodiments, the frequency of administration is daily frequency of administration for a period of time. In some embodiments, the period of time is one week, two weeks, three weeks, one month, two months, or three months. In some embodiments, the compound of Formula (A) or Formula (I) is administered in the form of a solution. In some embodiments, the solution comprises at least one alcohol and a buffer. In some embodiments, the solution comprises ethanol, propylene glycol, and PBS. In some embodiments, the solution comprises between about 5 to about 15% v / v of ethanol, between about 65 to about 75% w / v of propylene glycol, and between about 15 to about 25% v / v of PBS. In some embodiments, the solution comprises about 10% v / v of ethanol, about 70% w / v of propylene glycol, and about 20% v / v of PBS. In some embodiments, the subject is administered the compound of Formula (A) or Formula (I) via oral gavage at a dose of about 300 mg / kg body weight for the duration of the period of time, wherein the period of time is between about 20 to about 25 days or between about 75 to about 85 days. In some embodiments, the subject is administered the compound of Formula (A) or Formula (I) via oral gavage at a dose of about 300 mg / kg body weight for the duration of the period of time, wherein the period of time is about 22 days or about 80 days.

[0883] In some embodiments, the compound of Formula (A) or Formula (I) is co-administered with an antibody during the time period. In some embodiments, the compound of Formula (A) or Formula (I) is administered prior to administration of the antibody. In some embodiments, the compound of Formula (A) or Formula (I) is administered subsequent to administration of the antibody. In some embodiments, the antibody is anti-PD-1. In some embodiments, the anti-PD-1 in a buffer is administered to the subject by intraperitoneal injection. In some embodiments, the anti-PD-1 in PBS is administered to the subject by intraperitoneal injection at a dose of 10 mg / kg body weight twice a week for a period of time. In some embodiments, the anti-PD-1 in PBS is administered to the subject by intraperitoneal injection at a dose of about 10 mg / kg body weight twice a week for a period of two weeks. In some embodiments, administration of Compound 39 with anti-PD-1 reduces the weight of KPC tumors in the subject. In some embodiments, administration of Compound 39 with anti-PD-1 increases at least one of: CD8 + T cell infiltration, CD4 + T cell infiltration and survival of the subject having KPC tumors.

[0884] In some embodiments, a compound of Formula (A) or Formula (I) is administered to a subject having PDAC via a certain route of administration at a certain frequency of administration. In some embodiments, the compound of Formula (A) or Formula (I) is Compound 39. In some embodiments, the route of administration is oral gavage route of administration. In some embodiments, the route of administration is oral gavage route of administration at a certain level of administration. In some embodiments, the level of administration is about 300 mg / kg BID. In some embodiments, the frequency of administration is once a month.

[0885] In some embodiments, a compound of Formula (A) or Formula (I) is co-administered with a chemotherapeutic agent. In some embodiments, the compound of Formula (A) or Formula (I) is administered prior to administration of the chemotherapeutic agent. In some embodiments, the compound of Formula (A) or Formula (I) is administered subsequent to administration of the chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is gemcitabine or nab-paclitaxel. In some embodiments, administration of the chemotherapeutic agent in combination with the compound of Formula (A) or Formula (I) reduces at least one of: tumor weight in the subject and lung metastasis in the subject. In some embodiments, administration of the compound of Formula (A) or Formula (I) reduces lung metastasis in the subject.

[0886] In some embodiments, a compound of Formula (A) or Formula (I) is co-administered with a chemotherapy regimen. In some embodiments, the chemotherapy regimen comprises at least two chemotherapeutic agents. In some embodiments, the chemotherapy regimen comprises folfirinox (FNX). In some embodiments, a compound of Formula (A) or Formula (I) is administered prior to administration of the chemotherapy regimen. In some embodiments, a compound of Formula (A) or Formula (I) is administered subsequent to administration of the chemotherapy regimen. In some embodiments, administration of a chemotherapy regimen in combination with a compound of Formula (A) or Formula (I) reduces tumor weight in a subject. In some embodiments, administration of a chemotherapy regimen in combination with a compound of Formula (A) or Formula (I) reduces tumor weight in a subject, wherein the tumor is FNX-resistant.

[0887] In some embodiments, the subject has cancer. In some embodiments, the subject has a solid tumor. In some embodiments, the subject has an advanced solid tumor. In some embodiments, the subject has a metastatic solid tumor. In some embodiments, the cancer is treatment resistant. In some embodiments, the subject is a human subject who is at least 18 years of age. In some embodiments, the subject has received more than one dose of immunotherapy. In some embodiments, the subject has received at least three doses of immunotherapy. In some embodiments, the subject has received at least three doses (200 mg Q3W) of immunotherapy. In some embodiments, the immunotherapy is pembrolizumab. In some embodiments, the subject has shown signs of disease progression at least one month after starting immunotherapy. In some embodiments, the subject has shown signs of disease progression at least two months after starting immunotherapy. In some embodiments, the subject has shown signs of disease progression at least three months after starting immunotherapy. In some embodiments, the subject has no other treatment options available. In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. In some embodiments, the subject has adequate bone marrow and organ function. “Adequate bone marrow and organ function” includes hemoglobin > 10.0 g / dL and no transfusions (concentrated red blood cell and platelet transfusions) within the past 28 days prior to starting treatment, absolute neutrophil count (ANC) > 1.5 x 109 / L, no features on peripheral blood smear suggestive of myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML), platelet count > 100 x 109 / L, white blood cell (WBC) > 3 x 109 / L, total bilirubin < 1.5 x institutional upper limit of normal, and aspartate aminotransferase (AST) (SGOT) / alanine aminotransferase (ALT) (SGPT) < 2.5 x institutional upper limit of normal. In some embodiments, the subject is administered Compound 39 as monotherapy for a period of time. In some embodiments, the period of time is at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days. In some embodiments, the period of time is at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least three weeks, or at least one month. In some embodiments, the subject is administered immunotherapy in combination with Compound 39 at a frequency starting on day 15. In some embodiments, the frequency is daily, weekly, biweekly, triweekly, or monthly. In some embodiments, the subject is administered pembrolizumab (200 mg Q3W) in combination with Compound 39 on day 15 of every three weeks. In some embodiments, dose escalation is determined by a Bayesian Optimal Interval (BOIN) dose escalation design. In some embodiments, the dose levels include multiple levels.In some embodiments, a starting dose of Compound 39 is administered to a target number of subjects in a treatment arm. In some embodiments, administration of Compound 39 is stopped if a stopping rule is met. In some embodiments, a hypothetical dose-limiting toxicity (DLT) rate is calculated if the stopping rule is not met. The hypothetical DLT rate is calculated as (number of subjects who experienced at least one DLT at the current dose during the DLT evaluation period) / (total number of subjects exposed to the current dose). In some embodiments, the target DLT rate is 30%, and during the DLT evaluation period, less than one-third of the subjects experience at least one DLT at the current dose. In some embodiments, if no one of the three subjects has a DLT and the DLT rate is < 23.7%, then dose escalation is performed. In some embodiments, if one-third of the subjects have a DLT and the DLT rate is between 23.7% and 35.9% (e.g., 95% confidence interval), then the current dose is maintained and the arm is expanded. In some embodiments, if two-thirds of the subjects have a DLT and the DLT rate is > 35.9%, then dose de-escalation is performed. In some embodiments, after dose escalation and dose expansion arms, a Simon’s 2-stage design is employed. In some embodiments, a biomarker is collected from the subjects during a time period. In some embodiments, the time period is at day 28. In some embodiments, the biomarker includes circulating immune cells, circulating markers, circulating tumor DNA, and archival tissue. In some embodiments, circulating immune cells are obtained using a CyTOF Human Immune Detection Panel. In some embodiments, circulating markers include Pro-C3, C4G, GzmB, IFNy, IL-10, PD-1, PD-L1, TNFa, CXCL9, CCXL12, VEGFa, and a. V β8. In some embodiments, archival tissue is obtained using an RNA-Seq technique. In some embodiments, treatment is ended if one or more endpoints are reached.

[0888] The compounds described herein include inhibitors of at least one or more of the following: V β8, a V β1, and a V β6 integrin. For example, in some embodiments, the compound inhibits the a V β8 integrin. In some embodiments, the compound inhibits the a V β1 integrin. In some cases, it is desirable that the compound inhibits two or more integrins. For example, in some embodiments, the compound inhibits the a V β8 integrin and the a V β1 integrin. In some embodiments, the compound inhibits the a V β8 integrin and the aV β6 integrin. In some embodiments, the compound inhibits α V β8 integrin, α V β1 integrin and α V β6 integrin.

[0889] In some cases, it is desirable to avoid inhibiting other integrins. In some embodiments, the compound is a selective α V β8 integrin inhibitor. For example, in some embodiments, the compound is a selective α V β8 integrin inhibitor that does not substantially inhibit one or more integrins such as α V β1, α V β6, α V β3, α V β5, α4β1, or α5β1. In some embodiments, the compound is a selective α V β8 integrin inhibitor that does not substantially inhibit α V β1 integrin. In some embodiments, the compound is a selective α V β8 integrin inhibitor that does not substantially inhibit α V β6 integrin. In some embodiments, the compound is a selective α V β8 integrin inhibitor that does not substantially inhibit α V β1 integrin or α V β6 integrin. In some embodiments, the compound is a selective α V β8 integrin inhibitor that does not substantially inhibit α V β3 integrin. In some embodiments, the compound is a selective α V β8 integrin inhibitor that does not substantially inhibit α V β5 integrin. In some embodiments, the compound is a selective α V β8 integrin inhibitor that does not substantially inhibit α V β5 integrin. In some embodiments, the compound is a selective α V β8 integrin inhibitor that does not substantially inhibit α4β1 integrin. In some embodiments, the compound is a selective α V β8 integrin inhibitor that does not substantially inhibit α5β1 integrin. In some embodiments, the compound is a selective α V β8 integrin inhibitor that does not substantially inhibit α4β1 integrin or α5β1 integrin. In some embodiments, the compound is a selective α V β8 integrin inhibitor. In some embodiments, the compound is a selective α V β3 integrin, α Vselective a integrin of β5 integrin, α4β1 integrin, or α5β1 integrin V β8 integrin inhibitors. In some embodiments, the compound is substantially not an inhibitor of α V β6 integrin, α V β3 integrin, α V selective a integrin of β5 integrin, α4β1 integrin, or α5β1 integrin V β8 integrin inhibitors. In some embodiments, the compound is substantially not an inhibitor of α V β1 integrin, α V β3 integrin, α V selective a integrin of β5 integrin, α4β1 integrin, or α5β1 integrin V β8 integrin inhibitors. In some embodiments, the compound is substantially not an inhibitor of α V β1 integrin, α V β6 integrin, α V β3 integrin, α V selective a integrin of β5 integrin, α4β1 integrin, or α5β1 integrin V β8 integrin inhibitors.

[0890] In some embodiments, isotopically-labeled and / or isotopically-enriched forms of the compounds of Formula (A) or Formula (I) are included. The compounds herein can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compounds are isotopically-labeled, such as isotopically-labeled compounds of Formula (A) or Formula (I) or variations thereof as described herein, wherein one or more atoms are replaced by isotopes of the same element. Exemplary isotopes that can be incorporated into a compound of Formula (A) or Formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 17 O, 32 P, 35 S, 18 F, 36 Cl. Incorporation of isotopes such as deuterium ( 2The heavier isotopes of H or D) can confer certain therapeutic advantages due to greater metabolic stability, such as increased half-life in vivo or decreased dosage requirements, and thus can be preferred in some circumstances. In some embodiments, provided herein are isotopically enriched forms of any of the chemical formulas described herein, wherein the compound contains one or more deuterium atoms. In some embodiments, the compound of Formula (A) or Formula (I) has one or more hydrogen atoms replaced by deuterium. Particular groups can be preferentially labeled with deuterium; hydrogen atoms attached to a cyclopropyl group can be replaced by one or more deuterium atoms, or can be perdeuterated.

[0891] Isotopically-labeled compounds of Formula (A) or Formula (I) can generally be prepared by standard methods and techniques known to those skilled in the art, or by substituting analogous procedures described in the Examples appended hereto with appropriate isotopically-labeled reagents in place of the corresponding non-labeled reagents.

[0892] In some embodiments, any or all metabolites of any of the compounds are described. In some embodiments, metabolites include any chemical species resulting from the biotransformation of any of the described compounds, such as intermediates and metabolites of the compounds.

[0893] Articles comprising a compound of Formula (A) or Formula (I), or a salt or solvate thereof, in a suitable container are provided. In some embodiments, the container is a vial, jar, ampoule, pre-loaded syringe, IV bag, or the like.

[0894] Preferably, the compounds detailed herein are orally bioavailable. However, the compounds can also be formulated for parenteral (e.g., intravenous) administration.

[0895] One or more of the compounds described herein can be used to prepare a medicament by combining one or more of the compounds as an active ingredient with a pharmacologically acceptable carrier known in the art. The carrier can take many forms depending on the form of therapy administered.

[0896] General Synthetic Methods

[0897] The compounds of Formula (A) or Formula (I) can be prepared by a variety of methods as generally described below and more specifically described in the Examples below (schemes provided below). In the following method descriptions, the symbols are to be understood as representing the above-described groups associated with the chemical formulae herein.

[0898] Where it is desirable to obtain a particular stereoisomer of a compound, this can be achieved from a corresponding mixture of stereoisomers using any suitable conventional procedure for separating or resolving stereoisomers. Thus, for example, a mixture of enantiomers (e.g., a racemate) and an appropriate chiral compound can be reacted to produce diastereomeric derivatives. The diastereomeric derivatives can then be separated by any convenient means such as, for example, by crystallization and the desired enantiomer recovered. In another resolution method, chiral high pressure liquid chromatography can be employed to separate the racemate. Alternatively, a particular stereoisomer can be obtained by using an appropriate chiral intermediate in one of the processes described herein.

[0899] In cases where it is desirable to obtain a particular isomer of a compound or otherwise purify the reaction products, chromatography, recrystallization, and other conventional separation procedures can be used to isolate the intermediates or final products.

[0900] Solvates and / or polymorphs of the compounds provided herein, or pharmaceutically acceptable salts thereof, are also contemplated. Solvates contain either stoichiometric or non-stoichiometric amounts of the solvent, and are typically formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is an alcohol. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and / or solubility. Various factors can contribute to the prevalence of one crystal form over another, such as recrystallization solvent, rate of crystallization, and storage temperature.

[0901] The compounds provided herein can be prepared according to Schemes A, B, C, D, E, F, G, H, I, J, K, L, and M; General Procedures B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, and V; Examples 1-82 (i.e., Compounds 1-82) and Examples 83-104 (i.e., Compounds 83-104).

[0902] Scheme A

[0903]

[0904] Intermediate 1A is prepared according to US20200109141A1, which is incorporated by reference herein in its entirety.

[0905] Scheme B

[0906]

[0907] Intermediate 1B is prepared according to US20200109141A1, which is incorporated by reference herein in its entirety.

[0908] Scheme C

[0909]

[0910] The procedure was adapted from Greszler et al., Org. Lett. 2017, 19, 2490-2493, which is incorporated by reference in its entirety.

[0911] Scheme D

[0912]

[0913] Scheme E

[0914]

[0915] Scheme F

[0916]

[0917] Scheme G

[0918]

[0919] Scheme H

[0920]

[0921] Scheme I

[0922]

[0923] Scheme J

[0924]

[0925] Scheme K

[0926]

[0927] Scheme L

[0928]

[0929] It is to be understood that the above schemes can be modified to obtain various compounds of Formula (A) or Formula (I) by selecting appropriate reagents and starting materials. For a general description of protecting groups and their use, see P. G. M. Wuts and T. W. Greene, Greene’s Protective Groups in Organic Synthesis, 4th edition, Wiley-Interscience, New York, 2006, which is incorporated by reference in its entirety.

[0930] Additional methods of preparing compounds according to Formula (A) or Formula (I) and salts thereof are provided in the Examples. As will be recognized by the skilled artisan, the methods of preparation taught herein can be adapted to provide additional compounds within the scope of Formula (A) or Formula (I), for example, by selecting starting materials that will provide the desired compounds.

[0931] Pharmaceutical compositions and formulations

[0932] Also provided are pharmaceutical compositions of any of the compounds detailed herein, including compounds of Formula (A), (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), and (IV), or a pharmaceutically acceptable salt thereof, or a compound described in Table 1, Compounds 1-82, or Compounds 83-104 described in Table 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a mixture thereof. Thus, in some embodiments, pharmaceutical compositions comprising a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient are provided. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. The pharmaceutical compositions according to the present disclosure can take a form suitable for oral, buccal, parenteral, nasal, local, or rectal administration, or a form suitable for administration by inhalation. In some embodiments, the pharmaceutical compositions are prepared from a mixture of any of the compounds detailed herein or salts thereof. In some embodiments, the pharmaceutical compositions are compositions for controlled release of any of the compounds detailed herein.

[0933] Also provided are pharmaceutical compositions of any of the compounds detailed herein, including compounds of Formula (A), (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), and (IV), a compound of Table 1, or any of Compounds 1-82 described in Table 1 or any of Compounds 83-104 described in Table 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a mixture thereof.

[0934] In one aspect, the compounds as detailed herein can be in purified form, and compositions comprising the compounds in purified form are detailed herein. In some embodiments, the compositions have no more than about 35% impurities, wherein the impurities represent compounds other than the compound or pharmaceutically acceptable salt thereof that make up the majority of the composition, e.g., in some embodiments, compositions of compounds selected from Table 1 contain no more than about 35% impurities, wherein the impurities represent compounds other than the compounds of Table 1 or pharmaceutically acceptable salts thereof. In some embodiments, the compositions contain no more than about 25% impurities. In some embodiments, the compositions contain no more than about 20% impurities. In further embodiments, compositions comprising the compounds as detailed herein or pharmaceutically acceptable salts thereof are provided as compositions of substantially pure compounds. A "substantially pure" composition comprises no more than about 10% impurities, such as compositions comprising less than about 9%, about 7%, about 5%, about 3%, about 1%, or about 0.5% impurities. In some embodiments, compositions containing the compounds as detailed herein or pharmaceutically acceptable salts thereof are in substantially pure form. In still another variation, compositions of substantially pure compounds or pharmaceutically acceptable salts thereof are provided, wherein the compositions contain no more than about 10% impurities. In further variations, compositions of substantially pure compounds or pharmaceutically acceptable salts thereof are provided, wherein the compositions contain no more than about 9% impurities. In further variations, compositions of substantially pure compounds or pharmaceutically acceptable salts thereof are provided, wherein the compositions contain no more than about 7% impurities. In further variations, compositions of substantially pure compounds or pharmaceutically acceptable salts thereof are provided, wherein the compositions contain no more than about 5% impurities. In another variation, compositions of substantially pure compounds or pharmaceutically acceptable salts thereof are provided, wherein the compositions contain no more than about 3% impurities. In still another variation, compositions of substantially pure compounds or pharmaceutically acceptable salts thereof are provided, wherein the compositions contain no more than about 1% impurities. In further variations, compositions of substantially pure compounds or pharmaceutically acceptable salts thereof are provided, wherein the compositions contain no more than about 0.5% impurities. In yet other variations, compositions of substantially pure compounds mean that the compositions contain no more than about 10% or preferably no more than about 5% or more preferably no more than about 3% or even more preferably no more than about 1% or most preferably no more than about 0.5% impurities, which can be compounds of different stereochemical form. For example, compositions of substantially pure (S) compounds mean that the compositions contain no more than about 10% or no more than about 5% or no more than about 3% or no more than about 1% or no more than about 0.5% of the I form of the compound.

[0935] In further embodiments, the purified and substantially pure forms of the compounds are useful for any of the compounds of Formula (A), (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-l), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), and (IV), the compounds of Table 1, or any of Compounds 1-82, Compounds 83-104, or stereoisomers thereof.

[0936] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual, such as a human. In another variation, compositions containing the compounds in substantially pure form are provided. In another variation, pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier or excipient are provided. In another variation, methods of administering the compounds are provided. The purified forms, pharmaceutical compositions, and methods of administering the compounds are useful for any of the compounds detailed herein or forms thereof.

[0937] The compounds detailed herein, or pharmaceutically acceptable salts thereof, can be formulated into a form suitable for any available route of delivery, including oral, transmucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery. The compounds, or pharmaceutically acceptable salts thereof, can be formulated with suitable carriers to provide delivery forms including, but not limited to, tablets, caplets, capsules (such as hard or soft elastic gelatin capsules), cachets, troches, lozenges, pastilles, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs.

[0938] One or more compounds described herein, or pharmaceutically acceptable salts thereof, can be used in the preparation of formulations, such as pharmaceutical formulations, by combining one or more compounds, or pharmaceutically acceptable salts thereof, as the active ingredient in intimate admixture with a pharmaceutically acceptable carrier, such as those described above. The carrier can take a wide variety of forms depending on the form of the therapeutic that is to be delivered (e.g., transdermal patch versus oral tablet). Furthermore, a pharmaceutical formulation can contain suitable amounts of preservatives, solubilizers, stabilizers, re-wetting agents, emulsifiers, sweeteners, dyes, flavoring agents, and salts to adjust osmotic pressure, buffers, coating agents or anti-oxidants. Formulations comprising the compounds can also contain other therapeutically valuable substances. Pharmaceutical formulations can be prepared by known methods. Suitable formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21stedition (2005), which is incorporated herein by reference in its entirety.

[0939] Compounds as described herein can be administered to an individual (e.g., a human) in a form of generally accepted oral compositions, such as tablets, coated tablets and gel capsules in hard or soft shell, emulsions or suspensions. Examples of carriers that can be used to prepare such compositions are lactose, corn starch or derivatives thereof, talc, stearate or salts thereof, and the like. Acceptable carriers for gel capsules with soft shell are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols, and the like. Furthermore, pharmaceutical formulations can contain preservatives, solubilizers, stabilizers, re-wetting agents, emulsifiers, sweeteners, dyes, flavoring agents, and salts to adjust osmotic pressure, buffers, coating agents or antioxidants.

[0940] Any of the compounds described herein can be formulated into tablets of any of the dosage forms described, for example, a compound as described herein, or a pharmaceutically acceptable salt thereof, can be formulated into a tablet of about 10 mg.

[0941] Compositions comprising the compounds provided herein are also described. In one variation, the composition comprises a compound and a pharmaceutically acceptable carrier or excipient. In another variation, compositions of substantially pure compounds are provided. In some embodiments, the compositions are used as human or veterinary medicaments. In some embodiments, the compositions are used in the methods described herein. In some embodiments, the compositions are used to treat a disease or disorder described herein.

[0942] Methods of use

[0943] Compounds and compositions, such as pharmaceutical compositions containing a compound of any of the formulae provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, are useful for the methods of administration and treatment as provided herein. In some embodiments, the compounds and compositions are used in in vitro methods, such as in vitro methods in which a compound or composition is administered to a cell for screening purposes and / or for performing quality control assays.

[0944] In one aspect, a method of treating a fibrotic disease in an individual in need thereof is provided, comprising administering to the individual a therapeutically effective amount of a compound of Formula (A) or Formula (I), or any variation thereof, such as a compound of Formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-l), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds described in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, the individual is a human. In some embodiments, the individual, such as a human, is in need of treatment, such as a human having or suspected of having a fibrotic disease. In some embodiments, the variations of the compound include any stereoisomer thereof.

[0945] In a further aspect, a method of treating a fibrotic disease in an individual in need thereof is provided, comprising administering to the individual a therapeutically effective amount of a compound of Formula (A), Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-l), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds described in Table 1, or any one of Compounds 1-82 or any one of Compounds 83-104, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, the individual is a human. In some embodiments, the individual, such as a human, is in need of treatment, such as a human having or suspected of having a fibrotic disease. In some embodiments, the variations of the compound include any stereoisomer thereof.

[0946] In another aspect, methods of delaying the onset and / or development of a fibrotic disease in an individual (such as a human) at risk of developing a fibrotic disease are provided. It is to be appreciated that delaying development can encompass prevention if the individual does not have a fibrotic disease. In one aspect, the individual at risk of developing a fibrotic disease has or is suspected of having one or more risk factors for developing a fibrotic disease. Risk factors for a fibrotic disease can include the age of the individual (e.g., middle-aged or elderly), the presence of inflammation, having one or more genetic components associated with the development of a fibrotic disease, a medical history such as treatment with a drug or procedure (e.g., radiation) believed to be associated with an increased susceptibility to fibrosis or a medical condition believed to be associated with fibrosis, a history of smoking, the presence of occupational and / or environmental factors such as exposure to a contaminant associated with developing a fibrotic disease. In some embodiments, the individual at risk of developing a fibrotic disease is an individual having or suspected of having NAFLD, NASH, CKD, scleroderma, Crohn’s disease, NSIP, PSC, PBC, biliary atresia, or an individual who has or is suspected of having had a myocardial infarction.

[0947] In some embodiments, the fibrotic disease is fibrosis of a tissue such as the lung (pulmonary fibrosis), liver, skin, heart (cardiac fibrosis), kidney (renal fibrosis), or gastrointestinal tract (gastrointestinal fibrosis).

[0948] In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skin fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis (such as PBC).

[0949] In some embodiments, the fibrotic disease is pulmonary fibrosis, for example idiopathic pulmonary fibrosis (IPF), interstitial lung disease, systemic sclerosis-associated interstitial lung disease, or radiation-induced pulmonary fibrosis. In some embodiments, the individual at risk of developing a fibrotic disease is an individual who has or is suspected of having a history of viral lung infection.

[0950] In some embodiments, the fibrotic disease is primary sclerosing cholangitis or biliary fibrosis. In some embodiments, the fibrotic disease is primary biliary cholangitis (also known as primary biliary cirrhosis). In some embodiments, the fibrotic disease is biliary atresia.

[0951] In some embodiments, the fibrotic disease is fibrotic nonspecific interstitial pneumonia (NSIP).

[0952] In some embodiments, the fibrotic disease is liver fibrosis, for example infectious liver fibrosis (from a pathogen, such as HCV, HBV, or a parasite, such as schistosomiasis), NASH, alcohol-induced liver disease, alcoholic steatosis-induced liver fibrosis, non-alcoholic fatty liver disease, biliary atresia, and cirrhosis.

[0953] In some embodiments, the fibrotic disease is biliary fibrosis.

[0954] In some embodiments, the fibrotic disease is kidney fibrosis, for example diabetic nephropathy, diabetic renal sclerosis, hypertensive renal sclerosis, diabetic nephropathy, focal segmental glomerulosclerosis (“FSGS”), Alport syndrome, chronic kidney disease, and acute kidney injury induced by contrast agent-induced nephropathy.

[0955] In some embodiments, the fibrotic disease is systemic and local sclerosis or scleroderma, keloids and hypertrophic scars, or post-surgical adhesions.

[0956] In some embodiments, the fibrotic disease is atherosclerosis or restenosis.

[0957] In some embodiments, the fibrotic disease is gastrointestinal fibrosis, for example Crohn’s disease.

[0958] In some embodiments, the fibrotic disease is cardiac fibrosis, for example fibrosis induced after myocardial infarction and genetic cardiomyopathy.

[0959] In one aspect, there is provided a compound of Formula (A) or Formula (I), or any variation thereof, for example a compound of Formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds described in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a fibrotic disease.

[0960] Also provided is the use of a compound of Formula (A) or Formula (I), or any variation thereof, e.g., a compound of Formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-l), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds described in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a fibrotic disease.

[0961] In another aspect, a method of inhibiting an alpha V beta 8 integrin in an individual is provided, comprising administering a compound of Formula (A) or Formula (I), or any variation thereof, e.g., a compound of Formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-l), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a stereoisomer thereof, or a compound selected from the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0962] Also provided is a method of inhibiting TGF beta activation in a cell, comprising administering to the cell a compound of Formula (A) or Formula (I), or any variation thereof, e.g., a compound of Formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-l), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds described in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the cell expresses one or more of the following: alpha V beta 1; alpha V beta 6; and alpha V beta 8. In some embodiments, the cell expresses alpha V beta 1. In some embodiments, the cell expresses alpha V beta 6. In some embodiments, the cell expresses alpha V beta 8. In some embodiments, the cell expresses alpha Vβ1 and a V β6. In some embodiments, the cell expresses a V β1 and a V β8. In some embodiments, the cell expresses a V β6 and a V β8. In some embodiments, the cell expresses a V β1, a V β6 and a V β8. In some embodiments, the cell is associated with the eye.

[0963] In some embodiments, the method comprises administering to the cell a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor inhibits PD-1. In some embodiments, the checkpoint inhibitor inhibits PD-L1. In some embodiments, the checkpoint inhibitor inhibits CTLA-4. In some embodiments, the checkpoint inhibitor inhibits one or more of: PD-1, PD-L1, and CTLA-4. In some embodiments, the checkpoint inhibitor comprises one or more of: pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, toripalimab, tislelizumab, dostarlimab, INCMGA00012, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab. In some embodiments, the checkpoint inhibitor is pembrolizumab, which is marketed as KEYTRUDA® (https: / / www.keytrudahcp.com / , U.S. Patent Nos. 8,354,509 and 8,900,587, each of which is hereby incorporated by reference in its entirety). In some embodiments, the pembrolizumab is administered at about 200 mg every three weeks or about 400 mg every six weeks. In some embodiments, the pembrolizumab is administered as an injection (about 25 mg / mL) via infusion. KEYTRUDA® (https: / / www.keytrudahcp.com / , U.S. Patent Nos. 8,354,509 and 8,900,587, each of which is hereby incorporated by reference in its entirety). In some embodiments, the pembrolizumab is administered at about 200 mg every three weeks or about 400 mg every six weeks. In some embodiments, the pembrolizumab is administered as an injection (about 25 mg / mL) via infusion.

[0964] In some embodiments, the cells comprise cells associated with a solid tumor. In various embodiments, the cells comprise cells associated with one or more of the following: melanoma, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, lymphoma (e.g., Hodgkin’s lymphoma), cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, or mesothelioma. In some embodiments, the subject can have pancreatic cancer. In some embodiments, the subject has pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cells are associated with breast cancer. In some embodiments, the cells are associated with a disease (e.g., a fibrotic disease or a cancer) mediated by one or more of a V betal integrin, a V betal integrin, a V bet...

Claims

1. A compound of Formula (A): or a pharmaceutically acceptable salt thereof, wherein: wherein the 5- to 6-membered heteroaryl contains at least one nitrogen atom, and is optionally fused to a phenyl group; R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R 1a is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R 1b is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R 1c is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R 1d is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R R 2 is H or Ci-C6alkyl; R 3 is H or Ci-C6alkyl; or R 2 and R 3 together with the carbon atom to which they are attached form C3-C6cycloalkyl or 3- to 6-membered heterocyclyl, each of which is optionally substituted with R 2a substituents; R 4 is phenyl, 5- to 6-membered heteroaryl, 6-membered heterocyclyl, or Ci-C6haloalkyl; wherein the 6-membered heterocyclyl contains at least one nitrogen atom, and is optionally fused to a phenyl group; Q is H or C1-C8 alkyl; wherein said phenyl and 5- to 6-membered heteroaryl are optionally substituted with one or more R 4a substituents; and wherein said 6-membered heterocyclyl is optionally substituted with one or more groups selected from R 4a and oxo; or R 2 , R 3 and R 4 together form a 5-membered heteroaryl containing two nitrogen atoms and substituted by phenyl, wherein said phenyl is optionally substituted by one or more R 4a ; Each R 4a Independently, it is halogenated, CN, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -OH, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), -S(O)2(C1-C6 alkyl) or -C(=O)-NH2; or R 4a and R 2 together with the atoms to which they are attached form a 6-membered heterocyclyl group, wherein the heterocyclyl group contains one oxygen atom; Y is a bond; L 1 is C2-C4alkylene optionally substituted by one or more L 1a alkylene; L 2 is a bond or C1-C3alkylene optionally substituted with one or more L 2a substituted with one or more L L 3 is C2-C4alkylene optionally substituted with one or more L 3a substituted with one or more L 2. The compound of claim 1 according to Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1a , R 1b , R 1c , R 1d , R 2a , L 1a , L 2a and L 3a are each independently selected from R A ; two R on the same carbon atom 1a group optionally taken together with the carbon atom to which they are attached form C3-C6cycloalkyl; two R on the same carbon atom 1b group optionally taken together with the carbon atom to which they are attached form C3-C6cycloalkyl; each R A is independently deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -CN, -OR 14 , -SR 5 , -NR 5 R 6 , -NO2, -C=NH(OR 7 ), -C(O)R 5 , -OC(O)R 5 , -C(O)OR 5 , -C(O)NR 5 R 6 , -NR 7 C(O)R 5 , -NR 6 C(O)OR 5 , -NR 6 C(O)NR 5 R 6 , -S(O)R 7 , -S(O)2R 5 , -NR 5 S(O)R 5 , -NR 6 S(O)2R 5 , -S(O)NR 6 R 6 , -S(O)2NR 7 R 6 , or -P(O)(OR 7 )(OR 5 ), wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, C6-C10aryl, and 5- to 10-membered heteroaryl of R 6 are each independently optionally substituted with one or more R A ; and each R 14 is independently halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -CN, -OR Aa , -SR , -NR , -NO2, -C=NH(OR ), -C(O)R , -OC(O)R , -C(O)OR , -C(O)NR R , -NR C(O)R , -NR C(O)OR , -NR C(O)NR R , -S(O)R , -S(O)2R , -NR S(O)R , -NR S(O)2R , -S(O)NR R , -S(O)2NR R , or -P(O)(OR )(OR ). Each R Aa Independently deuterium, halogen, oxo, -OR 8 -NR 8 R 9 -C(O)R 8 -C(O)OR 8 -NR 8 C(O)OR 10 -CN, -S(O)R 8 -S(O)2R 8 -P(O)(OR) 8 (OR) 9 ), C3-C8 cycloalkyl, 3 to 12-membered heterocyclic, 5 to 10-membered heteroaryl, C6-C 14 aryl or C1-C6 alkyl, wherein R Aa 3- to 12-membered heterocyclic groups, 5- to 10-membered heteroaryl groups, C6-C 14 The aryl and C1-C6 alkyl groups are independently and optionally influenced by one or more R groups. Ab replace; each R is independently deuterium, oxo, -OH, -O Ab H), halogen, or Ci-C6alkyl optionally substituted with one or more of deuterium, halogen, -OH, -O 2 H), or oxo; each R is independently deuterium, oxo, -OH, -O 2 H), halogen, or Ci-C6alkyl optionally substituted with one or more of deuterium, halogen, -OH, -O H), or oxo; each R is independently deuterium, oxo, -OH, -O H), halogen, or Ci-C6alkyl optionally substituted with one or more of Each R 5 Independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic, wherein R 5 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic groups are each independently and optionally constituting one or more R groups. 5a replace; Each R 5a Independently halogen, deuterium, oxo, -CN, -OR 10 -NR 11 R 12 -P(O)(OR) 11 (OR) 12 ), 3 to 12-membered heterocyclic groups or optionally coated with deuterium, halogen, -OH, -O ( 2 C1-C6 alkyl groups substituted with one or more of the H or oxo groups; Each R 6 Independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl or 3- to 6-membered heterocyclic, wherein R 6 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 The aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclic groups are independently and optionally substituted by one or more of the following: deuterium, halogen, oxo, -CN, -OR. 10 -NR 11 R 12 Or optionally, deuterium, halogen, -OH, -O ( 2 C1-C6 alkyl groups substituted with one or more of the H or oxo groups; each R is independently hydrogen, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocycloalkyl, wherein R 7 is independently hydrogen, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocycloalkyl, wherein R 7 is independently hydrogen, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocycloalkyl are independently optionally substituted with one or more of deuterium, halogen, oxo, -CN, -OR 10 , -NR 11 R 12 , or C1-C6alkyl optionally substituted with one or more of deuterium, halogen, -OH, -O( 2 H), or oxo; or R 6 and R 7 together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl optionally substituted with one or more deuterium, halogen, oxo, -OR 10 , -NR 11 R 12 or C1-C6 alkyl optionally substituted with one or more deuterium, halogen, oxo, -OH, or -O 2 H); Each R 8 Independently hydrogen or deuterium; a C1-C6 alkyl group optionally substituted with one or more of deuterium, halogen or oxo; a C2-C6 alkenyl group optionally substituted with one or more of deuterium, halogen or oxo; or a C2-C6 alkynyl group optionally substituted with one or more of deuterium, halogen or oxo. Each R 9 Independently hydrogen or deuterium; a C1-C6 alkyl group optionally substituted with one or more of deuterium, halogen or oxo; a C2-C6 alkenyl group optionally substituted with one or more of deuterium, halogen or oxo; or a C2-C6 alkynyl group optionally substituted with one or more of deuterium, halogen or oxo. Each R 10 Independently hydrogen or deuterium; a C1-C6 alkyl group optionally substituted with one or more of deuterium, halogen or oxo; a C2-C6 alkenyl group optionally substituted with one or more of deuterium, halogen or oxo; or a C2-C6 alkynyl group optionally substituted with one or more of deuterium, halogen or oxo. Each R 11 Independently hydrogen or deuterium; a C1-C6 alkyl group optionally substituted with one or more of deuterium, halogen, or oxo; a C2-C6 alkenyl group optionally substituted with one or more of deuterium, halogen, or oxo; or a C2-C6 alkynyl group optionally substituted with one or more of deuterium, halogen, or oxo; and Each R 12 Independently hydrogen or deuterium; a C1-C6 alkyl group optionally substituted with one or more of deuterium, halogen or oxo; a C2-C6 alkenyl group optionally substituted with one or more of deuterium, halogen or oxo; or a C2-C6 alkynyl group optionally substituted with one or more of deuterium, halogen or oxo. or R 11 and R 12 with the atom to which they are attached come together to form a 3-6 membered heterocyclyl optionally substituted with one or more deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted with one or more deuterium, oxo, or halogen. wherein the 5- to 6-membered heteroaryl contains at least one nitrogen atom, and is optionally fused to a phenyl group; wherein the 6-membered heterocyclyl contains at least one nitrogen atom, and is optionally fused to a phenyl group; R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R 1a is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R 1b is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R 1c is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R 1d is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R R 2 is H or Ci-C6alkyl; R 3 is H or Ci-C6alkyl; or R 2 and R 3 together with the carbon atom to which they are attached form C3-C6cycloalkyl or 3- to 6-membered heterocyclyl; R 4 is phenyl, 5- to 6-membered heteroaryl or 6-membered heterocyclyl; Q is H or C1-C8 alkyl; Y is a bond; wherein said phenyl and 5- to 6-membered heteroaryl are optionally substituted with one or more R 4a substituents; and wherein said 6-membered heterocyclyl is optionally substituted with one or more groups selected from R 4a and oxo; Each R 4a It can be independently halogenated, CN, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl) or -S(O)2(C1-C6 alkyl); or R 4a and R 2 together with the atoms to which they are attached form a 6-membered heterocyclyl group, wherein the heterocyclyl group contains one oxygen atom; 42. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein Q is H. L 1 is C2-C4alkylene optionally substituted with one or more L 1a substituted with one or more L L 2 is a bond or C1-C3alkylene optionally substituted with one or more L 2a substituted with one or more L L 3 is C2-C4alkylene optionally substituted with one or more L 3a alkylene; 43. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1a , R 1b , R 1c , R 1d , L 1a , L 2a , and L 3a are each independently selected from R A ; two R on the same carbon atom 1a group optionally are taken together with the carbon atom to which they are attached to form a C3-C6cycloalkyl; two R on the same carbon atom 1b group optionally are taken together with the carbon atom to which they are attached to form a C3-C6cycloalkyl; Each R A Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3 to 12-membered heterocyclic, C6-C 14 Aryl, 5- to 10-membered heteroaryl, -CN, -OR 5 -SR 5 -NR 6 R 7 -NO2, -C = NH (OR 5 -C(O)R 5 -OC(O)R 5 -C(O)OR 5 -C(O)NR 6 R 7 -NR 5 C(O)R 6 -NR 5 C(O)OR 6 -NR 5 C(O)NR 6 R 7 -S(O)R 5 -S(O)2R 5 -NR 5 S(O)R 6 -NR 5 S(O)2R 6 -S(O)NR 6 R 7 -S(O)2NR 6 R 7 or -P(O)(OR 5 (OR) 6 ), where R A The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, C6-C 14 aryl and 5 to 10-membered heteroaryl groups are independently and optionally constituting one or more R Aa replace; Each R Aa Independently deuterium, halogen, oxo, -OR 8 -NR 8 R 9 -C(O)R 8 -C(O)OR 8 -NR 8 C(O)OR 10 -CN, -S(O)R 8 -S(O)2R 8 -P(O)(OR) 8 (OR) 9 ), C3-C8 cycloalkyl, 3 to 12-membered heterocyclic, 5 to 10-membered heteroaryl, C6-C 14 aryl or C1-C6 alkyl, wherein R Aa 3- to 12-membered heterocyclic groups, 5- to 10-membered heteroaryl groups, C6-C 14 The aryl and C1-C6 alkyl groups are independently and optionally influenced by one or more R groups. Ab replace; each R is independently deuterium, oxo, -OH, -O Ab independently deuterium, oxo, -OH, -O 2 H), halogen, or Ci-C6alkyl optionally substituted with one or more of deuterium, halogen, -OH, -O 2 H), or oxo; Each R 5 Independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic, wherein R 5 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic groups are each independently and optionally constituting one or more R groups. 5a replace; Each R 5a Independently halogen, deuterium, oxo, -CN, -OR 10 -NR 11 R 12 -P(O)(OR) 11 (OR) 12 ), 3 to 12-membered heterocyclic groups or optionally coated with deuterium, halogen, -OH, -O ( 2 C1-C6 alkyl groups substituted with one or more of the H or oxo groups; Each R 6 Independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl or 3- to 6-membered heterocyclic, wherein R 6 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 The aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclic groups are independently and optionally substituted by one or more of the following: deuterium, halogen, oxo, -CN, -OR. 10 -NR 11 R 12 Or optionally, deuterium, halogen, -OH, -O ( 2 C1-C6 alkyl groups substituted with one or more of the H or oxo groups; each R is independently hydrogen, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocycloalkyl, wherein R 7 is independently hydrogen, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocycloalkyl, wherein R 7 is independently hydrogen, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocycloalkyl are independently optionally substituted with one or more of deuterium, halogen, oxo, -CN, -OR 10 , -NR 11 R 12 , or C1-C6alkyl optionally substituted with one or more of deuterium, halogen, -OH, -O( 2 H), or oxo; or R 6 and R 7 together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl optionally substituted with one or more deuterium, halogen, oxo, -OR 10 , -NR 11 R 12 or C1-C6 alkyl optionally substituted with one or more deuterium, halogen, oxo, -OH, or -O 2 H); Each R 8 Independently hydrogen or deuterium; a C1-C6 alkyl group optionally substituted with one or more of deuterium, halogen or oxo; a C2-C6 alkenyl group optionally substituted with one or more of deuterium, halogen or oxo; or a C2-C6 alkynyl group optionally substituted with one or more of deuterium, halogen or oxo. Each R 9 Independently hydrogen or deuterium; a C1-C6 alkyl group optionally substituted with one or more of deuterium, halogen or oxo; a C2-C6 alkenyl group optionally substituted with one or more of deuterium, halogen or oxo; or a C2-C6 alkynyl group optionally substituted with one or more of deuterium, halogen or oxo. Each R 10 Independently hydrogen or deuterium; a C1-C6 alkyl group optionally substituted with one or more of deuterium, halogen or oxo; a C2-C6 alkenyl group optionally substituted with one or more of deuterium, halogen or oxo; or a C2-C6 alkynyl group optionally substituted with one or more of deuterium, halogen or oxo. Each R 11 Independently hydrogen or deuterium; a C1-C6 alkyl group optionally substituted with one or more of deuterium, halogen, or oxo; a C2-C6 alkenyl group optionally substituted with one or more of deuterium, halogen, or oxo; or a C2-C6 alkynyl group optionally substituted with one or more of deuterium, halogen, or oxo; and Each R 12 Independently hydrogen or deuterium; a C1-C6 alkyl group optionally substituted with one or more of deuterium, halogen or oxo; a C2-C6 alkenyl group optionally substituted with one or more of deuterium, halogen or oxo; or a C2-C6 alkynyl group optionally substituted with one or more of deuterium, halogen or oxo. or R 11 and R 12 with the atom to which they are attached come together to form a 3-6 membered heterocyclyl optionally substituted with one or more deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted with one or more deuterium, oxo, or halogen.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L 1 is -CH2CH2-.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein -L 1 -0-L 2 -Y-L 3 - taken together form 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are independently C1-C6 alkyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are the same.

7. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 is -CH3.

8. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 taken together with the carbon atom to which they are attached form cyclopropyl.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl optionally substituted with one or more R 4a .

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R 4 is unsubstituted phenyl.

11. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl substituted with 1-5 R 4a groups, wherein at least one R 4a group is F or Cl.

12. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl substituted with 1-5 R 4a groups, wherein at least one R 4a group is CN.

13. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl substituted with 1-5 R 4a groups, wherein at least one R 4a group is C1-C3 alkyl.

14. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl substituted with 1-5 R 4a groups, wherein at least one R 4a group is -0-(Ci-C3alkyl).

15. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl substituted with 1-5 R 4a groups, wherein at least one R 4a group is -S(O)2(Ci-C3alkyl).

16. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R 4 is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl contains at least one nitrogen atom, and is optionally substituted with one or more R 4a .

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R 4 is 5-membered heteroaryl, wherein the 5-membered heteroaryl contains two nitrogen atoms, and is optionally substituted with one or more R 4a .

18. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R 4 is 6-membered heteroaryl, wherein the 6-membered heteroaryl contains one nitrogen atom, and is optionally substituted with one or more R 4a .

19. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R 4 is 6-membered heteroaryl, wherein the 6-membered heteroaryl contains two nitrogen atoms, and is optionally substituted with one or more R 4a .

20. The compound of any one of claims 16-19, or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted with 1-4 R 4a groups, wherein at least one R 4a group is F or Cl.

21. The compound of any one of claims 16-19, or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted with 1-4 R 4a groups, wherein at least one R 4a group is CN.

22. The compound of any one of claims 16-19, or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted with 1-4 R 4a groups, wherein at least one R 4a group is C1-C3 alkyl.

23. The compound of any one of claims 16-19, or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted with 1-4 R 4a groups, wherein at least one R 4a group is C1-C3 haloalkyl.

24. The compound of any one of claims 16-19, or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted with 1-4 R 4a groups, wherein at least one R 4a group is -(Ci-C3alkylene)-0-(Ci-C3alkyl).

25. The compound of any one of claims 16-19, or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted with 1-4 R 4a groups, wherein at least one R 4a group is cyclopropyl.

26. The compound of any one of claims 16-19, or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted with 1-4 R 4a groups, wherein at least one R 4a group is -O-(Ci-C3alkyl).

27. The compound of any one of claims 16-19, or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted with 1-4 R 4a groups, wherein at least one R 4a group is -O-(C1-C3haloalkyl).

28. The compound of any one of claims 16-19, or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted with 2-4 R 4a groups, wherein at least one R 4a group is F, and wherein at least one R 4a group is Cl.

29. The compound of any one of claims 16-19, or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted with 2-4 R 4a groups, wherein at least one R 4a group is F, and wherein at least one R 4a group is C1-C3 alkyl.

30. The compound of any one of claims 16-19, or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted with 2-4 R 4a groups, wherein at least one R 4a group is CI, and wherein at least one R 4a group is C1-C3 alkyl.

31. The compound of any one of claims 16-19, or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted with 2-4 R 4a groups, wherein at least one R 4a group is CI, and wherein at least one R 4a group is -0-(Ci-C3alkyl).

32. The compound of any one of claims 16-19, or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted with 2-4 R 4a groups, wherein at least two R 4a groups are CI.

33. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R 4 is 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains at least one nitrogen atom, and is optionally substituted with one or more groups selected from R 4a and oxo.

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R 4 is 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains one nitrogen atom, and is optionally substituted with one or more groups selected from R 4a and oxo.

35. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R 4 is 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains two nitrogen atoms, and is optionally substituted with one or more groups selected from R 4a and oxo.

36. The compound of any one of claims 33-35, or a pharmaceutically acceptable salt thereof, wherein R 4 substituted with Cl and oxo.

37. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R 4 selected from:

38. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R 4 selected from:

39. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from:

40. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , and R 4 are taken together to form:

41. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted with one or more R 1a .

44. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is H; and R 1 is R 2 and R 3 are independently H or methyl, or R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl group; R 4 is phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, 2-oxopyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydropyridazinyl, or quinazolinyl, wherein: said phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, 2-oxopyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or quinazolinyl is optionally substituted with one or more R 4a groups, said dihydropyridyl, dihydropyrimidyl or dihydropyridazinyl is optionally substituted with one or more groups selected from R 4a and oxo, and Each R 4a Independently, it is halogenated, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl) or -S(O)2(C1-C3 alkyl); Q is H; and -L 1 -OL 2 -YL 3 -Combined to form 45. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is R 2 and R 3 and the carbon atom to which they are attached combine to form a cyclopropyl group; R 4 is phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, 2-oxopyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydropyridazinyl, or quinazolinyl; wherein: said phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, 2-oxopyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or quinazolinyl is optionally substituted with one or more R 4a groups, said dihydropyridyl, dihydropyrimidyl or dihydropyridazinyl is optionally substituted with one or more groups selected from R 4a and oxo, and Each R 4a It can be independently halogenated, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl) or -S(O)2(C1-C3 alkyl); Q is H; and - L 1 - O-L 2 - Y-L 3 - together form 46. A compound selected from the group consisting of compounds numbered 1-82 in Table 1, or a pharmaceutically acceptable salt thereof. R 1 is R 2 and R 3 and the carbon atom to which they are attached combine to form a cyclopropyl group; R 4 is pyrazolyl, imidazolyl, thiazolyl, pyridyl, 2-oxopyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydropyridazinyl, or quinazolinyl; wherein: said pyrazolyl, imidazolyl, thiazolyl, pyridyl, 2-oxopyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or quinazolinyl is optionally substituted with one or more R 4a groups, wherein said dihydropyridyl, dihydropyrimidyl or dihydropyridazinyl is optionally substituted with one or more groups selected from R 4a and oxo, and wherein said dihydropyridyl, dihydropyrimidyl or dihydropyridazinyl is optionally substituted with one or more groups selected from R Each R 4a It can be independently halogenated, CN, C1-C3 alkyl, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl) or -S(O)2(C1-C3 alkyl); 47. A compound selected from the group consisting of compounds numbered 83-104 in Table 1, or a pharmaceutically acceptable salt thereof. - L 1 - O-L 2 - Y-L 3 - together form 48. A pharmaceutical composition comprising a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

49. A method of treating a fibrotic disease in an individual in need thereof, comprising administering a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48.

50. The method of claim 49, wherein the fibrotic disease is pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis.

51. A kit comprising a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48.

52. The kit of claim 51, further comprising instructions for treating a fibrotic disease.

53. The kit of claim 51, further comprising instructions for a user to treat a cancer in a subject in need thereof, the instructions comprising instructing the user to administer the compound, or a pharmaceutically acceptable salt thereof, to the subject.

56. The method of claim 55, comprising inhibiting one of the following in the individual:

57. The method of any one of claims 54-56, wherein the individual is in need of treatment for a disease or condition.

54. A method of inhibiting an alpha V β8 integrin in an individual comprising administering a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of claim 48.

55. A method of inhibiting one or more of α V β1, α V β6, or α V β8 integrin in an individual in need thereof, comprising administering to the individual a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48.

58. The method of claim 57, wherein the disease or the condition comprises a solid tumor. α V β1； α V β8； α V β1 and α V β8; α V β6 and α V β8; or a V β1, a V β6 and a V β8. ​ ​ 59. The method of claim 57, wherein the disease or the condition is selected from the group consisting of melanoma, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, and mesothelioma.

60. The method of claim 57, wherein the disease or the condition is pancreatic ductal adenocarcinoma (PDAC).

61. The method of claim 57, wherein the disease or the condition is breast cancer.

62. The method of claim 57, wherein the disease or the condition is selected from the group consisting of pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal tract fibrosis, primary sclerosing cholangitis, and biliary tract fibrosis.

63. A method of inhibiting TGFp activation in a cell, comprising administering to the cell a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48.

64. The method of claim 63, wherein the cells express one or more of: a V β1; a V β6; and a V β8.

65. The method of claim 63, wherein the cell expresses one of: α V β1； α V β6； α V β8； α V β1 and α V β8; α V β1 and α V β6; α V β6 and α V β8; or a V β1, a V β6 and a V β8.

66. The method of claim 63, wherein the cell is a cancer cell associated with a solid tumor.

67. The method of claim 63, wherein the cell is a cancer cell associated with at least one of: melanoma, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, and mesothelioma.

68. The method of claim 63, wherein the cancer cell is associated with pancreatic ductal adenocarcinoma (PDAC).

69. The method of claim 63, wherein the cell is a breast cancer cell.

70. The method of claim 63, wherein the cell is a human cell.

71. The method of claim 63, wherein the cell is associated with a fibrotic disease, and wherein the fibrotic disease is selected from the group consisting of pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal tract fibrosis, primary sclerosing cholangitis, and biliary tract fibrosis.

72. Use of a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48, in the manufacture of a medicament for treating a fibrotic disease.

73. Use of a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48, for the manufacture of a medicament for the treatment of a disease mediated by cells expressing one or more of: α V β1; α V β6; and α V β8.

74. Use of a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48, in the manufacture of a medicament for treating a cancer.

75. A method of treating a subject in need thereof, comprising: administering to a subject in need of treatment of at least one tissue a therapeutically effective amount of a compound of any one of claims 1-47, or a pharmaceutical composition of claim 48, wherein the at least one tissue is characterized by an elevated value compared to a healthy value of the at least one tissue in a healthy state, and wherein the value is selected from the group consisting of: α V β1 integrin activity and / or expression; α V β6 integrin activity and / or expression; α V β8 integrin activity and / or expression; pSMAD / SMAD ratio; new collagen formation or accumulation; total collagen; Collagen type I gene Col1a1 expression; Perforin; Graziomerase B; and Interferon gamma.

76. The method of claim 75, wherein administering a therapeutically effective amount of the compound reduces the elevated value in the at least one tissue.

77. The method of claim 75, further comprising reducing at least one of activity and expression of one of: α V β1； α V β8； α V β1 and α V β8; α V β6 and α V β8; and a V β1, a V β6 and a V β8.

78. The method of claim 77, wherein it is combined with at least one other α-containing substance in the subject's body. V Compared to integrins, the reduction of at least one of the activity and the expression is selective.

79. The method of claim 77, wherein the case is one of: a V the activity of the β1 integrin is reduced in one or more fibroblast cells in the subject; a V the activity of the β6 integrin is reduced in one or more epithelial cells in the subject; or a V the activity of β8 integrin is reduced in one or more epithelial cells or cancer cells in the subject.

80. The method of any one of claims 75-79, wherein each of the at least one tissue in the subject is selected from the group consisting of: lung, liver, skin, heart, kidney, gastrointestinal, gallbladder, and bile duct.

81. The method of any one of claims 75-79, wherein each of the at least one tissue in the subject is selected from the group consisting of: skin, lung, brain, lymph node, stomach, urethra, kidney, bladder, prostate, liver, pancreatic cancer, mesothelium, and breast.

82. The method of any one of claims 75-81, wherein each of the at least one tissue has an elevated pSMAD2 / SMAD2 value or an elevated pSMAD3 / SMAD3 value compared to the healthy value of the at least one tissue in the healthy state.

83. The method of claim 82, wherein the subject comprises a solid tumor.

84. The method of claim 82, wherein the subject comprises at least one of: melanoma, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, and mesothelioma.

85. The method of claim 82, wherein the subject comprises pancreatic ductal adenocarcinoma (PDAC).

86. The method of claim 82, wherein the subject comprises at least one of: pulmonary fibrosis, liver fibrosis, skin fibrosis, heart fibrosis, kidney fibrosis, gastrointestinal tract fibrosis, primary sclerosing cholangitis, and biliary tract fibrosis.

87. A method of characterizing an anti-cancer activity of a small molecule inhibitor in a subject, comprising: providing a first live cell sample from the subject, wherein the first live cell sample is characterized by the presence of at least one integrin capable of activating transforming growth factor beta (TGF-beta) from a latency associated peptide-TGF-beta; determining a first value in the first live cell sample, wherein the first value is selected from the group consisting of: pSMAD2 / SMAD2 ratio, pSMAD3 / SMAD3 ratio, perforin level, graziomerase B level, and interferon gamma level; administering the small molecule to the subject; providing a second live cell sample from the subject, wherein the second live cell sample is taken from the same tissue of the subject as the first live cell sample; determining a second value in the second live cell sample, wherein the second value is selected from the group consisting of: pSMAD2 / SMAD2 ratio, pSMAD3 / SMAD3 ratio, perforin level, graziomerase B level, and interferon gamma level; and comparing the first value and the second value, wherein a difference between the first value and the second value indicates an anti-cancer activity of the small molecule in the subject. determining a second value in the second viable cell sample, wherein the second value corresponds to a pSMAD2 / SMAD2 ratio, a pSMAD3 / SMAD3 ratio, a perforin level, a granzyme B level, or an interferon gamma level of the first value; and characterizing the anti-cancer activity of the small molecule in the subject by comparing the second value to the first value.

88. The method of claim 87, wherein each viable cell sample comprises a plurality of cancer cells derived from a tissue of the subject or a blood cell of the subject.

89. The method of claim 87, wherein the tissue in the subject is selected from the group consisting of skin, lung, brain, lymph node, stomach, urethra, kidney, bladder, prostate, liver, pancreas, mesothelium, and breast.

90. The method of claim 87, wherein the subject comprises a solid tumor.

91. The method of claim 87, wherein the subject comprises melanoma, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, or mesothelioma.

92. The method of claim 87, wherein the subject comprises pancreatic ductal adenocarcinoma (PDAC).

93. The method of claim 87, wherein the at least one integrin comprises α V .

94. The method of claim 87, wherein the at least one integrin is selected from the group consisting of: α V β1, α V β6, and α V β8.

95. The method of claim 87, wherein the first and second values are a pSMAD2 / SMAD2 ratio or a pSMAD3 / SMAD3 ratio.

96. The method of claim 87, wherein administering the small molecule to the subject comprises administering a compound of any one of claims 1-47 or a pharmaceutical composition of claim 48 to the subject.

97. The method of any one of claims 54-56 and 62, wherein the individual is in need of treatment for biliary atresia.

98. The method of any one of claims 63-65 and 70-71, wherein the one or more cells are associated with the intrahepatic or extrahepatic biliary system.

99. The use of claim 72 or 73, wherein the fibrotic disease or condition is biliary atresia.

100. The method of any one of claims 75-82 and 86, wherein the subject is in need of treatment for biliary atresia.

101. The method of any one of claims 75-82 and 86, wherein the tissue is a tissue of the intrahepatic or extrahepatic biliary system.

102. The method of claim 98, wherein the one or more cells express α V β1 and α V β8.

103. The method of claim 101, wherein the tissue expresses α V β1 and α V β8.

104. The method of any one of claims 54-56, wherein the individual is in need of treatment for ocular fibrosis.

105. The method of any one of claims 54-56 or 104, wherein the individual is in need of treatment for pre-subcapsular cataract or postcapsular opacification.

106. The method of any one of claims 63-65, wherein the one or more cells are associated with the eye.

107. The use of claim 72 or 73, wherein the fibrotic disease or condition is ocular fibrosis.

108. The use of any one of claims 72, 73, or 104, wherein the fibrotic disease or condition is pre-subcapsular cataract or postcapsular opacification.

109. The method of any one of claims 75-77 and 82, wherein the tissue is a tissue of the eye.

110. The method of claim 96, wherein the one or more cells express one, two, or three integrins selected from the group consisting of: α V β1, α V β6, and α V β8.

111. The method of claim 109, wherein the tissue expresses one, two, or three integrins selected from the group consisting of: α V β1, α V β6, and α V β8.

112. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48.

113. The method of claim 112, wherein the cancer comprises a solid tumor.

114. The method of claim 112, wherein the cancer is selected from the group consisting of melanoma, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, and mesothelioma.

115. The method of claim 112, wherein the cancer is breast cancer.

116. The method of claim 112, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

117. The method of claim 112, further comprising: administering a chemotherapeutic agent before, concurrently with, or after the compound or pharmaceutical composition.

118. The method of claim 117, wherein the chemotherapeutic agent is selected from the group consisting of gemcitabine and nab-paclitaxel.

119. The method of claim 117, wherein administering the chemotherapeutic agent before, concurrently with, or after the compound or the pharmaceutical composition reduces at least one of tumor weight in the subject and lung metastasis in the subject.

120. The method of claim 112, further comprising: administering a chemotherapy regimen before, concurrently with, or after the compound or pharmaceutical composition.

121. The method of claim 120, wherein the chemotherapy regimen comprises folfirinox.

122. The method of claim 120, wherein administering the chemotherapy regimen before, concurrently with, or after the compound or the pharmaceutical composition reduces tumor weight in the subject.

123. The method of claim 122, wherein the tumor is resistant to a chemotherapy regimen.

124. The method of claim 122, wherein the tumor is resistant to folfirinox.

125. The method of claim 112, wherein the effective amount of the compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 48 is a therapeutically effective amount.

126. A compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48, for use in treating melanoma.

127. A compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48, for use in treating colon cancer.

128. A compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48, for use in treating non-small cell lung cancer.

129. A compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 48, for use in the treatment of head and neck squamous cell carcinoma.

130. A compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 48, for use in the treatment of squamous cell lung cancer.

131. A compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 48, for use in the treatment of renal cell carcinoma.

132. A compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 48, for use in the treatment of cutaneous squamous cell carcinoma (CSCC).

133. A compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 48, for use in the treatment of urothelial carcinoma.

134. A compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 48, for use in the treatment of metastatic Merkel cell carcinoma.

135. A compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 48, for use in the treatment of gastric cancer.

136. A compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 48, for use in the treatment of lung cancer.

137. A compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 48, for use in the treatment of pancreatic cancer.

138. A compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 48, for use in the treatment of mesothelioma.

139. A compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 48, for use in the treatment of breast cancer.

140. A compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 48, for use in the treatment of pancreatic ductal adenocarcinoma (PDAC).

141. The use of claim 74, wherein the cancer is selected from the group consisting of melanoma, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, mesothelioma, breast cancer, and pancreatic ductal adenocarcinoma (PDAC).

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