Alpha-V-Beta-8 Integrin Inhibitors and Uses Thereof

Abstract

The present disclosure provides compounds of formula (A) and formula (I), e.g., (I) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , Y, and Q are as described herein. The compounds of Formula (A) and Formula (I) and pharmaceutical compositions thereof are inhibitors of at least one of avPs, avPi, and avPe integrins. Also disclosed are methods for treating fibrosis, such as nonalcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF), and nonspecific interstitial pneumonia (NSIP), and cancer, comprising administering the compounds and pharmaceutical compositions thereof. JPEG2026500719000276.jpg64165

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS 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 which are incorporated herein by reference in their entirety.

[0002] The present disclosure generally relates to a V The present invention relates to a therapeutic agent that may be useful as a β8 integrin inhibitor. The therapeutic agent may be used for the treatment or prophylactic treatment of fibrosis, such as idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP). The therapeutic agent may also be used for the treatment of cancer. [Background technology]

[0003] Fibrosis, a pathological hallmark of many diseases, results from the dysfunction of the body's natural ability to repair damaged tissue. If left untreated, fibrosis can lead to scarring of vital organs, causing irreparable damage and eventual organ failure.

[0004] Patients with nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis to nonalcoholic steatohepatitis (NASH) and then to fibrosis. While early-stage liver fibrosis is reversible, progressive liver fibrosis can lead to cirrhosis.

[0005] Renal fibrosis, characterized by glomerular sclerosis and tubulointerstitial fibrosis, is a common and final manifestation of a wide variety of chronic kidney diseases (CKD). Regardless of the initial cause, progressive CKD often results in extensive tissue scarring that leads to the destruction of the renal parenchyma, culminating in end-stage renal failure, a devastating condition requiring dialysis or renal replacement.

[0006] Scleroderma encompasses a complex and diverse range of conditions characterized by fibrosis, vascular degeneration, and autoimmunity. The spectrum of scleroderma disorders shares the common feature of fibrosis, resulting in hardening or thickening of the skin. In some patients, this hardening occurs in limited areas, but in others, it can spread to other major organs.

[0007] Cardiac structural remodeling after myocardial infarction is associated with an inflammatory response, resulting in scar formation at the infarct site. This scar formation is the result of fibrous tissue deposition and can lead to a decline in cardiac function and disruption of electrical activity within the heart.

[0008] Crohn's disease is a chronic condition of unknown cause that tends to progress despite medical or surgical treatment. Intestinal fibrosis is one of the most common complications of Crohn's disease, resulting in the formation of strictures in the small intestine and colon.

[0009] 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 thickens, stiffens, and scars. As pulmonary fibrosis progresses, the lungs have difficulty pumping oxygen into the bloodstream, preventing organs from receiving the oxygen they need to function properly. IPF currently affects approximately 200,000 people in the United States and causes 40,000 deaths annually. Patients diagnosed with IPF experience progressive shortness of breath, eventually leading to complete respiratory failure.

[0010] Primary biliary cholangitis (PBC), also known as primary biliary cirrhosis, is a chronic liver disease that causes liver damage and fibrosis. PBC results from the slow and progressive destruction of the liver's small bile ducts, causing bile and other toxins to accumulate in the liver, a condition called cholestasis. Over time, scarring and fibrosis occur in both the liver and biliary tract.

[0011] Nonspecific interstitial pneumonia (NSIP) is a rare disease that affects the tissues that surround and separate the tiny air sacs in the lungs. These air sacs, called alveoli, are where oxygen and carbon dioxide are exchanged between the lungs and the bloodstream. Interstitial pneumonia is a disease in which the mesh-like walls of the alveoli become inflamed. The pleura (the thin covering that protects and cushions the lungs and their individual lobes) can also become inflamed. There are two main forms of NSIP: cellular and fibrotic. The cellular form is primarily defined by inflammation of interstitial cells. The fibrotic form is defined by thickening and scarring of lung tissue. This scarring, known as fibrosis, is irreversible. Thickening and scarring of lung tissue prevents the lungs from functioning effectively, leading to inefficient breathing and decreased blood oxygen levels. (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)

[0012] Biliary atresia (BA) is a fibroobstructive cholangiopathy that affects approximately 1 in 5,000–18,000 infants, causing inflammation that leads to end-stage liver disease. Patients typically die by the age of 2 years without surgical intervention. A hepatic portoenterostomy can be performed to restore biliary drainage. However, even with restored 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)).

[0013] Ocular fibrosis encompasses numerous ocular disorders. For example, TGFβ signaling in epithelial cells has been shown to induce epithelial-mesenchymal transition (EMT), resulting in fibrosis similar to cataract formation. Examples include anterior subcapsular cataract (ASC) and posterior capsule opacification (PCO), which can occur after cataract surgery. Research has shown that TGFβ-induced EMT is involved in the wound healing response of lens epithelial cells and can induce the expression of various extracellular matrix proteins and integrins associated with fibrosis, resulting in the production of myofibroblasts and lens fiber cells expressing α-smooth muscle actin (α-SMA), which can cause visual impairment.

[0014] Currently, there are limited treatment courses available, with no options on the market proven to improve long-term patient survival or symptom outcomes. There remains a need for treatments for fibrotic diseases.

[0015] α V β8 integrin is expressed in epithelial cells, binds to the latent peptide of transforming growth factor β1 (TGFβ1), and mediates TGFβ1 activation. Its expression level is significantly increased after lung and bile duct cell injury, and it plays an important role in tissue fibrosis in vivo. Increased levels are also associated with increased mortality in patients with IPF and NSIP.

[0016] Primary sclerosing cholangitis (PSC) involves bile duct inflammation and fibrosis that obstructs the bile ducts, resulting in obstruction of bile flow to the intestine, leading to liver cirrhosis and subsequent complications such as liver failure and liver cancer. αvβ6 expression is elevated in the liver and bile ducts of PSC patients. Summary of the Invention

[0017] α V Amino acid compounds that are β8 integrin inhibitors, compositions containing these compounds, and α V Methods for treating diseases such as fibrotic diseases or cancers mediated by β8 integrins are disclosed.

[0018] In one aspect, there is provided a compound of formula (A) as detailed herein, or any variation thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof).

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

[0020] Additionally, there is provided a pharmaceutical composition comprising a compound of formula (A), or any variation thereof detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient.

[0021] Additionally, there is provided a pharmaceutical composition comprising a compound of formula (I), or any variation thereof detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient.

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

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

[0024] In another aspect, there is provided a method of treating a fibrotic disease or condition in an individual (such as a human) in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method of treating a fibrotic disease or condition in an individual (such as a human) in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the fibrotic 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, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease-induced fibrosis, Alport syndrome, primary sclerosing cholangitis, primary biliary cholangitis (also known as primary biliary cirrhosis), systemic sclerosis-associated interstitial lung disease, scleroderma (also known as systemic sclerosis), diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, biliary atresia, and Crohn's disease.

[0025] In another aspect, there is provided a method of delaying the onset and / or occurrence of a fibrotic disease or condition in an individual (such as a human) at risk of developing such a disease or condition, comprising administering to the individual a therapeutically effective amount of a compound of Formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method of delaying the onset and / or occurrence of a fibrotic disease or condition in an individual (such as a human) at risk of developing such a disease or condition, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is fibrosis of the lung, liver, kidney, heart, skin, or gastrointestinal tract. In other embodiments, the fibrotic disease or condition is idiopathic pulmonary fibrosis, interstitial lung disease, radiation-induced pulmonary fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease-induced fibrosis, Alport syndrome, primary sclerosing cholangitis, primary biliary cholangitis (also known as primary biliary cirrhosis), systemic sclerosis-associated interstitial lung disease, scleroderma (also known as systemic sclerosis), diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, biliary atresia, and Crohn's disease.

[0026] Also provided is a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutical composition thereof, for the treatment of a fibrotic disease.

[0027] Also provided is a compound of formula (I), or any variation thereof as detailed herein, or a pharmaceutical composition thereof, for the treatment of a fibrotic disease.

[0028] Also provided is the use of a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.

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

[0030] Furthermore, α V β1 and / or α V There is provided the use of a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of a disease mediated by cells expressing β8. V β1 and / or α V Use of a compound of Formula (I), or any of its variations detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of a disease mediated by cells expressing β8 is provided. 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.

[0031] Further provided are kits comprising a compound of Formula (A), or any variation thereof as detailed herein, or a pharmaceutically acceptable salt thereof. Further provided are kits comprising a compound of Formula (I), or any variation thereof as detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the kit includes instructions for use according to the methods described herein, such as the method of treating a fibrotic disease in an individual. In some embodiments, the kit includes instructions for use according to the methods described herein, such as the method of treating cancer in an individual.

[0032] Also provided are kits comprising a compound of Formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, and a checkpoint inhibitor. Also provided are kits comprising a compound of Formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, and a checkpoint inhibitor. In some embodiments, the kit includes instructions for use according to the methods described herein, such as the method of treating a fibrotic disease in an individual. In some embodiments, the kit includes instructions for use according to the methods described herein, such as the method of treating cancer in an individual.

[0033] Furthermore, α in an individual V Provided is a method for inhibiting β8 integrin, comprising administering a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof.

[0034] Furthermore, α in an individual V Provided is a method for inhibiting β8 integrin, comprising administering a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof.

[0035] Also, α V β1 integrin, α V β6 integrin, or α V Also provided is a method of inhibiting one or more β8 integrins in an individual in need thereof, comprising administering to the individual a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0036] Also, α V β1 integrin, α V β6 integrin, or α VAlso provided is a method of inhibiting one or more β8 integrins in an individual in need thereof, comprising administering to the individual a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0037] Further provided is a method of inhibiting TGFβ activation in a cell, comprising administering to the cell a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0038] Further provided is a method of inhibiting TGFβ activation in a cell, comprising administering to the cell a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0039] Also provided is the use of a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.

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

[0041] Also, α V β1, α V β6 and α V Also provided is the use of a compound of formula (A), or any variation thereof detailed herein, 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 β8. V β1, α V β6 and α VAlso provided is the use of a compound of formula (I), or any variation thereof detailed herein, 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 β8. For example, in some embodiments, the disease is mediated by cells expressing α V In some embodiments, the disease is mediated by cells that express α V In some embodiments, the disease is mediated by cells that express α V In some embodiments, the disease is mediated by cells that express α V β1 and α V In some embodiments, the disease is mediated by cells that express α V β1 and α V In some embodiments, the fibrotic disease is mediated by cells that express αβ. V β6 and α V In some embodiments, the fibrotic disease is mediated by cells that express αβ. V β1, α V β6 and α V It is mediated by cells that express β8.

[0042] In another aspect, provided is a method of treating cancer in an individual in need thereof, comprising administering to the individual a compound of Formula (A), or any variation thereof detailed herein, 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.

[0043] In another aspect, provided is a method of treating cancer in an individual in need thereof, comprising administering to the individual a compound of Formula (I), or any variation thereof detailed herein, 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] Also provided is the use of a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of cancer.

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

[0046] Also, α V β1, α V β6 and α V Also provided is the use of a compound of formula (A), or any of its variations as detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in combination with a checkpoint inhibitor in the manufacture of a medicament for the treatment of a disease mediated by cells expressing one or more of β8. Also provided is the use of a compound of formula (A), or any of its variations as detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in combination with a checkpoint inhibitor in the manufacture of a medicament for the treatment of cancer.

[0047] Also, α V β1, α V β6 and α V Also provided is the use of a compound of formula (I), or any of its variations as detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in combination with a checkpoint inhibitor in the manufacture of a medicament for the treatment of a disease mediated by cells expressing one or more of β8. Also provided is the use of a compound of formula (I), or any of its variations as detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in combination with a checkpoint inhibitor in the manufacture of a medicament for the treatment of cancer.

[0048] Also provided are methods of treating in a subject in need thereof. In some embodiments, the method includes providing a subject. In some embodiments, the subject includes at least one tissue in need of treatment. In some embodiments, the at least one tissue is characterized by at least one elevated value compared to a normal value in the tissue in a healthy state. In some embodiments, the tissue is characterized by at least one elevated value in α V In some embodiments, the tissue contains elevated levels of β1 integrin activity and / or expression. V In some embodiments, the tissue contains elevated levels of β6 integrin activity and / or expression. V In some embodiments, the tissue comprises an elevated level of β8 integrin activity and / or expression. In some embodiments, the tissue comprises an elevated level of pSMAD / SMAD ratio. In some embodiments, the tissue comprises an elevated level of new collagen formation or accumulation. In some embodiments, the tissue comprises an elevated level of total collagen. In some embodiments, the tissue comprises an elevated level of type I collagen gene Col1a1 expression. In some embodiments, the tissue comprises an elevated level of perforin. In some embodiments, the tissue comprises an elevated level of granzyme B. In some embodiments, the tissue comprises 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), or any variation thereof detailed herein, 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), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0049] Also provided are methods for characterizing the anti-cancer activity of a small molecule inhibitor in a subject. In some embodiments, the method includes 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 β (TGF-β) from latent peptide TGF-β. In some embodiments, the method includes determining a first value from 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-γ level. In some embodiments, the method includes administering a small molecule to the subject. In some embodiments, the method includes providing a second live cell sample from the subject. In some embodiments, the second live cell sample is obtained from the same tissue as the first live cell sample from the subject. In some embodiments, the method includes determining a second value from a second live cell sample. In some embodiments, the second value corresponds to the pSMAD2 / SMAD2 ratio, pSMAD3 / SMAD3 ratio, perforin level, granzyme B level, or interferon-γ level of the first value. In some embodiments, the method includes characterizing the anti-cancer activity of the small molecule in the subject by comparing the second value to the first value.

[0050] In another aspect, methods for 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.

[0051] In another aspect, methods for 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.

[0052] In another aspect, there is provided a compound of formula (A) or any variation thereof produced by the processes disclosed herein.

[0053] In another aspect, there is provided a compound of formula (I) or any variation thereof produced by the processes disclosed herein.

[0054] It is understood that the embodiments and variations described herein also include "consisting of" and / or "consisting essentially of" embodiments and variations. [Brief explanation of the drawings]

[0055] [Figure 1] FIG. 1 shows the profile of integrin-mediated TGF-β activation in tumor adaptive immunity. [Figure 2A] FIG. 1 shows initial experiments in mice. [Figure 2B] 1 is a graph showing that EMT6 cell proliferation was not affected by anti-αVβ8 or IgG control in vitro. [Figure 3A] 1 is a graph showing tumor volume as a function of time for the short-term arm of the study in Example B3. [Figure 3B] 1 is a graph showing tumor volume as a function of time for the long-term arm of the study in Example B3. [Figure 4A] 1 is a graph showing tumor volume over time in Group 1 mice. [Figure 4B] 1 is a graph showing tumor volume over time in Group 2 mice. [Figure 4C] 1 is a graph showing tumor volume over time in mice from Group 3. [Figure 4D] 1 is a graph showing tumor volume over time in mice from Group 4. [Figure 4E] 1 is a graph showing tumor volume over time in mice from Group 5. [Figure 5] 1 is a graph of percent survival over time over a 5-week period, showing that the combination of anti-PD1 and anti-αVβ8 antibodies significantly improved long-term survival in Group 4. [Figure 6A] FIG. 10 is a graph showing that inhibition of αVβ8 significantly reduced SMAD3 phosphorylation in Groups 3 and 4, consistent with a significant reduction in TGFβ signaling in tumor cells. [Figure 6B] FIG. 10 is a graph showing that inhibition of αVβ8 significantly reduced integrin αVβ1 expression in myofibroblasts. [Figure 7A] 1 is a bar graph showing that granzyme B expression, assessed by immunohistochemical staining using anti-granzyme B antibody, was significantly enhanced in Groups 3 and 4 using anti-αVβ8 antibody. [Figure 7B] 1 is a graph showing that CD8+ cytotoxic T cells are increased in Group 3, which contains only anti-αVβ8 antibody, and significantly increased in Group 4, which contains both anti-PD-1 and anti-αVβ8 antibodies. [Figure 8A] 10 is a graph for perforin (PRF1) showing that αVβ8 inhibition results in cytotoxic T cell activation after 14 days of treatment. [Figure 8B] 1 is a graph for Granzyme B (GZMB) showing that αVβ8 inhibition results in cytotoxic T cell activation after 14 days of treatment. [Figure 8C] 1 is a graph for interferon gamma (IFNg) showing that αVβ8 inhibition results in activation of cytotoxic T cells after 14 days of treatment. [Figure 8D] FIG. 10 is a graph for Fas Ligand (FASL) showing that αVβ8 inhibition results in activation of cytotoxic T cells after 14 days of treatment. [Figure 9A] 1 is a graph of a cell profiling analysis showing that CD8 T cells were upregulated by αVβ8 inhibition. [Figure 9B]1 is a graph of a cell profiling analysis showing that NK cells were upregulated by αVβ8 inhibition. [Figure 9C] FIG. 10 is a graph of a cell profiling analysis showing that cytotoxic T cells were upregulated by αVβ8 inhibition. [Figure 10A] Tumor antibody concentration (left axis) and pSMAD3 / SMAD3 ratio (right axis) are shown, demonstrating a clear dose-response relationship for treatment with 0.4 mg / kg, 2 mg / kg, and 10 mg / kg of anti-αVβ8 antibody in combination with an anti-PD-1 antibody. [Figure 10B] A clear dose-response relationship is shown for granzyme B (pg / mL, left axis) and interferon gamma (IFNγ, pg / mL, right axis) of 0.4 mg / kg, 2 mg / kg, and 10 mg / kg of anti-αVβ8 antibody in combination with anti-PD-1 antibody. [Figure 11] We show that combining anti-αVβ8 antibody with anti-PD1, anti-PDL1, or anti-CTLA-4 resulted in similar T cell activation. [Figure 12A] FIG. 1 shows an experiment in mice. [Figure 12B] 1 is a table showing the compounds and dosages used in each group. [Figure 13] 1 is a graph showing tumor volume as a function of time for mice bearing EMT6 tumors in the study of Example B6. Compared to vehicle, treatment with compound 39 plus anti-mPD-1 significantly reduces tumor growth of EMT6 tumors by day 21 of treatment (*p<0.05, one-way ANOVA). Tumors were monitored for an additional 7 days, up to a maximum of 28 days. Bars: ± standard error of the mean. [Figure 14A] 1 is a bar graph comparing CD8+ T cell density in EMT6 tumors with different dosing regimens in the study of Example B6. Treatment with compound 39 plus anti-mPD-1 significantly increases the number of CD8+ T cells in the tumor. Bars: ± standard deviation; n=10 per group; ns: not significant. ****=p<0.0001 (by one-way ANOVA). [Figure 14B]Figure 1 shows CD8 staining of EMT6 tumors subjected to different dosing regimens in the study of Example B6. Treatment with compound 39 + anti-mPD-1 significantly increases the number of CD8+ T cells in the tumor. [Figure 14C] Figure 1 shows CD8 staining of EMT6 tumors subjected to different dosing regimens in the study of Example B6. CD8+ T cells are located at the periphery of tumors treated with vehicle or vehicle + anti-mPD-1, but are located internally and in greater numbers in tumors treated with compound 39 + anti-mPD-1. [Figure 15A] 1 is a graph showing tumor volume as a function of time for mice bearing EMT6 tumors in the study of Example B6. Compound 39 + anti-mPD-1 treatment significantly inhibits EMT6 tumor growth (*p<0.05 by two-way ANOVA compared to vehicle + rat IgG2A). Bars in growth curves: ± standard error of the mean. N (number of mice) = 9 for vehicle + anti-mPD-1, n = 10 for Compound 39 + anti-mPD-1 group. [Figure 15B] 1 is a bar graph comparing CD8+ T cell density in EMT6 tumors between different dosing regimens in the study of Example B6. Compound 39 + anti-mPD-1 treatment results in significantly more CD8+ T cell infiltration. Bars on histogram: ± standard deviation; ****=p<0.0001 (by unpaired two-tailed Student's t-test). N (number of mice) = 9 for vehicle + anti-mPD-1, n = 10 for Compound 39 + anti-mPD-1 group. [Figure 15C] 1 is a bar graph comparing the density of granzyme B+ cells in EMT6 tumors between different dosing regimens in the study of Example B6. Compound 39 + anti-mPD-1 treatment increases the number of granzyme B-positive cells. Bars on histogram: ± standard deviation; *p=0.0291 (for granzyme B) (by unpaired two-tailed Student's t-test). N (number of mice) = 9 for vehicle + anti-mPD-1, n = 10 for Compound 39 + anti-mPD-1 group. [Figure 15D]1 is a bar graph comparing the density of FoxP3+ cells in EMT6 tumors between different dosing regimens in the study of Example B6. Compound 39 + anti-mPD-1 treatment does not result in differences in the infiltration of Treg cells (= FoxP3+ cells). Bars on histograms: ± standard deviation; ns: not significant (by Student's t-test). N (number of mice) = 9 for vehicle + anti-mPD-1, n = 10 for compound 39 + anti-mPD-1 group. [Figure 15E] 1 is a bar graph comparing PD-L1+ cell density in EMT6 tumors between different dosing regimens in the study of Example B6. Compound 39 + anti-mPD-1 treatment results in increased PD-L1 expression compared to vehicle + anti-mPD-1 treatment. Bars on histogram: ± standard deviation; *p=0.0169 (for PD-L1) (by unpaired two-tailed Student's t-test). N (number of mice) = 9 for vehicle + anti-mPD-1, n = 10 for Compound 39 + anti-mPD-1 group. [Figure 16A] 1 is a graph showing tumor volume as a function of time for Pan02 tumor-bearing mice in the study of Example B6. Combination treatment with Compound 39 plus anti-mPD-1 was more effective in reducing tumor growth and tumor volume compared to anti-αVβ8 treatment plus anti-mPD-1. Error bars in growth curves: ± standard error of the mean, n=10 mice per group, ****=p<0.0001 (one-way ANOVA), and ns: not significant. [Figure 16B] 1 is a bar graph 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) results in a significant increase in CD8+ T cell infiltration compared to vehicle + anti-mPD-1 treatment (left bar). N=10 mice per group, bars on histogram: ± standard deviation, ****=p<0.0001 (Student's t-test), and ns: not significant. [Figure 16C]1 is a bar graph 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) results in a significant increase in granzyme B release compared to vehicle + anti-mPD-1 treatment (left bar). N=10 mice per group, bars on histogram: ± standard deviation, ****=p<0.0001 (Student's t-test), and ns: not significant. [Figure 16D] 1 is a bar graph 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) results in a significant increase in PD-L1 expression compared to vehicle + anti-mPD-1 treatment (left bar). N=10 mice per group, bars on histogram: ± standard deviation, ****=p<0.0001 (one-way ANOVA), and ns: not significant. [Figure 16E] 1 is a bar graph comparing FoxP3+ cell density in Pan02 tumors between different dosing regimens in the study of Example B6. Compound 39 + anti-mPD-1 treatment (right bar) does not result in any difference in Treg cells (characterized by FoxP3+ cells) compared to vehicle + anti-mPD-1 treatment (left bar). N=10 mice per group, bars on histogram: ± standard deviation, ****=p<0.0001 (one-way ANOVA), and ns: not significant. [Figure 17A] 1 is a graph showing tumor volume as a function of time for mice bearing CT26 tumors in the study of Example B6. Combination treatment with compound 39 and anti-mPD-1 significantly reduced tumor growth and tumor volume in CT26 tumor-bearing mice compared to anti-mPD-1 and vehicle treatment. Error bars in growth curves: ± standard error of the mean. ***=p<0.001 (two-way ANOVA). N=10 mice in each group. [Figure 17B]1 shows a bar graph comparing CD8+ T cell density in CT26 tumors with different dosing regimens in the study of Example B6. Compound 39 + anti-mPD-1 treatment (right bar) results in a significant increase in CD8+ T cell infiltration compared to vehicle + anti-mPD-1 treatment (left bar). Bars on histograms: ± standard deviation. *=p<0.05 (Student's t-test). N=10 mice in each group. [Figure 17C] 1 shows representative immunohistochemistry (IHC) images of CD8+ cells in CT26 tumors subjected to different dosing regimens in the study of Example B6. [Figure 18A] 1 is a graph showing tumor volume as a function of time for mice bearing A20 tumors in the study of Example B6. [Figure 18B] 10 is a graph showing tumor volume as a function of time for mice bearing RM-1 tumors in the study of Example B6. [Figure 18C] 1 is a graph showing tumor volume as a function of time for mice bearing B16F10 tumors in the study of Example B6. [Figure 18D] 1 is a bar graph comparing CD8+ T cell density in A20 tumors in the study of Example B6. N=10 mice in each group. Ns=not significant (using Student's t-test). [Figure 18E] 1 shows CD8 staining of A20 tumors subjected to different dosing regimens in the study of Example B6. [Figure 18F] 1 is a bar graph comparing CD8+ T cell density in RM-1 tumors in the study of Example B6. N=10 mice in each group. Ns=not significant (using Student's t-test). [Figure 18G] 1 shows CD8 staining of RM-1 tumors subjected to different dosing regimens in the study of Example B6. [Figure 18H] 1 is a bar graph comparing CD8+ T cell density in B16F10 tumors in the study of Example B6. N=10 mice in each group. Ns=not significant (using Student's t-test). [Figure 18I]1 shows CD8 staining of B16F10 tumors subjected to different dosing regimens in the study of Example B6. [Figure 19] An outline of the study design for the study in Example B10 is shown below. [Figure 20A] 1 shows a schematic diagram of the treatment regimen in the study of Example B11. [Figure 20B] Figure 1 shows tumor weights of KPC tumors in mice treated with Compound 39 alone or in combination with an anti-PD-1 antibody. Error bars are ±SD, p values ​​are from one-way ANOVA. [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 are ±SD, p values ​​are from one-way ANOVA. [Figure 21A] Graph showing the mean percentage of CD8+ cells per ROI at the invasion edge treated with Compound 39 alone or in combination with an anti-PD-1 antibody. Bars are ±SEM, p-values ​​are from one-way ANOVA. [Figure 21B] Graph showing the mean percentage of CD8+ cells per ROI within KPC tumors treated with Compound 39 alone or in combination with an anti-PD-1 antibody. Bars are ±SEM, p-values ​​are from one-way ANOVA. [Figure 21C] Graph showing the mean percentage of CD8+ cells per ROI at the invasive edge treated with ADWA-11 alone or in combination with anti-PD-1. Bars ± SEM, p-values ​​from one-way ANOVA. [Figure 21D] Graph showing the mean percentage of CD8+ cells per ROI within KPC tumors treated with ADWA-11 alone or in combination with anti-PD-1. Bars ± SEM, p-values ​​by one-way ANOVA. [Figure 21E] Graph showing the mean percentage of CD4+ cells per ROI at the invasion edge treated with Compound 39 alone or in combination with an anti-PD-1 antibody. Bars are ±SEM, p-values ​​are from one-way ANOVA. [Figure 21F]Graph showing the mean percentage of CD4+ cells per ROI within KPC tumors treated with Compound 39 alone or in combination with an anti-PD-1 antibody. Bars are ±SEM, p-values ​​are from one-way ANOVA. [Figure 22A] Paraffin-fixed KPC tumor sections stained with Picosirius Red (PSR) are shown for vehicle (left) and compound 39 (right) treated KPC tumors. [Figure 22B] Figure 22B shows a bar graph depicting the total birefringence of vehicle- and compound 39-treated KPC tumors from Figure 22A. Bars ± SEM and * = p-value 0.05 (by Student's t-test). [Figure 23A] FIG. 1 shows a schematic diagram of the treatment regimen for testing KPC tumor mice in a survival study related to Example B11. [Figure 23B] Figure 1 shows the first Kaplan-Meier survival curves for the indicated treatments in KPC tumor-bearing mice. P values ​​are from log-rank analysis. *p=0.015, **p=0.0059, and ***p=<0.0001. [Figure 23C] Secondary Kaplan-Meier survival curves for the indicated treatments in KPC tumor-bearing mice are shown. P values ​​are from log-rank analysis. *p=0.015, **p=0.0059, and ***p=<0.0001. [Figure 24A] FIG. 1 shows a schematic diagram of the treatment regimen in TKCC-10 mice for the study related to Example B12. [Figure 24B] 1 shows a graph showing final tumor weight in TKCC-10 PDX-bearing mice after treatment with Germcitabine / Abraxane (G / A), Compound 39, and Compound 39+G / A. P values ​​are from one-way ANOVA. [Figure 24C] Graph showing final tumor weight in TKCC-10 PDX-bearing mice after treatment with Germcitabine / Abraxane (G / A), ADWA-11, and ADWA-11+G / A. P values ​​are by one-way ANOVA. [Figure 25A] Images of lung metastases in vehicle-treated TKCC-10 PDX-bearing mice are shown. [Figure 25B]1 shows images of lung metastases in TKCC-10 PDX-bearing mice treated with Compound 39. [Figure 25C] 1 shows images of lung metastases in TKCC-10 PDX-bearing mice treated with Compound 39 plus germcitabine / Abraxane (G / A). [Figure 25D] 1 shows graphs relating to the quantification of total lung metastases in TKCC-10 tumor-bearing mice treated with germcitabine / Abraxane (G / A), Compound 39, and Compound 39+G / A in a study related to Example B12. P values ​​are from one-way ANOVA. [Figure 25E] 1 shows graphs relating to the quantification of total lung metastases in TKCC-10 tumor-bearing mice treated with Germcitabine / Abraxane (G / A), ADWA-11, and ADWA-11+G / A in a study related to Example B12. P values ​​are by one-way ANOVA. [Figure 26A] FIG. 1 shows a schematic of the treatment regimen in the TKCC-05 PDAC PDX model from a study related to Example B12. [Figure 26B] 1 shows graphs relating to the quantification of tumor weight in mice treated with Compound 39, Reference Compound B, and ADWA-11 antibody in studies relating to Example B12. P values ​​are from one-way ANOVA. [Figure 26C] 1 shows graphs relating to quantification of tumor weight in mice treated with Germcitabine / Abraxane (G / A), Compound 39 + G / A, Reference Compound B + G / A, and ADWA-11 + G / A in a study related to Example B12. P values ​​are from one-way ANOVA. [Figure 27A] 1 shows graphs relating to tumor growth curves for the TKCC-08 PDAC PDX (subcutaneous) model with the treatments specified for the study related to Example B12. [Figure 27B] Figure 1 shows graphs relating to quantification of tumor weight in mice treated with the indicated treatments for the study related to Example B12. P values ​​are from one-way ANOVA. *p=0.05, and ***p=0.001. [Figure 28A]Shown is a first image (left) of pSMAD3 and a second image (right) of the fibrosis / EMT marker αSMA at 0 hours after cataract surgery (PCS) in Example B5-1. [Figure 28B] Shown is a first image of pSMAD3 (left) and a second image of the fibrosis / EMT marker αSMA (right) relative to the reference Compound A control at 5 days post-cataract surgery (PCS) for Example B5-1. [Figure 28C] 1 shows a first image of pSMAD3 (left) and a second image of the fibrosis / EMT marker αSMA (right) associated with 3 mg / mL of reference Compound A at 5 days post-cataract surgery (PCS) for Example B5-1. [Figure 28D] 1 shows a first image of pSMAD3 (left) and a second image of the fibrosis / EMT marker αSMA (right) associated with 30 mg / mL of reference Compound A at 5 days post-cataract surgery (PCS) for Example B5-1. [Figure 28E] 1 shows a first image of pSMAD3 (left) and a second image of the fibrosis / EMT marker αSMA (right) associated with 300 mg / mL of reference Compound A at 5 days post-cataract surgery (PCS) for Example B5-1. [Figure 28F] Shown is a first image of pSMAD3 (left) and a second image of the fibrosis / EMT marker αSMA (right) relative to the Compound C control at 5 days post-cataract surgery (PCS) for Example B5-1. [Figure 28G] Shown is a first image (left) of pSMAD3 associated with Compound C and a second image (right) of the fibrosis / EMT marker αSMA 5 days after cataract surgery (PCS) in Example B5-1. [Figure 28H] Shown is a first image (left) of pSMAD3 associated with Compound D and a second image (right) of the fibrosis / EMT marker αSMA 5 days after cataract surgery (PCS) in Example B5-1. [Figure 28I] 1 shows a graph measuring the mean fluorescence intensity (MFI) of pSMAD3 for various amounts of Compound A, Compound C, and Compound D 5 days after cataract surgery (PCS) in Example B5-1. [Figure 28J]1 shows a graph measuring the mean fluorescence intensity (MFI) of αSMA at various doses of Compound A, Compound C, and Compound D 5 days after cataract surgery (PCS) in Example B5-1. [Figure 29A] 1 shows a first image (left) of the fibrosis marker tenascin-C and a second image (right) of the fibrosis / EMT marker αSMA at 0 hours after cataract surgery (PCS) in Example B5-1. [Figure 29B] 1 shows a first image (left) of the fibrosis marker tenascin-C and a second image (right) of the fibrosis / EMT marker αSMA relative to the control of reference Compound A at 5 days post-cataract surgery (PCS) for Example B5-1. [Figure 29C] 1 shows a first image (left) of the fibrosis marker tenascin-C and a second image (right) of the fibrosis / EMT marker αSMA associated with 3 mg / mL of reference Compound A at 5 days post-cataract surgery (PCS) in Example B5-1. [Figure 29D] 1 shows a first image (left) of the fibrosis marker tenascin-C and a second image (right) of the fibrosis / EMT marker αSMA associated with 30 mg / mL of reference Compound A at 5 days post-cataract surgery (PCS) in Example B5-1. [Figure 29E] 1 shows a first image (left) of the fibrosis marker tenascin-C and a second image (right) of the fibrosis / EMT marker αSMA associated with 300 mg / mL of reference Compound A at 5 days post-cataract surgery (PCS) in Example B5-1. [Figure 29F] 1 shows a first image (left) of the fibrosis marker tenascin-C and a second image (right) of the fibrosis / EMT marker αSMA relative to the Compound C control at 5 days post-cataract surgery (PCS) in Example B5-1. [Figure 29G] 1 shows a first image (left) of the fibrosis marker tenascin-C and a second image (right) of the fibrosis / EMT marker αSMA associated with Compound C at 5 days post-cataract surgery (PCS) in Example B5-1. [Figure 29H]1 shows a first image (left) of the fibrosis marker tenascin-C and a second image (right) of the fibrosis / EMT marker αSMA associated with Compound D at 5 days post-cataract surgery (PCS) in Example B5-1. [Figure 29I] 1 shows a graph measuring the mean fluorescence intensity (MFI) of tenascin-C at various doses of Compound A, Compound C, and Compound D 5 days after cataract surgery (PCS) in Example B5-1. [Figure 30A] 1 shows a first image (left) of the fibrosis marker fibronectin and a second image (right) of the fibrosis / EMT marker αSMA at 0 hours after cataract surgery (PCS) in Example B5-1. [Figure 30B] 1 shows a first image (left) of the fibrosis marker fibronectin and a second image (right) of the fibrosis / EMT marker αSMA relative to the reference Compound A control at 5 days post-cataract surgery (PCS) for Example B5-1. [Figure 30C] 1 shows a first image (left) of the fibrosis marker fibronectin and a second image (right) of the fibrosis / EMT marker αSMA associated with 3 mg / mL of reference Compound A at 5 days post-cataract surgery (PCS) in Example B5-1. [Figure 30D] 1 shows a first image (left) of the fibrosis marker fibronectin and a second image (right) of the fibrosis / EMT marker αSMA associated with 30 mg / mL of reference Compound A at 5 days post-cataract surgery (PCS) in Example B5-1. [Figure 30E] 1 shows a first image (left) of the fibrosis marker fibronectin and a second image (right) of the fibrosis / EMT marker αSMA associated with 300 mg / mL of reference Compound A at 5 days post-cataract surgery (PCS) in Example B5-1. [Figure 30F] 1 shows a first image (left) of the fibrosis marker fibronectin and a second image (right) of the fibrosis / EMT marker αSMA relative to the Compound C control at 5 days post-cataract surgery (PCS) for Example B5-1. [Figure 30G]1 shows a first image (left) of the fibrosis marker fibronectin and a second image (right) of the fibrosis / EMT marker αSMA associated with Compound C at 5 days post-cataract surgery (PCS) in Example B5-1. [Figure 30H] 1 shows a first image (left) of the fibrosis marker fibronectin and a second image (right) of the fibrosis / EMT marker αSMA associated with Compound D at 5 days post-cataract surgery (PCS) in Example B5-1. [Figure 30I] 1 shows a graph measuring the mean fluorescence intensity (MFI) of fibronectin at various doses of Compound A, Compound C, and Compound D 5 days after cataract surgery (PCS) in Example B5-1. [Figure 30J] 1 shows a graph measuring nuclei per section for various amounts of Compound A, Compound C, and Compound D 5 days after cataract surgery (PCS) in Example B5-1. [Figure 31] 1 shows a graph showing tumor growth inhibition in EMT6 tumors for vehicle and Compound 39 related to Example B6. [Figure 32A] FIG. 10 shows images of tumor-associated CD8+ T cells in vehicle as per Example B6. [Figure 32B] FIG. 10 shows images of tumor-associated CD8+ T cells in compound 39 related to Example B6. [Figure 32C] FIG. 10 shows a graph showing CD8+ T cells / mm2 (tissue) in vehicle and Compound 39 in relation to Example B6. [Figure 33] 1 shows a graph showing the reduction of TGFβ activity by Compound 39 compared to vehicle. [Figure 34] A shows a graph illustrating the increased expression of the IFNγ-regulated gene granzyme B by compound 39 compared to vehicle. B shows a graph illustrating the increased expression of the IFNγ-regulated gene IFNγ by compound 39 compared to vehicle. C shows a graph illustrating the increased expression of the IFNγ-regulated gene CXCL9 by compound 39 compared to vehicle. D shows a graph illustrating the increased expression of the IFNγ-regulated gene PDL1 by compound 39 compared to vehicle. [Figure 35]Survival curves showing the probability of survival over a 30-day period for vehicle, vehicle + anti-mPD-1, and Compound 39 + anti-mPD-1 are shown. [Figure 36] 1 shows a graph of the EMT-6 syngeneic model showing tumor volume in vehicle, anti-PD1+vehicle, compound 39, and anti-PD1+αVβ8 SMI over a 30 day period. [Figure 37] A graph showing CD8+ T cells / mm2 (tumor) in vehicle, anti-mPD-1, αVβ8 small molecule inhibitor (SMI), and anti-mPD-1 + αVβ8 SMI is shown. **p<0.01 by one-way ANOVA and ****p<0.0001 by one-way ANOVA. [Figure 38] IO of various enzymes in vehicle, anti-mPD-1 + vehicle, αVβ8 small molecule inhibitor (SMI), and anti-mPD-1 + αVβ8 SMI are shown. [Figure 39] 1 shows a graph depicting tumor volume in EMT6 tumors for vehicle and Compound 39 over a 15 day period. [Figure 40A] 1 shows a graph depicting plasma biomarker response of CXCL9 after 14 days of monotherapy with Compound 39. [Figure 40B] 1 shows a graph depicting VEGFα plasma biomarker response after 14 days of monotherapy with Compound 39. [Figure 41] 1 shows a graph depicting tumor growth inhibition of Pan02 tumors in rat IgG2a + vehicle, anti-mPD-1 + vehicle, and anti-mPD-1 + Compound 39 over a 30 day period. [Figure 42] Graphs comparing pSMAD3 / SMAD3 between vehicle + rat IgG2a, anti-mPD-1 + vehicle, and anti-mPD-1 + Compound 39 are shown. [Figure 43] Graph comparing the size of CD8+ T cells / mm2 (tumor) between vehicle, anti-mPD-1, and anti-mPD-1 + Compound 39 is shown. [Figure 44]1 shows a graph depicting tumor volume in an EMT6 allograft model up to 15 days post-treatment for IgG + vehicle, anti-mPD-1 + vehicle, and Compound 39 + anti-mPD-1. [Figure 45-1] A shows the percentage of total non-granulocytes associated with the healthy group, vehicle + IgG group, vehicle + α-mPD-1 group, and α-mPD-1 + Compound 39 group. B shows the percentage of total T cells associated with the healthy group, vehicle + IgG group, vehicle + α-mPD-1 group, and α-mPD-1 + Compound 39 group. C shows the percentage of total CD8+ T cells associated with the healthy group, vehicle + IgG group, vehicle + α-mPD-1 group, and α-mPD-1 + Compound 39 group. [Figure 45-2] D shows the percentage of non-granulocytes associated with the healthy group, vehicle + IgG group, vehicle + α-mPD-1 group, and α-mPD-1 + Compound 39 group. E shows the percentage of CD4+ T cells associated with the healthy group, vehicle + IgG group, vehicle + α-mPD-1 group, and α-mPD-1 + Compound 39 group. F shows the percentage of tissue-homing Treg cells associated with the healthy group, vehicle + IgG group, vehicle + α-mPD-1 group, and α-mPD-1 + Compound 39 group. [Figure 46] 1 shows a graph relating tumor weights of various groups in an immunodeficient KPC model, with statistical evaluation by one-way ANOVA. [Figure 47] Shown are survival curves of the various groups over 70 days in the immunodeficient KPC model. **p<0.01 (one-way ANOVA with Tukey) and ****p<0.0001 (one-way ANOVA with Tukey). [Figure 48] The IFN-γ gene signature (top) and TGFβ signature (bottom) for vehicle + αPD1 and compound 39 + α-PD1 are shown. [Figure 49] Schematic diagram related to compound 39, which promotes ICI reactivity. [Figure 50A] 1 shows images related to IHC detection of αVβ1 in lung adenocarcinoma. [Figure 50B]1 shows images related to IHC detection of αVβ1 in prostate cancer. [Figure 50C] 1 shows images related to IHC detection of αVβ1 in pancreatic adenocarcinoma. [Figure 51] A chart relating αVβ1 protein expression in various cancer-associated fibroblasts (CAFs) is shown. [Figure 52] Figure 52 shows a graph relating the percent adherent cells (fraction) of Compound 39 in cancer-associated fibroblasts (CAFs) of lung adenocarcinoma in Figure 51 . [Figure 53] A shows picrosirius red staining of two tumors: vehicle + anti-mPD-1 (top) and Compound 39 + anti-mPD-1 (bottom). B shows a graph showing the combined fibrosis scores of vehicle + anti-PD-1, anti-αVβ8 + anti-PD-1, and Compound 39 + anti-mPD-1. [Figure 54-1] A shows a graph relating to the changes in ACTA2 in vehicle + anti-PD-1, anti-αVβ8 + anti-PD-1, and compound 39 + anti-mPD-1. B shows a graph relating to the changes in SERPINE1 in vehicle + anti-PD-1, anti-αVβ8 + anti-PD-1, and compound 39 + anti-mPD-1. [Figure 54-2] C shows graphs relating to changes in CTHRC1 for vehicle + anti-PD-1, anti-αVβ8 + anti-PD-1, and compound 39 + anti-mPD-1. D shows graphs relating to changes in SMAD7 for vehicle + anti-PD-1, anti-αVβ8 + anti-PD-1, and compound 39 + anti-mPD-1. [Figure 55A] Graphs relating high birefringence (percentage) for vehicle and compound 39 are shown. Statistical evaluation was by one-way ANOVA with Tukey. [Figure 55B] Graphs relating the percentage of low birefringence for vehicle and compound 39 are shown. Statistical evaluation was by one-way ANOVA with Tukey's. [Figure 55C] Graphs relating median birefringence (percentage) for vehicle and compound 39 are shown. Statistical evaluation was by one-way ANOVA with Tukey. [Figure 56]Figure 1 shows a graph relating tumor weight in an orthotopic immunodeficient PDX-10 model for vehicle, gemcitabine / Abraxane (G / A), Compound 39, and Compound 39+G / A. *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). [Figure 57] Graph showing the mean number of lung metastases in an orthotopic immunodeficient PDX-10 model for vehicle, gemcitabine / Abraxane (G / A), Compound 39, and Compound 39+G / A. *p<0.05 (one-way ANOVA with Tukey). [Figure 58] 1 shows a graph relating the mean number of lung metastases in various groups of a 30-day study in the PDX-05 orthotopic model. [Figure 59] 1 shows a graph relating the mean number of liver metastases in various groups of a 30-day study in the PDX-05 orthotopic model. [Figure 60] 1 shows a graph relating the mean number of lung metastases in various groups of a 60-day study in the PDX-05 orthotopic model. [Figure 61] 1 shows a graph relating the mean number of liver metastases in various groups of a 60-day study in the PDX-05 orthotopic model. [Figure 62] Graph relating the number of mice with lung metastases in the various groups is shown. [Figure 63] Graph relating the number of mice with liver metastases in the various groups is shown. [Figure 64]

[0023] Figure 1 is a schematic diagram of the Phase 1 clinical profile: a two-part study to evaluate safety, tolerability, pharmacokinetics, and preliminary evidence of antitumor activity. [Figure 65] A schematic diagram of the clinical biomarker plan is shown. [Figure 66] FIG. 1 shows a schematic diagram of Bayesian optimal interval (BOIN) dose escalation and decision criteria for Example B10. [Figure 67] Schematic diagram of the Forfirinox-resistant PDA model. [Figure 68A]1 shows a graph depicting tumor volume (percentage) in the PDA model for vehicle 102 and Forfirinox 104 over a 120 day period. [Figure 68B] 1 shows a graph depicting tumor volume (percentage) in the PDA model for vehicle 102 and Forfirinox 104 over a 40 day period. [Figure 69A] 1 shows a graph depicting tumor volume (percentage) in the PDA model for vehicle 106, Forfirinox (FNX) 108, Compound 39 110, and Compound 39+FX 112 over a 25 day period. [Figure 69B] A chart showing tumor volume (grams) for vehicle 106, Forfirinox (FNX) 108, Compound 39 110, and Compound 39+FX 112 is shown in relation to Figure 69A. [Figure 70] Schematic representation of the overall epithelial-mesenchymal transition (EMT) signature of PDX-08. [Figure 71] Schematic representation of the overall epithelial-mesenchymal transition (EMT) signature of PDX-10. [Figure 72] A chart showing the protein amounts (ng / mg) of αVβ1 and αVβ8 in the PDX-10 orthotopic model is shown. [Figure 73] 1 shows a chart showing tumor weight (g) in the PDX-10 orthotopic model for vehicle 114, Compound 39 116, Germcitabine / Abraxane (G / A) 118, Compound 39+G / A 120, IgG2a control 122, ADWA-11 antibody 124, and ADWA-11+G / A 126. [Figure 74] 1 shows a chart depicting the number (percentage) of mice with lung metastases in the PDX-10 orthotopic model for vehicle 114, Compound 39 116, Germcitabine / Abraxane (G / A) 118, Compound 39+G / A 120, IgG2a control 122, ADWA-11 antibody 124, and ADWA-11+G / A 126. [Figure 75]1 shows a chart depicting the mean number of large lung metastases in the PDX-10 orthotopic model for vehicle 114, Compound 39 116, Germcitabine / Abraxane (G / A) 118, Compound 39+G / A 120, IgG2a control 122, ADWA-11 antibody 124, and ADWA-11+G / A 126. [Figure 76] 1 shows a chart depicting the mean number of lung micrometastases in the PDX-10 orthotopic model for vehicle 114, Compound 39 116, Gelmcitabine / Abraxane (G / A) 118, Compound 39+G / A 120, IgG2a control 122, ADWA-11 antibody 124, and ADWA-11+G / A 126. [Figure 77] 1 shows a chart depicting the mean number of lung metastases in the PDX-10 orthotopic model for vehicle 114, Compound 39 116, Germcitabine / Abraxane (G / A) 118, Compound 39+G / A 120, IgG2a control 122, ADWA-11 antibody 124, and ADWA-11+G / A 126. [Figure 78A] FIG. 1 shows a schematic diagram illustrating different major histocompatibility complex (MHC) gene expression in relation to anti-PD1 and Compound 39 + anti-PD1 in a syngeneic model of PDA (Pan02). [Figure 78B] FIG. 1 shows a schematic diagram illustrating differential type I interferon (IFN) gene expression in relation to anti-PD1 and Compound 39 + anti-PD1 in a syngeneic model of PDA (Pan02). [Figure 79] A chart showing tumor weight (g) for vehicle 128, compound 39 130, anti-PD-1 antibody 132, and compound 39 + anti-PD-1 antibody 134 is shown. [Figure 80] A chart showing tumor weight (g) for IgG2a control 136, ADWA-11 antibody 138, anti-PD-1 antibody 140, and ADWA-11 + anti-PD-1 antibody 142 is shown. [Figure 81] 1 shows uniform manifold approximation and projection (UMAP) plots of ducts exhibiting various tumors. [Figure 82]1 shows a graph depicting the overall epithelial-mesenchymal transition (EMT) signature for various tumors (Tumor A, Tumor C, Tumor E, Tumor B, Tumor G, Tumor F, and Tumor D) subjected to vehicle and Compound 39. [Figure 83] A graph showing differential expression for tumor A is shown. [Figure 84] A graph showing differential expression for tumor C is shown. [Figure 85] A graph showing differential expression for tumor E is shown. [Figure 86] Graph showing differential expression for tumor F is shown. [Figure 87] Schematic diagram related to the PDX-05 orthotopic model is shown. [Figure 88] A chart showing the protein amounts (ng / mg) of αVβ1 and αVβ8 in the PDX-05 orthotopic model is shown. [Figure 89] 1 shows a chart showing tumor weight (g) in the PDX-05 orthotopic model for vehicle 144, Compound 39 146, reference compound 148, ADWA-11 antibody 150, Gelmcitabine / Abraxane (G / A) 152, Compound 39+G / A 154, reference compound+G / A 156, and ADWA-11+G / A 158. [Figure 90] 1 shows a chart showing the number (percentage) of mice with lung metastases in the PDX-05 orthotopic model for vehicle 144, Compound 39 146, reference compound 148, ADWA-11 antibody 150, Gelmcitabine / Abraxane (G / A) 152, Compound 39+G / A 154, reference compound+G / A 156, and ADWA-11+G / A 158. [Figure 91] Schematic representation of the overall epithelial-mesenchymal transition (EMT) signature of PDX-05. [Figure 92] 1 shows a chart showing the ratio of pSMDA3 / SMAD3 in the PDX-05 orthotopic model for IgG, ADWA-11, Germcitabine / Abraxane (G / A), Compound 39+G / A, reference compound+G / A, and ADWA-11+G / A. [Figure 93]1 shows a chart showing the mean number of liver metastases in the PDX-05 orthotopic model for vehicle 160, Compound 39 162, reference compound 164, ADWA-11 antibody 166, Gelmcitabine / Abraxane (G / A) 168, Compound 39 + G / A 170, reference compound + G / A 172, and ADWA-11 + G / A 174. [Figure 94] 1 shows a chart depicting the mean number of liver micrometastases in the PDX-05 orthotopic model for vehicle 160, Compound 39 162, reference compound 164, ADWA-11 antibody 166, Gelmcitabine / Abraxane (G / A) 168, Compound 39 + G / A 170, reference compound + G / A 172, and ADWA-11 + G / A 174. [Figure 95] 1 shows a chart depicting the mean number of lung metastases in the PDX-05 orthotopic model for vehicle 160, Compound 39 162, reference compound 164, ADWA-11 antibody 166, Gelmcitabine / Abraxane (G / A) 168, Compound 39 + G / A 170, reference compound + G / A 172, and ADWA-11 + G / A 174. [Figure 96] 1 shows a chart depicting the mean number of lung micrometastases in the PDX-05 orthotopic model for vehicle 160, Compound 39 162, reference compound 164, ADWA-11 antibody 166, Gelmcitabine / Abraxane (G / A) 168, Compound 39 + G / A 170, reference compound + G / A 172, and ADWA-11 + G / A 174. [Figure 97] 1 shows various images of liver metastases stained with Picosirius Red (PSR) in a PDX-05 orthotopic model for vehicle, Compound 39, Germcitabine / Abraxane (G / A), Compound 39 + G / A, Reference Compound, ADWA-11, Reference Compound + G / A, and ADWA-11 + G / A. [Figure 98] 1 shows various images of lung metastases stained with Picosirius Red (PSR) in a PDX-05 orthotopic model for vehicle, Compound 39, Germcitabine / Abraxane (G / A), Compound 39 + G / A, Reference Compound, ADWA-11, Reference Compound + G / A, and ADWA-11 + G / A. [Figure 99] A schematic diagram of compound 39 (top) and a molecular rendering of it bound to αVβ8 (bottom) are shown. [Figure 100] 1 shows a heat map depicting the relative IC50 potency of compound 39 compared to the indicated integrin index. [Figure 101] 1 shows images of OCT-embedded human tissue cores showing expression of αVβ1 by IHC. [Figure 102] A chart showing the protein expression of αβ in CAFs isolated from the indicated carcinomas compared to normal human lung fibroblasts (NHLFs) as determined by electroluminescence mesoscale discovery assay is shown. [Figure 103] 1 shows a graph relating to a cell adhesion assay showing the percentage of adherent cells associated with cancer-associated fibroblasts (CAFs) of lung adenocarcinoma (LUAD) for various concentrations of compound 39 (log nM). [Figure 104A] 1 shows a graph relating to a cell adhesion assay showing the percentage of adherent cells associated with lung squamous cell carcinoma (LUSC) cancer-associated fibroblasts (CAFs) for various concentrations of Compound 39 (log nM). [Figure 104B] 1 shows a graph relating to a cell adhesion assay showing the percentage of adherent cells associated with pancreatic stellate carcinoma-associated fibroblasts (CAFs) for various concentrations of Compound 39 (log nM). [Figure 105] 1 shows images showing the adhesion of cancer-associated fibroblasts (CAFs) to LAP-coated plates in the presence or absence of compound 39. [Figure 106] A schematic of the process involved in treating freshly harvested human breast tumor tissue with compound 39 ex vivo for a period of time (left), a graph showing immunofluorescence analysis of αSMA+ cells (center), and representative images of αSMA and DAPI stained tissue (right) are shown. [Figure 107] We show that compound 39 in combination with anti-mPD-1 reduces the expression of fibrotic markers in EMT6 tumors. [Figure 108]Graphs showing connective tissue growth factor (CTGF) expression in vehicle + anti-mPD-1, anti-αVβ8 + anti-mPD-1, and compound 39 + anti-mPD-1. Error bars indicate ±SD. *p=0.05, **p=0.01, ***p=0.001, and ****p=0.0001 (calculated by one-way ANOVA). [Figure 109] Graphs showing periostin (POSTN) expression in vehicle + anti-mPD-1, anti-αVβ8 + anti-mPD-1, and Compound 39 + anti-mPD-1. Error bars indicate ±SD. *p=0.05, **p=0.01, ***p=0.001, and ****p=0.0001 (calculated by one-way ANOVA). [Figure 110] Graph showing plasminogen activator inhibitor-1 (SERPINE1) gene expression in vehicle + anti-mPD-1, anti-αVβ8 + anti-mPD-1, and Compound 39 + anti-mPD-1. Error bars indicate ±SD. *p=0.05, **p=0.01, ***p=0.001, and ****p=0.0001 (calculated by one-way ANOVA). [Figure 111] Images relating to Picosirius Red staining in vehicle + anti-mPD-1 (top) and vehicle + Compound 39 (bottom) are shown. [Figure 112] Graphs showing the fibrosis scores for vehicle + anti-mPD-1, anti-αVβ8 + anti-mPD-1, and Compound 39 + anti-mPD-1. Error bars indicate ±SD. *p=0.05, **p=0.01, ***p=0.001, and ****p=0.0001 (calculated by one-way ANOVA). DETAILED DESCRIPTION OF THE INVENTION

[0056] Provided herein are, inter alia, compounds of Formula (A) and variations thereof, pharmaceutical compositions comprising compounds of Formula (A), and methods of using such compounds and compositions in the treatment of fibrotic disorders. Also provided are compounds and pharmaceutical compositions comprising salts of compounds of Formula (A).

[0057] Also provided herein are, inter alia, compounds of formula (I) and variations thereof, pharmaceutical compositions comprising compounds of formula (I), and methods of using such compounds and compositions in the treatment of fibrotic disorders. Compounds and pharmaceutical compositions comprising salts of compounds of formula (I) are also provided.

[0058] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0059] definition For purposes of use herein, unless otherwise specified, the use of the terms "a," "an," etc. refers to one or more.

[0060] Reference herein to "about" a value or parameter includes (and describes) embodiments directed to that value or parameter itself. For example, a reference to "about X" includes a reference to "X." Similarly, a reference to a value "X" also includes a reference to "about X."

[0061] As used herein, unless otherwise specified, "alkyl" refers to an alkyl group having a specified number of carbon atoms (i.e., C-C 10 "C" refers to and includes monovalent saturated hydrocarbon chains, straight (i.e., unbranched), or branched, having 1 to 10 carbon atoms, or combinations thereof. Particular alkyl groups are groups having 1 to 20 carbon atoms ("C-C"). 20 alkyl), groups having 1 to 10 carbon atoms ("C1-C 10 alkyl), groups having 6 to 10 carbon atoms ("C6-C 10The alkyl groups may be 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, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0062] As used herein, "alkylene" refers to the same residues as alkyl, but with divalent character. Particular alkylene groups are groups having 1 to 20 carbon atoms ("C1-C 20 alkylene), groups having 1 to 10 carbon atoms ("C-C 10 alkylene), groups having 6 to 10 carbon atoms ("C6-C 10 a group having 1 to 6 carbon atoms ("C1-C6 alkylene"), a group having 1 to 5 carbon atoms ("C1-C5 alkylene"), a group having 1 to 4 carbon atoms ("C1-C4 alkylene"), or a group having 1 to 3 carbon atoms ("C1-C3 alkylene"). Examples of alkylene include, but are not limited to, groups such as methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), isopropylene (-CHCH(CH)-), butylene (-CH(CH)CH-), isobutylene (-CHCH(CH)CH-), pentylene (-CH(CH)CH-), hexylene (-CH(CH)CH-), heptylene (-CH(CH)CH-), octylene (-CH(CH)CH-). When an alkylene is substituted (e.g., with a cycloalkyl group), it is understood that the substituent is not either of the divalent moieties. For example, when propylene is substituted with cyclopropyl, [ka] can be obtained, [ka] where the wavy line indicates a divalent moiety.

[0063] As used herein, unless otherwise indicated, "alkenyl" refers to an alkyl group having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the specified number of carbon atoms (i.e., C-C 10 "C" refers to, and includes, straight (i.e., unbranched) or branched monovalent unsaturated hydrocarbon chains, or combinations thereof, of from 2 to 10 carbon atoms. Alkenyl groups may have the "cis" or "trans" configuration, or the "E" or "Z" configuration. Particular alkenyl groups are groups having from 2 to 20 carbon atoms ("C2-C 20 alkenyl), groups having 6 to 10 carbon atoms ("C6-C 10 alkenyl"), a group having 2 to 8 carbon atoms ("C2-C8 alkenyl"), a group having 2 to 6 carbon atoms ("C2-C6 alkenyl"), or a group having 2 to 4 carbon atoms ("C2-C4 alkenyl"). Examples of alkenyl groups include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbut-1,3-dienyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, and the like.

[0064] As used herein, "alkenylene" refers to the same residues as alkenyl, but with divalent character. Particular alkenylene groups are groups having 2 to 20 carbon atoms ("C-C 20 alkenylene), groups having 2 to 10 carbon atoms ("C2-C 10 alkenylene), groups having 6 to 10 carbon atoms ("C6-C 10C-C alkenylene), a group having 2 to 6 carbon atoms ("C-C alkenylene"), a group having 2 to 4 carbon atoms ("C-C alkenylene"), or a group having 2 to 3 carbon atoms ("C-C alkenylene"). Examples of alkenylene include, but are not limited to, groups such as ethenylene (or vinylene) (-CH=CH-), propenylene (-CH=CHCH-), 1,4-but-1-enylene (-CH=CH-CHCH-), 1,4-but-2-enylene (-CHCH=CHCH-), 1,6-hex-1-enylene (-CH=CH-(CH)CH-).

[0065] As used herein, unless otherwise indicated, "alkynyl" refers to an alkyl group having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and having the specified number of carbon atoms (i.e., C-C 10 "C" refers to and includes straight (i.e., unbranched) or branched monovalent unsaturated hydrocarbon chains or combinations thereof, having from 2 to 20 carbon atoms ("C-C" means 2 to 10 carbon atoms). Particular alkynyl groups are groups having from 2 to 20 carbon atoms ("C-C" means 2 to 10 carbon atoms). 20 alkynyl), groups having 6 to 10 carbon atoms ("C6-C 10 The alkynyl group may be a group having 2 to 8 carbon atoms ("C2-C8 alkynyl"), a group having 2 to 6 carbon atoms ("C2-C6 alkynyl"), or a group having 2 to 4 carbon atoms ("C2-C4 alkynyl"). Examples of alkynyl groups include, but are not limited to, ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.

[0066] As used herein, "alkynylene" refers to the same residues as alkynyl, but with divalent character. Particular alkynylene groups are groups having 2 to 20 carbon atoms ("C-C 20 alkynylene), groups having 2 to 10 carbon atoms ("C2-C 10alkynylene), groups having 6 to 10 carbon atoms ("C6-C 10 Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetylenylene) (-C≡C-), propynylene (-C≡CCH-), and the like.

[0067] As used herein, unless otherwise specified, "cycloalkyl" refers to a group having a specified number of carbon atoms (i.e., C-C 10 "Cycloalkyl" refers to and includes cyclic, monovalent, saturated hydrocarbon structures ("C3-C8 cycloalkyl" means 3 to 10 carbon atoms). Cycloalkyl can consist of a single ring, such as cyclohexyl, or multiple rings, such as adamantyl. Cycloalkyls containing more than one ring can be fused, spiro, or bridged, or combinations thereof. Specific cycloalkyl groups are those having 3 to 12 ring carbon atoms. Preferred cycloalkyls are cyclic hydrocarbons having 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"), cyclic hydrocarbons having 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"), or cyclic hydrocarbons having 3 to 4 ring carbon atoms ("C3-C4 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0068] As used herein, "cycloalkylene" refers to the same residue as cycloalkyl, but with divalent character. Cycloalkylene can consist of one ring or multiple rings, which can be fused, spiro, or bridged, or combinations thereof. Specific cycloalkylene groups are those having 3 to 12 ring carbon atoms. Preferred cycloalkylenes are cyclic hydrocarbons having 3 to 8 ring carbon atoms ("C3-C8 cycloalkylene"), cyclic hydrocarbons having 3 to 6 carbon atoms ("C3-C6 cycloalkylene"), or cyclic hydrocarbons having 3 to 4 ring carbon atoms ("C3-C4 cycloalkylene"). Examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, and the like. A cycloalkylene can be attached to the rest of the structure through the same ring carbon atom (e.g., 1,1-cyclopropylene) or different ring carbon atoms (e.g., 1,2-cyclopropylene). When a cycloalkylene is attached to the rest of the structure through two different ring carbon atoms, the connecting bonds can be cis or trans relative to each other (e.g., cis-1,2-cyclopropylene or trans-1,2-cyclopropylene). If the point of attachment is not specified, the moiety can include any chemically possible bond. For example, cyclopropylene can refer to 1,1-cyclopropylene or 1,2-cyclopropylene (e.g., cis-1,2-cyclopropylene, trans-1,2-cyclopropylene, or a mixture thereof), or a mixture thereof.

[0069] "Cycloalkenyl" means, unless otherwise specified, a cycloalkenyl having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the specified number of carbon atoms (i.e., C-C 10"C" refers to and includes cyclic, non-aromatic, monovalent unsaturated hydrocarbon structures ("C" means 3 to 10 carbon atoms). Cycloalkenyls can consist of one ring, such as cyclohexenyl, or multiple rings, such as norbornenyl. Preferred cycloalkenyls are cyclic unsaturated 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, norbornenyl, and the like.

[0070] As used herein, "cycloalkenylene" refers to the same residues as cycloalkenyl, but with divalent nature.

[0071] As used herein, "aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), where the condensed rings are carbocyclic and may or may not be aromatic, provided that at least one ring in a condensed polycyclic ring system is aromatic. Particular aryl groups have 6 to 14 ring carbon atoms ("C6-C 14 Aryl groups are groups having two or more rings, wherein at least one ring is non-aromatic. Aryl groups having two or more rings, wherein at least one ring is non-aromatic, can be connected to the parent structure at either an aromatic ring position or a non-aromatic ring position. In one variation, aryl groups having two or more rings, wherein at least one ring is non-aromatic, are connected to the parent structure at an aromatic ring position.

[0072] As used herein, "arylene" refers to the same residues as aryl, but with divalent character. Particular arylene groups are those having 6 to 14 ring carbon atoms ("C6-C6"). 14 It is a group having an alkyl group ("arylene").

[0073] 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., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl), which may be carbocyclic or may contain one or more ring heteroatoms and may or may not be aromatic, provided that at least one ring in a fused polycyclic structure is aromatic and contains at least one ring heteroatom. Exemplary heteroaryl groups are 5- to 14-membered rings having 1-12 ring carbon atoms and 1-6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 10-membered rings having 1-8 ring carbon atoms and 1-4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 5-, 6-, or 7-membered rings having 1-5 ring carbon atoms and 1-4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, exemplary heteroaryl groups are monocyclic aromatic 5-, 6-, or 7-membered rings having 1-6 ring carbon atoms and 1-4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, exemplary heteroaryl groups are polycyclic aromatic rings having 1-12 ring carbon atoms and 1-6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heteroaryl groups having more than one ring, where at least one ring is non-aromatic, can be connected to the parent structure at either an aromatic ring position or a non-aromatic ring position. In one variation, heteroaryl groups having more than one ring, wherein at least one ring is non-aromatic, are connected to the parent structure at an aromatic ring. The heteroaryl group can be connected to the parent structure at a ring carbon atom or a ring heteroatom.

[0074] As used herein, "heteroarylene" refers to the same residues as heteroaryl, but which are divalent.

[0075] As used herein, "heterocycle," "heterocyclic," or "heterocyclyl" refers to a saturated or unsaturated non-aromatic cyclic group having 1 to 14 ring carbon atoms and 1 to 6 ring heteroatoms, such as nitrogen, sulfur, or oxygen. Heterocyclic groups can have a single ring (e.g., pyrrolidinyl) or multiple fused rings (e.g., decahydroisoquinolin-1-yl), where the fused rings may or may not be aromatic, may be carbocyclic, or may contain one or more ring heteroatoms, but heteroaryl rings are excluded. Heterocycles containing two or more rings can be fused, bridged, or spirocyclic, or combinations thereof. In fused ring systems, one or more of the fused rings can be cycloalkyl or aryl, but heteroaryl groups are excluded. Heterocyclyl groups can be independently and optionally substituted with one or more substituents described herein. Specific heterocyclyl groups are 3- to 14-membered rings having 1 to 13 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 12-membered rings having 1 to 11 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 10-membered rings having 1 to 9 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 8-membered rings having 1 to 7 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 3- to 6-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, heterocyclyl includes a 3-, 4-, 5-, 6-, or 7-membered monocyclic ring having 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 ring carbon atoms and 1 to 2, 1 to 3, or 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, heterocyclyl includes a polycyclic non-aromatic ring having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0076] As used herein, "heterocyclylene" refers to the same residues as heterocyclyl, but which have bivalency.

[0077] "Halo" or "halogen" refers to Group 17 elements having atomic numbers 9-85. Preferred halo groups include fluorine, chlorine, bromine, and iodine radicals. When a residue is substituted with one or more halogens, it can be referred to using the prefix "halo." For example, haloaryl, haloalkyl, etc. refer to aryl and alkyl substituted with one or more halogen groups; when there is more than one halogen group, the halogen groups may, but need not, be the same halogen. When a residue is substituted with two or more halogens, it can be referred to by using a prefix corresponding to the number of halogen moieties attached; for example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halogen groups; these may, but need not, be the same halogen; thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a "perhaloalkyl." A preferred haloalkyl, e.g., perhaloalkyl, group is trifluoromethyl (-CF3). Similarly, "perhaloalkoxy" refers to an alkoxy group in which a halogen replaces each H in the hydrocarbon comprising the alkyl portion of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

[0078] "Carbonyl" refers to the group C=O.

[0079] "Thiocarbonyl" refers to the group C=S.

[0080] "Oxo" refers to the moiety =O.

[0081] "D" stands for deuterium ( 2 H).

[0082] "Boc" refers to tert-butyloxycarbonyl.

[0083] "Cbz" refers to carboxybenzyl.

[0084] "HATU" refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate.

[0085] "BOP" refers to benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate.

[0086] "PyBOP" refers to benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.

[0087] "Optionally substituted" means, unless otherwise specified, that a group can be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group, which 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.

[0088] Unless otherwise specified, "individual" or "subject" as used herein intends 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.

[0089] As used herein, "treatment" or "treating" is an approach to obtaining beneficial or desired results, including clinical results. For purposes of this application, beneficial or desired results include, but are not limited to, one or more of the following: alleviating one or more symptoms attributable to a disease, reducing the extent of the disease, stabilizing the disease (e.g., preventing or slowing the worsening of the disease), preventing or slowing the spread of the disease, delaying the onset or recurrence of the disease, slowing or slowing the progression of the disease, ameliorating the disease state, causing remission of the disease (whether partial or total), reducing the dose of one or more other medications required to treat the disease, enhancing the effectiveness of another medication, slowing the progression of the disease, improving quality of life, and / or prolonging survival. "Treatment" also includes reducing the pathological consequences of fibrosis. The methods herein contemplate any one or more of these aspects of treatment.

[0090] As used herein, the term "effective amount" refers to the amount of a compound herein that should be effective in a given therapeutic regime. As understood in the art, an effective amount may be one or more doses, i.e., a single administration or multiple administrations may be required to achieve a desired therapeutic endpoint. An effective amount may be considered in relation to the administration of one or more therapeutic agents (e.g., a compound, or a pharmaceutically acceptable salt thereof), and a single agent may be considered to be administered in an effective amount if a desired or beneficial result can be achieved or is achieved together with one or more other agents. The appropriate dose of any co-administered compound may optionally be reduced due to the combined effect (e.g., additive or synergistic) of the compounds.

[0091] A "therapeutically effective amount" refers to that amount of a compound or salt thereof sufficient to produce a desired therapeutic effect.

[0092] As used herein, "unit dosage form" refers to physically discrete units suitable as unitary dosages, each containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may include monotherapy or combination therapy.

[0093] As used herein, the term "controlled release" refers to a drug-containing formulation or portion thereof in which the release of the drug is not immediate; i.e., administration of a "controlled release" formulation 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 wide variety of drug delivery systems and generally involve mixing the drug compound with a carrier, polymer, or other compound having the desired release characteristics (e.g., pH-dependent or pH-independent 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.).

[0094] As used herein, the term "composition" or "pharmaceutical composition" refers to a combination of an active agent with an inert or active excipient or carrier, making the composition particularly suitable for diagnostic or therapeutic use in vivo or ex vivo. Pharmaceutical compositions can be prepared by known pharmaceutical methods. Suitable compositions, excipients, or carriers can be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 2002. st ed. (2005), which is incorporated herein by reference in its entirety.

[0095] As used herein, "pharmaceutically acceptable" or "pharmacologically acceptable" means that the material is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing significant undesired biological effects or interacting adversely with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients preferably have met required standards of toxicology and manufacturing testing and / or are listed in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0096] A "pharmaceutically acceptable salt" is a salt that retains at least some of the biological activity of the free (non-salt) compound and can be administered to an individual as a drug or pharmaceutical. See, for example, Handbook of Pharmaceutical Salts Properties, Selection, and Use, International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), the entire contents of which are incorporated herein by reference. Such salts include, for example, (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, etc.; (2) salts formed when an acidic proton present in the parent compound is replaced with a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion, or when coordinated with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, etc. Acceptable inorganic bases which can be used to prepare salts include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc. Pharmaceutically acceptable salts can be prepared in situ during the manufacturing process, or by separately reacting the purified compound in its organic acid or organic base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thereby formed during subsequent purification.

[0097] As used herein, the term "excipient" refers to an inactive or non-active substance that can be used in the manufacture of a drug or pharmaceutical product, such as a tablet, that contains a compound as an active ingredient. See, e.g., Handbook of Pharmaceutical Excipients.6 thEdition, Pharmaceutical Press (2008), which is incorporated herein by reference in its entirety. The term excipient can encompass a variety of substances, including, but not limited to, binders, disintegrants, coatings, compression / encapsulation aids, creams or lotions, lubricants, parenteral solutions, chewable materials, sweeteners or flavoring agents, suspending / gelling agents, or any substance used as a wet granulator. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coatings include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, , maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable materials include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0098] Unless otherwise specified, "substantially pure" contemplates a composition containing 10% or less impurities, e.g., the composition contains less than about 9%, 7%, 5%, 3%, 1%, 0.5% impurities.

[0099] It will be understood that the term "comprise" or variations such as "comprises" or "comprising" means the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. Aspects and embodiments described herein as "comprising" will be understood to include "consisting of" and "consisting essentially of" embodiments.

[0100] When a composition is described as "consisting essentially of" recited components, the composition contains the explicitly recited components and may contain other components, such as trace impurities, that do not substantially affect the disease or condition being treated. However, the composition does not contain any other components other than the explicitly recited components that substantially affect the disease or condition being treated, or, if the composition contains additional components other than the recited components that substantially affect the disease or condition being treated, the composition does not contain the additional components in concentrations or amounts sufficient to substantially affect the disease or condition being treated. When a method is described as "consisting essentially of" recited steps, the method contains the recited steps and may contain other steps that do not substantially affect the disease or condition being treated, but the method does not contain any other steps other than the explicitly recited steps that substantially affect the disease or condition being treated.

[0101] As used herein, when a given structure exists in enantiomeric and / or diastereomeric forms, a "planar bond" indicates that all stereoisomers of the depicted structure may exist (e.g., compound 1 in Table 1 shown below). [ka]

[0102] compound In one embodiment, provided is a compound of formula (A): [ka] or a pharmaceutically acceptable salt thereof; R 1 is one or more R 1a 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by one or more R 1b 1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by one or more R 1c 6-aminopyridin-2-yl optionally substituted by 1d (pyridin-2-yl)amino optionally substituted by R 2 is H or C1-C6 alkyl, R 3 is H or C1-C6 alkyl, Or, R 2 and R 3 together with the carbon atoms to which they are attached, form R 2a forming a C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl optionally substituted by R 4 is phenyl, 5- to 6-membered heteroaryl, 6-membered heterocyclyl, or C1-C6 haloalkyl wherein the 5- to 6-membered heteroaryl contains at least one nitrogen atom and is optionally fused to a phenyl group; The 6-membered heterocyclyl contains at least one nitrogen atom and is optionally fused to a phenyl group; Phenyl and 5- to 6-membered heteroaryl may be substituted with one or more R 4a and optionally replaced by 6-membered heterocyclyl is R 4a and oxo), or Or, R 2 , R 3 , and R4 taken together form a 5-membered heteroaryl containing two nitrogen atoms and substituted with phenyl, where the phenyl group is substituted with one or more R 4a and optionally replacing Each R 4a are independently halo, CN, C-C alkyl, C-C haloalkyl, -(C-C alkylene)-O-(C-C alkyl), C-C cycloalkyl, -OH, -O-(C-C alkyl), -O-(C-C haloalkyl), -S(O)(C-C alkyl), or -C(=O)-NH; Or, R 4a and R 2 together with the atom to which they are attached form a 6-membered heterocyclyl, where the heterocyclyl contains one oxygen atom, Q is H or C1-C8 alkyl; L 1 is one or more L 1a is a C2-C4 alkylene optionally substituted by L 2 is a bond, or one or more L 2a is a C1-C3 alkylene optionally substituted by L 3 is one or more L 3a is a C2-C4 alkylene optionally substituted by Y is a bond, R 1a , R 1b , R 1c , R 1d , R 2a , L 1a , L 2a , and L 3a are each independently R A is selected from Two R on the same carbon atom 1a groups optionally taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl; Two R on the same carbon atom 1bgroups optionally taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl; Each R A are independently selected from deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C 14 Aryl, 5-10 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)NR 6 R 7 , or -P(O)(OR 5 )(OR 6 ), where R A C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C 14 The aryl and 5- to 10-membered heteroaryl are independently one or more R Aa and optionally replaced by Each R Aa are 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, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C6-C 14 aryl, or C1-C6 alkyl, where R Aa 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C6-C 14 Aryl and C1-C6 alkyl may independently be one or more R Ab and optionally replaced by Each R Ab are independently deuterium, oxo, -OH, -O( 2 H), halogen, or deuterium, halogen, -OH, -O( 2 H), or oxo; Each R 5 are independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, where R 5 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 10-membered heterocyclyl each independently have one or more R 5a and optionally replaced by Each R 5a are independently halogen, deuterium, oxo, -CN, -OR 10 , -NR 11 R 12 , -P(O)(OR 11 )(OR 12 ), 3- to 12-membered heterocyclyl, or deuterium, halogen, -OH, -O( 2H), or oxo; Each R 6 are independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R 6 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 Aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from deuterium, halogen, oxo, -CN, -OR 10 , -NR 11 R 12 , or deuterium, halogen, -OH, -O( 2 H), or C1-C6 alkyl optionally substituted by one or more of oxo; Each R 7 are independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R 7 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 Aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from deuterium, halogen, oxo, -CN, -OR 10 , -NR 11 R 12 , or deuterium, halogen, -OH, -O( 2 H), or C1-C6 alkyl optionally substituted by one or more of oxo; Alternatively, R 6 and R 7 together with the atom to which they are attached, deuterium, halogen, oxo, -OR 10 , -NR11 R 12 , or deuterium, halogen, oxo, -OH, or -O( 2 H), forming a 3- to 10-membered heterocyclyl optionally substituted by one or more of C1-C6 alkyl optionally substituted by one or more of Each R 8 are 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; Each R 9 are 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; Each R 10 are 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; Each R 11 are 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; Each R 12are 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; Alternatively, R 11 and R 12 taken together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted by one or more of deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted by one or more of deuterium, oxo, or halogen.

[0103] In one embodiment, a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is one or more R 1a 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by one or more R 1b 1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by R 1c 6-aminopyridin-2-yl optionally substituted by 1d (pyridin-2-yl)amino optionally substituted by R 2 is H or C1-C6 alkyl, R 3 is H or C1-C6 alkyl, Or, R 2 and R 3 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl; R 4is phenyl, 5- to 6-membered heteroaryl, or 6-membered heterocyclyl wherein the 5- to 6-membered heteroaryl contains at least one nitrogen atom and is optionally fused to a phenyl group; The 6-membered heterocyclyl contains at least one nitrogen atom and is optionally fused to a phenyl group; Phenyl and 5- to 6-membered heteroaryl may be substituted with one or more R 4a and optionally replaced by 6-membered heterocyclyl is R 4a and oxo), or Each R 4a are independently halo, CN, C-C alkyl, C-C haloalkyl, -(C-C alkylene)-O-(C-C alkyl), C-C cycloalkyl, -O-(C-C alkyl), -O-(C-C haloalkyl), or -S(O)(C-C alkyl); Or, R 4a and R 2 together with the atom to which they are attached form a 6-membered heterocyclyl, where the heterocyclyl contains one oxygen atom, Q is H or C1-C8 alkyl; L 1 is one or more L 1a is a C2-C4 alkylene optionally substituted by L 2 is a bond, or one or more L 2a is a C1-C3 alkylene optionally substituted by L 3 is one or more L 3a is a C2-C4 alkylene optionally substituted by Y is a bond, R 1a , R 1b , R 1c , R 1d , L 1a , L 2a , and L 3a are each independently RA is selected from Two R on the same carbon atom 1a groups optionally taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl; Two R on the same carbon atom 1b groups optionally taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl; Each R A are independently selected from deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C 14 Aryl, 5-10 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)NR 6 R 7 , or -P(O)(OR 5 )(OR 6 ), where R A C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C 14 The aryl and 5- to 10-membered heteroaryl are independently one or more RAa and optionally replaced by Each R Aa are 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, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C6-C 14 aryl, or C1-C6 alkyl, where R Aa 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C6-C 14 Aryl and C1-C6 alkyl may independently be one or more R Ab and optionally replaced by Each R Ab are independently deuterium, oxo, -OH, -O( 2 H), halogen, or deuterium, halogen, -OH, -O( 2 H), or oxo; Each R 5 are independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, where R 5 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 10-membered heterocyclyl each independently have one or more R 5a and optionally replaced by Each R 5a are independently halogen, deuterium, oxo, -CN, -OR 10, -NR 11 R 12 , -P(O)(OR 11 )(OR 12 ), 3- to 12-membered heterocyclyl, or deuterium, halogen, -OH, -O( 2 H), or oxo; Each R 6 are independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R 6 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 Aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from deuterium, halogen, oxo, -CN, -OR 10 , -NR 11 R 12 , or deuterium, halogen, -OH, -O( 2 H), or C1-C6 alkyl optionally substituted by one or more of oxo; Each R 7 are independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R 7 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 Aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from deuterium, halogen, oxo, -CN, -OR 10 , -NR 11 R 12 , or deuterium, halogen, -OH, -O( 2H), or C1-C6 alkyl optionally substituted by one or more of oxo; Alternatively, R 6 and R 7 together with the atom to which they are attached, deuterium, halogen, oxo, -OR 10 , -NR 11 R 12 , or deuterium, halogen, oxo, -OH, or -O( 2 H), forming a 3- to 10-membered heterocyclyl optionally substituted by one or more of C1-C6 alkyl optionally substituted by one or more of Each R 8 are 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; Each R 9 are 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; Each R 10 are 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; Each R 11are 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; Each R 12 are 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; Alternatively, R 11 and R 12 taken together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted by one or more of deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted by one or more of deuterium, oxo, or halogen.

[0104] In one variation, COQ and N(H)C(O)C(R 2 )(R 3 )R 4

[0023] Provided are compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein the carbon bearing the moiety is in the "S" configuration. In another variation, COQ and N(H)C(O)C(R 2 )(R 3 )R 4 Compounds of formula (I), or pharmaceutically acceptable salts thereof, are provided, wherein the carbon bearing the moiety is in the "R" configuration. Mixtures of compounds of formula (I) are also encompassed, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0105] In the description herein, it is understood that every description, variation, embodiment, or aspect of one moiety can be combined with every description, variation, embodiment, or aspect of any other moiety, just as if every combination of descriptions were specifically and individually listed. For example, R 4 All descriptions, variations, embodiments or aspects provided herein relating to R 1 , R 2 , R 3 , L 1 , L 2 , L 3 , Y, and / or Q. It is also understood that all descriptions, variations, embodiments, or aspects of Formula (I) or Formula (A), where applicable, apply equally to other formulas detailed herein, and that any and all descriptions, variations, embodiments, or aspects are similarly described for all formulas as if each and every description were listed individually and individually. For example, any statement, variation, embodiment or aspect of Formula (I) or Formula (A), where applicable, applies equally to any of Formulas (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, and any statement, variation, embodiment or aspect is similarly described for all formulas as if each and every formula were listed individually and individually.

[0106] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, L 1 is an unsubstituted C-C alkylene. In certain variations, L 1 is -CH-CH-, -CH-CH-CH-, or CH-CH-CH-CH-. In certain variations, L1 is -CH2CH2-.

[0107] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, L 2 is a bond.

[0108] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, L 2 is an unsubstituted C1-C3 alkylene. In certain variations, L 2 is -CH2CH2-.

[0109] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, L 3 is an unsubstituted C-C alkylene. In certain variations, L 3 is -CH2CH2-. In certain variations, L 3 is -CH2CH2CH2CH2-.

[0110] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, -L 1 -OL 2 -YL 3 -Let's get together, [ka] Form.

[0111] 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 is deuterium.

[0112] In some embodiments, the compound of Formula (I) has the formula (II-a): [ka] or a pharmaceutically acceptable salt thereof, wherein R 4 is as defined for formula (I). In some embodiments of compounds of formula (II-a), R 4 is one or more R 4a In some embodiments of the compound of Formula (II-a), R 4 is a 5-6 membered heteroaryl containing at least one nitrogen atom and optionally fused to a phenyl group, wherein the 5-6 membered heteroaryl is optionally fused to 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 selected from one or more R 4a In some embodiments of the compound of Formula (II-a), R 4 is pyridyl or pyrimidinyl, where the pyridyl or pyrimidinyl is selected from the group consisting of one or more R 4a In some embodiments of the compound of Formula (II-a), R 4 is one or more R 4a In some embodiments of the compound of Formula (II-a), R 4 is 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 and optionally fused to a phenyl group, wherein the 6-membered heterocyclyl is 4a and oxo.

[0113] In some embodiments, the compound of Formula (I) has the formula (II-b): [ka] or a pharmaceutically acceptable salt thereof, wherein R 4 is as defined for formula (I). In some embodiments of compounds of formula (II-b), R 4 is one or more R 4a In some embodiments of compounds of Formula (II-b), R 4 is a 5-6 membered heteroaryl containing at least one nitrogen atom and optionally fused to a phenyl group, wherein the 5-6 membered heteroaryl is optionally fused to 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 selected from one or more R 4a In some embodiments of the compound of Formula (II-b), R 4 is pyridyl or pyrimidinyl, where the pyridyl or pyrimidinyl is selected from the group consisting of one or more R 4a In some embodiments of the compound of Formula (II-b), R 4 is one or more R 4a In some embodiments of the compound of Formula (II-b), R 4 is one or more R 4a In some embodiments of the compound of Formula (II-b), R 4 is a 6-membered heterocyclyl containing at least one nitrogen atom and optionally fused to a phenyl group, wherein the 6-membered heterocyclyl is 4a and oxo.

[0114] In some embodiments, the compound of Formula (I) has the formula (II-c): [ka] or a pharmaceutically acceptable salt thereof, wherein R 4 is as defined for formula (I). In some embodiments of compounds of formula (II-c), R 4 is one or more R 4a In some embodiments of compounds of Formula (II-c), R 4 is a 5-6 membered heteroaryl containing at least one nitrogen atom and optionally fused to a phenyl group, wherein the 5-6 membered heteroaryl is optionally fused to one or more R 4a In some embodiments of compounds of Formula (II-c), R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom, wherein the 5- to 6-membered heteroaryl is selected from one or more R 4a In some embodiments of compounds of Formula (II-c), R 4 is pyridyl or pyrimidinyl, where the pyridyl or pyrimidinyl is selected from the group consisting of one or more R 4a In some embodiments of compounds of Formula (II-c), R 4 is one or more R 4a In some embodiments of compounds of Formula (II-c), R 4 is one or more R 4a In some embodiments of compounds of Formula (II-c), R is pyrimidinyl optionally substituted by 4 is a 6-membered heterocyclyl containing at least one nitrogen atom and optionally fused to a phenyl group, wherein the 6-membered heterocyclyl is 4a and oxo.

[0115] In some embodiments, the compound of Formula (I) has the formula (II-d): [ka] or a pharmaceutically acceptable salt thereof, wherein R 4 is as defined for formula (I). In some embodiments of compounds of formula (II-d), R 4 is one or more R 4a In some embodiments of compounds of Formula (II-d), R 4 is a 5-6 membered heteroaryl containing at least one nitrogen atom and optionally fused to a phenyl group, wherein the 5-6 membered heteroaryl is optionally fused to one or more R 4a In some embodiments of compounds 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 selected from one or more R 4a In some embodiments of compounds of Formula (II-d), R 4 is pyridyl or pyrimidinyl, where the pyridyl or pyrimidinyl is selected from the group consisting of one or more R 4a In some embodiments of compounds of Formula (II-d), R 4 is one or more R 4a In some embodiments of compounds of Formula (II-d), R 4 is one or more R 4a In some embodiments of compounds of Formula (II-d), R 4 is a 6-membered heterocyclyl containing at least one nitrogen atom and optionally fused to a phenyl group, wherein the 6-membered heterocyclyl is 4a and oxo.

[0116] In some embodiments, the compound of Formula (I) has the formula (II-e): [ka] or a pharmaceutically acceptable salt thereof, wherein R 4 is as defined for formula (I). In some embodiments of compounds of formula (II-e), R 4 is one or more R 4a In some embodiments of compounds of Formula (II-e), R 4 is a 5-6 membered heteroaryl containing at least one nitrogen atom and optionally fused to a phenyl group, wherein the 5-6 membered heteroaryl is optionally fused to one or more R 4a In some embodiments of compounds of Formula (II-e), R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom, wherein the 5- to 6-membered heteroaryl is selected from one or more R 4a In some embodiments of compounds of Formula (II-e), R 4 is pyridyl or pyrimidinyl, where the pyridyl or pyrimidinyl is selected from the group consisting of one or more R 4a In some embodiments of compounds of Formula (II-e), R 4 is one or more R 4a In some embodiments of compounds of Formula (II-e), R 4 is one or more R 4a In some embodiments of compounds of Formula (II-e), R 4 is a 6-membered heterocyclyl containing at least one nitrogen atom and optionally fused to a phenyl group, wherein the 6-membered heterocyclyl is 4a and oxo.

[0117] In some embodiments, the compound of Formula (I) has the formula (II-f): [ka] or a pharmaceutically acceptable salt thereof, wherein R 4 is as defined for formula (I). In some embodiments of compounds of formula (II-f), R 4 is one or more R 4a In some embodiments of compounds of Formula (II-f), R 4 is a 5-6 membered heteroaryl containing at least one nitrogen atom and optionally fused to a phenyl group, wherein the 5-6 membered heteroaryl is optionally fused to one or more R 4a In some embodiments of compounds 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 selected from one or more R 4a In some embodiments of compounds of Formula (II-f), R 4 is pyridyl or pyrimidinyl, where the pyridyl or pyrimidinyl is selected from the group consisting of one or more R 4a In some embodiments of compounds of Formula (II-f), R 4 is one or more R 4a In some embodiments of compounds of Formula (II-f), R 4 is one or more R 4a In some embodiments of compounds of Formula (II-f), R 4 is a 6-membered heterocyclyl containing at least one nitrogen atom and optionally fused to a phenyl group, wherein the 6-membered heterocyclyl is 4a and oxo.

[0118] In some embodiments, the compound of Formula (I) has the formula (II-g): [ka] or a pharmaceutically acceptable salt thereof, wherein R 4 is as defined for formula (I). In some embodiments of compounds of formula (II-g), R 4 is one or more R 4a In some embodiments of compounds of Formula (II-g), R 4 is a 5-6 membered heteroaryl containing at least one nitrogen atom and optionally fused to a phenyl group, wherein the 5-6 membered heteroaryl is optionally fused to one or more R 4a In some embodiments of compounds of Formula (II-g), R 4 is a 5- to 6-membered heteroaryl containing at least one nitrogen atom, wherein the 5- to 6-membered heteroaryl is selected from one or more R 4a In some embodiments of compounds of Formula (II-g), R 4 is pyridyl or pyrimidinyl, where the pyridyl or pyrimidinyl is selected from the group consisting of one or more R 4a In some embodiments of compounds of Formula (II-g), R 4 is one or more R 4a In some embodiments of compounds of Formula (II-g), R 4 is one or more R 4a In some embodiments of compounds of Formula (II-g), R 4 is a 6-membered heterocyclyl containing at least one nitrogen atom and optionally fused to a phenyl group, wherein the 6-membered heterocyclyl is 4a and oxo.

[0119] In some embodiments, the compound of Formula (I) has the formula (III-a): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , and R 4a is as defined for formula (I). In some embodiments of compounds of formula (III-a), R 2 and R 3 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-a), R 2 and R 3 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments of the compound 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 compound of Formula (III-a), R 2 and R 3 together with the carbon atom to which they are attached form a cyclobutyl. In some embodiments of the compound of Formula (III-a), R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. In some embodiments of the compound of Formula (III-a), R 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-a), R 2 and R 4 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-a), R 2 and R 3together with the carbon atom to which they are attached form an oxetane or a pyran. In some embodiments of the compound of Formula (III-a), R 2 and R 3 together with the carbon atom to which they are attached form an oxetane or a pyran. In some embodiments of the compound of Formula (III-a), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of the compound of Formula (III-a), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of the compound of Formula (III-a), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] Form.

[0120] In some embodiments, the compound of Formula (I) has the formula (III-b-1): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , and R 4a is as defined for formula (I). In some embodiments of the compound of formula (III-b-1), R 2 and R 3 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-1), R 2 and R3 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments of the compound of Formula (III-b-1), R 2 and R 3 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 together with the carbon atom to which they are attached to form a cyclobutyl. In some embodiments of the compound of Formula (III-b-1), R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. In some embodiments of the compound of Formula (III-b-1), R 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-1), R 2 and R 4 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-1), R 2 and R 3 together with the carbon atom to which they are attached form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-1), R 2 and R 3 together with the carbon atom to which they are attached form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-1), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of the compound of Formula (III-b-1), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of the compound of Formula (III-b-1), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] Form.

[0121] In some embodiments, the compound of Formula (I) has the formula (III-b-2): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , and R 4a is as defined for formula (I). In some embodiments of compounds of formula (III-b-2), R 2 and R 3 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl. In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 together with the carbon atom to which they are attached to form a cyclobutyl. In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. In some embodiments of the compound of Formula (III-b-2), R2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-2), R 2 and R 4 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 together with the carbon atom to which they are attached form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 together with the carbon atom to which they are attached form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of the compound of Formula (III-b-2), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] Form.

[0122] In some embodiments, the compound of Formula (I) has the formula (III-b-3): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , and R 4a is as defined for formula (I). In some embodiments of compounds of formula (III-b-3), R 2 and R 3 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-3), R 2 and R 3 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments of the compound of Formula (III-b-3), R 2 and R 3 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 together with the carbon atom to which they are attached to form a cyclobutyl. In some embodiments of the compound of Formula (III-b-3), R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. In some embodiments of the compound of Formula (III-b-3), R 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-3), R 2 and R 4 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-3), R 2 and R 3 together with the carbon atom to which they are attached to form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-3), R 2 and R 3together with the carbon atom to which they are attached to form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-3), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of compounds of Formula (III-b-3), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of compounds of Formula (III-b-3), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] Form.

[0123] In some embodiments, the compound of Formula (I) has the formula (III-b-4): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , and R 4a is as defined for formula (I). In some embodiments of compounds of formula (III-b-4), R 2 and R 3 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments of the compound of Formula (III-b-4), R2 and R 3 together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl. In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 together with the carbon atom to which they are attached to form a cyclobutyl. In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-4), R 2 and R 4 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 together with the carbon atom to which they are attached form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 together with the carbon atom to which they are attached form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-4), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of compounds of Formula (III-b-4), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of compounds of Formula (III-b-4), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] Form.

[0124] In some embodiments, the compound of Formula (I) has the formula (III-b-5): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , and R 4a is as defined for formula (I). In some embodiments of compounds of formula (III-b-5), R 2 and R 3 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-5), R 2 and R 3 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments of the compound of Formula (III-b-5), R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl. In some embodiments of the compound of Formula (III-b-5), R 2 and R 3 together with the carbon atom to which they are attached to form a cyclobutyl. In some embodiments of the compound of Formula (III-b-5), R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. In some embodiments of the compound of Formula (III-b-5), R 2 and R 3together with the carbon atoms to which they are attached form a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-5), R 2 and R 4 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-5), R 2 and R 3 together with the carbon atom to which they are attached form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-5), R 2 and R 3 together with the carbon atom to which they are attached form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-5), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of compounds of Formula (III-b-5), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of compounds of Formula (III-b-5), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] Form.

[0125] In some embodiments, the compound of Formula (I) has the formula (III-b-6): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R3 , and R 4a is as defined for formula (I). In some embodiments of compounds of formula (III-b-6), R 2 and R 3 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-6), R 2 and R 3 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments of the compound of Formula (III-b-6), R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl. In some embodiments of the compound of Formula (III-b-6), R 2 and R 3 together with the carbon atom to which they are attached to form a cyclobutyl. In some embodiments of the compound of Formula (III-b-6), R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. 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 form a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-6), R 2 and R 4 together with the carbon atoms to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-6), R 2 and R 3 together with the carbon atom to which they are attached form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-6), R 2 and R 3 together with the carbon atom to which they are attached form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-6), R2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of compounds of Formula (III-b-6), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of compounds of Formula (III-b-6), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] Form.

[0126] In some embodiments, the compound of Formula (I) has the formula (III-b-7): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , and R 4a is as defined for formula (I). In some embodiments of compounds of formula (III-b-7), R 2 and R 3 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-7), R 2 and R 3 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments of the compound of Formula (III-b-7), R 2 and R 3together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl. In some embodiments of the compound of Formula (III-b-7), R 2 and R 3 together with the carbon atom to which they are attached to form a cyclobutyl. In some embodiments of the compound of Formula (III-b-7), R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. In some embodiments of the compound of Formula (III-b-7), R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-7), R 2 and R 4 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-7), R 2 and R 3 together with the carbon atom to which they are attached form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-7), R 2 and R 3 together with the carbon atom to which they are attached form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-7), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of compounds of Formula (III-b-7), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of compounds of Formula (III-b-7), R 2 and R3 together with the carbon atoms to which they are attached, [ka] Form.

[0127] In some embodiments, the compound of Formula (I) has the formula (III-b-8): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , and R 4a is as defined for formula (I). In some embodiments of compounds of formula (III-b-8), R 2 and R 3 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-8), R 2 and R 3 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments of the compound of Formula (III-b-8), R 2 and R 3 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 together with the carbon atom to which they are attached to form a cyclobutyl. In some embodiments of the compound of Formula (III-b-8), R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. In some embodiments of compounds of Formula (III-b-8), R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-8), R 2 and R4 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments of the compound of Formula (III-b-8), R 2 and R 3 together with the carbon atom to which they are attached form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-8), R 2 and R 3 together with the carbon atom to which they are attached form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-8), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of compounds of Formula (III-b-8), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of compounds of Formula (III-b-8), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] Form.

[0128] In some embodiments, the compound of Formula (I) has the formula (III-b-9): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , and R 4a is as defined for formula (I). In some embodiments of compounds of formula (III-b-9), R 2and R 3 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl. 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 a C3-C6 cycloalkyl. 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 cyclopropyl or cyclobutyl. In some embodiments of compounds of Formula (III-b-9), R 2 and R 3 together with the carbon atom to which they are attached to form a cyclobutyl. 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 a cyclopropyl. 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 a 3- to 6-membered heterocyclyl. In some embodiments of compounds of Formula (III-b-9), R 2 and R 4 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl. 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 to form an oxetane or a pyran. 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 to form an oxetane or a pyran. In some embodiments of the compound of Formula (III-b-9), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of compounds of Formula (III-b-9), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In some embodiments of compounds of Formula (III-b-9), R 2 and R 3 together with the carbon atoms to which they are attached, [ka] Form.

[0129] In some embodiments, the compound of formula (I) has formula (IV): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3 is as defined for formula (I).

[0130] In some embodiments, the compound of formula (I) is [ka] is.

[0131] In another embodiment, R 1 but one or more R 1a 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by one or more R 1b 1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by one or more R 1c 6-aminopyridin-2-yl optionally substituted by 1dAlso provided are compounds of formula (I) wherein R is (pyridin-2-yl)amino optionally substituted by 1 is one or more R 1a In one aspect of the foregoing embodiment, R 1 is unsubstituted 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl. In one aspect of the foregoing embodiment, R 1 is two R on the same carbon atom. 1a 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl substituted by a group, wherein two R 1a The groups, taken together with the carbon atom to which they are attached, form a C-C cycloalkyl (e.g., cyclopropyl). In one aspect of the foregoing embodiment, R 1 is one or more R 1b In one aspect of the foregoing embodiment, R 1 is unsubstituted 1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl. In one aspect of the foregoing embodiment, R 1 is two R on the same carbon atom. 1b 1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl substituted by a group, wherein two R 1b The groups, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl (eg, cyclopropyl).

[0132] In another embodiment, R 2 and R 3 Also provided are compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein R is independently H or C1-C6 alkyl. 2 and R 3 In one aspect of the foregoing embodiment, R 2 and R 3In one aspect of the foregoing embodiment, R 2 and R 3 are both H. In one aspect of the foregoing embodiment, R 2 is H and R 3 is C1-C6 alkyl. In one aspect of the foregoing embodiment, R 2 is H and R 3 is C1-C3 alkyl. In one aspect of the foregoing embodiment, R 2 is H and R 3 is —CH3. In one aspect of the foregoing embodiment, R 2 and R 3 is independently C1-C6 alkyl. In one aspect of the foregoing embodiment, R 2 and R 3 is independently C1-C3 alkyl. In one aspect of the foregoing embodiment, R 2 and R 3 is independently methyl, ethyl, n-propyl, or isopropyl. In one aspect of the foregoing embodiment, R 2 and R 3 are both -CH3.

[0133] In another embodiment, R 2 and R 3 Also provided are compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein R, taken together with the carbon atom to which they are attached, form a C-C cycloalkyl. 2 and R 3 taken together with the carbon atom to which they are attached form a C3-C4 cycloalkyl. In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. 2 and R 3 together with the carbon atom to which they are attached to form cyclobutyl.

[0134] In another embodiment, R2 and R 3 Also provided are compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein R, taken together with the carbon atom to which they are attached, form a 3- to 6-membered heterocyclyl. 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 6-membered heterocyclyl, where the heterocyclyl contains at least one oxygen atom. In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atoms to which they are attached form a 4- to 6-membered heterocyclyl. 2 and R 4 taken together with the carbon atoms to which they are attached form a 4- to 6-membered heterocyclyl, where 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 atoms to which they are attached form tetrahydropyranyl. In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atoms to which they are attached, [ka] In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atoms to which they are attached, [ka] Form.

[0135] In another embodiment, R 2 and R 3 together with the carbon atoms to which they are attached, form R 2a Also provided are compounds of formula (A), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 taken together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl substituted by deuterium; or a C1-C6 alkyl optionally substituted by halogen. In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atoms to which they are attached, form R 2a In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atoms to which they are attached, [ka] Form.

[0136] In another embodiment, R 2 and R 3 together with the carbon atoms to which they are attached, form R 2a Also provided are compounds of formula (A), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 taken together with the carbon atoms to which they are attached form a 3-6 membered heterocyclyl substituted by deuterium; or C1-C6 alkyl optionally substituted by halogen. In one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atoms to which they are attached, form R 2aIn one aspect of the foregoing embodiment, R 2 and R 3 together with the carbon atoms to which they are attached, [ka] Form.

[0137] In another embodiment, R 4 but one or more R 4a Also provided are compounds of formula (A) wherein R is phenyl optionally substituted by 4 is unsubstituted phenyl. In one aspect of the foregoing embodiment, R 4 is 1 to 5 R 4a groups, where each R 4a is independently selected from halo, CN, C-C alkyl, C-C haloalkyl, —(C-C alkylene)-O—(C-C alkyl), C-C cycloalkyl, —OH, —O—(C-C alkyl), —O—(C-C haloalkyl), —S(O)(C-C alkyl), or —C(═O)—NH.

[0138] In another embodiment, R 4 but one or more R 4a Also provided are compounds of formula (I) wherein R is phenyl optionally substituted by 4 is unsubstituted phenyl. In one aspect of the foregoing embodiment, R 4 is 1 to 5 R 4a groups, where each R 4ais independently selected from halo, CN, C-C alkyl, C-C haloalkyl, —(C-C alkylene)-O—(C-C alkyl), C-C cycloalkyl, —O—(C-C alkyl), —O—(C-C haloalkyl), and —S(O)(C-C alkyl). In one aspect of the foregoing embodiment, R 4 is 1 to 5 R 4a groups, where each R 4a is independently selected from F, Cl, CN, C-C alkyl, C-C haloalkyl, —(C-C alkylene)-O—(C-C alkyl), C-C cycloalkyl, —O—(C-C alkyl), —O—(C-C haloalkyl), and —S(O)(C-C alkyl). In one aspect of the foregoing embodiment, R 4 is 1 to 5 R 4a phenyl substituted by a group, wherein at least one R 4a The group is halo (e.g., F or Cl). In one aspect of the foregoing embodiment, R 4 is 1 to 5 R 4a phenyl substituted by a group, wherein at least one R 4a The group is CN. In one aspect of the foregoing embodiment, R 4 is 1 to 5 R 4a phenyl substituted by a group, wherein at least one R 4a The group is C1-C3 alkyl (e.g., -CH3). In one aspect of the foregoing embodiment, R 4 is 1 to 5 R 4a phenyl substituted by a group, wherein at least one R 4a The group is —O—(C1-C3 alkyl) (e.g., —O—CH3). In one aspect of the foregoing embodiment, R 4 is 1 to 5 R 4a phenyl substituted by a group, wherein at least one R 4a The group is —O—(C1-C3 haloalkyl) (e.g., —O—CHF2). In one aspect of the foregoing embodiment, R 4 is 1 to 5 R4a phenyl substituted by a group, wherein at least one R 4a The group is -S(O)2(C1-C3 alkyl). In another aspect of the foregoing embodiment, R 4 is 2 to 5 R 4a groups, where each R 4a is independently selected from halo, CN, —O—(C1-C6 alkyl), and —O—(C1-C6 haloalkyl). 4 is 2 to 5 R 4a phenyl substituted by a group, where R 4a At least two of the groups are halo (e.g., fluoro or chloro). In another aspect of the foregoing embodiment, R 4 is 2 to 5 R 4a phenyl substituted by a group, where R 4a At least one of the groups is halo (e.g., fluoro or chloro), and R 4a At least one of the groups is CN. In another aspect of the foregoing embodiment, R 4 is 2 to 5 R 4a phenyl substituted by a group, where R 4a At least one of the groups is halo (e.g., fluoro or chloro), and R 4a At least one of the groups is -O-(C1-C3 alkyl) (e.g., -O-CH3). In another aspect of the foregoing embodiment, R 4 is 2 to 5 R 4a phenyl substituted by a group, where R 4a At least one of the groups is halo (e.g., fluoro or chloro), and R 4a At least one of the groups is -O-(C1-C3 haloalkyl) (e.g., -O-CHF2). In another aspect of the foregoing embodiment, R 4 is 2 to 5 R 4a phenyl substituted by a group, where R 4a At least one of the groups is CN and R 4aAt least one of the groups is -O-(C1-C3 alkyl) (e.g., -O-CH3).

[0139] In another embodiment, R 4 is a 5-6 membered heteroaryl containing at least one nitrogen atom, wherein the 5-6 membered heteroaryl is optionally fused to a phenyl group, and the 5-6 membered heteroaryl is optionally fused to one or more R 4a Also provided are compounds of formula (A), or pharmaceutically acceptable salts thereof, optionally substituted by 4 is a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl contains at least one nitrogen atom and one or more R 4a In another aspect of the foregoing embodiment, R 4 is a 5-membered heteroaryl, where the 5-membered heteroaryl contains two nitrogen atoms (e.g., R 4 is pyrazolyl, imidazolyl, or thiazolyl), one or more R 4a In another aspect of the foregoing embodiment, R 4 is a 6-membered heteroaryl, where the 6-membered heteroaryl contains one nitrogen atom and one or more R 4a In another aspect of the foregoing embodiment, R 4 is one or more R 4a In another aspect of the foregoing embodiment, R 4 is a 6-membered heteroaryl, where the 6-membered heteroaryl contains two nitrogen atoms (e.g., R 4 is pyrimidinyl or pyrazinyl), one or more R 4a In another aspect of the foregoing embodiment, R 4 is pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is selected from 1 to 4 R 4a substituted by a group, where R 4aThe groups are independently selected from the group consisting of halo, CN, C-C alkyl, C-C haloalkyl, -(C-C alkylene)-O-(C-C alkyl), C-C cycloalkyl, -OH, -O-(C-C alkyl), -O-(C-C haloalkyl), -S(O)(C-C alkyl), or -C(=O)-NH.

[0140] In another embodiment, R 4 is a 6-membered heterocyclyl containing at least one nitrogen atom, wherein the 6-membered heterocyclyl is optionally fused to a phenyl group, and the 6-membered heterocyclyl is optionally fused to one or more R 4a or oxo. In another aspect of the foregoing embodiment, R 4 is a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains one nitrogen atom and one or more R 4a or oxo. In another aspect of the foregoing embodiment, R 4 is a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains two nitrogen atoms and one or more R 4a or oxo. In another aspect of the foregoing embodiment, R 4 is a 6-membered heterocyclyl optionally fused to a phenyl group, wherein the 6-membered heterocyclyl contains one nitrogen atom and is substituted by one oxo group and has one or more R 4a In another aspect of the foregoing embodiment, R 4 is 1 to 4 R 4a or oxo group, where R 4aThe groups are independently selected from the group consisting of halo, CN, C-C alkyl, C-C haloalkyl, -(C-C alkylene)-O-(C-C alkyl), C-C cycloalkyl, -OH, -O-(C-C alkyl), -O-(C-C haloalkyl), -S(O)(C-C alkyl), or -C(=O)-NH. 4 is optionally fused to a phenyl group [ka] and one or more R 4a In another aspect of the foregoing embodiment, R 4 teeth, [ka] In another aspect of the foregoing embodiment, R 4 teeth, [ka] In another aspect of the foregoing embodiment, R 4 teeth, [ka] is.

[0141] In another embodiment, R 4 is a 5-6 membered heteroaryl containing at least one nitrogen atom, wherein the 5-6 membered heteroaryl is optionally fused to a phenyl group, and the 5-6 membered heteroaryl is optionally fused to one or more R 4a Also provided are compounds of formula (I), or pharmaceutically acceptable salts thereof, optionally substituted by 4 is a 6-membered heteroaryl (e.g., pyrimidinyl) fused to a phenyl. 4 is a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl contains at least one nitrogen atom and one or more R4a In another aspect of the foregoing embodiment, R 4 is a 5-membered heteroaryl, where the 5-membered heteroaryl contains two nitrogen atoms (e.g., R 4 is pyrazolyl, imidazolyl, or thiazolyl), one or more R 4a In another aspect of the foregoing embodiment, R 4 is a 6-membered heteroaryl, where the 6-membered heteroaryl contains one nitrogen atom and one or more R 4a In another aspect of the foregoing embodiment, R 4 is one or more R 4a In another aspect of the foregoing embodiment, R 4 is a 6-membered heteroaryl, where the 6-membered heteroaryl contains two nitrogen atoms (e.g., R 4 is pyrimidinyl or pyrazinyl), one or more R 4a In another aspect of the foregoing embodiment, R 4 is pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted. 4 is pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is selected from 1 to 4 R 4a substituted by a group, where R 4a The groups are independently selected from the group consisting of halo, CN, C-C alkyl, C-C haloalkyl, -(C-C alkylene)-O-(C-C alkyl), C-C cycloalkyl, -O-(C-C alkyl), and -O-(C-C haloalkyl). 4 is pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is selected from 1 to 4 R 4a substituted by a group, where R 4aThe groups are independently selected from the group consisting of halo, CN, C-C alkyl, C-C haloalkyl, -(C-C alkylene)-O-(C-C alkyl), C-C cycloalkyl, -O-(C-C alkyl), and -O-(C-C haloalkyl). 4 is pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is selected from 1 to 4 R 4a substituted by a group, where R 4a The groups are independently selected from the group consisting of F, Cl, CN, -CH, -CF, -CHF, -CHF, -CH-O-CH, cyclopropyl, -O-CH, and -O-CHF. 4 is 1 to 4 R 4a substituted by a group, wherein at least one R 4a The group is F or Cl. In one aspect of the foregoing embodiment, R 4 is 1 to 4 R 4a substituted by a group, wherein at least one R 4a The group is CN. In one aspect of the foregoing embodiment, R 4 is 1 to 4 R 4a substituted by a group, wherein at least one R 4a The group is C1-C3 alkyl. In one aspect of the foregoing embodiment, R 4 is 1 to 4 R 4a substituted by a group, wherein at least one R 4a The group is C1-C3 haloalkyl. In one aspect of the foregoing embodiment, R 4 is 1 to 4 R 4a substituted by a group, wherein at least one R 4a The group is -(C1-C3 alkylene)-O-(C1-C3 alkyl). In one aspect of the foregoing embodiment, R 4 is 1 to 4 R 4a substituted by a group, wherein at least one R 4a In one aspect of the foregoing embodiment, R 4is 1 to 4 R 4a substituted by a group, wherein at least one R 4a The group is —O—(C1-C3 alkyl). In one aspect of the foregoing embodiment, R 4 is 1 to 4 R 4a substituted by a group, wherein at least one R 4a The group is —O—(C1-C3 haloalkyl). In one aspect of the foregoing embodiment, R 4 is 2 to 4 R 4a substituted by a group, wherein at least one R 4a The group is F and at least one R 4a The group is Cl. In one aspect of the foregoing embodiment, R 4 is 2 to 4 R 4a substituted by a group, wherein at least one R 4a The group is F and at least one R 4a The group is C1-C3 alkyl. In one aspect of the foregoing embodiment, R 4 is 2 to 4 R 4a substituted by a group, wherein at least one R 4a group is Cl and at least one R 4a The group is C1-C3 alkyl. In one aspect of the foregoing embodiment, R 4 is 2 to 4 R 4a substituted by a group, wherein at least one R 4a group is Cl and at least one R 4a The group is —O—(C1-C3 alkyl). In one aspect of the foregoing embodiment, R 4 is 2 to 4 R 4a groups, where at least two R 4a The group is Cl.

[0142] In another embodiment, R 4 However, 1 to 4 R 4a pyridinyl substituted by a group, where R 4aAlso provided are compounds of Formula (A), or pharmaceutically acceptable salts thereof, wherein the group is selected from the group consisting of halo, CN, C-C alkyl, C-C haloalkyl, —(C-C alkylene)-O—(C-C alkyl), C-C cycloalkyl, —OH, —O—(C-C alkyl), —O—(C-C haloalkyl), —S(O)(C-C alkyl), or —C(═O)—NH.

[0143] In another embodiment, R 4 However, 1 to 4 R 4a pyridinyl substituted by a group, where R 4a Also provided are compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein R is selected from the group consisting of halo, CN, C-C alkyl, C-C haloalkyl, -(C-C alkylene)-O-(C-C alkyl), C-C cycloalkyl, -O-(C-C alkyl), and -O-(C-C haloalkyl). 4 is 1 to 4 R 4a pyridinyl substituted by a group, where R 4a The groups are independently selected from the group consisting of halo, CN, C-C alkyl, C-C haloalkyl, -(C-C alkylene)-O-(C-C alkyl), C-C cycloalkyl, -O-(C-C alkyl), and -O-(C-C haloalkyl). In one aspect of the foregoing embodiment, R 4 is 1 to 4 R 4a pyridinyl substituted by a group, where R 4a The groups are independently selected from the group consisting of F, Cl, CN, -CH, -CF, -CHF, -CHF, -CH-O-CH, cyclopropyl, -O-CH, and -O-CHF. 4 is 2 to 4 R 4a pyridinyl substituted by a group, where R 4aThe groups are independently selected from the group consisting of 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 2 to 4 R 4a pyridinyl substituted by a group, where R 4a At least two of the groups are halo (e.g., fluoro or chloro). In one aspect of the foregoing embodiment, R 4 is 2 to 4 R 4a pyridinyl substituted by a group, where R 4a At least one of the groups is halo (e.g., fluoro or chloro), and R 4a At least one of the groups is C1-C3 alkyl (e.g., -CH3). In one aspect of the foregoing embodiment, R 4 is 2 to 4 R 4a pyridinyl substituted by a group, where R 4a At least one of the groups is halo (e.g., fluoro or chloro), and R 4a At least one of the groups is -O-(C1-C3 alkyl) (e.g., -O-CH3).

[0144] In another embodiment, R 4 is a 5-membered heteroaryl, wherein the 5-membered heteroaryl contains at least one nitrogen atom and one or more R 4a Also provided are compounds of formula (I), or pharmaceutically acceptable salts thereof, optionally substituted by 4 is a 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), one or more R 4a In one aspect of the foregoing embodiment, R 4 is a 5-membered heteroaryl, wherein the 5-membered heteroaryl contains one nitrogen atom and one or more R 4aIn one aspect of the foregoing embodiment, R 4 is a 5-membered heteroaryl, where the 5-membered heteroaryl contains two nitrogen atoms (e.g., R 4 is pyrazolyl or imidazolyl), one or more R 4a In one aspect of the foregoing embodiment, R 4 is an unsubstituted 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl). In one aspect of the foregoing embodiment, R 4 is 1 to 3 R 4a a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted by a group, where R 4a The groups are independently selected from the group consisting of halo, CN, C1-C6 alkyl, and C1-C6 haloalkyl. 4 is 1 to 3 R 4a a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted by a group, where R 4a The groups are independently selected from the group consisting of 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 2 to 3 R 4a a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted by a group, where R 4a The groups are independently selected from the group consisting of halo (e.g., F or 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 2 to 3 R 4a a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted by a group, where R 4a At least two of the groups are halo (e.g., chloro). In one aspect of the foregoing embodiment, R 4 is 2 to 3 R 4aa 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted by a group, where R 4a At least one of the groups is halo (e.g., chloro), and R 4a At least one of the groups is C1-C3 alkyl (e.g., -CH3). In one aspect of the foregoing embodiment, R 4 is 2 to 3 R 4a a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted by a group, where R 4a At least one of the groups is CN and R 4a At least one of the groups is C1-C3 alkyl (e.g., -CH3). In one aspect of the foregoing embodiment, R 4 is 2 to 3 R 4a a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted by a group, where R 4a At least one of the groups is C1-C3 alkyl (e.g., -CH3), and R 4a At least one of the groups is a C1-C3 haloalkyl (eg, -CF3).

[0145] In another embodiment, R 4 is a 6-membered heteroaryl, where the 6-membered heteroaryl contains two nitrogen atoms (e.g., R 4 is pyrimidinyl or pyrazinyl), one or more R 4a Also provided are compounds of formula (I), or pharmaceutically acceptable salts thereof, optionally substituted by 4 is an unsubstituted 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl). In one aspect of the foregoing embodiment, R 4 is 1 to 3 R 4a a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted by a group, where R 4aThe groups are independently selected from the group consisting of halo, C-C alkyl, C-C haloalkyl, and —O—(C-C alkyl). In one aspect of the foregoing embodiment, R 4 is 1 to 3 R 4a a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted by a group, where R 4a The groups are independently selected from the group consisting of halo, C-C alkyl, C-C haloalkyl, and —O—(C-C alkyl). In one aspect of the foregoing embodiment, R 4 is 1 to 3 R 4a a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted by a group, where R 4a groups are independently selected from the group consisting of Cl, CH, —CF, —CHF, and —O—CH. In one aspect of the foregoing embodiment, R 4 is 2 to 3 R 4a a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted by a group, where R 4a The groups are independently selected from the group consisting of 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 embodiment, R 4 is 2 to 3 R 4a a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted by a group, where R 4a At least one of the groups is halo (e.g., chloro), and R 4a At least one of the groups is C1-C3 alkyl (e.g., -CH3). In one aspect of the foregoing embodiment, R 4 is 2 to 3 R 4a a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted by a group, where R 4a At least one of the groups is halo (e.g., chloro), and R 4aAt least one of the groups is —O—(C1-C3 alkyl) (e.g., —O—CH3). In one aspect of the foregoing embodiment, R 4 is 2 to 3 R 4a a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted by a group, where R 4a At least two of the groups are C1-C3 alkyl (e.g., -CH3). In one aspect of the foregoing embodiment, R 4 is 2 to 3 R 4a a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted by a group, where R 4a At least one of the groups is C1-C3 alkyl (e.g., -CH3), and R 4a At least one of the groups is -O-(C1-C3 alkyl) (e.g., -O-CH3).

[0146] In another embodiment, R 4 is a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains at least one nitrogen atom and is optionally fused to a phenyl group; R 4a Also provided are compounds of formula (I), or pharmaceutically acceptable salts thereof, optionally substituted with one or more groups selected from the group consisting of (e.g., Cl) and oxo. In one aspect of the foregoing embodiment, R 4 is a 6-membered heterocyclyl containing one nitrogen atom, wherein the 6-membered heterocyclyl is fused to a phenyl group and substituted by oxo. In one aspect of the foregoing embodiment, R 4 is a 6-membered heterocyclyl, where the 6-membered heterocyclyl contains one nitrogen atom, and R 4a (e.g., Cl) and oxo. 4 is a 6-membered heterocyclyl, where the 6-membered heterocyclyl contains two nitrogen atoms, and R 4a(e.g., Cl) and oxo. 4 is substituted by Cl and oxo. In one aspect of the foregoing embodiment, R 4 is a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains one nitrogen atom and is substituted by Cl and oxo. In one aspect of the foregoing embodiment, R 4 is a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains two nitrogen atoms and is substituted by Cl and oxo.

[0147] In another embodiment, R 4 Also provided are compounds of formula (A), or pharmaceutically acceptable salts thereof, wherein R is C1-C6 haloalkyl. 4 is C1-C6 fluoroalkyl. In one of the foregoing embodiments, R 4 is C haloalkyl. In one of the foregoing embodiments, R 4 is C1-C6 fluoroalkyl. In one aspect of the foregoing embodiment, R 4 teeth, [ka] is.

[0148] In another embodiment, R 2 , R 3 , and R 4 together form a 5-membered heteroaryl containing two nitrogen atoms and substituted with phenyl, wherein the phenyl group is substituted with one or more R 4a Also provided are compounds of formula (A), or pharmaceutically acceptable salts thereof, optionally substituted by 2 , R 3 , and R 4 Let's get together and [ka] Form.

[0149] In another embodiment, each R 4a is independently selected from the group consisting of halo, CN, C-C alkyl, C-C haloalkyl, —(C-C alkylene)-O—(C-C alkyl), C-C cycloalkyl, —OH, —O—(C-C alkyl), —O—(C-C haloalkyl), —S(O)(C-C alkyl), or —C(═O)—NH. Also provided are compounds of Formula (A), or pharmaceutically acceptable salts thereof.

[0150] In another embodiment, each R 4a Also provided are compounds of Formula (I), or pharmaceutically acceptable salts thereof, wherein each R is independently selected from the group consisting of halo, CN, C-C alkyl, C-C haloalkyl, -(C-C alkylene)-O-(C-C alkyl), C-C cycloalkyl, -O-(C-C alkyl), -O-(C-C haloalkyl), and -S(O)(C-C alkyl). In one aspect of the foregoing embodiment, each R 4a is independently selected from the group consisting of halo, CN, C-C alkyl, C-C haloalkyl, —(C-C alkylene)-O—(C-C alkyl), C-C cycloalkyl, —O—(C-C alkyl), —O—(C-C haloalkyl), and —S(O)(C-C alkyl). In one aspect of the foregoing embodiment, each R 4a are independently selected from the group consisting of F, Cl, CN, -CH3, -CH2F, -CHF2, -CF3, -CH2-O-CH3, cyclopropyl, -OCH3, -OCHF2, and -S(O)2CH3.

[0151] 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.

[0152] In some embodiments, R 4a is CN.

[0153] 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 isopropyl. In some embodiments, R 4a is methyl, ethyl, or isopropyl. 4a is -CH3.

[0154] In some embodiments, R 4a is C1-C6 haloalkyl. In some embodiments, R 4a is C1-C3 haloalkyl. 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 chlorine atoms. In some embodiments, R 4a is —CF, —CCl, —CFCl, —CFCl, —CHF, —CHF, —CHCl, —CHCl, or —CHFCl. 4a is -CF, -CHF, -CHF. In some embodiments, R 4a is —CF. In some embodiments, R 4a is -CHF2. In some embodiments, R 4a is -CH2F.

[0155] In some embodiments, R 4a is -(C1-C6 alkylene)-O-(C1-C6 alkyl). In some embodiments, R 4a is -(C1-C3 alkylene)-O-(C1-C3 alkyl). In some embodiments, R 4ais —CH—O—CH, —CH—O—CHCH, —CH—O—CHCHCH, or —CH—O—CH(CH). 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). In some embodiments, R 4a is -CH2-O-CH3.

[0156] In some embodiments, R 4a is C-C cycloalkyl. In some embodiments, R 4a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 4a is cyclopropyl.

[0157] In some embodiments, R 4a is —O—(C1-C6 alkyl). In some embodiments, R 4a is —O—(C1-C3 alkyl). In some embodiments, R 4a is —O—CH, —O—CHCH, —O—CHCHCH, or —O—CH(CH). In some embodiments, R 4a is -O-CH3.

[0158] In some embodiments, R 4a is —O—(C1-C6 haloalkyl). In some embodiments, R 4ais -O-(C1-C3 haloalkyl). 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 chlorine atoms. In some embodiments, R 4a is —O—CF, —O—CCl, —O—CFCl, —O—CFCl, —O—CHF, —O—CHF, —O—CHCl, —O—CHCl, or —O—CHFCl. 4a is -O-CHF2.

[0159] In some embodiments, R 4a is —S(O)2(C1-C6 alkyl). In some embodiments, R 4a is —S(O)2(C1-C4 alkyl). In some embodiments, R 4a is -S(O)2CH3.

[0160] In some embodiments, R 4a is —OH. In some embodiments, R 4a is -C(=O)-NH2.

[0161] In another embodiment, R 4a and R 2 Also provided are compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein R 4a and R 2 are taken together with the atom to which they are attached to form a 6-membered heterocyclyl, where the heterocyclyl contains one oxygen atom. In some embodiments, R 4 is phenyl and R 4a and R 2 together with the atom to which they are attached form a 6-membered heterocyclyl, where the heterocyclyl contains 1 oxygen atom. In some embodiments, R 2 , R3 , and R 4 together with the carbon atoms to which they are attached, [ka] In some embodiments, R 2 , R 3 , and R 4 together with the carbon atoms to which they are attached, [ka] In some embodiments, R 2 , R 3 , and R 4 together with the carbon atoms to which they are attached, [ka] Form.

[0162] Also, R 4 but, [ka] Also provided is a compound of formula (I), selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0163] Also, R 4 but, [ka] Also provided is a compound of formula (I), selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0164] Also, R 4 but, [ka] Also provided is a compound of formula (I), selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0165] Also provided in another embodiment are compounds of Formula (I), or pharmaceutically acceptable salts 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.

[0166] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound has any one or more of the following characteristics: (I)R 1 teeth, [ka] is; (II)-L 1 -OL 2 -YL 3 -Let's get together, [ka] form; (III) Q is H or C1-C6 alkyl (e.g., -CH3 or -CH2CH3); (IV)R 2 and R 3 teeth, (i) Either both are H, or (ii) both are -CH3, or (iii) together with the carbon atom to which they are attached form cyclopropyl; and (V)R 4 teeth, (i) 0 to 5 R 4a a phenyl substituted by a group; (ii) a group containing at least one nitrogen atom and 0 to 4 R 4a a 5-membered heteroaryl substituted by a group (e.g., pyrazolyl or imidazolyl); (iii) a group containing at least one nitrogen atom and 0 to 4 R 4a a 6-membered heteroaryl substituted by a group (e.g., pyridinyl, pyrimidinyl, or pyrazinyl); or (iv) contains at least one nitrogen atom and R 4a and 6-membered heterocyclyl (for example) substituted by 0-4 groups selected from the group consisting of oxo. In one aspect of this variation, (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.

[0167] It is understood that in the variations in the preceding paragraphs, each combination of variables is described. For example, it is understood that each variation of feature (IV) can be combined with each variation of feature (V), as if all variations of each of features (IV) and (V) were specifically and individually listed. Thus, the following combinations are understood to be 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).

[0168] In some embodiments, R 1 teeth, [ka] and R 2 and R 3 are independently H or methyl, or R 2 and R 3together with the carbon atom to which they are attached to form a cyclopropyl, and R 4 is phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, 2-oxopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyridazinyl, or quinazolinyl, wherein phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, 2-oxopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or quinazolinyl is selected from the group consisting of one or more R 4a groups, and dihydropyridinyl, dihydropyrimidinyl, or dihydropyridazinyl is R 4a and oxo, wherein each R 4a are 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 -OL 2 -YL 3 -Let's get together, [ka] Form.

[0169] In some embodiments, R 1 teeth, [ka] and R 2 and R 3 together with the carbon atom to which they are attached to form a cyclopropyl, and R 4is phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, 2-oxopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyridazinyl, or quinazolinyl, wherein phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, 2-oxopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or quinazolinyl is selected from the group consisting of one or more R 4a groups, and dihydropyridinyl, dihydropyrimidinyl, or dihydropyridazinyl is R 4a and oxo, wherein each R 4a are 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 -OL 2 -YL 3 -Let's get together, [ka] Form.

[0170] In some embodiments, R 1 teeth, [ka] and R 2 and R 3 together with the carbon atom to which they are attached to form a cyclopropyl, and R 4 is pyrazolyl, imidazolyl, thiazolyl, pyridinyl, 2-oxopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyridazinyl, or quinazolinyl, wherein pyrazolyl, imidazolyl, thiazolyl, pyridinyl, 2-oxopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or quinazolinyl is selected from the group consisting of one or more R4a groups, and dihydropyridinyl, dihydropyrimidinyl, or dihydropyridazinyl is R 4a and oxo, wherein each R 4a are 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 -OL 2 -YL 3 -Let's get together, [ka] Form.

[0171] Where a moiety is contemplated, it is understood that the moiety may be attached to the remainder of the structure at any available position. For example, 3-chloro-6-methoxypyridinyl may be attached to the remainder of the structure at the 2-, 4-, or 5-position (e.g., 3-chloro-6-methoxypyridin-2-yl, 3-chloro-6-methoxypyridin-4-yl, or 3-chloro-6-methoxypyridin-5-yl, respectively). R as described herein 4 Although groups are shown as being attached at a particular position (e.g., pyridin-2-yl or pyrimidin-5-yl), they can also be attached via any other available valence (e.g., pyridin-3-yl or pyrimidin-4-yl, respectively).

[0172] Any embodiment of a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, provided herein also applies, where applicable, to any other formula detailed herein, as if every embodiment were specifically and individually recited. In particular, any embodiment of a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, provided herein also applies, where applicable, to a compound of Formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, as if every embodiment were specifically and individually recited for Formula (A). Thus, each embodiment of a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, provided herein, e.g., 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 Ab Embodiments relating to CI 147891, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are understood and described to the same extent as if every embodiment were specifically and individually recited, and all such embodiments are understood and described as may be used in any of the pharmaceutical compositions, methods, kits, uses, or other aspects detailed herein.

[0173] Representative compounds are listed in FIG. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0174] In some embodiments, provided is a compound selected from the compounds shown 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 compound selected from the compounds shown in Table 1, or a salt of a stereoisomer thereof. "Planar" versions of all compounds shown in Table 1 are also contemplated in the present disclosure, including planar versions of any specific stereoisomer in the table. In some embodiments, provided is a compound selected from compounds 1-82 shown 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 compound selected from compounds 1-82 shown in Table 1, or a salt of a stereoisomer thereof. "Planar" versions of compounds 1-82 shown in Table 1 are also contemplated in the present disclosure, including planar versions of any specific stereoisomer of compounds 1-82 in the table.

[0175] In some embodiments, provided is a compound selected from compounds 83-104 shown in Table 1, or a stereoisomer thereof (including a mixture of two or more thereof), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound selected from compounds 83-104 shown in Table 1, or a salt of a stereoisomer thereof. "Planar" versions of compounds 83-104 shown in Table 1 are also contemplated in the present disclosure, including planar versions of any specific stereoisomer of compounds 83-104 in the table.

[0176] In one variation, the compounds detailed herein are selected from the group consisting of: N-(2-methyl-2-phenylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(2-phenylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(2-(2,3-difluoro-6-methoxyphenyl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(2-(2-(difluoromethoxy)-6-fluorophenyl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(2-chlorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(2,6-dichlorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(2-(2-chlorophenyl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(2-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-phenylcyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(pyrazin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(2-methylpyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3-chloro-5-fluoropyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3-chloropyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(4-methylpyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(o-tolyl)cyclopropane-1-carbonyl)homoserine; N-(1-(6-methoxypyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(4-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(6-methylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(2,5-difluoropyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(pyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(2-(2-chloro-5-fluoropyridin-3-yl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3,5-dichloropyridin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(3-(trifluoromethyl)pyridin-2-yl)cyclopropane-1-carbonyl)homoserine; N-(1-(3-chloro-6-methoxypyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(5-cyanopyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(5-fluoro-2-methylpyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3-methylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3-methoxypyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(quinazolin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3-chloro-5-methoxypyridin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(2-methoxypyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3-chloro-5-methylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(2-cyano-6-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3-(difluoromethoxy)pyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; 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; N-(1-(3-(difluoromethyl)pyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(4,6-dimethylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3-methylpyrazin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(2-cyano-4-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(4-chloro-2-methoxypyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(2-cyanophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(2-(methylsulfonyl)phenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3-fluoro-5-methylpyridin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(4-(trifluoromethyl)pyrimidin-5-yl)cyclopropane-1-carbonyl)homoserine; N-(1-(5-chloropyrimidin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3-methoxypyrazin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; 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)homoserine; N-(1-(3-(fluoromethyl)pyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3-(methoxymethyl)pyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3-chloro-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(2-cyano-6-methoxyphenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(2-(difluoromethyl)pyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3-cyclopropylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(4-(difluoromethyl)pyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; 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)homoserine; N-(1-(4-methoxy-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(4-chloro-6-methoxypyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(4-chloro-6-oxo-1,6-dihydropyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(5-(difluoromethyl)-1H-imidazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(6-chloro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3-chloro-6-oxo-1,6-dihydropyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(3-(trifluoromethyl)pyrazin-2-yl)cyclopropane-1-carbonyl)homoserine; N-(1-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(3,5-dichloro-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(2-(trifluoromethyl)-1H-imidazol-1-yl)cyclopropane-1-carbonyl)homoserine; N-(1-(4-chloro-1H-pyrazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(5-chloro-3-methyl-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(5-chloro-2-methylpyrimidin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(5-chloro-1H-pyrazol-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(4-cyano-1-methyl-1H-pyrazol-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(5-chloro-3-oxo-2,3-dihydropyridazin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(4-cyano-1H-pyrazol-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(4-chloro-1H-imidazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(1-(4-chloro-1-methyl-1H-imidazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(2-phenylacetyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; and N-(1-(5-chlorothiazol-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine, or a pharmaceutically acceptable salt thereof.

[0177] In one variation, the compounds detailed herein are selected from the group consisting of: N-(3-(difluoromethyl)tetrahydrofuran-3-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(trifluoromethyl)cyclohexane-1-carbonyl)-L-homoserine; N-(4-(4-fluorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; N-(4-(3-methoxyphenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(4-(3-fluorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(4-(3-chlorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; 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; N-(1-(6-methoxy-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(6-fluoro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(6-bromo-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-carbamoyl-6-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; O-(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; N-(1-phenyl-1H-pyrazole-3-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-phenyl-1H-pyrazole-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-phenyl-1H-pyrazole-5-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(4-(trifluoromethyl)tetrahydro-2H-pyran-4-carbonyl)-L-homoserine; 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; 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; 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-homoserinic acid methyl ester; 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; or a pharmaceutically acceptable salt thereof.

[0178] In various embodiments, the compound is selected from the group consisting of the compounds of the listed examples, e.g., compounds 1-82, or a pharmaceutically acceptable salt thereof. For example, the compound can be selected from the group consisting of: N-(2-methyl-2-phenylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine; N-(2-methyl-2-phenylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-((S)-2-phenylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(2-(2,3-difluoro-6-methoxyphenyl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(2-(2-(difluoromethoxy)-6-fluorophenyl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-chlorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2,6-dichlorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(2-(2-chlorophenyl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-phenylcyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(pyrazin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-methylpyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-chloro-5-fluoropyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-chloropyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4-methylpyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(o-tolyl)cyclopropane-1-carbonyl)-L-homoserine; N-(1-(6-methoxypyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(6-methylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; N-(1-(pyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; 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; 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; 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; N-(1-(5-cyanopyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; N-(1-(3-methylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-methoxypyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(quinazolin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-chloro-5-methoxypyridin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-methoxypyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-chloro-5-methylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-cyano-6-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-(difluoromethoxy)pyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; N-(1-(3-(difluoromethyl)pyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4,6-dimethylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-methylpyrazin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-cyano-4-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4-chloro-2-methoxypyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-cyanophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-(methylsulfonyl)phenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; 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; N-(1-(5-chloropyrimidin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-methoxypyrazin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; 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; 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; N-(1-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-chloro-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-cyano-6-methoxyphenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; N-(1-(3-cyclopropylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; 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; 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; N-(1-(4-chloro-6-methoxypyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4-chloro-6-oxo-1,6-dihydropyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(5-(difluoromethyl)-1H-imidazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(6-chloro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-chloro-6-oxo-1,6-dihydropyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(3-(trifluoromethyl)pyrazin-2-yl)cyclopropane-1-carbonyl)-L-homoserine; N-(1-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3,5-dichloro-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; O-(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; N-(1-(4-chloro-1H-pyrazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(5-chloro-3-methyl-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(5-chloro-2-methylpyrimidin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(5-chloro-1H-pyrazol-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4-cyano-1-methyl-1H-pyrazol-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(5-chloro-3-oxo-2,3-dihydropyridazin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4-cyano-1H-pyrazol-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4-chloro-1H-imidazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4-chloro-1-methyl-1H-imidazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(2-phenylacetyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; and N-(1-(5-chlorothiazol-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine, or a pharmaceutically acceptable salt thereof.

[0179] In various embodiments, the compound is selected from the group consisting of the compounds of the listed examples, e.g., compounds 83-104, or a pharmaceutically acceptable salt thereof. For example, the compound can be selected from the group consisting of:

[0180] N-(3-(difluoromethyl)tetrahydrofuran-3-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0181] O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(trifluoromethyl)cyclohexane-1-carbonyl)-L-homoserine;

[0182] N-(4-(4-fluorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0183] 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;

[0184] N-(4-(3-methoxyphenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0185] N-(4-(3-fluorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0186] N-(4-(3-chlorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0187] 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;

[0188] 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;

[0189] N-(1-(6-methoxy-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0190] N-(1-(6-fluoro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0191] N-(1-(6-bromo-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0192] N-(1-(2-carbamoyl-6-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0193] O-(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;

[0194] N-(1-phenyl-1H-pyrazole-3-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0195] N-(1-phenyl-1H-pyrazole-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0196] N-(1-phenyl-1H-pyrazole-5-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine;

[0197] O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(4-(trifluoromethyl)tetrahydro-2H-pyran-4-carbonyl)-L-homoserine;

[0198] 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;

[0199] 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;

[0200] 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-homoserinic acid methyl ester;

[0201] 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;

[0202] or a pharmaceutically acceptable salt thereof.

[0203] In one variation, the compounds detailed herein are selected from the group consisting of: N-((S)-2-phenylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-chlorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2,6-dichlorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-methylpyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-chloro-5-fluoropyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-chloropyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4-methylpyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(o-tolyl)cyclopropane-1-carbonyl)-L-homoserine; N-(1-(6-methoxypyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; 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; 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; 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; 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; N-(1-(3-methylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(quinazolin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-chloro-5-methoxypyridin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-chloro-5-methylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-cyano-6-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-(difluoromethoxy)pyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; N-(1-(3-(difluoromethyl)pyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-methylpyrazin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-cyano-4-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; 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; N-(1-(5-chloropyrimidin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; 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; N-(1-(2-cyano-6-methoxyphenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; 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; 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; N-(1-(4-chloro-6-methoxypyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(6-chloro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-chloro-6-oxo-1,6-dihydropyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(3-(trifluoromethyl)pyrazin-2-yl)cyclopropane-1-carbonyl)-L-homoserine; N-(1-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3,5-dichloro-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; O-(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; N-(1-(4-chloro-1H-pyrazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(5-chloro-3-methyl-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(5-chloro-2-methylpyrimidin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(5-chloro-1H-pyrazol-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4-cyano-1-methyl-1H-pyrazol-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(5-chloro-3-oxo-2,3-dihydropyridazin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4-cyano-1H-pyrazol-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4-chloro-1H-imidazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4-chloro-1-methyl-1H-imidazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(5-chlorothiazol-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; and or a pharmaceutically acceptable salt thereof.

[0204] In one variation, the compounds detailed herein are selected from the group consisting of: N-(2-methyl-2-phenylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(2-(2,3-difluoro-6-methoxyphenyl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(2-(2-(difluoromethoxy)-6-fluorophenyl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(2-(2-chlorophenyl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-phenylcyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(pyrazin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(6-methylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(pyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; N-(1-(5-cyanopyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-methoxypyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-methoxypyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4,6-dimethylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4-chloro-2-methoxypyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-cyanophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-(methylsulfonyl)phenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-methoxypyrazin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; N-(1-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(3-chloro-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; N-(1-(3-cyclopropylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(4-chloro-6-oxo-1,6-dihydropyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(5-(difluoromethyl)-1H-imidazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; and N-(2-phenylacetyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; or a pharmaceutically acceptable salt thereof.

[0205] In one variation, the compounds detailed herein are selected from the group consisting of: N-(3-(difluoromethyl)tetrahydrofuran-3-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(trifluoromethyl)cyclohexane-1-carbonyl)-L-homoserine; N-(4-(4-fluorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; N-(4-(3-methoxyphenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(4-(3-fluorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(4-(3-chlorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; 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; 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; N-(1-(6-methoxy-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(6-fluoro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(6-bromo-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-(2-carbamoyl-6-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; O-(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; N-(1-phenyl-1H-pyrazole-3-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-phenyl-1H-pyrazole-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; N-(1-phenyl-1H-pyrazole-5-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine; O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(4-(trifluoromethyl)tetrahydro-2H-pyran-4-carbonyl)-L-homoserine; 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; 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; 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-homoserinic acid methyl ester; 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; or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments of the species cited herein, alkyl esters of the free acid species are also included, e.g., C1-C8 alkyl esters or C1-C4 alkyl esters. In such embodiments, alkyl esters of the free acid (e.g., homoseric acid esters), e.g., methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, sec-butyl ester, isobutyl ester, and tert-butyl ester, as well as various structural isomers of higher alkyl groups, such as C5-C8 alkyl esters, are also included.

[0207] In some embodiments, compositions, such as pharmaceutical compositions, are provided, comprising a compound selected from the group consisting of one or more of the compounds set forth in Table 1, or stereoisomers thereof (including mixtures of two or more thereof), or pharmaceutically acceptable salts thereof. In some embodiments, the composition comprises a compound selected from the group consisting of one or more salts of the compounds set forth in Table 1. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0208] In some embodiments, all salts of the compounds referred to herein, e.g., pharmaceutically acceptable salts, are included. In some embodiments, any or all stereochemical forms, including any enantiomeric or diastereomeric forms of the compounds, and any tautomeric or other forms, are included. Unless stereochemistry is explicitly stated in a chemical structure or chemical name, the structure or name is intended to encompass all possible stereoisomers of the depicted compound. In some embodiments, all forms of the compounds, such as crystalline or amorphous forms, are included. In some embodiments, prodrugs, solvates, and metabolites of the compounds are included. Compositions comprising compounds of Formula (A) or Formula (I), e.g., compositions of substantially pure compounds comprising a particular stereochemical form thereof, are also contemplated. In some embodiments, compositions comprising mixtures of compounds of Formula (A) or Formula (I) in any ratio are also included, including mixtures of two or more stereochemical forms of a compound of Formula (A) or Formula (I) in any ratio, e.g., racemic, non-racemic, enantiomerically enriched, and scameric mixtures of the compounds. In some embodiments, when one or more tertiary amine moieties are present in the compound, an N-oxide is also provided and described.

[0209] Additionally, there is provided a pharmaceutical composition comprising a compound of formula (A), or any variation thereof detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient.

[0210] Additionally, there is provided a pharmaceutical composition comprising a compound of formula (I), or any variation thereof detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient.

[0211] Also provided is a pharmaceutical composition comprising a compound of Formula (A), or any variation thereof detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), a checkpoint inhibitor, and a pharmaceutically acceptable carrier or excipient.

[0212] Also provided is a pharmaceutical composition comprising a compound of formula (I), or any variation thereof detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), a checkpoint inhibitor, and a pharmaceutically acceptable carrier or excipient.

[0213] 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.

[0214] As used herein, "PD-1" checkpoint inhibitors can include, for example, pembrolizumab (also known as MK-3475, lambrolizumab, or Keytruda), which targets melanoma, non-small cell lung cancer, and squamous cell carcinoma of the head and neck; 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; tislelizumab, which targets, for example, solid tumors and hematological cancers; toripalimab; dostallimab; INCMGA00012 (MGA012); AMP-224; and AMP-514.

[0215] As used herein, "PD-L1" checkpoint inhibitors can include, for example, atezolizumab (Tecentriq), which targets 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 (e.g., unresectable non-small cell lung cancer after chemoradiation therapy); KN035; CK-301; and BMS-986189.

[0216] As used herein, "CTLA4" checkpoint inhibitors can include, for example, ipilimumab, which targets melanoma, lung cancer, and pancreatic cancer; and tremelimumab, which targets, for example, melanoma, mesothelioma, and non-small cell lung cancer.

[0217] Other checkpoint inhibitors may include dual acting compounds, such as AUNP12, a PD-1 / PD-L1 dual inhibitor; and CA-170, a PD-L1 and VISTA antagonist.

[0218] Thus, in various embodiments, the checkpoint inhibitor comprises at least one of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, INCMGA00012, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab.

[0219] Furthermore, α V β1, α V β6 and α V Provided is the use of a compound of Formula (A) or Formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of a disease mediated by cells expressing one or more of β8.

[0220] In various embodiments, α in combination with a checkpoint inhibitor. V β1, α V β6 and α VFurther provided is the use of a compound of Formula (A) or Formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of a disease mediated by cells expressing one or more of β8. In some 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. For example, in some embodiments, the checkpoint inhibitor comprises at least one of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, INCMGA00012, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab. In some embodiments, pembrolizumab is administered at about 200 mg every three weeks or about 400 mg every six weeks. In some embodiments, pembrolizumab is administered as an injection (about 25 mg / mL) via an infusion.

[0221] Also provided are methods of treating a subject in need thereof. In some embodiments, the method includes providing a 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 elevated value compared to a normal value in the tissue in a healthy state. In some embodiments, the tissue is characterized by at least one elevated value in α V In some embodiments, the tissue has elevated levels of β1 integrin activity and / or expression. V In some embodiments, the tissue has elevated levels of β6 integrin activity and / or expression. VIn some embodiments, the tissue has an elevated level of β8 integrin activity and / or expression. In some embodiments, the tissue has an elevated level of pSMAD / SMAD ratio. In some embodiments, the tissue has an elevated level of new collagen formation or accumulation. In some embodiments, the tissue has an elevated level of total collagen. In some embodiments, the tissue has an elevated level of type I collagen gene Col1a1 expression. In some embodiments, the tissue has an elevated level of perforin. In some embodiments, the tissue has an elevated level of granzyme B. In some embodiments, the tissue has 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) or Formula (I), or any variation thereof detailed herein, 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 at least one of the values.

[0222] In some embodiments, administering a therapeutically effective amount of the compound reduces at least one value.For example, in some embodiments, at least one value is measured after at least one administration of the compound to a subject, and the post-administration value is determined.In some embodiments, at least one administration of the compound is therapeutically effective if the post-administration value is reduced compared to at least one value.In some embodiments, at least one administration of the compound is therapeutically effective if the post-administration value is approximately the same as a healthy value.

[0223] In some embodiments, the methods include decreasing the activity and / or expression, e.g., activity, of a particular integrin. For example, in some embodiments, the methods include decreasing the activity and / or expression, e.g., activity, of a particular integrin. V In some embodiments, the method comprises decreasing the activity and / or expression of α V In some embodiments, the method comprises decreasing the activity and / or expression of α V β1 and αV In some embodiments, the method comprises decreasing the activity and / or expression of α V β6 and α V In some embodiments, the method comprises decreasing the activity and / or expression of α V β1, α V β6 and α V In some embodiments, decreasing the activity and / or expression of each integrin comprises decreasing the activity and / or expression of at least one other αβ in the subject. V It is selective compared to the containing integrin.

[0224] In some embodiments, α V The activity of β1 integrin is decreased in one or more fibroblasts of the subject. V The activity of β6 integrin is decreased in one or more epithelial cells of the subject. V The activity of β8 integrin is decreased in one or more epithelial or cancer cells of the subject.

[0225] In various embodiments, the at least one tissue of the subject comprises lung tissue. In some embodiments, the at least one tissue of the subject comprises liver tissue. In some embodiments, the at least one tissue of the subject comprises skin tissue. In some embodiments, the at least one tissue of the subject comprises heart tissue. In some embodiments, the at least one tissue of the subject comprises kidney tissue. In some embodiments, the at least one tissue of the subject comprises gastrointestinal tissue. In some embodiments, the at least one tissue of the subject comprises gallbladder tissue. In some embodiments, the at least one tissue of the subject comprises bile duct tissue. In some embodiments, the at least one tissue of the subject comprises intrahepatic biliary tissue. In some embodiments, the at least one tissue of the subject comprises extrahepatic biliary tissue. In some embodiments, the at least one tissue of the subject comprises intrahepatic biliary tissue and extrahepatic biliary tissue.

[0226] In some embodiments, the at least one tissue of the subject comprises brain tissue. In some embodiments, the at least one tissue of the subject comprises lymph node tissue. In some embodiments, the at least one tissue of the subject comprises stomach tissue. In some embodiments, the at least one tissue of the subject comprises urethral tissue. In some embodiments, the at least one tissue of the subject comprises bladder tissue. In some embodiments, the at least one tissue of the subject comprises prostate tissue. In some embodiments, the at least one tissue of the subject comprises pancreatic tissue. In some embodiments, the at least one tissue of the subject comprises mesothelial tissue. In some embodiments, the at least one tissue of the subject comprises breast tissue.

[0227] In various embodiments, the tissue has elevated pSMAD2 / SMAD2 levels compared to the tissue in a healthy state. In some embodiments, the tissue has elevated pSMAD3 / SMAD3 levels compared to the tissue in a healthy state.

[0228] In various embodiments, the tissue comprises ocular tissue. In some embodiments, the ocular tissue comprises α V β1, α V β6 and α V They express one, two, or three integrins selected from β8.

[0229] In some embodiments, the subject has cancer. In some embodiments, the subject has cancer selected from the group consisting of melanoma, colon cancer, breast cancer, prostate cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung carcinoma, 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 carcinoma. 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.

[0230] In some embodiments, the subject has a solid tumor. In some embodiments, the subject has a cancer selected from the group consisting of breast cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung carcinoma, 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).

[0231] 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.

[0232] Also provided are methods for characterizing the anti-cancer activity of a small molecule inhibitor in a subject. In some embodiments, the method includes 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 β (TGF-β) from latent peptide TGF-β. In some embodiments, the method includes determining a first value from 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-γ level. In some embodiments, the method includes administering a small molecule to the subject. In some embodiments, the method includes providing a second live cell sample from the subject. In some embodiments, the second live cell sample is obtained from the same tissue as the first live cell sample from the subject. In some embodiments, the method includes determining a second value from a second live cell sample. In some embodiments, the second value corresponds to the pSMAD2 / SMAD2 ratio, pSMAD3 / SMAD3 ratio, perforin level, granzyme B level, or interferon-γ level of the first value. In some embodiments, the method includes characterizing the anti-cancer activity of the small molecule in the subject by comparing the second value to the first value.

[0233] 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 the blood of the subject. In some embodiments, at least one tissue of the subject comprises skin. In some embodiments, at least one tissue of the subject comprises lung. In some embodiments, at least one tissue of the subject comprises brain. In some embodiments, at least one tissue of the subject comprises lymph node. In some embodiments, at least one tissue of the subject comprises stomach. In some embodiments, at least one tissue of the subject comprises urethra. In some embodiments, at least one tissue of the subject comprises kidney. In some embodiments, at least one tissue of the subject comprises bladder. In some embodiments, at least one tissue of the subject comprises prostate. In some embodiments, at least one tissue of the subject comprises liver. In some embodiments, at least one tissue of the subject comprises pancreas. In some embodiments, at least one tissue of the subject comprises mesothelium. In some embodiments, at least one tissue of the subject comprises breast.

[0234] In some embodiments, at least one integrin is α V In some embodiments, at least one integrin comprises α V In some embodiments, at least one integrin is α V In some embodiments, at least one integrin is α V In some embodiments, at least one integrin is α V β1 and α V In some embodiments, at least one integrin is α V β6 and α V In some embodiments, at least one integrin is α V β1, α V β6 and α VIn some embodiments, the first value and the second value are pSMAD2 / SMAD2 ratios or pSMAD3 / SMAD3 ratios.

[0235] In various embodiments, administering the small molecule to the subject comprises administering any aspect of a compound of Formula (A) or Formula (I), or a salt thereof, or a pharmaceutical composition thereof, as described herein. In some embodiments, the method further comprises administering a checkpoint inhibitor to the subject. 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 in combination with a checkpoint inhibitor.

[0236] In some embodiments, the subject has breast cancer. In some embodiments, an effective amount of Compound 39 is administered to the subject. In some embodiments, the effective amount of Compound 39 is administered to the subject 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, an effective amount of Compound 39 is administered to the subject in a dose over a period of time. In some embodiments, the dose is about 135 mg to about 150 mg per kg of the subject's body weight. In some embodiments, the dose is about 144 mg per kg of the subject's body weight. In some embodiments, the period is about 20 days, about 25 days, or about 30 days. In some embodiments, the period is about 28 days. In some embodiments, the mAbs anti-mPD-1 and anti-α V In some embodiments, the mAbs anti-mPD-1 and anti-α are administered to the subject. VAt least one of the β8 is administered to the subject by intraperitoneal injection in PBS. In some embodiments, the mAbs are anti-mPD-1 and anti-α V In some embodiments, at least one of the β8 is administered to the subject by intraperitoneal injection in PBS at a dose of about 10 mg / kg of the subject's body weight at a frequency over a period of time. V At least one of β8 is administered to a subject by intraperitoneal injection in PBS at a dose of about 10 mg per kg of the subject's body weight twice a week for a period of two weeks. In some embodiments, administering Compound 39 plus anti-mPD-1 to a subject reduces tumor volume in a subject with breast cancer. In some embodiments, administering Compound 39 plus anti-α8 to a subject with breast cancer reduces tumor volume in a subject with breast cancer. V Administration of β8+ anti-mPD-1 reduces tumor growth and volume. In some embodiments, administration of Compound 39 to a subject with breast cancer reduces tumor growth.

[0237] In some embodiments, the subject has pancreatic cancer. In some embodiments, an effective amount of Compound 39 is administered to the subject. In some embodiments, the effective amount of Compound 39 is administered to the subject 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, an effective amount of Compound 39 is administered to the subject in a dose over a period of time. In some embodiments, the dose is about 135 mg to about 150 mg per kg of the subject's body weight. In some embodiments, the dose is about 144 mg per kg of the subject's body weight. In some embodiments, the period is about 20 days, about 25 days, or about 30 days. In some embodiments, the period is about 28 days. In some embodiments, the mAbs anti-mPD-1 and anti-α V In some embodiments, the mAbs anti-mPD-1 and anti-α are administered to the subject. V At least one of the β8 is administered to the subject by intraperitoneal injection in PBS. In some embodiments, the mAbs are anti-mPD-1 and anti-α V In some embodiments, at least one of the β8 is administered to the subject by intraperitoneal injection in PBS at a dose of about 10 mg / kg of the subject's body weight at a frequency over a period of time. V At least one of β8 is administered to a subject by intraperitoneal injection in PBS at a dose of about 10 mg per kg of the subject's body weight twice a week for a period of two weeks. In some embodiments, administering compound 39 to a subject with pancreatic cancer reduces tumor growth.

[0238] In some embodiments, the subject has colon cancer. In some embodiments, an effective amount of Compound 39 is administered to the subject. In some embodiments, the effective amount of Compound 39 is administered to the subject 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, an effective amount of Compound 39 is administered to the subject in a dose over a period of time. In some embodiments, the dose is about 135 mg to about 150 mg per kg of the subject's body weight. In some embodiments, the dose is about 144 mg per kg of the subject's body weight. In some embodiments, the period is about 20 days, about 25 days, or about 30 days. In some embodiments, the period is about 28 days. In some embodiments, the mAbs anti-mPD-1 and anti-α V In some embodiments, the mAbs anti-mPD-1 and anti-α are administered to the subject. V At least one of the β8 is administered to the subject by intraperitoneal injection in PBS. In some embodiments, the mAbs are anti-mPD-1 and anti-α V In some embodiments, at least one of the β8 is administered to the subject by intraperitoneal injection in PBS at a dose of about 10 mg / kg of the subject's body weight at a frequency over a period of time. V At least one of β8 is administered to a subject by intraperitoneal injection in PBS at a dose of about 10 mg per kg of the subject's body weight twice a week for a period of two weeks. In some embodiments, administering compound 39 to a subject with colon cancer reduces tumor growth.

[0239] In some embodiments, the subject has pancreatic ductal adenocarcinoma (PDAC). In some embodiments, a compound of Formula (A) or Formula (I) is administered to a subject with PDAC via an administration route at a dosing frequency. In some embodiments, the compound of Formula (A) or Formula (I) is Compound 39. In some embodiments, the administration route is oral gavage. In some embodiments, the administration route is oral gavage at a dosage level and a dosage amount. In some embodiments, the dosage level is about 300 mg / kg BID and the dosage amount is about 5 to about 10 mL / kg. In some embodiments, the administration frequency is once daily for a period of time. In some embodiments, the period of time is 1 week, 2 weeks, 3 weeks, 1 month, 2 months, or 3 months. In some embodiments, the compound of Formula (A) or Formula (I) is administered in a solution. In some embodiments, the solution comprises at least one of an alcohol and a buffer. 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, a compound of Formula (A) or Formula (I) is administered to a subject via oral gavage at a dose of about 300 mg / kg body weight for a period of about 20 to about 25 days or about 75 to about 85 days. In some embodiments, a compound of Formula (A) or Formula (I) is administered to a subject via oral gavage at a dose of about 300 mg / kg body weight for a period of about 22 days or about 80 days.

[0240] In some embodiments, the compound of Formula (A) or Formula (I) is co-administered with an antibody for a period of time. In some embodiments, the compound of Formula (A) or Formula (I) is administered before administration of the antibody. In some embodiments, the compound of Formula (A) or Formula (I) is administered after administration of the antibody. In some embodiments, the antibody is anti-PD-1. In some embodiments, the subject is administered anti-PD-1 in a buffer solution by intraperitoneal injection. In some embodiments, the subject is administered anti-PD-1 in PBS at a dose of 10 mg / kg body weight by intraperitoneal injection twice weekly for a period of time. In some embodiments, the subject is administered anti-PD-1 in PBS at a dose of about 10 mg / kg body weight by intraperitoneal injection twice weekly for a period of two weeks. In some embodiments, administration of Compound 39 with anti-PD-1 reduces the weight of a KPC tumor in the subject. In some embodiments, administration of Compound 39 with anti-PD-1 reduces CD8 expression in the subject's KPC tumor. + T cell infiltration, CD4 in KPC tumors of interest + At least one of T cell infiltration and survival of subjects with KPC tumors is increased.

[0241] In some embodiments, a compound of Formula (A) or Formula (I) is administered to a subject with PDAC via an administration route at a dosing frequency. In some embodiments, the compound of Formula (A) or Formula (I) is Compound 39. In some embodiments, the administration route is oral gavage. In some embodiments, the administration route is oral gavage at a dosage level. In some embodiments, the dosage level is about 300 mg / kg BID. In some embodiments, the administration frequency is once a month.

[0242] In some embodiments, the 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 before the administration of the chemotherapeutic agent. In some embodiments, the compound of Formula (A) or Formula (I) is administered after the administration of the chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is gemcitabine or abraxane. In some embodiments, administering 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 metastases in the subject. In some embodiments, administering the compound of Formula (A) or Formula (I) reduces lung metastases in the subject.

[0243] In some embodiments, the 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, the compound of Formula (A) or Formula (I) is administered before the administration of the chemotherapy regimen. In some embodiments, the compound of Formula (A) or Formula (I) is administered after the administration of the chemotherapy regimen. In some embodiments, administering a chemotherapy regimen in combination with a compound of Formula (A) or Formula (I) reduces tumor weight in a subject. In some embodiments, administering 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.

[0244] 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 refractory. In some embodiments, the subject is a human subject at least 18 years of age. In some embodiments, the subject has received immunotherapy multiple times. In some embodiments, the subject has received immunotherapy at least three times. In some embodiments, the subject has received immunotherapy at least three times (200 mg Q3W). In some embodiments, the immunotherapy is pembrolizumab. In some embodiments, the subject has evidence of disease progression at least 1 month after initiation of immunotherapy. In some embodiments, the subject has evidence of disease progression at least 2 months after initiation of immunotherapy. In some embodiments, the subject has evidence of disease progression at least 3 months after initiation of immunotherapy. In some embodiments, the subject has no other available treatment options. In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status 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, no transfusions (packed red blood cells and platelets) in the past 28 days prior to treatment initiation, absolute neutrophil count (ANC) > 1.5 x 10 / L, absence of features on peripheral blood smear suggestive of myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML), platelet count > 100 x 10 / L, white blood cells (WBC) > 3 x 10 / L, total bilirubin < 1.5 x the institutional upper limit of normal, and aspartate transaminase (AST) (SGOT) / alanine transaminase (ALT) (SGPT) < 2.5 x the institutional upper limit of normal. In some embodiments, compound 39 is administered to the subject as monotherapy over a period of time.In some embodiments, the duration 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 duration 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 3 weeks, or at least 1 month. In some embodiments, immunotherapy is administered to a subject in combination with Compound 39 at a frequency starting on day 15. In some embodiments, the frequency is daily, weekly, every 2 weeks, every 3 weeks, or monthly. In some embodiments, pembrolizumab (200 mg Q3W) in combination with Compound 39 is administered to a subject on day 15 every 3 weeks. In some embodiments, dose escalation is determined by a Bayesian optimal interval (BOIN) dose escalation design. In some embodiments, dose levels include multiple levels. In some embodiments, the starting dose of Compound 39 is administered to a target number of subjects in a treatment cohort. In some embodiments, administration of Compound 39 is discontinued if a stopping rule is met. In some embodiments, if the stopping rules are not met, a hypothetical dose-limiting toxicity (DLT) incidence rate is calculated. The hypothetical DLT incidence rate is calculated as (the number of subjects who experience at least one DLT at the current dose during the DLT assessment period) / (the total number of subjects exposed to the current dose). In some embodiments, the target DLT incidence rate is 30%, indicating that fewer than one in three subjects experience at least one DLT at the current dose during the DLT assessment period. In some embodiments, if zero subjects experience a DLT and the DLT incidence rate is 23.7% or less, dose escalation is performed. In some embodiments, if one in three subjects experience a DLT and the DLT incidence rate is 23.7% to 35.9% (e.g., 95% confidence interval), the current dose is maintained and the cohort is expanded. In some embodiments, if two in three subjects experience a DLT and the DLT incidence rate is greater than 35.9%, dose deescalation is performed.In some embodiments, a Simon two-stage design is used following the dose escalation and dose expansion cohorts. In some embodiments, biomarkers are collected from subjects over a period of time. In some embodiments, the period is 28 days. In some embodiments, the biomarkers include circulating immune cells, circulating markers, circulating tumor DNA, and archived tissue. In some embodiments, the circulating immune cells are obtained using a CyTOF human immune panel. In some embodiments, the circulating markers include Pro-C3, C4G, GzmB, IFNγ, IL-10, PD-1, PD-L1, TNFα, CXCL9, CCXL12, VEGFα, and α. V β8 is included. In some embodiments, archival tissue is obtained using RNA-Seq technology. In some embodiments, treatment is terminated when one or more endpoints are reached.

[0245] The compounds described herein are V β8 integrin, α V β1 integrin and α V For example, in some embodiments, the compound comprises an inhibitor of at least one of β6 integrin. V In some embodiments, the compound inhibits β8 integrin. V In some cases, it is desirable for the compound to inhibit more than one integrin. For example, in some embodiments, the compound inhibits α V β8 integrin and α V In some embodiments, the compound inhibits β1 integrin. V β8 integrin and α V In some embodiments, the compound inhibits β6 integrin. V β8 integrin, α V β1 integrin and α V Inhibits β6 integrin.

[0246] In some cases, it is desirable to avoid inhibition of other integrins. In some embodiments, the compound is a selective α V β8 integrin inhibitors. For example, in some embodiments, the compound is an α V β1, α V β6, α V β3, α V Selective α that does not substantially inhibit one or more integrins, such as β5, α4β1, or α5β1 V In some embodiments, the compound is an α8 integrin inhibitor. V Selective α with virtually no inhibition of β1 integrin V In some embodiments, the compound is an α8 integrin inhibitor. V Selective α with virtually no inhibition of β6 integrin V In some embodiments, the compound is an α8 integrin inhibitor. V β1 integrin or α V Selective α with virtually no inhibition of β6 integrin V In some embodiments, the compound is an α8 integrin inhibitor. V Selective α with virtually no inhibition of β3 integrin V In some embodiments, the compound is an α8 integrin inhibitor. V Selective α with virtually no inhibition of β5 integrin V In some embodiments, the compound is an α8 integrin inhibitor. V β3 integrin or α V Selective α with virtually no inhibition of β5 integrin V In some embodiments, the compound is a selective α4β1 integrin inhibitor that does not substantially inhibit α4β1 integrin. V In some embodiments, the compound is a selective αβ integrin inhibitor that does not substantially inhibit αβ integrin. V In some embodiments, the compound is a selective αβ integrin inhibitor that does not substantially inhibit α4β1 integrin or α5β1 integrin.V In some embodiments, the compound is an α8 integrin inhibitor. V β3 integrin, α V A selective α that does not substantially inhibit β5 integrin, α4β1 integrin, or α5β1 integrin V In some embodiments, the compound is an α8 integrin inhibitor. V β6 integrin, α V β3 integrin, α V A selective α that does not substantially inhibit β5 integrin, α4β1 integrin, or α5β1 integrin V In some embodiments, the compound is an α8 integrin inhibitor. V β1 integrin, α V β3 integrin, α V A selective α that does not substantially inhibit β5 integrin, α4β1 integrin, or α5β1 integrin V In some embodiments, the compound is an α8 integrin inhibitor. V β1 integrin, α V β6 integrin, α V β3 integrin, α V A selective α that does not substantially inhibit β5 integrin, α4β1 integrin, or α5β1 integrin V It is a β8 integrin inhibitor.

[0247] In some embodiments, isotopically labeled and / or isotopically enriched forms of compounds of Formula (A) or Formula (I) are included. The compounds herein may also contain unconventional proportions of atomic isotopes at one or more of the atoms constituting such compounds. In some embodiments, the compounds are isotopically labeled, e.g., are isotopically labeled compounds of Formula (A) or Formula (I) or variations thereof described herein, in which one or more atoms are replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into compounds of Formula (A) or Formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and chlorine, e.g., 2 H, 3H, 11 C. 13 C. 14 C. 13 N, 15 O. 17 O. 32 P, 35 S, 18 F, 36 Cl. Deuterium ( 2 Incorporation of heavier isotopes, such as H or D, may be preferred in some circumstances because they may confer certain therapeutic advantages due to increased metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, provided herein are isotopically enriched forms of any of the formulas described herein, wherein the compound contains one or more deuterium atoms. In some embodiments, compounds of Formula (A) or Formula (I) have one or more of their hydrogen atoms replaced by deuterium. Certain groups may be preferentially labeled with deuterium, for example, a cyclopropyl group may have one or more attached hydrogen atoms replaced with deuterium atoms, or may be perdeuterated.

[0248] 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 procedures similar to those described in the accompanying Examples, substituting the corresponding, appropriately isotopically labeled reagent for the unlabeled reagent.

[0249] In some embodiments, the metabolites include any or all of the metabolites of the described compounds. In some embodiments, the metabolites include any chemical species produced by the biotransformation of any of the described compounds, for example, intermediates and products of metabolism of the compounds.

[0250] An article of manufacture is provided comprising a compound of Formula (A) or Formula (I), or a salt or solvate thereof, in a suitable container. In some embodiments, the container is a vial, jar, ampoule, pre-filled syringe, or intravenous bag, etc.

[0251] Preferably, the compounds detailed herein are orally bioavailable. However, the compounds can also be formulated for parenteral (e.g., intravenous) administration.

[0252] One or more compounds described herein can be used to prepare a medicament by combining one or more compounds as an active ingredient with a pharmacologically acceptable carrier known in the art. Depending on the therapeutic form of the medicament, the carrier can be in various forms.

[0253] General synthesis method Compounds of Formula (A) or Formula (I) can be prepared by a number of processes (such as the schemes provided below) outlined below and detailed in the Examples below. In describing the processes below, it will be understood that the symbols used in the formulas shown represent the groups described above in connection with the formulas herein.

[0254] If it is desired to obtain a specific stereoisomer of a compound, this can be achieved by using any conventional procedure suitable for separating stereoisomers or separating enantiomers from the corresponding stereoisomeric mixture.Thus, for example, diastereomeric derivatives can be produced by reacting an enantiomeric mixture, for example, a racemate, with a suitable chiral compound.The diastereomers can then be separated by any convenient means, for example, by crystallization, and the desired enantiomer can be recovered.In another resolution process, chiral high performance liquid chromatography can be used to separate the racemate.Alternatively, if desired, a specific stereoisomer can be obtained by using a suitable chiral intermediate in one of the processes described.

[0255] Chromatography, recrystallization, and other conventional separation procedures may also be used on intermediates or final products when it is desired to obtain a particular isomer of a compound or to otherwise purify a reaction product.

[0256] Solvates and / or polymorphs of the compounds provided herein or their pharmaceutically acceptable salts are also contemplated. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are often formed during crystallization. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Polymorphs involve different crystal packing arrangements for compounds with the same elemental composition. 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, such as the recrystallization solvent, crystallization rate, and storage temperature, can lead to the formation of a single crystal.

[0257] 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).

[0258] Scheme A [ka] Intermediate 1A was prepared according to US20200109141A1, which is incorporated herein by reference in its entirety.

[0259] Scheme B [ka] Intermediate 1B was prepared according to US20200109141A1, which is incorporated herein by reference in its entirety.

[0260] Scheme C [ka] The procedure of Greszler et al. Org. Lett. 2017, 19, 2490-2493, which is incorporated herein by reference in its entirety, was adapted.

[0261] Scheme D [ka] Scheme E [ka] Scheme F [ka] Scheme G [ka] Scheme H [ka] Scheme I [ka] Scheme J [ka] Scheme K [ka] Scheme L [ka] It is understood that the above schemes can be modified to arrive at a variety of 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 4" thedition, Wiley-Interscience, New York, 2006, which is incorporated herein by reference in its entirety.

[0262] Additional methods for preparing compounds according to Formula (A) or Formula (I) and salts thereof are provided in the Examples. As one of ordinary skill in the art will recognize, the preparative methods taught herein can be modified to provide additional compounds within the scope of Formula (A) or Formula (I), for example, by selecting starting materials that will provide the desired compound.

[0263] Pharmaceutical Compositions and Formulations Also provided are pharmaceutical compositions of any of the compounds detailed herein, e.g., 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 compounds 1-82 shown in Table 1, or compounds 83-104 shown in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a mixture thereof. Thus, in some embodiments, a pharmaceutical composition is provided comprising a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions according to the present disclosure may be in a form suitable for oral, buccal, parenteral, nasal, topical, or rectal administration, or in a form suitable for administration by inhalation. In some embodiments, the pharmaceutical composition is prepared from a mixture of any of the compounds detailed herein or their salts. In some embodiments, the pharmaceutical composition is a controlled-release composition of any of the compounds detailed herein.

[0264] Pharmaceutical compositions of any of the compounds detailed herein, e.g., 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 one of compounds 1-82 or a stereoisomer thereof, or any one of compounds 83-104 or a stereoisomer thereof shown in Table 1, or a pharmaceutically acceptable salt thereof, or a mixture thereof, are also provided.

[0265] In one aspect, the compounds detailed herein can be in purified form, and compositions comprising the compounds in purified form are described herein. In some embodiments, the compositions have about 35% or less impurities, where impurities refer to compounds other than the compound or a pharmaceutically acceptable salt thereof that make up the majority of the composition. For example, in some embodiments, a composition of a compound selected from the compounds of Table 1 contains about 35% or less impurities, where impurities refer to compounds other than the compound of Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains about 25% or less impurities. In some embodiments, the composition contains about 20% or less impurities. In still further embodiments, a composition comprising a compound detailed herein or a pharmaceutically acceptable salt thereof is provided as a composition of substantially pure compound. A "substantially pure" composition is a composition containing about 10% or less impurities, e.g., less than about 9%, about 7%, about 5%, about 3%, about 1%, or about 0.5% impurities. In some embodiments, a composition containing a compound detailed herein or a pharmaceutically acceptable salt thereof is in substantially pure form. In yet another variation, a composition of a substantially pure compound or a pharmaceutically acceptable salt thereof is provided, wherein the composition contains about 10% or less of impurities. In a further variation, a composition of a substantially pure compound or a pharmaceutically acceptable salt thereof is provided, wherein the composition contains about 9% or less of impurities. In a further variation, a composition of a substantially pure compound or a pharmaceutically acceptable salt thereof is provided, wherein the composition contains about 7% or less of impurities. In a further variation, a composition of a substantially pure compound or a pharmaceutically acceptable salt thereof is provided, wherein the composition contains about 5% or less of impurities. In another variation, a composition of a substantially pure compound or a pharmaceutically acceptable salt thereof is provided, wherein the composition contains about 3% or less of impurities. In yet another variation, a composition of a substantially pure compound or a pharmaceutically acceptable salt thereof is provided, wherein the composition contains about 1% or less of impurities.In a further variation, a composition of a substantially pure compound or a pharmaceutically acceptable salt thereof is provided, wherein the composition contains about 0.5% or less of impurities. In yet another variation, a composition of a substantially pure compound means that the composition contains about 10% or less, or preferably about 5% or less, or more preferably about 3% or less, or even more preferably about 1% or less of impurities, or most preferably about 0.5% or less of impurities, which may be compounds of different stereochemical forms. For example, a composition of a substantially pure (S) compound means that the composition contains about 10% or less, or about 5% or less, or about 3% or less, or about 1% or less, or about 0.5% or less of the I form of the compound.

[0266] In further embodiments, purified and substantially pure forms of compounds are provided 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-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 one of Compounds 1-82, Compounds 83-104, or stereoisomers thereof.

[0267] 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 are provided herein comprising the compounds detailed herein and a pharmaceutically acceptable carrier or excipient. In another variation, methods of administering the compounds are provided. Purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for any of the compounds or forms thereof detailed herein.

[0268] The compounds detailed herein, or pharmaceutically acceptable salts thereof, can be formulated for any available delivery route, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. The compounds, or pharmaceutically acceptable salts thereof, can be formulated with a suitable carrier to provide a delivery form, including, but not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, poultices (cowplasters), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal drops or inhalants), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs.

[0269] One or more compounds described herein or pharmaceutically acceptable salts thereof can be used to prepare formulations such as pharmaceutical preparations by combining one or more compounds or pharmaceutically acceptable salts thereof as active ingredients with pharmaceutically acceptable carriers such as those described above. Depending on the therapeutic form of the system (e.g., transdermal patch or oral tablet), the carrier can be in various forms. In addition, pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, colorants, adjusters, salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants. Formulations containing compounds can also contain other substances with beneficial therapeutic properties. Pharmaceutical preparations can be prepared by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21 st ed. (2005), which is incorporated herein by reference in its entirety.

[0270] The compounds described herein can be administered to individuals (e.g., humans) in the form of commonly accepted oral compositions, such as tablets, coated tablets, and hard or soft-shelled gel capsules, emulsions, or suspensions. Examples of carriers that can be used to prepare such compositions include lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. Acceptable carriers for soft-shelled gel capsules include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, colorants, adjusters, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants.

[0271] Any of the compounds described herein can be formulated into a tablet of any of the dosage forms described, for example, a compound described herein or a pharmaceutically acceptable salt thereof can be formulated as an approximately 10 mg tablet.

[0272] Compositions comprising the compounds provided herein are also described. In one variation, the composition comprises the compound and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of a substantially pure compound is provided. In some embodiments, the composition is for use in human or veterinary medicine. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in treating a disease or disorder described herein.

[0273] How to use Compounds and compositions, e.g., pharmaceutical compositions containing a compound of any formula provided herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient, can be used in the methods of administration and treatment provided herein. In some embodiments, the compounds and compositions are used in in vitro methods, such as in vitro methods in which the compound or composition is administered to cells for screening purposes and / or to perform quality control assays.

[0274] 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, e.g., 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 set forth 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, e.g., has or is suspected of having a fibrotic disease. In some embodiments, variations of a compound include any stereoisomer thereof.

[0275] In a further aspect, there is provided a method of treating a fibrotic disease in an individual in need thereof, 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-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 set forth 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, e.g., a human having or suspected of having a fibrotic disease. In some embodiments, variations of the compound include any stereoisomer thereof.

[0276] In another aspect, a method is provided for delaying the onset and / or development of a fibrotic disease in an individual (e.g., a human) at risk of developing a fibrotic disease. It is recognized that delaying development can encompass prevention if the individual has not developed a fibrotic disease. In one aspect, an individual at risk of developing a fibrotic disease has or is suspected of developing one or more risk factors for developing a fibrotic disease. Risk factors for fibrotic disease can include the individual's age (e.g., middle-aged or elderly), the presence of inflammation, having one or more genetic factors associated with the development of a fibrotic disease, a medical history such as treatment with a drug or procedure believed to be associated with an increased susceptibility to fibrosis (e.g., radiation) or a medical condition believed to be associated with fibrosis, a smoking history, or the presence of occupational and / or environmental factors such as exposure to pollutants associated with the development of a fibrotic disease. In some embodiments, an individual at risk of developing a fibrotic disease has or is suspected of having NAFLD, NASH, CKD, scleroderma, Crohn's disease, NSIP, PSC, PBC, biliary atresia, or has suffered or is suspected of having a myocardial infarction.

[0277] 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).

[0278] 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).

[0279] In some embodiments, the fibrotic disease is pulmonary fibrosis, e.g., idiopathic pulmonary fibrosis (IPF), interstitial lung disease, interstitial lung disease associated with systemic sclerosis, or radiation-induced pulmonary fibrosis. In some embodiments, the individual at risk for developing a fibrotic disease has a history of, or is suspected of having, a viral lung infection.

[0280] 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.

[0281] In some embodiments, the fibrotic disease is fibrotic nonspecific interstitial pneumonia (NSIP).

[0282] In some embodiments, the fibrotic disease is liver fibrosis, for example, infectious liver fibrosis (caused by pathogens such as HCV, HBV, or parasites such as schistosomiasis), NASH, alcoholic liver disease-induced fibrosis, alcoholic steatosis-induced liver fibrosis, non-alcoholic fatty liver disease, biliary atresia, and cirrhosis.

[0283] In some embodiments, the fibrotic disease is biliary fibrosis.

[0284] In some embodiments, the fibrotic disease is renal fibrosis, e.g., diabetic kidney disease, diabetic nephrosclerosis, hypertensive nephrosclerosis, diabetic nephropathy, focal segmental glomerulosclerosis ("FSGS"), Alport syndrome, chronic kidney disease, and acute kidney injury due to contrast-induced nephropathy.

[0285] In some embodiments, the fibrotic disorder is systemic and localized sclerosis or scleroderma, keloids and hypertrophic scars, or post-surgical adhesions.

[0286] In some embodiments, the fibrotic disease is atherosclerosis or restenosis.

[0287] In some embodiments, the fibrotic disease is gastrointestinal fibrosis, for example, Crohn's disease.

[0288] In some embodiments, the fibrotic disease is cardiac fibrosis, for example, induced fibrosis after myocardial infarction and hereditary cardiomyopathies.

[0289] In one aspect, there is provided 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-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 a compound shown in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating a fibrotic disease.

[0290] Also provided is the use 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-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 shown in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.

[0291] In another embodiment, α in an individual V

[0013] Provided are methods of inhibiting β8 integrin, comprising administering a compound selected from 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-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 stereoisomer thereof, or a compound shown in Table 1, or a pharmaceutically acceptable salt thereof.

[0292] Also provided are methods of inhibiting TGFβ 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-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 shown in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. V β1, α V β6 and α V In some embodiments, the cells express one or more of α V In some embodiments, the cells express α V In some embodiments, the cells express α V In some embodiments, the cells express α V β1 and α V In some embodiments, the cells express α V β1 and α V In some embodiments, the cells express α V β6 and α V In some embodiments, the cells express α V β1, α V β6 and α V In some embodiments, the one or more cells are associated with the eye.

[0293] In some embodiments, the method includes administering a checkpoint inhibitor to the cell. 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 includes one or more of 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 checkpoint inhibitor is pembrolizumab, sold as Keytruda® (https: / / www.keytrudahcp.com / ; U.S. Patent Nos. 8,354,509 and 8,900,587, each of which is incorporated by reference in its entirety). In some embodiments, pembrolizumab is administered at about 200 mg every three weeks or about 400 mg every six weeks. In some embodiments, pembrolizumab is administered as an injection (about 25 mg / mL) via an infusion.

[0294] 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 melanoma, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung carcinoma, 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 may 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 alpha- V β1 integrin, α V β6 integrin and / or α V The cell is associated with a disease mediated by one or more of β8 integrins, such as a fibrotic disease or cancer. For example, in some embodiments, the cell is associated with one or more of pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis. In some embodiments, the cell is a human cell. In some embodiments, the one or more cells are associated with the eye. In some embodiments, the one or more cells are associated with α v β1, α v β6 and α v They express one, two, or three integrins selected from β8.

[0295] Also provided are methods of inhibiting at least one integrin in an individual in need thereof, comprising administering to the individual 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-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 shown in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In various embodiments of the methods, the compounds described herein are V β8 integrin, α V β1 integrin and α V In some embodiments, the compound inhibits at least one or more of the β6 integrins. V In some embodiments, the compound inhibits β8 integrin. V In some cases, it is desirable for the compound to inhibit more than one integrin. For example, in some embodiments, the compound inhibits α V β8 integrin and α V In some embodiments, the compound inhibits β1 integrin. V β8 integrin and α V In some embodiments, the compound inhibits β6 integrin. V β8 integrin, α V β1 integrin and α V In some embodiments, the compound inhibits the β6 integrin. In some cases, it is desirable to avoid inhibiting other integrins. In some embodiments, the compound inhibits the selective α V β8 integrin inhibitors. For example, in some embodiments, the compound is an α V β1, α V β6, α V β3, α VSelective α that does not substantially inhibit one or more integrins, such as β5, α4β1, or α5β1 V In some embodiments, the compound is an α8 integrin inhibitor. V Selective α with virtually no inhibition of β1 integrin V In some embodiments, the compound is an α8 integrin inhibitor. V Selective α with virtually no inhibition of β6 integrin V In some embodiments, the compound is an α8 integrin inhibitor. V β1 integrin or α V Selective α with virtually no inhibition of β6 integrin V In some embodiments, the compound is an α8 integrin inhibitor. V Selective α with virtually no inhibition of β3 integrin V In some embodiments, the compound is an α8 integrin inhibitor. V Selective α with virtually no inhibition of β5 integrin V In some embodiments, the compound is an α8 integrin inhibitor. V β3 integrin or α V Selective α with virtually no inhibition of β5 integrin V In some embodiments, the compound is a selective α4β1 integrin inhibitor that does not substantially inhibit α4β1 integrin. V In some embodiments, the compound is a selective αβ integrin inhibitor that does not substantially inhibit αβ integrin. V In some embodiments, the compound is a selective αβ integrin inhibitor that does not substantially inhibit α4β1 integrin or α5β1 integrin. V In some embodiments, the compound is an α8 integrin inhibitor. V β3 integrin, α V A selective α that does not substantially inhibit β5 integrin, α4β1 integrin, or α5β1 integrin VIn some embodiments, the compound is an α8 integrin inhibitor. V β6 integrin, α V β3 integrin, α V A selective α that does not substantially inhibit β5 integrin, α4β1 integrin, or α5β1 integrin V In some embodiments, the compound is an α8 integrin inhibitor. V β1 integrin, α V β3 integrin, α V A selective α that does not substantially inhibit β5 integrin, α4β1 integrin, or α5β1 integrin V In some embodiments, the compound is an α8 integrin inhibitor. V β1 integrin, α V β6 integrin, α V β3 integrin, α V A selective α that does not substantially inhibit β5 integrin, α4β1 integrin, or α5β1 integrin V β8 integrin inhibitors. In various embodiments of the methods, the compounds described herein inhibit at least one integrin and / or selectively inhibit one or more integrins in any combination described herein.

[0296] In all such embodiments, in one aspect, the inhibitory method is for an individual in need thereof, such as an individual having or suspected of having a fibrotic disease, and the method comprises administering to the individual 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-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 shown in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0297] Also provided is a method of modulating TGFβ activation in a cell, comprising contacting the cell with 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-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 stereoisomer thereof, or a compound selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof. In another embodiment, modulating comprises inhibiting TGFβ activation in the cell. In another embodiment, TGFβ activation is mediated by α in the cell. V β8 integrin, α V β1 integrin and α V It is mediated by at least one of the β6 integrins.

[0298] Also provided are methods of treating in a subject in need thereof, comprising administering to the subject a therapeutically effective amount 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-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 stereoisomer thereof, or a compound selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof, wherein the subject has at least one tissue in need of treatment, and the tissue exhibits TGFβ activation and / or expression; V β8 integrin activity and / or expression; α V β1 integrin activity and / or expression; or α VAlso provided are methods for treating a subject with an elevated level of at least one of β6 integrin activity and / or expression, wherein the at least one elevated level is elevated compared to healthy tissue. In some embodiments, the methods include administering to a subject an α6 integrin-containing compound, e.g., as described herein for compounds. V For example, in some embodiments, the method selectively inhibits at least one integrin as described herein relative to at least one other integrin, such as a α-containing integrin, for a compound. V α compared with β6 integrin V In some embodiments, the method selectively inhibits β8 integrin in a subject. V α compared to β1 integrins V In some embodiments, the method selectively inhibits β8 integrin in a subject. V β1 integrin and α V Compared with β6 integrin, α V In some embodiments, the method comprises administering to a subject an α8 integrin, e.g., as described herein, V α-containing integrins relative to one or more other integrins V β8 integrin and α V In some embodiments, the method comprises administering to a subject an α6 integrin, e.g., as described herein. V α-containing integrins relative to one or more other integrins V β8 integrin and α V In some embodiments, the method comprises selectively inhibiting β1 integrin in a subject, e.g., as described herein. V α-containing integrins relative to one or more other integrins V β8 integrin, α V β1 integrin and α V In some embodiments, the α6 integrin is selectively inhibited. Vβ1 integrin is inhibited in one or more fibroblasts of the subject. V β6 integrin is inhibited in one or more epithelial cells of the subject. In some embodiments, at least one tissue of the subject comprises one or more of lung tissue, liver tissue, skin tissue, heart tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue.

[0299] In some embodiments, the method includes administering a checkpoint inhibitor to the individual. 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 includes one or more of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, 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, sold as Keytruda® (https: / / www.keytrudahcp.com / ; U.S. Patent Nos. 8,354,509 and 8,900,587, each of which is incorporated by reference in its entirety). In some embodiments, pembrolizumab is administered at about 200 mg every three weeks or about 400 mg every six weeks. In some embodiments, pembrolizumab is administered as an injection (about 25 mg / mL) via an infusion.

[0300] In various embodiments, the individual in need of treatment has a solid tumor. In various embodiments, the individual in need of treatment has at least one of melanoma, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung carcinoma, 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 has pancreatic cancer. In some embodiments, the subject has pancreatic ductal adenocarcinoma (PDAC). In some embo...

Claims

1. Compound of formula (A): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, R １ is one or more R １ａ 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by one or more R １ｂ 1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by one or more R １ｃ 6-aminopyridin-2-yl optionally substituted by １ｄ (pyridin-2-yl)amino optionally substituted by R ２ is H or C １ -C ６ is alkyl, R ３ is H or C １ -C ６ Is it alkyl? Or, R ２ and R ３ together with the carbon atoms to which they are attached, form C ３ -C ６ cycloalkyl or 3- to 6-membered heterocyclyl, each of which is R ２ａ and optionally replaced by R ４ is phenyl, 5- to 6-membered heteroaryl, 6-membered heterocyclyl, or C １ -C ６ Haloalkyl wherein said 5- to 6-membered heteroaryl contains at least one nitrogen atom and is optionally fused to a phenyl group; said 6-membered heterocyclyl contains at least one nitrogen atom and is optionally fused to a phenyl group; The phenyl and the 5- to 6-membered heteroaryl may be one or more R ４ａ and optionally replaced by The 6-membered heterocyclyl is R ４ａ and oxo), or Or, R ２ , R ３ , and R ４ taken together form a 5-membered heteroaryl containing two nitrogen atoms and substituted with phenyl, wherein the phenyl group is substituted with one or more R ４ａ and optionally substituted by Each R ４ａ are independently halo, CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -(C １ -C ６ alkylene)-O-(C １ -C ６ alkyl), C ３ -C ６ Cycloalkyl, —OH, —O—(C １ -C ６ alkyl), —O—(C １ -C ６ haloalkyl), -S(O) ２ (C １ -C ６ alkyl), or —C(═O)—NH ２ Or Or, R ４ａ and R ２ together with the atom to which they are attached form a 6-membered heterocyclyl, wherein said heterocyclyl contains 1 oxygen atom; Q is H or C １ -C ８ is alkyl, L １ is one or more L １ａ C optionally substituted by ２ -C ４ is alkylene, L ２ is a bond or one or more L ２ａ C optionally substituted by １ -C ３ is alkylene, L ３ is one or more L ３ａ C optionally substituted by ２ -C ４ is alkylene, Y is a bond; R １ａ , R １ｂ , R １ｃ , R １ｄ , R ２ａ , L １ａ , L ２ａ , and L ３ａ are each independently R Ａ is selected from Two R on the same carbon atom １ａ The groups, optionally together with the carbon atoms to which they are attached, are C ３ -C ６ forming a cycloalkyl, Two R on the same carbon atom １ｂ The groups, optionally together with the carbon atoms to which they are attached, are C ３ -C ６ forming a cycloalkyl, Each R Ａ are independently deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 12-membered heterocyclyl, C ６ -C １４ Aryl, 5- to 10-membered heteroaryl, —CN, —OR ５ , -SR ５ , -NR ６ R ７ , -NO ２ , -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) ２ R ５ , -NR ５ S(O)R ６ , -NR ５ S (O) ２ R ６ , -S(O)NR ６ R ７ , -S(O) ２ NR ６ R ７ , or -P(O)(OR ５ ) (OR ６ ), where R Ａ The above C １ -C ６ alkyl, the C ２ -C ６ alkenyl, the C ２ -C ６ Alkynyl, the C ３ -C ８ cycloalkyl, the 3- to 12-membered heterocyclyl, the C ６ -C １４ The aryl and the 5- to 10-membered heteroaryl may independently be one or more R Ａａ and optionally replaced by Each R Ａａ are 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) ２ R ８ , -P(O)(OR ８ ) (OR ９ ), C ３ -C ８ cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C ６ -C １４ aryl, or C １ -C ６ alkyl, where R Ａａ the 3- to 12-membered heterocyclyl, the 5- to 10-membered heteroaryl, the C ６ -C １４ Aryl, and the C １ -C ６ Alkyl is independently one or more R Ａｂ and optionally replaced by Each R Ａｂ are independently deuterium, oxo, -OH, -O( ２ H), halogen, or deuterium, halogen, -OH, -O( ２ C optionally substituted by one or more of: １ -C ６ is alkyl, Each R ５ are independently hydrogen, deuterium, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ６ -C １４ aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, where R ５ The above C １ -C ６ alkyl, the C ２ -C ６ alkenyl, the C ２ -C ６ Alkynyl, the C ３ -C ６ cycloalkyl, the C ６ -C １４ The aryl, the 5- to 10-membered heteroaryl, and the 3- to 10-membered heterocyclyl each independently represent one or more R ５ａ and optionally replaced by Each R ５ａ are independently halogen, deuterium, oxo, —CN, —OR １０ , -NR １１ R １２ , -P(O)(OR １１ ) (OR １２ ), 3- to 12-membered heterocyclyl, or deuterium, halogen, —OH, —O( ２ C optionally substituted by one or more of: １ -C ６ is alkyl, Each R ６ are independently hydrogen, deuterium, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ６ -C １４ aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R ６ The above C １ -C ６ alkyl, the C ２ -C ６ alkenyl, the C ２ -C ６ Alkynyl, the C ３ -C ６ cycloalkyl, the C ６ -C １４ The aryl, the 5- to 10-membered heteroaryl, and the 3- to 6-membered heterocyclyl are independently selected from deuterium, halogen, oxo, —CN, —OR １０ , -NR １１ R １２ , or deuterium, halogen, -OH, -O( ２ C optionally substituted by one or more of: １ -C ６ optionally substituted by one or more of alkyl, Each R ７ are independently hydrogen, deuterium, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ６ -C １４ aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R ７ The above C １ -C ６ alkyl, the C ２ -C ６ alkenyl, the C ２ -C ６ Alkynyl, the C ３ -C ６ cycloalkyl, the C ６ -C １４ The aryl, the 5- to 10-membered heteroaryl, and the 3- to 6-membered heterocyclyl are independently selected from deuterium, halogen, oxo, —CN, —OR １０ , -NR １１ R １２ , or deuterium, halogen, -OH, -O( ２ C optionally substituted by one or more of: １ -C ６ optionally substituted by one or more of alkyl, Or, R ６ and R ７ together with the atom to which they are attached, deuterium, halogen, oxo, -OR １０ , -NR １１ R １２ , or deuterium, halogen, oxo, —OH, or —O( ２ C optionally substituted by one or more of １ -C ６ forming a 3- to 10-membered heterocyclyl optionally substituted by one or more of alkyl; Each R ８ are independently hydrogen; deuterium; C optionally substituted by one or more of deuterium, halogen, or oxo. １ -C ６ alkyl; C optionally substituted with one or more of deuterium, halogen, or oxo ２ -C ６ alkenyl; or C optionally substituted by one or more of deuterium, halogen, or oxo ２ -C ６ is alkynyl, Each R ９ are independently hydrogen; deuterium; C optionally substituted by one or more of deuterium, halogen, or oxo. １ -C ６ alkyl; C optionally substituted with one or more of deuterium, halogen, or oxo ２ -C ６ alkenyl; or C optionally substituted by one or more of deuterium, halogen, or oxo ２ -C ６ is alkynyl, Each R １０ are independently hydrogen; deuterium; C optionally substituted by one or more of deuterium, halogen, or oxo. １ -C ６ alkyl; C optionally substituted with one or more of deuterium, halogen, or oxo ２ -C ６ alkenyl; or C optionally substituted by one or more of deuterium, halogen, or oxo ２ -C ６ is alkynyl, Each R １１ are independently hydrogen; deuterium; C optionally substituted by one or more of deuterium, halogen, or oxo. １ -C ６ alkyl; C optionally substituted with one or more of deuterium, halogen, or oxo ２ -C ６ alkenyl; or C optionally substituted by one or more of deuterium, halogen, or oxo ２ -C ６ is alkynyl, Each R １２ are independently hydrogen; deuterium; C optionally substituted by one or more of deuterium, halogen, or oxo. １ -C ６ alkyl; C optionally substituted with one or more of deuterium, halogen, or oxo ２ -C ６ alkenyl; or C optionally substituted by one or more of deuterium, halogen, or oxo ２ -C ６ is alkynyl, or Or, R １１ and R １２ are, together with the atoms to which they are attached, deuterium, halogen, oxo, or C optionally substituted by one or more of deuterium, oxo, or halogen. １ -C ６ forming a 3- to 6-membered heterocyclyl optionally substituted by one or more of alkyl).

2. The compound of claim 1 according to formula (I): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, R １ is one or more R １ａ 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by one or more R １ｂ 1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by one or more R １ｃ 6-aminopyridin-2-yl optionally substituted by １ｄ (pyridin-2-yl)amino optionally substituted by R ２ is H or C １ -C ６ is alkyl, R ３ is H or C １ -C ６ Is it alkyl? Or, R ２ and R ３ together with the carbon atoms to which they are attached, form C ３ -C ６ forming a cycloalkyl or a 3- to 6-membered heterocyclyl, R ４ is phenyl, 5- to 6-membered heteroaryl, or 6-membered heterocyclyl wherein said 5- to 6-membered heteroaryl contains at least one nitrogen atom and is optionally fused to a phenyl group; said 6-membered heterocyclyl contains at least one nitrogen atom and is optionally fused to a phenyl group; The phenyl and the 5- to 6-membered heteroaryl may be one or more R ４ａ and optionally replaced by The 6-membered heterocyclyl is R ４ａ and oxo), or Each R ４ａ are independently halo, CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -(C １ -C ６ alkylene)-O-(C １ -C ６ alkyl), C ３ -C ６ cycloalkyl, —O—(C １ -C ６ alkyl), —O—(C １ -C ６ haloalkyl), or -S(O) ２ (C １ -C ６ alkyl) or Or, R ４ａ and R ２ together with the atom to which they are attached form a 6-membered heterocyclyl, wherein said heterocyclyl contains 1 oxygen atom; Q is H or C １ -C ８ is alkyl, L １ is one or more L １ａ C optionally substituted by ２ -C ４ is alkylene, L ２ is a bond or one or more L ２ａ C optionally substituted by １ -C ３ is alkylene, L ３ is one or more L ３ａ C optionally substituted by ２ -C ４ is alkylene, Y is a bond; R １ａ , R １ｂ , R １ｃ , R １ｄ , L １ａ , L ２ａ , and L ３ａ are each independently R Ａ is selected from Two R on the same carbon atom １ａ The groups, optionally together with the carbon atoms to which they are attached, are C ３ -C ６ forming a cycloalkyl, Two R on the same carbon atom １ｂ The groups, optionally together with the carbon atoms to which they are attached, are C ３ -C ６ forming a cycloalkyl, Each R Ａ are independently deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 12-membered heterocyclyl, C ６ -C １４ Aryl, 5- to 10-membered heteroaryl, —CN, —OR ５ , -SR ５ , -NR ６ R ７ , -NO ２ , -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) ２ R ５ , -NR ５ S(O)R ６ , -NR ５ S (O) ２ R ６ , -S(O)NR ６ R ７ , -S(O) ２ NR ６ R ７ , or -P(O)(OR ５ ) (OR ６ ), where R Ａ The above C １ -C ６ alkyl, the C ２ -C ６ alkenyl, the C ２ -C ６ Alkynyl, the C ３ -C ８ cycloalkyl, the 3- to 12-membered heterocyclyl, the C ６ -C １４ The aryl and the 5- to 10-membered heteroaryl may independently be one or more R Ａａ and optionally replaced by Each R Ａａ are 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) ２ R ８ , -P(O)(OR ８ ) (OR ９ ), C ３ -C ８ cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C ６ -C １４ aryl, or C １ -C ６ alkyl, where R Ａａ the 3- to 12-membered heterocyclyl, the 5- to 10-membered heteroaryl, the C ６ -C １４ Aryl, and the C １ -C ６ Alkyl is independently one or more R Ａｂ and optionally replaced by Each R Ａｂ are independently deuterium, oxo, -OH, -O( ２ H), halogen, or deuterium, halogen, -OH, -O( ２ C optionally substituted by one or more of: １ -C ６ is alkyl, Each R ５ are independently hydrogen, deuterium, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ６ -C １４ aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, where R ５ The above C １ -C ６ alkyl, the C ２ -C ６ alkenyl, the C ２ -C ６ Alkynyl, the C ３ -C ６ cycloalkyl, the C ６ -C １４ The aryl, the 5- to 10-membered heteroaryl, and the 3- to 10-membered heterocyclyl each independently represent one or more R ５ａ and optionally replaced by Each R ５ａ are independently halogen, deuterium, oxo, —CN, —OR １０ , -NR １１ R １２ , -P(O)(OR １１ ) (OR １２ ), 3- to 12-membered heterocyclyl, or deuterium, halogen, —OH, —O( ２ C optionally substituted by one or more of: １ -C ６ is alkyl, Each R ６ are independently hydrogen, deuterium, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ６ -C １４ aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R ６ The above C １ -C ６ alkyl, the C ２ -C ６ alkenyl, the C ２ -C ６ Alkynyl, the C ３ -C ６ cycloalkyl, the C ６ -C １４ The aryl, the 5- to 10-membered heteroaryl, and the 3- to 6-membered heterocyclyl are independently selected from deuterium, halogen, oxo, —CN, —OR １０ , -NR １１ R １２ , or deuterium, halogen, -OH, -O( ２ C optionally substituted by one or more of: １ -C ６ optionally substituted by one or more of alkyl, Each R ７ are independently hydrogen, deuterium, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ６ -C １４ aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R ７ The above C １ -C ６ alkyl, the C ２ -C ６ alkenyl, the C ２ -C ６ Alkynyl, the C ３ -C ６ cycloalkyl, the C ６ -C １４ The aryl, the 5- to 10-membered heteroaryl, and the 3- to 6-membered heterocyclyl are independently selected from deuterium, halogen, oxo, —CN, —OR １０ , -NR １１ R １２ , or deuterium, halogen, -OH, -O( ２ C optionally substituted by one or more of: １ -C ６ optionally substituted by one or more of alkyl, Or, R ６ and R ７ together with the atom to which they are attached, deuterium, halogen, oxo, -OR １０ , -NR １１ R １２ , or deuterium, halogen, oxo, —OH, or —O( ２ C optionally substituted by one or more of １ -C ６ forming a 3- to 10-membered heterocyclyl optionally substituted by one or more of alkyl; Each R ８ are independently hydrogen; deuterium; C optionally substituted by one or more of deuterium, halogen, or oxo. １ -C ６ alkyl; C optionally substituted with one or more of deuterium, halogen, or oxo ２ -C ６ alkenyl; or C optionally substituted by one or more of deuterium, halogen, or oxo ２ -C ６ is alkynyl, Each R ９ are independently hydrogen; deuterium; C optionally substituted by one or more of deuterium, halogen, or oxo. １ -C ６ alkyl; C optionally substituted with one or more of deuterium, halogen, or oxo ２ -C ６ alkenyl; or C optionally substituted by one or more of deuterium, halogen, or oxo ２ -C ６ is alkynyl, Each R １０ are independently hydrogen; deuterium; C optionally substituted by one or more of deuterium, halogen, or oxo. １ -C ６ alkyl; C optionally substituted with one or more of deuterium, halogen, or oxo ２ -C ６ alkenyl; or C optionally substituted by one or more of deuterium, halogen, or oxo ２ -C ６ is alkynyl, Each R １１ are independently hydrogen; deuterium; C optionally substituted by one or more of deuterium, halogen, or oxo. １ -C ６ alkyl; C optionally substituted with one or more of deuterium, halogen, or oxo ２ -C ６ alkenyl; or C optionally substituted by one or more of deuterium, halogen, or oxo ２ -C ６ is alkynyl, Each R １２ are independently hydrogen; deuterium; C optionally substituted by one or more of deuterium, halogen, or oxo. １ -C ６ alkyl; C optionally substituted with one or more of deuterium, halogen, or oxo ２ -C ６ alkenyl; or C optionally substituted by one or more of deuterium, halogen, or oxo ２ -C ６ is alkynyl, or Or, R １１ and R １２ are, together with the atoms to which they are attached, deuterium, halogen, oxo, or C optionally substituted by one or more of deuterium, oxo, or halogen. １ -C ６ forming a 3- to 6-membered heterocyclyl optionally substituted by one or more of alkyl).

3. L １ But -CH ２ CH ２ 3. The compound of claim 1 or 2, wherein: -, or a pharmaceutically acceptable salt thereof.

4. -L １ -O-L ２ -Y-L ３ -But together, 【Transformation 3】 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, which forms:

5. R ２ and R ３ But independently, C １ -C ６ The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

6. R ２ and R ３ The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein:

7. R ２ and R ３ But -CH ３ 9. The compound of claim 8, wherein:

8. R ２ and R ３ 5. The compound of claim 1, wherein, together with the carbon atom to which they are attached, form a cyclopropyl, or a pharmaceutically acceptable salt thereof.

9. R ４ However, one or more R ４ａ 9. The compound of any one of claims 1 to 8, wherein R is phenyl optionally substituted by: or a pharmaceutically acceptable salt thereof.

10. R ４ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein is unsubstituted phenyl.

11. R ４ But 1 to 5 R ４ａ phenyl substituted by a group, wherein at least one R ４ａ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein the group is F or Cl.

12. R ４ But 1 to 5 R ４ａ phenyl substituted by a group, wherein at least one R ４ａ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein the group is CN.

13. R ４ But 1 to 5 R ４ａ phenyl substituted by a group, wherein at least one R ４ａ The group is C １ -C ３ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

14. R ４ But 1 to 5 R ４ａ phenyl substituted by a group, wherein at least one R ４ａ The group is —O—(C １ -C ３ 10. The compound of claim 9, wherein R is 1 or 2; R is 2 or 3; R is 3 or 4; R is 4 or 5; R is 5 or 6; R is 6 or 7; R is 7 or 8; R is 8 or 9; R is 9 or 10; R is 10 or 11; R is 11 or 12; R is 13 or 14; R is 15 or 16; R is

15. R ４ But 1 to 5 R ４ａ phenyl substituted by a group, wherein at least one R ４ａ The group is —S(O) ２ (C １ -C ３ 10. The compound of claim 9, wherein R is 1 or 2; R is 2 or 3; R is 3 or 4; R is 4 or 5; R is 5 or 6; R is 6 or 7; R is 7 or 8; R is 8 or 9; R is 9 or 10; R is 10 or 11; R is 11 or 12; R is 13 or 14; R is 15 or 16; R is

16. R ４ is a 5- to 6-membered heteroaryl, wherein said 5- to 6-membered heteroaryl contains at least one nitrogen atom and one or more R ４ａ 9. The compound of any one of claims 1 to 8, optionally substituted by: or a pharmaceutically acceptable salt thereof.

17. R ４ is a 5-membered heteroaryl, wherein said 5-membered heteroaryl contains two nitrogen atoms and one or more R ４ａ 17. The compound of claim 16, optionally substituted by: or a pharmaceutically acceptable salt thereof.

18. R ４ is a 6-membered heteroaryl, wherein said 6-membered heteroaryl contains one nitrogen atom and one or more R ４ａ 17. The compound of claim 16, optionally substituted by: or a pharmaceutically acceptable salt thereof.

19. R ４ is a 6-membered heteroaryl, wherein said 6-membered heteroaryl contains two nitrogen atoms and one or more R ４ａ 17. The compound of claim 16, optionally substituted by: or a pharmaceutically acceptable salt thereof.

20. R ４ But 1 to 4 R ４ａ group, where at least one R ４ａ 20. The compound of any one of claims 16 to 19, or a pharmaceutically acceptable salt thereof, wherein the group is F or Cl.

21. R ４ But 1 to 4 R ４ａ group, where at least one R ４ａ 20. The compound of any one of claims 16 to 19, or a pharmaceutically acceptable salt thereof, wherein the group is CN.

22. R ４ But 1 to 4 R ４ａ group, where at least one R ４ａ The group is C １ -C ３ 20. The compound of any one of claims 16 to 19, or a pharmaceutically acceptable salt thereof, which is alkyl.

23. R ４ But 1 to 4 R ４ａ group, where at least one R ４ａ The group is C １ -C ３ 20. The compound of any one of claims 16 to 19, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

24. R ４ But 1 to 4 R ４ａ group, where at least one R ４ａ The group is -(C １ -C ３ alkylene)-O-(C １ -C ３ 20. The compound of any one of claims 16 to 19, or a pharmaceutically acceptable salt thereof, wherein R is 1 or 2;

25. R ４ But 1 to 4 R ４ａ group, where at least one R ４ａ 20. The compound of any one of claims 16 to 19, or a pharmaceutically acceptable salt thereof, wherein the group is cyclopropyl.

26. R ４ But 1 to 4 R ４ａ group, where at least one R ４ａ The group is —O—(C １ -C ３ 20. The compound of any one of claims 16 to 19, or a pharmaceutically acceptable salt thereof, wherein R is 1 or 2;

27. R ４ But 1 to 4 R ４ａ group, where at least one R ４ａ The group is —O—(C １ -C ３ 20. The compound of any one of claims 16 to 19, or a pharmaceutically acceptable salt thereof, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 2

28. R ４ But 2 to 4 R ４ａ group, where at least one R ４ａ The group is F and at least one R ４ａ 20. The compound of any one of claims 16 to 19, or a pharmaceutically acceptable salt thereof, wherein the group is Cl.

29. R ４ But 2 to 4 R ４ａ group, where at least one R ４ａ The group is F and at least one R ４ａ The group is C １ -C ３ 20. The compound of any one of claims 16 to 19, or a pharmaceutically acceptable salt thereof, which is alkyl.

30. R ４ But 2 to 4 R ４ａ group, where at least one R ４ａ group is Cl and at least one R ４ａ The group is C １ -C ３ 20. The compound of any one of claims 16 to 19, or a pharmaceutically acceptable salt thereof, which is alkyl.

31. R ４ But 2 to 4 R ４ａ group, where at least one R ４ａ group is Cl and at least one R ４ａ The group is —O—(C １ -C ３ 20. The compound of any one of claims 16 to 19, or a pharmaceutically acceptable salt thereof, wherein R is 1 or 2;

32. R ４ But 2 to 4 R ４ａ groups, where at least two R ４ａ 20. The compound of any one of claims 16 to 19, or a pharmaceutically acceptable salt thereof, wherein the group is Cl.

33. R ４ is a 6-membered heterocyclyl, wherein said 6-membered heterocyclyl contains at least one nitrogen atom; R ４ａ 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more groups selected from the group consisting of: and oxo.

34. R ４ is a 6-membered heterocyclyl, wherein said 6-membered heterocyclyl contains one nitrogen atom, and R ４ａ 34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more groups selected from the group consisting of: and oxo.

35. R ４ is a 6-membered heterocyclyl, wherein said 6-membered heterocyclyl contains two nitrogen atoms, and R ４ａ 34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more groups selected from the group consisting of: and oxo.

36. R ４ 36. The compound of any one of claims 33 to 35, or a pharmaceutically acceptable salt thereof, wherein is substituted by Cl and oxo.

37. R ４ but, 【Chemistry 4】 9. The compound according to any one of claims 1 to 8, selected from the group consisting of:

38. R ４ but, 【Transformation 5】 9. The compound according to any one of claims 1 to 8, selected from the group consisting of:

39. R ４ but, 【Transformation 6】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

40. R ２ , R ３ , and R ４ But together, 【Transformation 7】 2. The compound of claim 1, wherein the compound forms:

41. R １ However, one or more R １ａ 39. The compound of any one of claims 1 to 38, which is 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by: or a pharmaceutically acceptable salt thereof.

42. 40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein Q is H.

43. R １ but, 【Transformation 8】 and 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 cyclopropyl, R ４ is phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, 2-oxopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyridazinyl, or quinazolinyl, wherein The phenyl, the pyrazolyl, the imidazolyl, the thiazolyl, the pyridinyl, the 2-oxopyridinyl, the pyridazinyl, the pyrimidinyl, the pyrazinyl, or the quinazolinyl may be one or more R ４ａ optionally substituted by a group, The dihydropyridinyl, the dihydropyrimidinyl, or the dihydropyridazinyl is R ４ａ and oxo, Each R ４ａ are independently halo, CN, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, -(C １ -C ３ alkylene)-O-(C １ -C ３ alkyl), C ３ -C ６ cycloalkyl, —O—(C １ -C ３ alkyl), —O—(C １ -C ３ haloalkyl), or —S(O) ２ (C １ -C ３ alkyl), and Q is H; -L １ -O-L ２ -Y-L ３ -But together, 【Chemistry 9】 2. The compound of claim 1, wherein the compound forms:

44. R １ but, 【Chemistry 10】 and R ２ and R ３ together with the carbon atom to which they are attached form cyclopropyl, R ４ is phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, 2-oxopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyridazinyl, or quinazolinyl, wherein The phenyl, the pyrazolyl, the imidazolyl, the thiazolyl, the pyridinyl, the 2-oxopyridinyl, the pyridazinyl, the pyrimidinyl, the pyrazinyl, or the quinazolinyl may be one or more R ４ａ optionally substituted by a group, The dihydropyridinyl, the dihydropyrimidinyl, or the dihydropyridazinyl is R ４ａ and oxo, Each R ４ａ are independently halo, CN, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, -(C １ -C ３ alkylene)-O-(C １ -C ３ alkyl), C ３ -C ６ cycloalkyl, —O—(C １ -C ３ alkyl), —O—(C １ -C ３ haloalkyl), or —S(O) ２ (C １ -C ３ alkyl), Q is H, -L １ -O-L ２ -Y-L ３ -But together, 【Chemistry 11】 2. The compound of claim 1, wherein the compound forms:

45. R １ but, 【Chemistry 12】 and R ２ and R ３ together with the carbon atom to which they are attached form cyclopropyl, R ４ is pyrazolyl, imidazolyl, thiazolyl, pyridinyl, 2-oxopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyridazinyl, or quinazolinyl, wherein The pyrazolyl, the imidazolyl, the thiazolyl, the pyridinyl, the 2-oxopyridinyl, the pyridazinyl, the pyrimidinyl, the pyrazinyl, or the quinazolinyl may be one or more R ４ａ optionally substituted by a group, The dihydropyridinyl, the dihydropyrimidinyl, or the dihydropyridazinyl is R ４ａ and oxo, Each R ４ａ are independently halo, CN, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, -(C １ -C ３ alkylene)-O-(C １ -C ３ alkyl), C ３ -C ６ cycloalkyl, —O—(C １ -C ３ alkyl), —O—(C １ -C ３ haloalkyl), or —S(O) ２ (C １ -C ３ alkyl), Q is H, -L １ -O-L ２ -Y-L ３ -But together, 【Chemistry 13】 2. The compound of claim 1, wherein the compound forms:

46. A compound selected from one of compound numbers 1 to 82 in Table 1, or a pharmaceutically acceptable salt thereof.

47. A compound selected from one of compound numbers 83-104 in Table 1, or a pharmaceutically acceptable salt thereof.

48. 48. A pharmaceutical composition comprising a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

49. 49. A method of treating a fibrotic disease in an individual in need thereof, comprising administering a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48.

50. 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 the compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 48.

52. 52. The kit of claim 51, further comprising instructions for treating a fibrotic disorder.

53. 52. The kit of claim 51 , further comprising instructions instructing a user to treat cancer in a subject in need thereof, said instructions comprising instructing the user to administer said compound or said pharmaceutically acceptable salt thereof to said subject.

54. Alpha in an individual Ｖ β ８ A method for inhibiting an integrin, the method comprising administering a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48.

55. α Ｖ β １ Integrin, α Ｖ β ６ Integrin, or α Ｖ β ８ 49. A method of inhibiting one or more integrins in an individual in need thereof, comprising administering to said individual a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48.

56. In the individual, α Ｖ β １ ； α Ｖ β ８ ； a Ｖ b １ and a Ｖ b ８ ; α Ｖ β ６ and α Ｖ β ８ ;or a Ｖ b １ ,a Ｖ b ６ 、 & a Ｖ b ８ 56. The method of claim 55, comprising inhibiting one of:

57. 57. The method of any one of claims 54 to 56, wherein the individual is in need of treatment for a disease or condition.

58. 58. The method of claim 57, wherein the disease or condition comprises a solid tumor.

59. 58. The method of claim 57, wherein the disease or 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 carcinoma, renal cell carcinoma, cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, and mesothelioma.

60. 58. The method of claim 57, wherein the disease or condition is pancreatic ductal adenocarcinoma (PDAC).

61. 58. The method of claim 57, wherein the disease or condition is breast cancer.

62. 58. The method of claim 57, wherein the disease or condition is selected from the group consisting of pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, and biliary fibrosis.

63. 49. A method for inhibiting TGFβ activation in a cell, comprising administering to the cell a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48.

64. The cells are Ｖ β １ , α Ｖ β ６ , and α Ｖ β ８ 64. The method of claim 63, wherein the vector expresses one or more of:

65. The cells α Ｖ β １ ； α Ｖ β ６ ； α Ｖ β ８ ； a Ｖ b １ and a Ｖ b ８ ; a Ｖ b １ and a Ｖ b ６ ; α Ｖ β ６ and α Ｖ β ８ ;or a Ｖ b １ ,a Ｖ b ６ 、 & a Ｖ b ８ 64. The method of claim 63, wherein the vector expresses one of:

66. 64. The method of claim 63, wherein the cell is a cancer cell associated with a solid tumor.

67. 64. The method of claim 63, wherein the cells are cancer cells associated with at least one of melanoma, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung carcinoma, renal cell carcinoma, cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, and mesothelioma.

68. 64. The method of claim 63, wherein the cancer cells are associated with pancreatic ductal adenocarcinoma (PDAC).

69. 64. The method of claim 63, wherein the cell is a breast cancer cell.

70. 64. The method of claim 63, wherein the cell is a human cell.

71. 64. The method of claim 63, wherein the cells are associated with a fibrotic disease, wherein the fibrotic disease is selected from the group consisting of pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, and biliary fibrosis.

72. Use of a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, in the manufacture of a medicament for the treatment of a fibrotic disease.

73. α Ｖ β １ , α Ｖ β ６ , and α Ｖ β ８ 49. Use of a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, in the manufacture of a medicament for the treatment of a disease mediated by cells expressing one or more of:

74. Use of a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, in the manufacture of a medicament for the treatment of cancer.

75. 1. A method of treatment for a subject in need thereof, comprising:

49. A method for treating a subject having at least one tissue in need of therapy, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 47, or a pharmaceutical composition according to claim 48, wherein the at least one tissue is characterized by an elevated level of: α Ｖ β １ integrin activity and / or expression; α Ｖ β ６ integrin activity and / or expression; α Ｖ β ８ integrin activity and / or expression; pSMAD / SMAD ratio; the formation or accumulation of new collagen; Total collagen; Type I collagen gene Col1a1 expression; Perforin; Granzyme B; and Interferon-gamma The method is selected from the group consisting of:

76. 76. The method of claim 75, wherein administering the therapeutically effective amount of the compound reduces elevated levels in the at least one tissue.

77. α Ｖ β １ ； α Ｖ β ８ ； a Ｖ b １ and a Ｖ b ８ ; α Ｖ β ６ and α Ｖ β ８ and a Ｖ b １ ,a Ｖ b ６ 、 & a Ｖ b ８ 76. The method of claim 75, further comprising decreasing at least one of the activity and expression of one of:

78. Reducing at least one of the activity and expression of at least one other α Ｖ 78. The method of claim 77, which is selective compared to the containing integrin.

79. One of the following: α Ｖ β １ the activity of an integrin is decreased in one or more fibroblasts of said subject; α Ｖ β ６ the activity of an integrin is decreased in one or more epithelial cells of said subject; or α Ｖ β ８ 78. The method of claim 77, wherein the activity of an integrin is decreased in one or more epithelial or cancer cells of the subject.

80. 80. The method of any one of claims 75-79, wherein each tissue of the at least one tissue of the subject is selected from the group consisting of lung, liver, skin, heart, kidney, gastrointestinal tract, gallbladder, and bile duct.

81. 80. The method of any one of claims 75-79, wherein each tissue of the at least one tissue of 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. 82. The method of any one of claims 75 to 81, wherein each tissue of said at least one tissue has an elevated pSMAD2 / SMAD2 value or an elevated pSMAD3 / SMAD3 value compared to a healthy value in said at least one tissue in a healthy state.

83. 83. The method of claim 82, wherein the subject has a solid tumor.

84. 83. The method of claim 82, wherein the subject has 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. 83. The method of claim 82, wherein the subject has pancreatic ductal adenocarcinoma (PDAC).

86. 83. The method of claim 82, wherein the subject has at least one of pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, and biliary fibrosis.

87. 1. A method for characterizing the anti-cancer activity of a small molecule inhibitor in a subject, comprising: providing a first live cell sample from the subject, the first live cell sample being characterized by the presence of at least one integrin capable of activating transforming growth factor β (TGF-β) from a latent peptide TGF-β; determining a first value from the first live cell sample, wherein the first value is selected from the group consisting of a pSMAD2 / SMAD2 ratio, a pSMAD3 / SMAD3 ratio, a perforin level, a granzyme B level, and an interferon gamma level; administering the small molecule to the subject; providing a second live cell sample from the subject, the second live cell sample being taken from the same tissue as the first live cell sample from the subject; determining a second value for the second live cell sample, the second value corresponding to the pSMAD2 / SMAD2 ratio, the pSMAD3 / SMAD3 ratio, the perforin level, the granzyme B level, or the interferon gamma level of the first value; comparing the second value to the first value to characterize the anti-cancer activity of the small molecule in the subject.

88. 88. The method of claim 87, wherein each live cell sample comprises a plurality of cancer cells derived from a tissue of the subject or a blood cell of the subject.

89. 88. The method of claim 87, wherein the tissue of 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. 88. The method of claim 87, wherein the subject has a solid tumor.

91. 88. The method of claim 87, wherein the subject has 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. 88. The method of claim 87, wherein the subject has pancreatic ductal adenocarcinoma (PDAC).

93. The at least one integrin is α Ｖ 88. The method of claim 87, comprising:

94. The at least one integrin is α Ｖ β １ , α Ｖ β ６ , and α Ｖ β ８ 88. The method of claim 87, selected from the group consisting of:

95. 88. The method of claim 87, wherein the first value and the second value are a pSMAD2 / SMAD2 ratio or a pSMAD3 / SMAD3 ratio.

96. 88. The method of claim 87, wherein administering the small molecule to the subject comprises administering to the subject a compound of any one of claims 1 to 47 or a pharmaceutical composition of claim 48.

97. 63. The method of any one of claims 54 to 56 and 62, wherein the individual is in need of treatment for biliary atresia.

98. 72. 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. 74. The use according to claim 72 or 73, wherein the fibrotic disease or disorder is biliary atresia.

100. 87. The method of any one of claims 75 to 82 and 86, wherein the subject is in need of treatment for biliary atresia.

101. 87. The method of any one of claims 75 to 82 and 86, wherein the tissue is tissue of the intrahepatic or extrahepatic biliary system.

102. The one or more cells are Ｖ β １ and α Ｖ β ８ 99. The method of claim 98, wherein the vector expresses

103. The tissue is α Ｖ β １ and α Ｖ β ８ The method of claim 101, wherein the gene is expressed.

104. 57. The method of any one of claims 54 to 56, wherein the individual is in need of treatment for ocular fibrosis.

105. 105. The method of any one of claims 54-56 or 104, wherein the individual is in need of treatment for an anterior subcapsular cataract or posterior capsular opacification.

106. 66. The method of any one of claims 63 to 65, wherein the one or more cells are associated with the eye.

107. 74. The use of claim 72 or 73, wherein the fibrotic disorder or disease is ocular fibrosis.

108. 105. The use of any one of claims 72, 73, or 104, wherein the fibrotic disease or disorder is anterior subcapsular cataract or posterior capsular opacification.

109. 83. The method of any one of claims 75 to 77 and 82, wherein the tissue is an ocular tissue.

110. The one or more cells are Ｖ β １ , α Ｖ β ６ , and α Ｖ β ８ 97. The method of claim 96, wherein the cell expresses one, two, or three integrins selected from the group consisting of:

111. The tissue is α Ｖ β １ , α Ｖ β ６ , and α Ｖ β ８ 110. The method of claim 109, wherein the cell expresses one, two, or three integrins selected from the group consisting of:

112. 49. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48.

113. 113. The method of claim 112, wherein the cancer comprises a solid tumor.

114. 113. 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 carcinoma, renal cell carcinoma, cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, and mesothelioma.

115. 113. The method of claim 112, wherein the cancer is breast cancer.

116. 113. The method of claim 112, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

117. 113. The method of claim 112, further comprising administering a chemotherapeutic agent before, simultaneously with, or after said compound or said pharmaceutical composition.

118. 118. The method of claim 117, wherein the chemotherapeutic agent is selected from the group consisting of gemcitabine and abraxane.

119. 118. The method of claim 117, wherein administering the chemotherapeutic agent before, simultaneously with, or after the compound or pharmaceutical composition reduces at least one of tumor weight in the subject and lung metastases in the subject.

120. 113. The method of claim 112, further comprising administering a chemotherapy regimen before, concurrently with, or after said compound or said pharmaceutical composition.

121. 121. The method of claim 120, wherein the chemotherapy regimen comprises Forfirinox.

122. 121. The method of claim 120, wherein administering the chemotherapy regimen before, concurrently with, or after the compound or pharmaceutical composition reduces tumor weight in the subject.

123. 123. The method of claim 122, wherein the tumor is resistant to a chemotherapy regimen.

124. 123. The method of claim 122, wherein the tumor is resistant to forfirinox.

125. The method of claim 112, wherein the effective amount of the compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 48 is a therapeutically effective amount.

126. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, for use in the treatment of melanoma.

127. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, for use in the treatment of colon cancer.

128. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, for use in treating non-small cell lung cancer.

129. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, for use in treating head and neck squamous cell carcinoma.

130. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, for use in treating squamous cell lung cancer.

131. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, for use in treating renal cell carcinoma.

132. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, for use in the treatment of cutaneous squamous cell carcinoma (CSCC).

133. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, for use in treating urothelial carcinoma.

134. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, for use in the treatment of metastatic Merkel cell carcinoma.

135. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, for use in the treatment of gastric cancer.

136. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, for use in treating lung cancer.

137. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, for use in the treatment of pancreatic cancer.

138. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, for use in the treatment of mesothelioma.

139. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, for use in the treatment of breast cancer.

140. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, for use in the treatment of pancreatic ductal adenocarcinoma (PDAC).

141. 75. 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 carcinoma, 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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