Expanded dosing regimens of integrin inhibitors

Abstract

The present invention relates to compounds of formula (A) and formula (I): JPEG2024517765000212.jpg78164 or a salt thereof (wherein, R 1 , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 wherein q and p are as described herein. The compounds of formula (A), compounds of formula (I), and pharmaceutical compositions thereof are αvβ6 integrin inhibitors that are useful for treating fibrosis, such as idiopathic pulmonary fibrosis (IFF) and non-specific interstitial pneumonia (NSIP).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 182,757, filed April 30, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] 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.

[0003] 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.

[0004] 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.

[0005] Scleroderma encompasses a complex and diverse range of conditions primarily characterized by fibrosis, vascular alterations, 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, while in others it can spread to other major organs.

[0006] 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.

[0007] 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.

[0008] 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.

[0009] 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.

[0010] 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)

[0011] Currently, available treatment courses are limited because there are no options on the market that have been proven to improve long-term survival or overall symptoms for patients. For example, agents such as pirfenidone and nintedanib have been studied for the treatment of fibrosis. Although pirfenidone and nintedanib are used to treat IPF, their therapeutic effects are not as high as expected and they have numerous side effects. There remains a need for treatments for fibrotic diseases.

[0012] The αvβ6 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.

[0013] 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.

[0014] The present disclosure provides αvβ6 integrin inhibitors that may be useful in the treatment of fibrosis. Summary of the Invention

[0015] Amino acid compounds that are αvβ6 integrin inhibitors, compositions containing these compounds, and methods for treating diseases, such as fibrotic diseases, mediated by αvβ6 integrin are disclosed.

[0016] 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).

[0017] 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.

[0018] In another aspect, provided is a method of treating a fibrotic disease in an individual (e.g., 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 some embodiments, the fibrotic disease is pulmonary fibrosis (e.g., IPF), liver fibrosis, skin fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis (e.g., PBC). In some embodiments, the fibrotic disease is pulmonary fibrosis (e.g., IPF), liver fibrosis, skin fibrosis, psoriasis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis (e.g., PBC). In some embodiments, the fibrotic disease is pulmonary fibrosis (e.g., IPF). In some embodiments, the fibrotic disease is liver fibrosis. In some embodiments, the fibrotic disease is skin fibrosis. In some embodiments, the fibrotic disease is psoriasis. In some embodiments, the fibrotic disease is scleroderma. In some embodiments, the fibrotic disease is cardiac fibrosis. In some embodiments, the fibrotic disease is renal fibrosis. In some embodiments, the fibrotic disease is gastrointestinal fibrosis. In some embodiments, the fibrotic disease is primary sclerosing cholangitis. In some embodiments, the fibrotic disease is biliary fibrosis (PBC).

[0019] In another aspect, provided are methods for delaying the onset and / or development of a fibrotic disease in an individual (e.g., a human) at risk of developing the disease, comprising administering to the individual a therapeutically effective amount of a compound of Formula (A), or any of the variations thereof detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the fibrotic disease is pulmonary fibrosis (e.g., IPF), liver fibrosis, skin fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or PBC. In some embodiments, the fibrotic disease is pulmonary fibrosis (e.g., IPF), liver fibrosis, skin fibrosis, psoriasis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis (e.g., PBC). In some embodiments, the fibrotic disease is psoriasis. In some embodiments, the individual at risk of developing a fibrotic disease has or is suspected of having NAFLD, NASH, CKD, scleroderma, Crohn's disease, NSIP, PSC, PBC, or has suffered from or is suspected of having myocardial infarction. In some embodiments, the individual at risk of developing a fibrotic disease has or is suspected of having psoriasis.

[0020] 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.

[0021] 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 comprising any of the foregoing, in the manufacture of a medicament for the treatment of a fibrotic disease.

[0022] Additionally provided are kits comprising a compound of Formula (A), or any of the variations thereof detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the kits include instructions for use in accordance with the methods described herein, such as the methods for treating a fibrotic disease in an individual.

[0023] In another aspect, methods for preparing a compound of formula (A) or any variation thereof, or a pharmaceutically acceptable salt thereof are provided. Also provided are compound intermediates useful in the synthesis of a compound of formula (A) or any variation thereof.

[0024] 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).

[0025] 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.

[0026] In another aspect, provided is a method of treating a fibrotic disease 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 of the variations thereof detailed herein, or a pharmaceutically acceptable salt thereof. 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). In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skin fibrosis, psoriasis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis (such as PBC). In some embodiments, the fibrotic disease is psoriasis.

[0027] In another aspect, provided are methods for delaying the onset and / or development of a fibrotic disease in an individual (e.g., a human) at risk of developing the disease, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or any of the variations thereof detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the fibrotic disease is pulmonary fibrosis (e.g., IPF), liver fibrosis, skin fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or PBC. In some embodiments, the fibrotic disease is pulmonary fibrosis (e.g., IPF), liver fibrosis, skin fibrosis, psoriasis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis (e.g., PBC). In some embodiments, the fibrotic disease is psoriasis. In some embodiments, the individual at risk of developing a fibrotic disease has or is suspected of having NAFLD, NASH, CKD, scleroderma, Crohn's disease, NSIP, PSC, PBC, or has suffered from or is suspected of having myocardial infarction. In some embodiments, the individual at risk of developing a fibrotic disease has or is suspected of having psoriasis.

[0028] 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.

[0029] 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 comprising any of the foregoing, in the manufacture of a medicament for the treatment of a fibrotic disease.

[0030] Additionally provided are kits comprising a compound of Formula (I), or any of the variations thereof detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the kits include instructions for use in accordance with the methods described herein, such as the methods for treating a fibrotic disorder in an individual.

[0031] In another aspect, methods for preparing a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof are provided. Also provided are compound intermediates useful in the synthesis of a compound of formula (I) or any variation thereof. [Brief explanation of the drawings]

[0032] [Figure 1] Compounds 1 to 780 disclosed herein are shown. [Figure 2] Biological data for various compounds disclosed herein are shown in Table B-3. [Figure 3A] 1 is a graph showing that both compound 5 and the selective antibody αVβ6 inhibitor 3G9, in contrast to αVβ1 selective small molecule inhibitors, substantially inhibited adhesion of normal bronchial epithelial cells to LAP. [Figure 3B] 1 shows that both compound 5 and the αVβ1 selective small molecule inhibitor substantially inhibited cell adhesion in IPF-derived lung fibroblasts, in contrast to the selective antibody αVβ6 inhibitor 3G9. [Figure 4A] 1 is a graph of PSMAD3 / SMAD3 in lung tissue of healthy mice treated with PBS vehicle and various concentrations of Compound 5 for 4 days. [Figure 4B] 1 is a graph of PSMAD3 / SMAD3 in BALF collected from the same healthy mice treated with PBS vehicle and various concentrations of Compound 5 for 4 days. [Figure 4C] 1 is a graph showing that SMAD3 phosphorylation was substantially increased in lung tissue from vehicle-treated mice compared to healthy mice. [Figure 4D] 1 is a graph showing that compared to healthy mice, lung tissue from vehicle-treated mice underwent substantial accumulation of new collagen, as evidenced by the percentage of lung collagen containing 2H-labeled hydroxyproline. [Figure 4E] Figure 1 shows that total lung collagen, as measured by μg of hydroxyproline, was significantly increased in vehicle-treated mice compared to healthy mice. [Figure 4F]High-resolution second harmonic generation images of fibrillar collagen (types I and III collagen) from formalin-fixed, paraffin-embedded lung tissue sections from healthy mouse lungs. [Figure 4G] High-resolution second harmonic generation images of fibrillar collagen (types I and III collagen) from formalin-fixed, paraffin-embedded lung tissue sections from vehicle-treated mice. [Figure 4H] High-resolution second harmonic generation images of fibrillar collagen (type I and III collagen) from formalin-fixed, paraffin-embedded lung tissue sections from test article-treated mice (compound 5 at 500 mg / kg BID). [Figure 4I] 4F, 4G, and 4H are graphs showing percent total collagen area in second harmonic generation mouse lung images. [Figure 4J] Graph of sequential measurements in bleomycin-treated mice showing a close inverse correlation between lung pSMAD3 levels and plasma drug exposure. [Figure 4K] Graph of sequential measurements in bleomycin-treated mice showing a close inverse correlation between cellular pSMAD3 levels and plasma drug exposure. [Figure 5A] Bar graph normalized to DMSO-treated control sections showing that all test treatments reduced expression of the type I collagen gene Col1a1. [Figure 5B] Bar graph normalized to DMSO-treated control sections showing that all test treatments reduced lung Col1a1 expression. [Figure 6A] 1 is a bar graph showing that both nintedanib and pirfenidone slightly increased lung Col1a1 expression compared to DMSO vehicle control sections. [Figure 6B] 1 is a bar graph showing the concentration of compound required to reduce Col1a1 expression in lung sections by 50% compared to DMSO control sections. [Figure 6C]Bar graph normalized to DMSO-treated control sections showing that all test treatments reduced lung Col1a1 expression. [Figure 6D] Bar graph showing the relative expression of COL1A1 in precision-cut lung sections (PCLS) of idiopathic pulmonary fibrosis (IPF) lung tissue upon exposure to compound 5, the clinical standard of care compounds nintedanib (Nin) and pirfenidone (Pirf), and an ALK5 inhibitor, all relative to the DMSO control. [Figure 6E] 1 is a bar graph showing that treatment with compound 5 at concentrations ranging from 200 pM to 1 μM dose-dependently reduced COL1A1 expression in PCLS from human IPF lung tissue. COL1A1 expression in PCLS in the presence of a 0.1% DMSO control and 1 μM Alk5 inhibitor is also graphed. [Figure 6F] 1 is a bar graph showing the effect of selective αVβ6 and αVβ1 dual inhibition (1.82 μM Compound 5) on the ratio of pSMAD2 / SMAD2 in PCLS from human IPF lung tissue samples. The ratio of pSMAD2 / SMAD2 in PCLS in the presence of 0.1% DMSO control and 1 μM Alk5 inhibitor is also graphed. [Figure 7A] 1 shows data from a single ascending dose (SAD) study in which Compound 5 was administered at doses of 15, 30, 50, and 75 mg. [Figure 7B] 1 shows data from a multiple ascending dose (MAD) study in which 10, 20, and 40 mg of Compound 5 were administered. [Figure 8A] 1 is a series of graphs showing data from subjects administered 40 mg / day of a select integrin inhibitor (Compound 5). Data include plasma concentrations of the administered integrin inhibitor ("PK," round dots) and the relative change from baseline (day -1) in pSMAD2:SMAD2 ratios in BAL (bronchoalveolar lavage) samples ("pSMAD," square dots) over the indicated time course (hours) from administration of the inhibitor on day 7. The peak plasma concentration ("PK" curve) is recorded as Cmax. [Figure 8B]1 is a series of graphs showing data from subjects administered 40 mg / day of a select integrin inhibitor (Compound 5). Data include plasma concentrations of the administered integrin inhibitor ("PK," round dots) and the relative change from baseline (day -1) in pSMAD2:SMAD2 ratios in BAL (bronchoalveolar lavage) samples ("pSMAD," square dots) over the indicated time course (hours) from administration of the inhibitor on day 7. The peak plasma concentration ("PK" curve) is recorded as Cmax. [Figure 8C] 1 is a series of graphs showing data from subjects administered 40 mg / day of a select integrin inhibitor (Compound 5). Data include plasma concentrations of the administered integrin inhibitor ("PK," round dots) and the relative change from baseline (day -1) in pSMAD2:SMAD2 ratios in BAL (bronchoalveolar lavage) samples ("pSMAD," square dots) over the indicated time course (hours) from administration of the inhibitor on day 7. The peak plasma concentration ("PK" curve) is recorded as Cmax. [Figure 8D] 1 is a series of graphs showing data from subjects administered 40 mg / day of a select integrin inhibitor (Compound 5). Data include plasma concentrations of the administered integrin inhibitor ("PK," round dots) and the relative change from baseline (day -1) in pSMAD2:SMAD2 ratios in BAL (bronchoalveolar lavage) samples ("pSMAD," square dots) over the indicated time course (hours) from administration of the inhibitor on day 7. The peak plasma concentration ("PK" curve) is recorded as Cmax. [Figure 8E] 1 is a series of graphs showing data from subjects administered 40 mg / day of a select integrin inhibitor (Compound 5). Data include plasma concentrations of the administered integrin inhibitor ("PK," round dots) and the relative change from baseline (day -1) in pSMAD2:SMAD2 ratios in BAL (bronchoalveolar lavage) samples ("pSMAD," square dots) over the indicated time course (hours) from administration of the inhibitor on day 7. The peak plasma concentration ("PK" curve) is recorded as Cmax. [Figure 8F]1 is a series of graphs showing data from subjects administered 40 mg / day of a select integrin inhibitor (Compound 5). Data include plasma concentrations of the administered integrin inhibitor ("PK," round dots) and the relative change from baseline (day -1) in pSMAD2:SMAD2 ratios in BAL (bronchoalveolar lavage) samples ("pSMAD," square dots) over the indicated time course (hours) from administration of the inhibitor on day 7. The peak plasma concentration ("PK" curve) is recorded as Cmax. [Figure 8G] The percent change in BAL SMAD2 phosphorylation levels (pSMAD2:SMAD2 ratio) on day 7 compared to baseline levels recorded on day -1 is shown for placebo-treated subjects and subjects with integrin inhibitor Cmax measured below 700 ng / mL, between 700 ng / mL and 900 ng / mL, and above 900 ng / mL. [Figure 8H] Figure 1 shows that the percent change in SMAD2 phosphorylation (pSMAD2:SMAD2 ratio) (all time points) compared to baseline levels recorded on day -1 correlates with Cmax in subjects administered a 40 mg dose of Compound 5). [Figure 9] Pharmacokinetic / pharmacodynamic results comparing plasma exposure (day 7) and the pSMAD2 / SMAD2 ratio in BAL cells (baseline to day 7) are shown. BAL: bronchoalveolar lavage; IC50: 50% inhibitory concentration; IC80: 80% inhibitory concentration; IC90: 90% inhibitory concentration; pSMAD2: phosphorylated SMAD2; SMAD2: a protein family similar to the gene products of the Drosophila gene "mothers against decapentaplegic" (Mad) and the C. elegans gene Sma2. DETAILED DESCRIPTION OF THE INVENTION

[0033] The present disclosure provides, inter alia, compounds of formula (A) and variants thereof or salts thereof, pharmaceutical compositions comprising compounds of formula (A) or salts thereof, and methods of using such compounds and compositions in the treatment of fibrotic disorders.

[0034] The present disclosure provides, inter alia, compounds of formula (I) and variants thereof or salts thereof, pharmaceutical compositions comprising compounds of formula (I) or salts thereof, and methods of using such compounds and compositions in the treatment of fibrotic disorders.

[0035] definition For purposes of use herein, unless otherwise specified, the use of the terms "a," "an," etc. refers to one or more.

[0036] Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to that value or parameter itself. For example, a reference to "about X" includes a description of "X."

[0037] As used herein, a "small molecule" is an organic molecule characterized by a mass of less than 900 daltons. Non-limiting examples of small molecules include the compounds shown in Figure 1 or salts thereof.

[0038] 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 10 The 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.

[0039] 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 (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), butylene (-CH2(CH2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), pentylene (-CH2(CH2)3CH2-), hexylene (-CH2(CH2)4CH2-), heptylene (-CH2(CH2)5CH2-), octylene (-CH2(CH2)6CH2-), and the like.

[0040] 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 10alkenyl"), 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.

[0041] 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 10 C-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-).

[0042] 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.

[0043] 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 10 alkynylene), 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.

[0044] 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.

[0045] As used herein, "cycloalkylene" refers to the same residue as cycloalkyl, but with divalent character. Cycloalkylene can consist of a single 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 cycloalkylenes include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, and the like. Cycloalkylenes can be attached to the rest of the structure through the same ring carbon atom or different ring carbon atoms. 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 to each other, for example, cyclopropylene can include 1,1-cyclopropylene and 1,2-cyclopropylene (e.g., cis-1,2-cyclopropylene or trans-1,2-cyclopropylene), or mixtures thereof.

[0046] "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.

[0047] As used herein, "cycloalkenylene" refers to the same residues as cycloalkenyl, but with divalent nature.

[0048] As used herein, "aryl" or "Ar" refers to an aromatic unsaturated carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which may or may not be aromatic. Particular aryl groups have 6 to 14 ring carbon atoms ("C-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.

[0049] 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").

[0050] 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, 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 or may not be aromatic. Specific heteroaryl groups are 5- to 14-membered rings having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered rings having 1 to 8 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-, 6-, or 7-membered rings having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, specific heteroaryl groups are monocyclic aromatic 5-, 6-, or 7-membered rings having 1 to 6 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, specific heteroaryl groups are polycyclic aromatic rings having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heteroaryl groups having two or more rings, in which 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 two or more rings, in which at least one ring is non-aromatic, can be connected to the parent structure at an aromatic ring position. Heteroaryl groups can be connected to the parent structure at a ring carbon atom or a ring heteroatom.

[0051] As used herein, "heteroarylene" refers to the same residues as heteroaryl, but which are divalent.

[0052] As used herein, "heterocycle," "heterocyclic," or "heterocyclyl" refers to a saturated or unsaturated non-aromatic cyclic group having a single ring or multiple fused rings, 1 to 14 ring carbon atoms, and 1 to 6 ring heteroatoms such as nitrogen, sulfur, or oxygen. Heterocycles containing two or more rings can be fused, bridged, or spirocyclic, or combinations thereof, but exclude heteroaryl groups. Heterocyclyl groups can be optionally substituted independently 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.

[0053] As used herein, "heterocyclylene" refers to the same residues as heterocyclyl, but which have bivalency.

[0054] "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 more than one halogen, 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") halo groups, which 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 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. One example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

[0055] "Carbonyl" refers to the group C=O.

[0056] "Thiocarbonyl" refers to the group C=S.

[0057] "Oxo" refers to the moiety =O.

[0058] "D" stands for deuterium ( 2 H).

[0059] "T" stands for tritium ( 3 H).

[0060] An alkyl group in which each hydrogen is replaced with a deuterium is called "perdeuterated." An alkyl group in which each hydrogen is replaced with a tritium is called "pertritiated."

[0061] "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 one embodiment, 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 one embodiment, an optionally substituted group is unsubstituted.

[0062] It is understood that an optionally substituted moiety can be substituted with more than six substituents, if permitted by the number of valences available for substitution on that moiety. For example, a propyl group can be substituted with seven halogen atoms to provide a perhalopropyl group. The substituents can be the same or different.

[0063] Unless otherwise specified, "individual" 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 is a human.

[0064] As used herein, "treatment" or "treating" refers to an approach to obtaining beneficial or desired results, including clinical results. Beneficial or desired results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from a disease, reducing the severity 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 of the present invention contemplate any one or more of these aspects of treatment.

[0065] As used herein, the term "effective amount" refers to the amount of the compound of the present invention 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 of the co-administered compounds may optionally be reduced due to the combined effect (e.g., additive or synergistic) of the compounds.

[0066] A "therapeutically effective amount" refers to that amount of a compound or salt thereof sufficient to produce a desired therapeutic effect.

[0067] 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.

[0068] 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.).

[0069] 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.

[0070] A "pharmaceutically acceptable salt" is a salt that retains at least some biological activity of the free (non-salt) compound and can be administered to an individual as a drug or pharmaceutical. Examples of such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, and tartaric acid; and (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., 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, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Pharmaceutically acceptable salts can be prepared in situ during the manufacturing process, or can be prepared by separately reacting the purified compound of the invention 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.

[0071] The term "excipient," as used herein, 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, containing a compound of the present invention as an active ingredient. The term excipient can encompass a variety of substances, including, but not limited to, binders, disintegrants, coating agents, 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, Examples of suitable lubricants include maltodextrin, carrageenan, etc.; lubricants include magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable materials include dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulating agents include calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0072] Unless otherwise specified, "substantially pure" contemplates a composition containing 10% or less impurities, e.g., the composition contains less than 9%, 7%, 5%, 3%, 1%, 0.5% impurities.

[0073] It should be understood that aspects and embodiments described herein as "comprising" include "consisting of" and "consisting essentially of" the embodiment.

[0074] compound In one embodiment, provided is a compound of formula (A): [ka] or a salt thereof (wherein R 1 is C6-C 14 aryl or 5-10 membered heteroaryl, where C-C 14 Aryl and 5- to 10-membered heteroaryl are R 1a is optionally replaced by R 2 is hydrogen; deuterium; R 2a C1-C6 alkyl optionally substituted by -OH; R 2a -O-C1-C6 alkyl optionally substituted by R 2b C3-C6 cycloalkyl optionally substituted by R 2b -O-C3-C6 cycloalkyl optionally substituted by R 2c 3- to 12-membered heterocyclyl optionally substituted by -S(O)R 2d provided that any carbon atom directly bonded to a nitrogen atom is R other than a halogen. 2a optionally replaced by a moiety, Each R 1a are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-C 14 Aryl, deuterium, halogen, -CN, -OR 3 , -SR 3 , -NR 4 R 5 , -NO2, -C=NH(OR 3 ), -C(O)R3 , -OC(O)R 3 , -C(O)OR 3 , -C(O)NR 4 R 5 , -NR 3 C(O)R 4 , -NR 3 C(O)OR 4 , -NR 3 C(O)NR 4 R 5 , -S(O)R 3 , -S(O)2R 3 , -NR 3 S(O)R 4 , -NR 3 S(O)2R 4 , -S(O)NR 4 R 5 , -S(O)NR 4 R 5 , or -P(O)(OR 4 )(OR 5 ) where each R 1a are independently deuterium, halogen, oxo, -OR, if possible. 6 , -NR 6 R 7 , -C(O)R 6 , -CN, -S(O)R 6 , -S(O)2R 6 , -P(O)(OR 6 )(OR 7 ), C3-C8 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C6-C 14 optionally substituted by aryl, or C1-C6 alkyl optionally substituted by deuterium, oxo, —OH or halogen; Each R 2a , R 2b , R 2c , R 2e , and R 2f are independently oxo or R 1a and R 2d is R 2e C1-C6 alkyl optionally substituted by R 2f is a C3-C5 cycloalkyl optionally substituted by R 3 are independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R 3 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 Aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from halogen, deuterium, oxo, -CN, -OR 8 , -NR 8 R 9 , -P(O)(OR 8 )(OR 9 ), or C1-C6 alkyl optionally substituted by deuterium, halogen, —OH or oxo; R 4 and R 5 are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R 4 and R 5 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 Aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from deuterium, halogen, oxo, -CN, -OR 8 , -NR 8 R 9 or C1-C6 alkyl optionally substituted by deuterium, halogen, —OH or oxo; Alternatively, R 4 and R 5 together with the atom to which they are attached, deuterium, halogen, oxo, -OR 8 , -NR 8 R 9or a 3- to 6-membered heterocyclyl optionally substituted by C1-C6 alkyl optionally substituted by deuterium, halogen, oxo, or —OH; R 6 and R 7 are each independently hydrogen; deuterium; C1-C6 alkyl optionally substituted with deuterium, halogen, or oxo; C2-C6 alkenyl optionally substituted with deuterium, halogen, or oxo; or C2-C6 alkynyl optionally substituted with deuterium, halogen, or oxo; Alternatively, R 6 and R 7 together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted by deuterium, halogen, or oxo; R 8 and R 9 are each independently hydrogen; deuterium; C1-C6 alkyl optionally substituted with deuterium, halogen, or oxo; C2-C6 alkenyl optionally substituted with deuterium, halogen, or oxo; or C2-C6 alkynyl optionally substituted with deuterium, halogen, or oxo; Alternatively, R 8 and R 9 together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted by deuterium, oxo, or halogen; Each R 10 , R 11 , R 12 and R 13 are independently hydrogen or deuterium, R 14 is deuterium, q is 0, 1, 2, 3, 4, 5, 6, 7, or 8; Each R 15are independently selected from hydrogen, deuterium, or a halogen; Each R 16 are independently selected from hydrogen, deuterium, or a halogen; p is 3, 4, 5, 6, 7, 8, or 9).

[0075] In one variation, it is provided that the free base of (2S)-4-[2-methoxyethyl-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]amino]-2-(quinazolin-4-ylamino)butanoic acid is omitted: [ka]

[0076] In various embodiments, the claimed compounds exclude the free base of the compound represented by formula A, where R 1 is unsubstituted quinazolin-4-yl, and R 2 is -CH2CH2OCH3, and R 10 , R 11 , R 12 , R 13 , R 15 , and R 16 are H, p is 3, q ​​is 0, and R 1 The carbon to which NH— is attached is in the S configuration, for example, in some embodiments, compounds of Formula A exclude the free base of (2S)-4-[2-methoxyethyl-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]amino]-2-(quinazolin-4-ylamino)butanoic acid: [ka]

[0077] In some embodiments, the claimed compounds exclude the free base of the compound represented by formula A, wherein R 2 is -CH2CH2OCH3, and R 10 , R 11 , R 12, R 13 , R 15 , and R 16 are H, p is 3, q ​​is 0, and R 1 The carbon atom to which NH- is attached is in the S configuration, and the R 1 is one or more of the following embodiments (a) through (k) designated by separate letters: (a) R 1 (b) R is unsubstituted quinazolin-4-yl. 1 is R 1a quinazolin-4-yl substituted by 1a is methyl. (c) R 1 is R 1a quinazolin-4-yl substituted by 1a is methyl or ethyl. (d) R 1 is R 1a quinazolin-4-yl substituted by 1a is C1-C6 alkyl. (e) R 1 is R 1a (f) R is a quinazolin-4-yl substituted with 1 is a 10-membered bicyclic fused heterocycle containing two ring nitrogen atoms, and R 1 is unsubstituted or R 1a (g)R 1 is unsubstituted quinazolinyl. (h) R 1 is R 1a quinazolinyl substituted by, wherein R 1a is methyl. (i) R 1 is R 1a quinazolinyl substituted by, where R 1a is methyl or ethyl. (j)R 1 is R 1a quinazolinyl substituted by, wherein R 1a is C1-C6 alkyl. (k) R 1 is R 1a and quinazolinyl substituted by:

[0078] In some embodiments, the claimed compounds exclude the free base of the compound represented by formula A, wherein R 1 is unsubstituted quinazolin-4-yl, and R 10 , R 11 , R 12 , R 13 , R 15 , and R 16 are H, p is 3, q ​​is 0, and R 1 The carbon atom to which NH- is attached is in the S configuration, and the R 2 is one or more of the following embodiments (l) to (p) indicated by separate letters: (l) R 2 is R 2a is 2-substituted ethylene with R 2a is methoxy. (m)R 2 is R 2a methylene, ethylene, or propylene substituted by R 2a is methoxy. (n)R 2 is R 2a is ethylene substituted by R 2a is methoxy or hydroxy. 2 is R 2a is ethylene substituted by R 2a is hydroxy. (p)R 2 is R 2a methylene, ethylene, or propylene substituted by R 2a is hydroxy, methoxy, or ethoxy.

[0079] In some embodiments, the claimed compounds exclude the free base of the compound represented by formula A, wherein R 1 is unsubstituted quinazolin-4-yl, and R 2 is -CH2CH2OCH3, and R 15 and R 16 are H, p is 3, q ​​is 0, and R 1 The carbon atom to which NH- is attached is in the S configuration, and the R 10 , R 11 , R12 , and R 13 together represent one or more of the following embodiments (q) to (u) indicated by separate letters: (q) R 10 , R 11 , R 12 , and R 13 Each of (r)R is hydrogen. 10 , R 11 , R 12 , and R 13 One of the atoms is deuterium and the rest are hydrogen. (s)R 10 , R 11 , R 12 , and R 13 Two of the atoms are deuterium and the rest are hydrogen. (t)R 10 , R 11 , R 12 , and R 13 Three of the atoms are deuterium and the rest are hydrogen. (u)R 10 , R 11 , R 12 , and R 13 Each of is deuterium.

[0080] In some embodiments, the claimed compounds exclude the free base of the compound represented by formula A, wherein R 1 is unsubstituted quinazolin-4-yl, and R 2 is -CH2CH2OCH3, and R 10 , R 11 , R 12 , and R 13 are H, p is 3, q ​​is 0, and R 1 The carbon atom to which NH- is attached is in the S configuration, and the R 15 and R 16 together represent one or more of the following embodiments (v) through (aa) designated by separate letters: (v) R 15 and R 16 Each of (w)R is hydrogen. 15 is hydrogen and R 16 is deuterium or R 15 is deuterium and R 16 is hydrogen. (x)R 15and R 16 is deuterium. (y)R 15 is hydrogen and R 16 is a halogen, e.g., fluorine, or R 15 is a halogen, e.g., fluorine, and R 16 is hydrogen. (z)R 15 is deuterium and R 16 is a halogen, e.g., fluorine, or R 15 is a halogen, e.g., fluorine, and R 16 is deuterium. (aa)R 15 and R 16 are each halogen, for example, fluorine.

[0081] In some embodiments, the claimed compounds exclude the free base of the compound represented by formula A, wherein R 1 is unsubstituted quinazolin-4-yl, and R 2 is -CH2CH2OCH3, and R 10 , R 11 , R 12 , R 13 , R 15 , and R 16 are H, q is 0, and R 1 The carbon to which NH- is attached is in the S configuration, and p is one of the following separate letter embodiments (ab) to (ad): (ab) p is 3. (ac) p is 4. (ad) p is 5.

[0082] In some embodiments, the claimed compounds exclude the free base of the compound represented by formula A, wherein R 1 is unsubstituted quinazolin-4-yl, and R 2 is -CH2CH2OCH3, and R 10 , R 11 , R 12 , R 13 , R 15 , and R 16 are H, p is 3, and R 1The carbon to which NH- is attached is in the S configuration, and q is one of the following embodiments (ae) to (ah), designated by separate letters: (ae) q is 0; (af) q is 1; (ag) q is 2; (ah) q is 3.

[0083] In some embodiments, R 1 ;R 2 ;R 10 , R 11 , R 12 , and R 13 ;R 15 and R 16 The free base of any combination of the lettered embodiments selected for each of variable p and variable q is excluded. For example, R is one of (a) through (k). 1 ;R is one of (l)~(p) 2 ;R is one of (q)~(u) 10 , R 11 , R 12 , and R 13 ;(v)~(aa) is one of R 15 and R 16and a variable p that is one of (ab) through (ad); and a variable q that is one of (ae) through (ah). Exemplary combinations of lettered embodiments include, for example, (a), (l), (q), (v), (ab), and (ae); (b), (l), (q), (v), (ab), and (ae); (c), (l), (q), (v), (ab), and (ae); (d), (l), (q), (v), (ab), and (ae); (e), (l), (q), (v), (ab), and (ae); (f), (l), (q), (v), (ab), and (ae); (g), (l), (q), (v), (ab), and (ae); (h), ( l), (q), (v), (ab), and (ae);(i), (l), (q), (v), (ab), and (ae);(j), (l), (q), (v), (ab), and (ae);(k), (l), (q), (v), (ab), and (ae);(a), (m), (q), (v), (ab), and (ae);(b), (m), (q), (v), (ab), and (ae);(c), (m), (q), (v), (ab), and (ae);(d), (m), (q), (v), (ab), and (ae);(e), (m), (q), ( v), (ab), and (ae); (f), (m), (q), (v), (ab), and (ae); (g), (m), (q), (v), (ab), and (ae); (h), (m), (q), (v), (ab), and (ae); (i), (m), (q), (v), (ab), and (ae); (j), (m), (q), (v), (ab), and (ae); (k), (m), (q), (v), (ab), and (ae); (a), (n), (q), (v), (ab), and (ae); (b), (n), (q), (v), (ab) , and (ae); (c), (n), (q), (v), (ab), and (ae); (d), (n), (q), (v), (ab), and (ae); (e), (n), (q), (v), (ab), and (ae); (f), (n), (q), (v), (ab), and (ae); (g), (n), (q), (v), (ab), and (ae); (h), (n), (q), (v), (ab), and (ae); (i), (n), (q), (v), (ab), and (ae); (j), (n), (q), (v), (ab), and (ae);(k), (n), (q), (v), (ab), and (ae); (a), (o), (q), (v), (ab), and (ae); (b), (o), (q), (v), (ab), and (ae); (c), (o), (q), (v), (ab), and (ae); (d), (o), (q), (v), (ab), and (ae); (e), (o), (q), (v), (ab), and (ae); (f), (o), (q), (v), (ab), and (ae); (g) , (o), (q), (v), (ab), and (ae); (h), (o), (q), (v), (ab), and (ae); (i), (o), (q), (v), (ab), and (ae); (j), (o), (q), (v), (ab), and (ae); (k), (o), (q), (v), (ab), and (ae); (a), (p), (q), (v), (ab), and (ae); (b), (p), (q), (v), (ab), and (ae); (c), (p) , (q), (v), (ab), and (ae);(d), (p), (q), (v), (ab), and (ae);(e), (p), (q), (v), (ab), and (ae);(f), (p), (q), (v), (ab), and (ae);(g), (p), (q), (v), (ab), and (ae);(h), (p), (q), (v), (ab), and (ae);(i), (p), (q), (v), (ab), and (ae);(j), (p), (q ), (v), (ab), and (ae); (k), (p), (q), (v), (ab), and (ae); any one of the above combinations in which (v) is replaced by (y); any one of the above combinations in which (v) is replaced by (aa); any one of the above combinations in which (ab) is replaced by (ad); or any one of the above combinations in which (ab) is replaced by (ae);

[0084] In some embodiments, salts of the compound of any one of the above embodiments (a)-(ah) or any combination thereof designated by a letter are excluded. In some embodiments, pharmaceutical compositions comprising a compound of any one of the above embodiments (a)-(ah) or any combination thereof designated by a letter, or a salt thereof are excluded. In some embodiments, kits comprising a compound of any one of the above embodiments (a)-(ah) or any combination thereof designated by a letter, or a salt thereof are excluded. In some embodiments, dosage forms comprising a compound of any one of the above embodiments (a)-(ah) or any combination thereof designated by a letter are excluded. In some embodiments, methods comprising a compound of any one of the above embodiments (a)-(ah) or any combination thereof designated by a letter, or a salt thereof are excluded.

[0085] In one variation, COH and NHR 1 In another variation, a compound of formula (A) or a salt thereof is provided, wherein the carbon bearing the moiety is in the "S" configuration. 1 Compounds of formula (A), or salts thereof, are provided, wherein the carbon bearing the moiety is in the "R" configuration. Mixtures of compounds of formula (A) are also encompassed, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0086] In one variation of formula (A), R 2 has the proviso that any carbon atom directly attached to a nitrogen atom is either unsubstituted or substituted with deuterium.

[0087] In the description herein, it is understood that every description, variation, embodiment, or aspect of a 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 1All descriptions, variations, embodiments or aspects provided herein relating to R 2 and the like.

[0088] In one embodiment, provided is a compound of formula (I): [ka] or a salt thereof (wherein R 1 is C6-C 14 aryl or 5-10 membered heteroaryl, where C-C 14 Aryl and 5- to 10-membered heteroaryl are R 1a is optionally replaced by R 2 is R 2a C1-C6 alkyl optionally substituted by R 2b C3-C6 cycloalkyl optionally substituted by R 2c 3- to 12-membered heterocyclyl optionally substituted by -S(O)R 2d and Each R 1a are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-C 14 Aryl, deuterium, halogen, -CN, -OR 3 , -SR 3 , -NR 4 R 5 , -NO2, -C=NH(OR 3 ), -C(O)R 3 , -OC(O)R 3 , -C(O)OR 3 , -C(O)NR 4 R 5 , -NR 3 C(O)R 4 , -NR 3 C(O)OR 4, -NR 3 C(O)NR 4 R 5 , -S(O)R 3 , -S(O)2R 3 , -NR 3 S(O)R 4 , -NR 3 S(O)2R 4 , -S(O)NR 4 R 5 , -S(O)NR 4 R 5 , or -P(O)(OR 4 )(OR 5 ) where each R 1a are independently deuterium, halogen, oxo, -OR, if possible. 6 , -NR 6 R 7 , -C(O)R 6 , -CN, -S(O)R 6 , -S(O)2R 6 , -P(O)(OR 6 )(OR 7 ), C3-C8 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C6-C 14 optionally substituted by aryl, or C1-C6 alkyl optionally substituted by deuterium, oxo, —OH or halogen; Each R 2a , R 2b , R 2c , R 2e , and R 2f are independently oxo or R 1a and R 2d is R 2e C1-C6 alkyl optionally substituted by R 2f is a C3-C5 cycloalkyl optionally substituted by R 3 are independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R 3C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 Aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from halogen, deuterium, oxo, -CN, -OR 8 , -NR 8 R 9 , -P(O)(OR 8 )(OR 9 ), or C1-C6 alkyl optionally substituted by deuterium, halogen, —OH or oxo; R 4 and R 5 are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R 4 and R 5 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 Aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from deuterium, halogen, oxo, -CN, -OR 8 , -NR 8 R 9 or C1-C6 alkyl optionally substituted by deuterium, halogen, —OH or oxo; Alternatively, R 4 and R 5 together with the atom to which they are attached, deuterium, halogen, oxo, -OR 8 , -NR 8 R 9 or a 3- to 6-membered heterocyclyl optionally substituted by C1-C6 alkyl optionally substituted by deuterium, halogen, oxo, or —OH; R 6 and R 7are each independently hydrogen; deuterium; C1-C6 alkyl optionally substituted with deuterium, halogen, or oxo; C2-C6 alkenyl optionally substituted with deuterium, halogen, or oxo; or C2-C6 alkynyl optionally substituted with deuterium, halogen, or oxo; Alternatively, R 6 and R 7 together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted by deuterium, halogen, or oxo; R 8 and R 9 are each independently hydrogen; deuterium; C1-C6 alkyl optionally substituted with deuterium, halogen, or oxo; C2-C6 alkenyl optionally substituted with deuterium, halogen, or oxo; or C2-C6 alkynyl optionally substituted with deuterium, halogen, or oxo; Alternatively, R 8 and R 9 together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted by deuterium, oxo, or halogen; Each R 10 , R 11 , R 12 and R 13 are independently hydrogen or deuterium, R 14 is deuterium, q is 0, 1, 2, 3, 4, 5, 6, 7, or 8; p is 3, 4, 5, 6, 7, 8, or 9).

[0089] In one variation, COH and NHR 1In another variation, a compound of formula (I) or a salt thereof is provided, wherein the carbon bearing the moiety is in the "S" configuration. 1 Compounds of formula (I), or 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.

[0090] In one variation of formula (I), R 2 means that any carbon atom directly bonded to a nitrogen atom is R other than halogen. 2a In one variation of formula (I), R 2 includes the proviso that any carbon atom directly attached to a nitrogen atom is either unsubstituted or substituted with deuterium.

[0091] 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 1 All descriptions, variations, embodiments or aspects provided herein relating to R 2 and the like.

[0092] In some embodiments of the compound of Formula (I) or salt thereof, R 1a , R 2a , R 2b , R 2c , R 2e , R 2f , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R11 , R 12 , R 13 , R 14 , R 15 , or R 16 At least one of is deuterium.

[0093] In some embodiments of the compound of Formula (I) or salt thereof, R 1 is R 1a In some embodiments, R is a 5-10 membered heteroaryl optionally substituted by 1 is R 1a In some embodiments, R is pyrimidin-4-yl optionally substituted by 1 is R 1a pyrimidin-4-yl optionally substituted by 1a is a 5-10 membered heteroaryl (e.g., pyrazolyl) or a C1-C6 alkyl optionally substituted with halogen (e.g., methyl, difluoromethyl, and trifluoromethyl). 1 is R 1a pyrimidin-4-yl optionally substituted by 1a is a 5-10 membered heteroaryl (e.g., pyrazolyl or pyridinyl) or a C1-C6 alkyl optionally substituted with halogen (e.g., methyl, difluoromethyl, and trifluoromethyl). 1 is pyrimidin-4-yl substituted with both methyl and trifluoromethyl. 1 is pyrimidin-4-yl substituted with both methyl and pyridinyl. In some embodiments, R 1 is R 1a pyrimidin-4-yl optionally substituted by 1a is C6-C 14 aryl (e.g., phenyl). In some embodiments, R 1 is R 1apyrimidin-4-yl optionally substituted by 1a In some embodiments, R 1 is R 1a In some embodiments, R is pyrimidin-2-yl optionally substituted by 1 is R 1a pyrimidin-2-yl optionally substituted by 1a is halogen, C1-C6 alkyl optionally substituted with halogen (e.g., methyl or trifluoromethyl), —CN, or C3-C8 cycloalkyl (e.g., cyclopropyl). In some embodiments of a compound of Formula (I) or a salt thereof, R 1 is R 1a In some embodiments, R is quinazolin-4-yl optionally substituted by 1 is R 1a quinazolin-4-yl optionally substituted by 1a is halogen (e.g., fluoro and chloro), C-C alkyl optionally substituted with halogen (e.g., methyl or trifluoromethyl), or C-C alkoxy (e.g., methoxy). 1 is R 1a quinazolin-4-yl optionally substituted by 1a is a 5-10 membered heteroaryl (e.g., pyridinyl). 1 is R 1a In some embodiments, R is a pyrazolopyrimidinyl optionally substituted by 1 is R 1a pyrazolopyrimidinyl optionally substituted by 1a is C1-C6 alkyl (e.g., methyl). 1 R 1a In some embodiments, R is indicated as being optionally substituted by 1 The moiety is unsubstituted.1 R 1a In some embodiments, R is indicated as being optionally substituted by 1 The part is one R 1a is replaced by R 1 R 1a In some embodiments, R is indicated as being optionally substituted by 1 The moieties may be the same or different and may consist of 2 to 6, 2 to 5, 2 to 4, or 2 to 3 R 1a is replaced by the part.

[0094] R 1 In some embodiments of Formula (I), including embodiments recited in the variable 10 , R 11 , R 12 and R 13 is hydrogen. 1 Variables of and / or R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (I), including embodiments recited in the variable 1 Variables of and / or R 10 , R 11 , R 12 and R 13 In some embodiments, including those recited in the above variables and / or the q variable, p is 3, 4, or 5.

[0095] In some embodiments of Formula (I), R 10 , R 11 , R 12 and R 13 is hydrogen, p is 3, and q is 0, and the compound has the formula (II): [ka] or a salt thereof, wherein R 1 and R 2 is as defined for formula (I).

[0096] R 1 R 1a In some embodiments of compounds of Formula (I), wherein the compound is a 5-10 membered heteroaryl optionally substituted by [ka] or a salt thereof, wherein R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), m is 0, 1, 2, or 3, and the positions on the pyrimidine and tetrahydronaphthyridine rings are as shown.

[0097] In one embodiment, a compound of formula (IA), or a salt thereof, is provided, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, a compound of formula (IA), or a salt thereof, is provided, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Mixtures of compounds of formula (IA) are also encompassed, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0098] In some embodiments of compounds of Formula (IA), m is 0, 1, 2, or 3, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of a compound of formula (IA), m is 0, 1, 2, or 3, and each R 1aare, if applicable, independently deuterium, halogen, C-C alkyl, C-C haloalkyl (which in one variation may be C-C perhaloalkyl), C-C alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a In some embodiments of Formula (IA), m is 1, 2, or 3.

[0099] In some embodiments of the compound of Formula (IA), m is 0. In some embodiments of the compound of Formula (IA), m is 1 and R 1a is at the 2-position. In some embodiments of compounds of Formula (IA), m is 1 and R 1a is at the 5-position. In some embodiments of compounds of Formula (IA), m is 1 and R 1a is at the 6-position. In some embodiments of compounds of Formula (IA), m is 2 and R 1a In some embodiments of compounds of Formula (IA), m is 2 and R 1a In some embodiments of compounds of Formula (IA), m is 2 and R 1a In some embodiments of compounds of Formula (IA), m is 3 and R 1a Groups are located at positions 2, 5, and 6. Two or more R 1a Whenever a group is present, R 1a The groups can be independently selected. In any of these embodiments of the compound of formula (IA) or salt thereof, the carbon bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0100] R 1a In some embodiments of formula (IA), including embodiments reciting variables of and m, R 10 , R 11 , R12 and R 13 Each of R is hydrogen. 1a and m variables, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (IA), including embodiments recited in the variable 1a and m variables, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (IA), including embodiments reciting variables of and / or q, p is 3, 4, or 5.

[0101] In some embodiments of Formula (IA), R 10 , R 11 , R 12 and R 13 is hydrogen, p is 3, and q is 0, and the compound has formula (II-A): [ka] or a salt thereof, wherein R 1a and R 2 is as defined for formula (I), m is 0, 1, 2, or 3, and the positions on the pyrimidine ring are as shown. R for formula (I) 1a , R 2 All descriptions of and m apply equally to formulas (IA) and (II-A).

[0102] R 1 R 1a In some embodiments of the compound of Formula (I), wherein the compound is a 5-10 membered heteroaryl optionally substituted by [ka] or a salt thereof, wherein R 1a , R 2 , R 10 , R11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), m is 0, 1, 2, 3, 4, or 5, and the positions on the quinazoline ring are as shown.

[0103] In one embodiment, a compound of formula (IB), or a salt thereof, is provided, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, a compound of formula (IB), or a salt thereof, is provided, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Mixtures of compounds of formula (IB) are also encompassed, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0104] In some embodiments of compounds of Formula (IB), m is 0, 1, 2, 3, 4, or 5, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of a compound of formula (IB), m is 0, 1, 2, 3, 4, or 5, and each R 1a are, if applicable, independently deuterium, halogen, C-C alkyl, C-C haloalkyl (which in one variation may be C-C perhaloalkyl), C-C alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a wherein C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5-10 membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of a compound of Formula (IB), m is 1, 2, 3, 4, or 5.

[0105] In some embodiments of the compound of Formula (IB), m is 0. In some embodiments of the compound of Formula (IB), m is 1 and R 1a is at the 2-position. In some embodiments of compounds of Formula (IB), m is 1 and R 1a is at the 5-position. In some embodiments of compounds of Formula (IB), m is 1 and R 1a is at the 6-position. In some embodiments of compounds of Formula (IB), m is 1 and R 1a is at the 7-position. In some embodiments of compounds of Formula (IB), m is 1 and R 1a is at the 8-position. In some embodiments of compounds of Formula (IB), m is 2 and R 1a In some embodiments of compounds of Formula (IB), m is 2 and R 1a In some embodiments of compounds of Formula (IB), m is 2 and R 1a In some embodiments of compounds of Formula (IB), m is 2 and R 1a In some embodiments of compounds of Formula (IB), m is 2 and R 1a In some embodiments of compounds of Formula (IB), m is 2 and R 1a In some embodiments of compounds of Formula (IB), m is 2 and R 1a In some embodiments of compounds of Formula (IB), m is 2 and R 1a In some embodiments of compounds of Formula (IB), m is 2 and R 1a In some embodiments of compounds of Formula (IB), m is 2 and R 1a In some embodiments of compounds of Formula (IB), m is 3 and R 1aIn some embodiments of the compound of Formula (IB), m is 3 and R 1a groups are at the 2-, 5-, and 7-positions. In some embodiments of compounds of Formula (IB), m is 3 and R 1a groups are at positions 2, 5, and 8. In some embodiments of compounds of Formula (IB), m is 3 and R 1a groups are at the 2-, 6-, and 7-positions. In some embodiments of compounds of Formula (IB), m is 3 and R 1a groups are at positions 2, 6, and 8. In some embodiments of compounds of Formula (IB), m is 3 and R 1a groups are at positions 2, 7, and 8. In some embodiments of compounds of Formula (IB), m is 3 and R 1a groups are at the 5, 6, and 7 positions. In some embodiments of compounds of Formula (IB), m is 3 and R 1a groups are at positions 5, 6, and 8. In some embodiments of compounds of Formula (IB), m is 3 and R 1a groups are at positions 5, 7, and 8. In some embodiments of compounds of Formula (IB), m is 3 and R 1a groups are at positions 6, 7, and 8. In some embodiments of compounds of Formula (IB), m is 4 and R 1a groups are at positions 2, 5, 6, and 7. In some embodiments of compounds of Formula (IB), m is 4 and R 1a groups are at positions 2, 5, 6, and 8. In some embodiments of compounds of Formula (IB), m is 4 and R 1a groups are at positions 2, 5, 7, and 8. In some embodiments of compounds of Formula (IB), m is 4 and R 1a groups are at positions 2, 6, 7, and 8. In some embodiments of compounds of Formula (IB), m is 4 and R 1a groups are at positions 5, 6, 7, and 8. In some embodiments of compounds of Formula (IB), m is 5 and R 1aGroups are located at positions 2, 5, 6, 7, and 8. Two or more R 1a Whenever a group is present, R 1a The groups can be independently selected. In any of these embodiments of the compound of formula (IB) or a salt thereof, the carbon bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0106] R 1a In some embodiments of formula (IB), including embodiments reciting variables of and m, R 10 , R 11 , R 12 and R 13 Each of R is hydrogen. 1a and m variables, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (IB), including embodiments recited in the variable 1a and m variables, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (IB), including embodiments reciting variables of and / or q, p is 3, 4, or 5.

[0107] In some embodiments of Formula (IB), R 10 , R 11 , R 12 and R 13 is hydrogen, p is 3, and q is 0, and the compound has formula (II-B): [ka] or a salt thereof, wherein R 1a and R 2 is as defined for formula (I), m is 0, 1, 2, 3, 4, or 5, and the positions on the quinazoline ring are as shown. 1a , R 2All descriptions of and m apply equally to formulas (IB) and (II-B).

[0108] R 1 R 1a In some embodiments of the compound of Formula (I), wherein the compound is a 5-10 membered heteroaryl optionally substituted by [ka] or a salt thereof, wherein R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q, and p are as defined for formula (I), m is 0, 1, 2, 3, or 4, and the positions on the pyrido[3,2-d]pyrimidine ring are as shown.

[0109] In one embodiment, a compound of formula (IC), or a salt thereof, is provided, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, a compound of formula (IC), or a salt thereof, is provided, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Mixtures of compounds of formula (IC) are also encompassed, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0110] In some embodiments of compounds of Formula (IC), m is 0, 1, 2, 3, or 4, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of a compound of formula (IC), m is 0, 1, 2, 3, or 4, and each R 1aare, if applicable, independently deuterium, halogen, C-C alkyl, C-C haloalkyl (which in one variation may be C-C perhaloalkyl), C-C alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a wherein C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5-10 membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of a compound of Formula (IC), m is 1, 2, 3, or 4.

[0111] In some embodiments of the compound of Formula (IC), m is 0. In some embodiments of the compound of Formula (IC), m is 1 and R 1a is at the 2-position. In some embodiments of compounds of Formula (IC), m is 1 and R 1a is at the 6-position. In some embodiments of compounds of Formula (IC), m is 1 and R 1a is at the 7-position. In some embodiments of compounds of Formula (IC), m is 1 and R 1a is at the 8-position. In some embodiments of compounds of Formula (IC), m is 2 and R 1a In some embodiments of compounds of Formula (IC), m is 2 and R 1a In some embodiments of compounds of Formula (IC), m is 2 and R 1a In some embodiments of compounds of Formula (IC), m is 2 and R 1a groups are at the 6 and 7 positions. In some embodiments of compounds of Formula (IC), m is 2 and R 1a In some embodiments of compounds of Formula (IC), m is 2 and R 1a In some embodiments of compounds of Formula (IC), m is 3 and R 1agroups are at positions 2, 6, and 7. In some embodiments of compounds of Formula (IC), m is 3 and R 1a groups are at positions 2, 6, and 8. In some embodiments of compounds of Formula (IC), m is 3 and R 1a In some embodiments of compounds of Formula (IC), m is 3 and R 1a groups are at positions 6, 7, and 8. In some embodiments of compounds of Formula (IC), m is 4 and R 1a Groups are located at positions 2, 6, 7, and 8. Two or more R 1a Whenever a group is present, R 1a The groups can be independently selected. In any of these embodiments of the compound of formula (IC) or salt thereof, the carbon bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0112] R 1a In some embodiments of formula (IC), including embodiments reciting variables of and m, R 10 , R 11 , R 12 and R 13 Each of R is hydrogen. 1a and m variables, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (IC), including embodiments recited in the variable 1a and m variables, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (IC), including embodiments reciting variables of and / or q, p is 3, 4, or 5.

[0113] In some embodiments of Formula (IC), R 10 , R 11 , R 12 and R 13is hydrogen, p is 3, and q is 0, and the compound has formula (II-C): [ka] or a salt thereof, wherein R 1a and R 2 is as defined for formula (I), m is 0, 1, 2, 3, or 4, and the positions on the pyrido[3,2-d]pyrimidine ring are as shown. 1a , R 2 All descriptions of and m apply equally to formulas (IC) and (II-C).

[0114] R 1 R 1a In some embodiments of the compound of Formula (I), wherein the compound is a 5-10 membered heteroaryl optionally substituted by [ka] or a salt thereof, wherein R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), m is 0, 1, 2, 3, or 4, and the positions on the pyrido[3,4-d]pyrimidine ring are as shown.

[0115] In one embodiment, a compound of formula (ID), or a salt thereof, is provided, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, a compound of formula (ID), or a salt thereof, is provided, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Mixtures of compounds of formula (ID) are also encompassed, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0116] In some embodiments of compounds of Formula (ID), m is 0, 1, 2, 3, or 4, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of a compound of formula (ID), m is 0, 1, 2, 3, or 4, and each R 1a are, if applicable, independently deuterium, halogen, C-C alkyl, C-C haloalkyl (which in one variation may be C-C perhaloalkyl), C-C alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a wherein C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5-10 membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of a compound of Formula (ID), m is 1, 2, 3, or 4.

[0117] In some embodiments of the compound of Formula (ID), m is 0. In some embodiments of the compound of Formula (ID), m is 1 and R 1a is at the 2-position. In some embodiments of compounds of Formula (ID), m is 1 and R 1a is at the 5-position. In some embodiments of compounds of Formula (ID), m is 1 and R 1a is at the 6-position. In some embodiments of compounds of Formula (ID), m is 1 and R 1a is at the 8-position. In some embodiments of compounds of Formula (ID), m is 2 and R 1a In some embodiments of compounds of Formula (ID), m is 2 and R 1a In some embodiments of compounds of Formula (ID), m is 2 and R 1aIn some embodiments of compounds of Formula (ID), m is 2 and R 1a In some embodiments of compounds of Formula (ID), m is 2 and R 1a groups are at positions 5 and 8. In some embodiments of compounds of Formula (ID), m is 2 and R 1a In some embodiments of compounds of Formula (ID), m is 3 and R 1a groups are at positions 2, 5, and 6. In some embodiments of compounds of Formula (ID), m is 3 and R 1a groups are at positions 2, 5, and 8. In some embodiments of compounds of Formula (ID), m is 3 and R 1a groups are at positions 2, 6, and 8. In some embodiments of compounds of Formula (ID), m is 3 and R 1a groups are at positions 5, 6, and 8. In some embodiments of compounds of Formula (ID), m is 4 and R 1a Groups are located at positions 2, 5, 6, and 8. Two or more R 1a Whenever a group is present, R 1a The groups can be independently selected. In any of these embodiments of the compound of formula (ID) or salt thereof, the carbon bearing the CO2H and NH moieties can be in the "S" or "R" configuration.

[0118] R 1a In some embodiments of formula (ID), including embodiments reciting variables of and m, R 10 , R 11 , R 12 and R 13 Each of R is hydrogen. 1a and m variables, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (ID), including embodiments recited in the variable 1a and m variables, and / or R 10 , R11 , R 12 and R 13 In some embodiments of formula (ID), including those embodiments reciting the variable q, and / or the variable q, p is 3, 4, or 5.

[0119] In some embodiments of Formula (ID), R 10 , R 11 , R 12 and R 13 is hydrogen, p is 3, and q is 0, and the compound has formula (II-D): [ka] or a salt thereof, wherein R 1a and R 2 is as defined for formula (I), m is 0, 1, 2, 3, or 4, and the positions on the pyrido[3,4-d]pyrimidine ring are as shown. 1a , R 2 All descriptions of and m apply equally to formulas (ID) and (II-D).

[0120] R 1 R 1a In some embodiments of compounds of Formula (I), wherein the compound is a 5-10 membered heteroaryl optionally substituted by [ka] or a salt thereof, wherein R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), m is 0, 1, 2, 3, or 4, and the positions on the pyrido[2,3-d]pyrimidine ring are as shown.

[0121] In one embodiment, compounds of formula (IE), or salts thereof, are provided wherein the carbons bearing the COH and NH moieties are in the "S" configuration. In another embodiment, compounds of formula (IE), or salts thereof, are provided wherein the carbons bearing the COH and NH moieties are in the "R" configuration. Mixtures of compounds of formula (IE) are also encompassed, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0122] In some embodiments of compounds of Formula (IE), m is 0, 1, 2, 3, or 4, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of a compound of formula (IE), m is 0, 1, 2, 3, or 4, and each R 1a are, if applicable, independently deuterium, halogen, C-C alkyl, C-C haloalkyl (which in one variation may be C-C perhaloalkyl), C-C alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a wherein C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5-10 membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of a compound of Formula (IE), m is 1, 2, 3, or 4.

[0123] In some embodiments of the compound of Formula (IE), m is 0. In some embodiments of the compound of Formula (IE), m is 1 and R 1a is at the 2-position. In some embodiments of compounds of Formula (IE), m is 1 and R 1a is at the 5-position. In some embodiments of compounds of Formula (IE), m is 1 and R 1ais at the 6-position. In some embodiments of compounds of Formula (IE), m is 1 and R 1a is at the 7-position. In some embodiments of compounds of Formula (IE), m is 2 and R 1a In some embodiments of compounds of Formula (IE), m is 2 and R 1a In some embodiments of compounds of Formula (IE), m is 2 and R 1a In some embodiments of compounds of Formula (IE), m is 2 and R 1a In some embodiments of compounds of Formula (IE), m is 2 and R 1a groups are at the 5 and 7 positions. In some embodiments of compounds of Formula (IE), m is 2 and R 1a In some embodiments of compounds of Formula (IE), m is 3 and R 1a groups are at positions 2, 5, and 6. In some embodiments of compounds of Formula (IE), m is 3 and R 1a groups are at positions 2, 5, and 7. In some embodiments of compounds of Formula (IE), m is 3 and R 1a groups are at positions 2, 6, and 7. In some embodiments of compounds of Formula (IE), m is 3 and R 1a groups are at positions 5, 6, and 7. In some embodiments of compounds of Formula (IE), m is 4 and R 1a Groups are located at positions 2, 5, 6, and 7. Two or more R 1a Whenever a group is present, R 1a The groups can be independently selected. In any of these embodiments of the compound of formula (IE) or a salt thereof, the carbon bearing the CO2H and NH moieties can be in the "S" or "R" configuration.

[0124] R 1a In some embodiments of formula (IE), including embodiments reciting variables of and m, R 10 , R11 , R 12 and R 13 Each of R is hydrogen. 1a and m variables, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (IE), including embodiments recited in the variable 1a and m variables, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (IE), including those embodiments reciting variables of and / or q, p is 3, 4, or 5.

[0125] In some embodiments of Formula (IE), R 10 , R 11 , R 12 and R 13 is hydrogen, p is 3, and q is 0, and the compound has the formula (II-E): (II-E) [ka] or a salt thereof, wherein R 1a and R 2 is as defined for formula (I), m is 0, 1, 2, 3, or 4, and the positions on the pyrido[2,3-d]pyrimidine ring are as shown. 1a , R 2 All descriptions of and m apply equally to formulas (IE) and (II-E).

[0126] R 1 R 1a In some embodiments of compounds of Formula (I), wherein the compound is a 5-10 membered heteroaryl optionally substituted by [ka] or a salt thereof, wherein R 1a, R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), m is 0, 1, 2, 3, 4, 5, or 6, and the positions on the quinoline ring are as shown.

[0127] In one embodiment, a compound of formula (IF), or a salt thereof, is provided, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, a compound of formula (IF), or a salt thereof, is provided, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Mixtures of compounds of formula (IF) are also encompassed, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0128] In some embodiments of compounds of Formula (IF), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of a compound of formula (IF), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1a are, if applicable, independently deuterium, halogen, C-C alkyl, C-C haloalkyl (which in one variation may be C-C perhaloalkyl), C-C alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a In some embodiments of the compound of Formula (IF), m is 1, 2, 3, 4, 5, or 6.

[0129] In some embodiments of the compound of Formula (IF), m is 0. In some embodiments of the compound of Formula (IF), m is 1 and R 1a is at position 2. In some embodiments of compounds of Formula (IF), m is 1 and R 1a In some embodiments of compounds of Formula (IF), m is 1 and R 1a is at the 5-position. In some embodiments of compounds of Formula (IF), m is 1 and R 1a is at the 6-position. In some embodiments of compounds of Formula (IF), m is 1 and R 1a is at the 7-position. In some embodiments of compounds of Formula (IF), m is 1 and R 1a is at the 8-position. In some embodiments of compounds of Formula (IF), m is 2 and R 1a In some embodiments of compounds of Formula (IF), m is 2 and R 1a In some embodiments of compounds of Formula (IF), m is 2 and R 1a In some embodiments of compounds of Formula (IF), m is 2 and R 1a In some embodiments of compounds of Formula (IF), m is 2 and R 1a In some embodiments of compounds of Formula (IF), m is 2 and R 1a In some embodiments of compounds of Formula (IF), m is 2 and R 1a In some embodiments of compounds of Formula (IF), m is 2 and R 1a In some embodiments of compounds of Formula (IF), m is 2 and R 1a In some embodiments of compounds of Formula (IF), m is 2 and R 1a In some embodiments of compounds of Formula (IF), m is 2 and R1a In some embodiments of compounds of Formula (IF), m is 2 and R 1a In some embodiments of compounds of Formula (IF), m is 2 and R 1a In some embodiments of compounds of Formula (IF), m is 2 and R 1a In some embodiments of compounds of Formula (IF), m is 2 and R 1a In some embodiments of compounds of Formula (IF), m is 3 and R 1a In some embodiments of compounds of Formula (IF), m is 3 and R 1a In some embodiments of compounds of Formula (IF), m is 3 and R 1a In some embodiments of compounds of Formula (IF), m is 3 and R 1a groups are at positions 2, 3, and 8. In some embodiments of compounds of Formula (IF), m is 3 and R 1a groups are at positions 2, 5, and 6. In some embodiments of compounds of Formula (IF), m is 3 and R 1a groups are at positions 2, 5, and 7. In some embodiments of compounds of Formula (IF), m is 3 and R 1a groups are at positions 2, 5, and 8. In some embodiments of compounds of Formula (IF), m is 3 and R 1a groups are at positions 2, 6, and 7. In some embodiments of compounds of Formula (IF), m is 3 and R 1a groups are at positions 2, 6, and 8. In some embodiments of compounds of Formula (IF), m is 3 and R 1a groups are at positions 2, 7, and 8. In some embodiments of compounds of Formula (IF), m is 3 and R 1agroups are at positions 3, 5, and 6. In some embodiments of compounds of Formula (IF), m is 3 and R 1a groups are at positions 3, 5, and 7. In some embodiments of compounds of Formula (IF), m is 3 and R 1a groups are at positions 3, 5, and 8. In some embodiments of compounds of Formula (IF), m is 3 and R 1a groups are at positions 3, 6, and 7. In some embodiments of compounds of Formula (IF), m is 3 and R 1a groups are at positions 3, 6, and 8. In some embodiments of compounds of Formula (IF), m is 3 and R 1a groups are at positions 3, 7, and 8. In some embodiments of compounds of Formula (IF), m is 3 and R 1a groups are at positions 5, 6, and 7. In some embodiments of compounds of Formula (IF), m is 3 and R 1a groups are at positions 5, 6, and 8. In some embodiments of compounds of Formula (IF), m is 3 and R 1a groups are at positions 5, 7, and 8. In some embodiments of compounds of Formula (IF), m is 3 and R 1a groups are at positions 6, 7, and 8. In some embodiments of compounds of Formula (IF), m is 4 and R 1a groups are at positions 2, 3, 5, and 6. In some embodiments of compounds of Formula (IF), m is 4 and R 1a groups are at positions 2, 3, 5, and 7. In some embodiments of compounds of Formula (IF), m is 4 and R 1a groups are at positions 2, 3, 5, and 8. In some embodiments of compounds of Formula (IF), m is 4 and R 1a groups are at positions 2, 3, 6, and 7. In some embodiments of compounds of Formula (IF), m is 4 and R 1a groups are at positions 2, 3, 6, and 8. In some embodiments of compounds of Formula (IF), m is 4 and R 1aIn some embodiments of the compound of Formula (IF), m is 4 and R 1a groups are at positions 2, 5, 6, and 7. In some embodiments of compounds of Formula (IF), m is 4 and R 1a groups are at positions 2, 5, 6, and 8. In some embodiments of compounds of Formula (IF), m is 4 and R 1a groups are at positions 2, 5, 7, and 8. In some embodiments of compounds of Formula (IF), m is 4 and R 1a groups are at positions 2, 6, 7, and 8. In some embodiments of compounds of Formula (IF), m is 4 and R 1a groups are at positions 3, 5, 6, and 7. In some embodiments of compounds of Formula (IF), m is 4 and R 1a groups are at positions 3, 5, 6, and 8. In some embodiments of compounds of Formula (IF), m is 4 and R 1a groups are at positions 3, 5, 7, and 8. In some embodiments of compounds of Formula (IF), m is 4 and R 1a groups are at positions 3, 6, 7, and 8. In some embodiments of compounds of Formula (IF), m is 4 and R 1a groups are at positions 5, 6, 7, and 8. In some embodiments of compounds of Formula (IF), m is 5 and R 1a groups are at positions 2, 3, 5, 6, and 7. In some embodiments of compounds of Formula (IF), m is 5 and R 1a groups are at positions 2, 3, 5, 6, and 8. In some embodiments of compounds of Formula (IF), m is 5 and R 1a In some embodiments of the compound of Formula (IF), m is 5 and R 1a In some embodiments of the compound of Formula (IF), m is 5 and R 1agroups are at positions 2, 5, 6, 7, and 8. In some embodiments of compounds of Formula (IF), m is 5 and R 1a groups are at positions 3, 5, 6, 7, and 8. In some embodiments of compounds of Formula (IF), m is 6 and R 1a Groups are located at positions 2, 3, 5, 6, 7, and 8. Two or more R 1a Whenever a group is present, R 1a The groups can be independently selected. In any of these embodiments of the compound of formula (IF) or salt thereof, the carbon bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0130] R 1a In some embodiments of formula (IF), including embodiments reciting variables of and m, R 10 , R 11 , R 12 and R 13 Each of R is hydrogen. 1a and m variables, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (IF), including embodiments recited in the variable 1a and m variables, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (IF), including embodiments reciting variables of and / or q, p is 3, 4, or 5.

[0131] In some embodiments of Formula (IF), R 10 , R 11 , R 12 and R 13 is hydrogen, p is 3, and q is 0, and the compound has formula (II-F): [ka] or a salt thereof, wherein R1a and R 2 is as defined for formula (I), m is 0, 1, 2, 3, 4, 5, or 6, and the positions on the quinoline ring are as shown. 1a , R 2 All descriptions of and m apply equally to formulas (IF) and (II-F).

[0132] R 1 R 1a In some embodiments of a compound of Formula (I), wherein the compound is a 5-10 membered heteroaryl optionally substituted by [ka] or a salt thereof, wherein R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), m is 0, 1, 2, 3, 4, 5, or 6, and the positions on the isoquinoline ring are as shown.

[0133] In one embodiment, a compound of formula (IG) or a salt thereof is provided, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, a compound of formula (IG) or a salt thereof is provided, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Mixtures of compounds of formula (IG) are also encompassed, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0134] In some embodiments of compounds of Formula (IG), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1aIn a further embodiment of a compound of formula (IG), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1a are, if applicable, independently deuterium, halogen, C-C alkyl, C-C haloalkyl (which in one variation may be C-C perhaloalkyl), C-C alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a In some embodiments of the compound of Formula (IG), m is 1, 2, 3, 4, 5, or 6.

[0135] In some embodiments of the compound of Formula (IG), m is 0. In some embodiments of the compound of Formula (IG), m is 1 and R 1a is at the 3-position. In some embodiments of compounds of Formula (IG), m is 1 and R 1a is at the 4-position. In some embodiments of compounds of Formula (IG), m is 1 and R 1a is at the 5-position. In some embodiments of compounds of Formula (IG), m is 1 and R 1a is at the 6-position. In some embodiments of compounds of Formula (IG), m is 1 and R 1a is at the 7-position. In some embodiments of compounds of Formula (IG), m is 1 and R 1a is at the 8-position. In some embodiments of compounds of Formula (IG), m is 2 and R 1a In some embodiments of compounds of Formula (IG), m is 2 and R 1a In some embodiments of compounds of Formula (IG), m is 2 and R 1a In some embodiments of compounds of Formula (IG), m is 2 and R1a In some embodiments of compounds of Formula (IG), m is 2 and R 1a In some embodiments of compounds of Formula (IG), m is 2 and R 1a In some embodiments of compounds of Formula (IG), m is 2 and R 1a In some embodiments of compounds of Formula (IG), m is 2 and R 1a In some embodiments of compounds of Formula (IG), m is 2 and R 1a In some embodiments of compounds of Formula (IG), m is 2 and R 1a In some embodiments of compounds of Formula (IG), m is 2 and R 1a In some embodiments of compounds of Formula (IG), m is 2 and R 1a In some embodiments of compounds of Formula (IG), m is 2 and R 1a In some embodiments of compounds of Formula (IG), m is 2 and R 1a In some embodiments of compounds of Formula (IG), m is 2 and R 1a In some embodiments of compounds of Formula (IG), m is 3 and R 1a In some embodiments of compounds of Formula (IG), m is 3 and R 1a In some embodiments of compounds of Formula (IG), m is 3 and R 1a In some embodiments of compounds of Formula (IG), m is 3 and R 1a In some embodiments of compounds of Formula (IG), m is 3 and R 1agroups are at positions 4, 5, and 6. In some embodiments of compounds of Formula (IG), m is 3 and R 1a In some embodiments of compounds of Formula (IG), m is 3 and R 1a groups are at positions 4, 5, and 8. In some embodiments of compounds of Formula (IG), m is 3 and R 1a groups are at positions 4, 6, and 7. In some embodiments of compounds of Formula (IG), m is 3 and R 1a groups are at positions 4, 6, and 8. In some embodiments of compounds of Formula (IG), m is 3 and R 1a groups are at positions 4, 7, and 8. In some embodiments of compounds of Formula (IG), m is 3 and R 1a In some embodiments of compounds of Formula (IG), m is 3 and R 1a In some embodiments of compounds of Formula (IG), m is 3 and R 1a groups are at positions 3, 5, and 8. In some embodiments of compounds of Formula (IG), m is 3 and R 1a In some embodiments of compounds of Formula (IG), m is 3 and R 1a In some embodiments of compounds of Formula (IG), m is 3 and R 1a In some embodiments of compounds of Formula (IG), m is 3 and R 1a groups are at the 5, 6, and 7 positions. In some embodiments of compounds of Formula (IG), m is 3 and R 1a groups are at positions 5, 6, and 8. In some embodiments of compounds of Formula (IG), m is 3 and R 1a groups are at positions 5, 7, and 8. In some embodiments of compounds of Formula (IG), m is 3 and R 1agroups are at positions 6, 7, and 8. In some embodiments of compounds of Formula (IG), m is 4 and R 1a In some embodiments of compounds of Formula (IG), m is 4 and R 1a groups are at positions 3, 4, 5, and 7. In some embodiments of compounds of Formula (IG), m is 4 and R 1a groups are at positions 3, 4, 5, and 8. In some embodiments of compounds of Formula (IG), m is 4 and R 1a groups are at positions 3, 4, 6, and 7. In some embodiments of compounds of Formula (IG), m is 4 and R 1a groups are at positions 4, 3, 6, and 8. In some embodiments of compounds of Formula (IG), m is 4 and R 1a groups are at positions 3, 4, 7, and 8. In some embodiments of compounds of Formula (IG), m is 4 and R 1a In some embodiments of compounds of Formula (IG), m is 4 and R 1a groups are at positions 4, 5, 6, and 8. In some embodiments of compounds of Formula (IG), m is 4 and R 1a groups are at positions 4, 5, 7, and 8. In some embodiments of compounds of Formula (IG), m is 4 and R 1a In some embodiments of compounds of Formula (IG), m is 4 and R 1a groups are at positions 3, 5, 6, and 7. In some embodiments of compounds of Formula (IG), m is 4 and R 1a groups are at positions 3, 5, 6, and 8. In some embodiments of compounds of Formula (IG), m is 4 and R 1a groups are at positions 3, 5, 7, and 8. In some embodiments of compounds of Formula (IG), m is 4 and R 1a In some embodiments of compounds of Formula (IG), m is 4 and R 1aIn some embodiments of compounds of Formula (IG), m is 5 and R 1a groups are at positions 3, 4, 5, 6, and 7. In some embodiments of compounds of Formula (IG), m is 5 and R 1a groups are at positions 3, 4, 5, 6, and 8. In some embodiments of compounds of Formula (IG), m is 5 and R 1a In some embodiments of the compound of Formula (IG), m is 5 and R 1a groups are at positions 3, 4, 6, 7, and 8. In some embodiments of compounds of Formula (IG), m is 5 and R 1a groups are at positions 4, 5, 6, 7, and 8. In some embodiments of compounds of Formula (IG), m is 5 and R 1a In some embodiments of compounds of Formula (IG), m is 6 and R 1a Groups are located at positions 3, 4, 5, 6, 7, and 8. Two or more R 1a Whenever a group is present, R 1a The groups can be independently selected. In any of these embodiments of the compound of formula (IG) or a salt thereof, the carbon bearing the CO2H and NH moieties can be in the "S" or "R" configuration.

[0136] R 1a In some embodiments of formula (IG), including embodiments reciting variables of and m, R 10 , R 11 , R 12 and R 13 Each of R is hydrogen. 1a and m variables, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (IG), including embodiments recited in the variable 1a and m variables, and / or R 10 , R11 , R 12 and R 13 In some embodiments of formula (IG), including embodiments reciting variables of and / or q, p is 3, 4, or 5.

[0137] In some embodiments of Formula (IG), R 10 , R 11 , R 12 and R 13 is hydrogen, p is 3, and q is 0, and the compound has formula (II-G): [ka] or a salt thereof, wherein R 1a and R 2 is as defined for formula (I), m is 0, 1, 2, 3, 4, 5, or 6, and the positions on the isoquinoline ring are as shown. 1a , R 2 All descriptions of and m apply equally to formulas (IG) and (II-G).

[0138] R 1 R 1a In some embodiments of compounds of Formula (I), wherein the compound is a 5-10 membered heteroaryl optionally substituted by [ka] or a salt thereof, wherein R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), m is 0, 1, or 2, and the positions on the 1-methyl-1H-pyrazolo[3,4-d]pyrimidine ring are as shown.

[0139] In one embodiment, compounds of formula (IH), or salts thereof, are provided wherein the carbons bearing the COH and NH moieties are in the "S" configuration. In another embodiment, compounds of formula (IH), or salts thereof, are provided wherein the carbons bearing the COH and NH moieties are in the "R" configuration. Mixtures of compounds of formula (IH) are also encompassed, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0140] In some embodiments of compounds of Formula (IH), m is 0, 1, or 2, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of a compound of Formula (IH), m is 0, 1, or 2, and each R 1a are, if applicable, independently deuterium, halogen, C-C alkyl, C-C haloalkyl (which in one variation may be C-C perhaloalkyl), C-C alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a wherein C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5-10 membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of the compound of Formula (IH), m is 1 or 2.

[0141] In some embodiments of the compound of Formula (IH), m is 0. In some embodiments of the compound of Formula (IH), m is 1 and R 1a is at the 3-position. In some embodiments of compounds of Formula (IH), m is 1 and R 1a is at the 6-position. In some embodiments of compounds of Formula (IH), m is 2 and R 1a The groups are at the 3 and 6 positions. 1aWhenever a group is present, R 1a The groups can be independently selected. In any of these embodiments of the compound of formula (IH) or salt thereof, the carbon bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0142] R 1a In some embodiments of formula (IH), including embodiments reciting variables of and m, R 10 , R 11 , R 12 and R 13 Each of R is hydrogen. 1a and m variables, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (IH), including embodiments recited in the variable 1a and m variables, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (IH), including embodiments reciting variables of and / or q, p is 3, 4, or 5.

[0143] In some embodiments of Formula (IH), R 10 , R 11 , R 12 and R 13 is hydrogen, p is 3, and q is 0, and the compound has formula (II-H): [ka] or a salt thereof, wherein R 1a and R 2 is as defined for formula (I), m is 0, 1, or 2, and the positions on the 1-methyl-1H-pyrazolo[3,4-d]pyrimidine ring are as shown. 1a , R 2 All descriptions of and m apply equally to formulae (IH) and (II-H).

[0144] Also, R 1 R 1a Also provided are compounds of Formula (I) or (II), or salts thereof, wherein R is a 5-10 membered heteroaryl optionally substituted by 1 is an unsubstituted 5-10 membered heteroaryl (e.g., pyridinyl, pyrimidinyl, quinoxalinyl, quinazolinyl, pyrazolopyrimidinyl, quinolinyl, pyridopyrimidinyl, thienopyrimidinyl, pyridinyl, pyrrolopyrimidinyl, benzothiazolyl, isoquinolinyl, purinyl, or benzoxazolyl). 1 is 1, 2, 3, 4, or 5 R's which may be the same or different 1a group, where each R 1a is halogen (e.g., fluoro, chloro, or bromo), C1-C6 alkyl optionally substituted with halogen (e.g., —CH3, —CHF2, —CF3, or C(CH3)3), C3-C6 cycloalkyl (e.g., cyclopropyl), 5-10 membered heteroaryl (e.g., pyridinyl or pyrazolyl), C6-C 14 Aryl (e.g., phenyl), -CN, -OR 3 (e.g., -OCH3), and -NR 4 R 5 (e.g., —N(CH3)2). In some embodiments, R 1 is 1, 2, 3, or 4 R, which may be the same or different, selected from -CH, -CHF, -CHF, and -CF; 1a In some embodiments, R is a 5-membered heteroaryl (e.g., pyrazolyl) substituted with a group. 1 is halogen (e.g., fluoro, chloro, or bromo), C3-C6 cycloalkyl (e.g., cyclopropyl), 5-6 membered heteroaryl (e.g., pyridinyl or pyrazolyl), C6-C 10Aryl (e.g., phenyl), C1-C4 alkyl optionally substituted with halogen (e.g., —CH3, —CF3 or C(CH3)3), —CN, —OR 3 (e.g., -OCH3), and -NR 4 R 5 (e.g., —N(CH3)2), 1, 2, 3, 4, or 5 R, which may be the same or different, selected from 1a In some embodiments, R is a 6-membered heteroaryl substituted with a group (e.g., pyridinyl, pyrimidinyl, or pyrazinyl). 1 is 1, 2, 3, 4, or 5 R, which may be the same or different, selected from -CH, -CHF, -CHF, and -CF; 1a In some embodiments, R is a 9-membered heteroaryl substituted with a group (e.g., pyrazolopyrimidinyl, pyrrolopyrimidinyl, thienopyrimidinyl, indazolyl, indolyl, or benzimidazolyl). 1 is halogen (e.g., fluoro or chloro), 5-6 membered heteroaryl (e.g., pyridinyl), C alkyl optionally substituted with halogen (e.g., —CH or —CF), and —OR 3 (e.g., —OCH3), 1, 2, 3, 4, or 5 R, which may be the same or different, selected from 1a and 10-membered heteroaryl substituted by a group (eg, quinazolinyl).

[0145] Also, R 1 but, [ka] and any of the foregoing groups in which any one or more hydrogen atom(s) is / are replaced with deuterium atom(s). 1Also provided are compounds of formula (I) or (II), or salts thereof, selected from any of the aforementioned groups, wherein any one or more hydrogen atoms are replaced with tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon in the aforementioned groups can be replaced with a corresponding isotope, e.g., deuterium or tritium. Each hydrogen bonded to an acyclic carbon in the aforementioned groups, e.g., a methyl or methoxy carbon, can be replaced with a corresponding isotope, e.g., deuterium or tritium. Further, for example, the aforementioned groups can be perdeuterated groups in which all hydrogens are replaced with deuterium, or pertritiated groups in which all hydrogens are replaced with tritium. In some embodiments, one or more ring carbons in the aforementioned groups can be 13 For example, in the polycyclic rings of the aforementioned groups, one or more of the ring carbons in the ring that is directly bonded to the remainder of the compound may be replaced by 13 In the polycyclic rings of the aforementioned groups, one or more of the ring carbons in the ring that replace or are fused to the ring that is attached to the remainder of the compound may be replaced by 13 C. Further, for example, all ring carbons in the aforementioned groups may be replaced by 13 It may be replaced by C.

[0146] Also, R 1 but, [ka] and any of the foregoing groups in which any one or more hydrogen atom(s) is / are replaced with deuterium atom(s). 1Also provided are compounds of formula (I) or (II), or salts thereof, selected from any of the aforementioned groups, wherein any one or more hydrogen atoms are replaced with tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon in the aforementioned groups can be replaced with a corresponding isotope, e.g., deuterium or tritium. Each hydrogen bonded to an acyclic carbon in the aforementioned groups, e.g., a methyl or methoxy carbon, can be replaced with a corresponding isotope, e.g., deuterium or tritium. Further, for example, the aforementioned groups can be perdeuterated groups in which all hydrogens are replaced with deuterium, or pertritiated groups in which all hydrogens are replaced with tritium. In some embodiments, one or more ring carbons in the aforementioned groups can be 13 For example, in the polycyclic rings of the aforementioned groups, one or more of the ring carbons in the ring that is directly bonded to the remainder of the compound may be replaced by 13 In the polycyclic rings of the aforementioned groups, one or more of the ring carbons in the ring that replace or are fused to the ring that is attached to the remainder of the compound may be replaced by 13 C. Further, for example, all ring carbons in the aforementioned groups may be replaced by 13 It may be replaced by C.

[0147] Also, R 1 but, [ka] and any of the foregoing groups in which any one or more hydrogen atom(s) is / are replaced with deuterium atom(s). 1Also provided are compounds of formula (I) or (II), or salts thereof, selected from any of the aforementioned groups, wherein any one or more hydrogen atoms are replaced with tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon in the aforementioned groups can be replaced with a corresponding isotope, e.g., deuterium or tritium. Each hydrogen bonded to an acyclic carbon in the aforementioned groups, e.g., a methyl or methoxy carbon, can be replaced with a corresponding isotope, e.g., deuterium or tritium. Further, for example, the aforementioned groups can be perdeuterated groups in which all hydrogens are replaced with deuterium, or pertritiated groups in which all hydrogens are replaced with tritium. In some embodiments, one or more ring carbons in the aforementioned groups can be 13 For example, in the polycyclic rings of the aforementioned groups, one or more of the ring carbons in the ring that is directly bonded to the remainder of the compound may be replaced by 13 In the polycyclic rings of the aforementioned groups, one or more of the ring carbons in the ring that replace or are fused to the ring that is attached to the remainder of the compound may be replaced by 13 C. Further, for example, all ring carbons in the aforementioned groups may be replaced by 13 It may be replaced by C.

[0148] Also, R 1 but, [ka] and any of the foregoing groups in which any one or more hydrogen atom(s) is / are replaced with deuterium atom(s). 1Also provided are compounds of formula (I) or (II), or salts thereof, selected from any of the aforementioned groups, wherein any one or more hydrogen atoms are replaced with tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon in the aforementioned groups can be replaced with a corresponding isotope, e.g., deuterium or tritium. Each hydrogen bonded to an acyclic carbon in the aforementioned groups, e.g., a methyl or methoxy carbon, can be replaced with a corresponding isotope, e.g., deuterium or tritium. Further, for example, the aforementioned groups can be perdeuterated groups in which all hydrogens are replaced with deuterium, or pertritiated groups in which all hydrogens are replaced with tritium. In some embodiments, one or more ring carbons in the aforementioned groups can be 13 For example, in the polycyclic rings of the aforementioned groups, one or more of the ring carbons in the ring that is directly bonded to the remainder of the compound may be replaced by 13 In the polycyclic rings of the aforementioned groups, one or more of the ring carbons in the ring that replace or are fused to the ring that is attached to the remainder of the compound may be replaced by 13 C. Further, for example, all ring carbons in the aforementioned groups may be replaced by 13 It may be replaced by C.

[0149] Also, R 1 but, [ka] and any of the foregoing groups in which any one or more hydrogen atom(s) is / are replaced with deuterium atom(s). 1Also provided are compounds of formula (I) or (II), or salts thereof, selected from any of the aforementioned groups, wherein any one or more hydrogen atoms are replaced with tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon in the aforementioned groups can be replaced with a corresponding isotope, e.g., deuterium or tritium. Each hydrogen bonded to an acyclic carbon in the aforementioned groups, e.g., a methyl or methoxy carbon, can be replaced with a corresponding isotope, e.g., deuterium or tritium. Further, for example, the aforementioned groups can be perdeuterated groups in which all hydrogens are replaced with deuterium, or pertritiated groups in which all hydrogens are replaced with tritium. In some embodiments, one or more ring carbons in the aforementioned groups can be 13 For example, in the polycyclic rings of the aforementioned groups, one or more of the ring carbons in the ring that is directly bonded to the remainder of the compound may be replaced by 13 In the polycyclic rings of the aforementioned groups, one or more of the ring carbons in the ring that replace or are fused to the ring that is attached to the remainder of the compound may be replaced by 13 C. Further, for example, all ring carbons in the aforementioned groups may be replaced by 13 It may be replaced by C.

[0150] R as described herein as a moiety 1 Group (symbol [ka] Although shown as being attached at a particular position (e.g., pyrimid-4-yl, quinazolin-4-yl, isoquinolin-1-yl), R can also be attached through other available valences (e.g., pyrimid-2-yl). In some embodiments of compounds of Formula (I) or (II) or salts thereof, R 1 teeth, [ka] wherein m is 0, 1, 2, or 3; and each R 1aare independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of a compound of Formula (I) or (II) or a salt thereof, R 1 teeth, [ka] wherein m is 1, 2, or 3, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a The alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl in R are independently optionally substituted with deuterium. 1 teeth, [ka] wherein m is 0, 1, 2, 3, 4, or 5; and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of a compound of Formula (I) or (II) or a salt thereof, R 1 teeth, [ka] wherein m is 0, 1, 2, 3, 4, or 5; and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1aThe alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of are independently optionally substituted with deuterium. In a further variation of such an embodiment, each R 1a are, if applicable, independently deuterium, halogen, C-C alkyl, C-C haloalkyl (which in one variation may be C-C perhaloalkyl), C-C alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a wherein C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl are independently optionally substituted with deuterium.

[0151] In some embodiments of a compound of Formula (I), (II), (IA), (II-A), (IB), (II-B), (IC), (II-C), (ID), (II-D), (IE), (II-E), (IF), (II-F), (IG), (II-G), (IH) or (II-H), or a salt thereof, R 2 is R 2a In some embodiments, R 2 is R 2a C1-C6 alkyl optionally substituted by, where R 2a is halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted with halogen (e.g., cyclobutyl optionally substituted with fluoro); 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl (e.g., pyrazolyl optionally substituted with methyl); -S(O)2R 3 ;-NR 4 R 5 ;-NR 3 C(O)R 4 ;Oxo;Or -OR 3 In some embodiments, R 2 is R 2a C1-C6 alkyl optionally substituted by, where R 2ais halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted with halogen (e.g., cyclobutyl optionally substituted with fluoro); 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl (e.g., pyrazolyl optionally substituted with methyl); 3-12 membered heterocyclyl optionally substituted with halogen (e.g., oxetanyl optionally substituted with fluoro), -S(O)R 3 ;-NR 4 R 5 ;-NR 3 C(O)R 4 ;Oxo;Or -OR 3 In some embodiments, R 2 -OR 3 C1-C6 alkyl optionally substituted by, where R 3 is hydrogen; C1-C6 alkyl optionally substituted with halogen (e.g., methyl, ethyl, difluoromethyl, -CH2CHF2, and -CH2CF3); C3-C6 cycloalkyl optionally substituted with halogen (e.g., cyclopropyl substituted with fluoro); C6-C 14 aryl (e.g., phenyl optionally substituted with fluoro); or 5-6 membered heteroaryl optionally substituted with halogen or C1-C6 alkyl (e.g., pyridinyl optionally substituted with fluoro or methyl). In some embodiments, R 2 is —CH2CH2OCH3. In some embodiments, R 2 is halogen and OR 3 In some embodiments, R is a C1-C6 alkyl substituted with both 2 is n-propyl substituted with both halogen and alkoxy (e.g., —CHCH(F)CHOCH). 2 R 2a In some embodiments, R is indicated as being optionally substituted by 2The moiety is unsubstituted. 2 R 2a In some embodiments, R is indicated as being optionally substituted by 2 The part is one R 2a is replaced by R 2 R 2a In some embodiments, R is indicated as being optionally substituted by 2 The moieties may be the same or different and may consist of 2 to 6, 2 to 5, 2 to 4, or 2 to 3 R 2a is replaced by the part.

[0152] In some embodiments of a compound of Formula (I), (II), (IA), (II-A), (IB), (II-B), (IC), (II-C), (ID), (II-D), (IE), (II-E), (IF), (II-F), (IG), (II-G), (IH) or (II-H), or a salt thereof, R 2 is R 2a In some embodiments, R 2 is R 2a C1-C6 alkyl optionally substituted by, where R 2a is halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted with halogen (e.g., cyclobutyl optionally substituted with fluoro); 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl (e.g., pyrazolyl optionally substituted with methyl); -S(O)2R 3 ;-NR 4 R 5 ;-NR 3 C(O)R 4 ;Oxo;Or -OR 3 In some embodiments, R 2 is R 2a C1-C6 alkyl optionally substituted by, where R 2ais halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted with halogen (e.g., cyclobutyl optionally substituted with fluoro); 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl (e.g., pyrazolyl optionally substituted with methyl); 3-12 membered heterocyclyl optionally substituted with halogen (e.g., oxetanyl optionally substituted with fluoro); -S(O)R 3 ;-NR 4 R 5 ;-NR 3 C(O)R 4 ;Oxo;Or -OR 3 In some embodiments, R 2 is R 2a C1-C6 alkyl optionally substituted by, where R 2a is halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted with halogen (e.g., cyclobutyl optionally substituted with fluoro); C6-C 14 Aryl (e.g., phenyl); 5-10 membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., thiazolyl or pyrazolyl optionally substituted by methyl); 3-12 membered heterocyclyl optionally substituted by halogen or oxo (e.g., R 2a is oxetanyl optionally substituted by fluoro; tetrahydrofuranyl; pyrrolidinyl optionally substituted by oxo; morpholinyl optionally substituted by oxo; or dioxanyl); —S(O)R 3 ;-NR 4 R 5 ;-NR 3 C(O)R 4 ;Oxo;-OR 3 or -CN. In some embodiments, R 2 -OR 3 C1-C6 alkyl optionally substituted by, where R 3is hydrogen; C1-C6 alkyl optionally substituted with halogen (e.g., methyl, ethyl, difluoromethyl, -CH2CHF2, and -CH2CF3); C3-C6 cycloalkyl optionally substituted with halogen (e.g., cyclopropyl substituted with fluoro); C6-C 14 aryl (e.g., phenyl optionally substituted with fluoro); or 5-6 membered heteroaryl optionally substituted with halogen or C1-C6 alkyl (e.g., pyridinyl optionally substituted with fluoro or methyl). In some embodiments, R 2 is —CH2CH2OCH3. In some embodiments, R 2 is halogen and OR 3 In some embodiments, R is a C1-C6 alkyl substituted with both 2 is n-propyl substituted with both halogen and alkoxy (e.g., —CHCH(F)CHOCH). 2 R 2a In some embodiments, R is indicated as being optionally substituted by 2 The moiety is unsubstituted. 2 R 2a In some embodiments, R is indicated as being optionally substituted by 2 The part is one R 2a is replaced by R 2 R 2a In some embodiments, R is indicated as being optionally substituted by 2 The moieties may be the same or different and may consist of 2 to 6, 2 to 5, 2 to 4, or 2 to 3 R 2a In some embodiments, R 2 is a C1-C6 alkyl substituted by two halogen groups (e.g., two fluoro groups), which may be the same or different. In some embodiments, R 2 is two -ORs that may be the same or different 3In some embodiments, R is a C1-C6 alkyl substituted with a group (e.g., two -OH groups, one -OH group and one -OCH3 group, or two -OCH3 groups). 2 contains one halogen group (e.g., fluoro) and one -OR 3 In some embodiments, R is a C1-C6 alkyl substituted with a group (e.g., —OH or —OCH3). 2 is two halogen groups (e.g., two fluoro groups), which may be the same or different, and one -OR 3 In some embodiments, R is a C1-C6 alkyl substituted with a group (e.g., —OH or —OCH3). 2 is a group consisting of one halogen group (e.g., fluoro) and two -OR groups which may be the same or different. 3 and C1-C6 alkyl substituted with groups (e.g., two -OH groups, one -OH group and one -OCH3 group, or two -OCH3 groups).

[0153] In some embodiments of a compound of Formula (I), (II), (IA), (II-A), (IB), (II-B), (IC), (II-C), (ID), (II-D), (IE), (II-E), (IF), (II-F), (IG), (II-G), (IH) or (II-H), or a salt thereof, R 2 is R 2b In some embodiments, R 2 is one or two R's which may be the same or different 2b In some embodiments, R is a C-C cycloalkyl substituted by a moiety. 2 is C-C cycloalkyl optionally substituted with halogen (e.g., unsubstituted cyclopropyl or cyclobutyl optionally substituted with fluoro). In some embodiments, R 2is a C3-C4 cycloalkyl optionally substituted with deuterium or tritium atom(s). For example, in some embodiments, each hydrogen bonded to a ring carbon in the aforementioned groups can be replaced with a corresponding isotope, e.g., deuterium or tritium. Each hydrogen bonded to an acyclic carbon in the aforementioned groups, e.g., a methyl or methoxy carbon, can be replaced with a corresponding isotope, e.g., deuterium or tritium. Further, for example, the aforementioned groups can be perdeuterated groups in which all hydrogens have been replaced with deuterium, or pertritiated groups in which all hydrogens have been replaced with tritium. In some embodiments, one or more ring carbons in the aforementioned groups can be 13 For example, in the polycyclic rings of the aforementioned groups, one or more of the ring carbons in the ring that is directly bonded to the remainder of the compound may be replaced by 13 In the polycyclic rings of the aforementioned groups, one or more of the ring carbons in the ring that replace or are fused to the ring that is attached to the remainder of the compound may be replaced by 13 C. Further, for example, all ring carbons in the aforementioned groups may be replaced by 13 It may be replaced by C.

[0154] In some embodiments of a compound of Formula (I), (II), (IA), (II-A), (IB), (II-B), (IC), (II-C), (ID), (II-D), (IE), (II-E), (IF), (II-F), (IG), (II-G), (IH) or (II-H), or a salt thereof, R 2 is hydrogen.

[0155] In some embodiments of a compound of Formula (I), (II), (IA), (II-A), (IB), (II-B), (IC), (II-C), (ID), (II-D), (IE), (II-E), (IF), (II-F), (IG), (II-G), (IH) or (II-H), or a salt thereof, R 2 is R 2aIn some embodiments, R 2 is -OCH3.

[0156] Also, R 2 but, [ka] and any of the foregoing groups in which any one or more hydrogen atom(s) is / are replaced with deuterium atom(s), or a salt thereof, is provided.

[0157] Also, R 2 but, [ka] and any of the foregoing groups in which any one or more hydrogen atom(s) is / are replaced with deuterium atom(s), or a salt thereof, is provided.

[0158] Also, R 2 but, [ka] where R 3 and each R 2aAlso provided are compounds of formula (I), (II), (IA), (II-A), (IB), (II-B), (IC), (II-C), (ID), (II-D), (IE), (II-E), (IF), (II-F), (IG), (II-G), (IH) or (II-H), or salts thereof, wherein:

[0159] Also, R 2 but [ka] where each R 2a Also provided are compounds of formula (I), (II), (IA), (II-A), (IB), (II-B), (IC), (II-C), (ID), (II-D), (IE), (II-E), (IF), (II-F), (IG), (II-G), (IH) or (II-H), or salts thereof, wherein:

[0160] Also, R 2 but, [ka] where R 3 Also provided are compounds of formula (I), (II), (IA), (II-A), (IB), (II-B), (IC), (II-C), (ID), (II-D), (IE), (II-E), (IF), (II-F), (IG), (II-G), (IH) or (II-H), or salts thereof, wherein:

[0161] In one embodiment of Formula (I), the tetrahydronaphthyridine group is disubstituted with deuterium at the 2-position.

[0162] In one embodiment, there is provided a compound of formula (I), or a salt thereof (including a pharmaceutically acceptable salt thereof), wherein the compound or salt thereof has any one or more of the following structural features (“SF”): (SFI)p is 3; (SFII) Each R 10 , R 11 , R 12 , R 13 is hydrogen; (SFIII)R 1 teeth, (A) unsubstituted 5- to 10-membered heteroaryl; (B) 1, 2, 3, 4, or 5 R's, which may be the same or different. 1a 5-10 membered heteroaryl substituted by a group (wherein the 5- to 10-membered heteroaryl of (III)(A) and (III)(B) is (i) pyridinyl; (ii) pyrimidinyl; (iii) quinoxalinyl; (iv) quinazolinyl; (v) pyrazolopyrimidinyl; (vi) quinolinyl; (vii) pyridopyrimidinyl; (viii) thienopyrimidinyl; (ix) Purinil; (x) pyrrolopyrimidinyl; (xi) benzoxazolyl; (xii) benzothiazolyl; (xiii) isoquinolinyl; (xiv) indolyl; (xv) benzimidazolyl; (xvi) pyrazinyl; (xvii) indazolyl; or (xviii) is pyrazolyl; (C) unsubstituted naphthalenyl; or (D) 1, 2, 3, 4, or 5 R's, which may be the same or different. 1a naphthalenyl substituted by a group; (SFIV)Each R 1a teeth, (A) halogen, such as fluoro, chloro, or bromo; (B) C1-C6 alkyl optionally substituted with halogen, for example, -CH3, -CHF2, -CF3, or C(CH3)3; (C) C3-C6 cycloalkyl, for example, cyclopropyl; (D) 5-10 membered heteroaryl, for example, pyridinyl or pyrazolyl; (E)C6-C 14 aryl, for example, phenyl; (F)-CN; (G)-OR 3 , e.g., -OCH3; or (H)-NR 4 R 5 , for example, -N(CH3)2; (SFV)R 2 teeth, (A) unsubstituted C1-C6 alkyl, for example, C1-C2 alkyl; (B) C1-C6 alkyl, e.g., C1-C2 alkyl (each of which may be the same or different, 1, 2, 3, 4, or 5 R 2a substituted by a group); (C) unsubstituted —O—C1-C6 alkyl, for example, —O—C1-C2 alkyl; (D) —O—C1-C6 alkyl, for example, —O—C1-C2 alkyl (each of which may be the same or different, 1, 2, 3, 4, or 5 R 2a substituted by a group); (E) unsubstituted C3-C6 cycloalkyl, for example, cyclopropyl or cyclobutyl; or (F) C3-C6 cycloalkyl, e.g., cyclopropyl or cyclobutyl (each of which may be the same or different and may contain 1, 2, 3, 4, or 5 R 2b substituted by a group); (SFVI)R 2a teeth, (A) halogens, for example, fluoro; (B) C3-C8 cycloalkyl, for example, cyclopropyl or cyclobutyl, each of which is optionally substituted with halogen; (C) 5-10 membered heteroaryl optionally substituted by C1-C6 alkyl, for example, pyrazolyl substituted by methyl; (D) 3- to 12-membered heterocyclyl optionally substituted by halogen or oxo, for example, oxetanyl optionally substituted by fluoro, unsubstituted tetrahydrofuranyl, pyrrolidinyl substituted by oxo, unsubstituted morpholinyl, morpholinyl substituted by oxo, or dioxanyl; (E)-S(O)2R 3 , e.g., -S(O)2CH3; (F)-C(O)NR 4 R 5 , e.g., -C(O)N(CH3)2; (G)-NR 3 C(O)R 4 , for example, -NHC(O)CH3; or (H)-OR 3 (where R 3 teeth, (i) Hydrogen; (ii) -CH3; (iii) -CH2CH3; (iv) -CH2CHF2; (v)-CH2CF3; (vi) phenyl substituted by 0 to 2 fluoro groups; or (vii) pyridinyl substituted by 0 to 1 methyl groups.

[0163] It is understood that, in one embodiment, a compound of formula (I) or any of its variations described herein, or a salt thereof, has any one or more of the above structural features. For example, in one embodiment, a compound of formula (I) or any of its variations described herein, or a salt thereof, can have one, two, three, or all of the following structural features: (SFI), (SFII), (SFIII), and (SFV). In one such example, a compound of formula (I) or any of its variations described herein, or a salt thereof, can have, in one embodiment, the following structural features: (SFI) and any one, two, or all of (SFII), (SFIII), and (SFV), or any subembodiments thereof. In one such example, a compound of formula (I) or any of its variations described herein, or a salt thereof, can have, in one embodiment, the following structural features: (SFII) and any one, two, or all of (SFI), (SFIII), and (SFV), or any subembodiments thereof. In one such example, a compound of formula (I) or any variation thereof described herein, or a salt thereof, can have, in one embodiment, the following structural features: (SFIII) and any one, two, or all of (SFI), (SFII), and (SFV), or any subembodiments thereof. In one such example, a compound of formula (I) or any variation thereof described herein, or a salt thereof, can have, in one embodiment, the following structural features: (SFV) and any one, two, or all of (SFI), (SFII), and (SFIII), or any subembodiments thereof. It is understood that subembodiments of structural features can likewise be combined in any manner. While particular combinations of structural features are specifically set forth below, it is understood that all combinations of features are encompassed. In one aspect of this variation, (SFI) and (SFII) apply. In another variation, (SFI) and (SFIII) apply. In another variation, (SFI) and (SFV) apply.In another variant, (SFII) and (SFIII) apply. In another variant, (SFII) and (SFV) apply. In another variant, (SFIII) and (SFV) apply. In another variant, (SFI), (SFII), and (SFIII) apply. In another variant, (SFI), (SFII), and (SFV) apply. In another variant, (SFI), (SFIII), and (SFV) apply. In another variant, (SFII), (SFIII), and (SFV) apply. It is understood that each subembodiment of the structural feature applies. For example, (SFIII) is (SFIII)(A)(i), (SFIII)(A)(ii),(SFIII)(A)(iii), (SFIII)(A)(iv), (SFIII)(A)(v), (SFIII)(A)(vi), (SFIII)(A)(vii), (SFIII)(A)(viii), (SFIII)(A)(ix), (SFIII)(A)(x), (SFIII)(A)(xi), (SFIII)(A)(xii), (SFIII)(A)(xiii), (SFIII)(A)(xiv), (SFIII)(A)(xv), (SFIII)(A)(xvi), (SFIII)(A)(xvii), (SFIII)(A)(xviii), (SFIII) (B)(i), (SFIII)(B)(ii), (SFIII)(B)(iii), (SFIII)(B)(iv), (SFIII)(B)(v), (SFIII)(B)(vi), (SFIII)(B)(vii), (SFIII)(B)(viii), (SFIII)(B)(ix), (SFIII)(B)(x), (SFIII) (B)(xi), (SFIII)(B)(xii), (SFIII)(B)(xiii), (SFIII)(B)(xiv), (SFIII)(B)(xv), (SFIII)(B)(xvi), (SFIII)(B)(xvii), (SFIII)(B)(xviii), (SFIII)(C), or (SFIII)(D). In one embodiment of this variation, (SFV) is (SFV)(A), (SFV)(B), (SFV)(C), (SFV)(D), (SFV)(E), or (SFV)(F).

[0164] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(A) apply.In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(A) apply.In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(A) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply.

[0165] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply.

[0166] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) apply.In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) apply.In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply.

[0167] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) apply.In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) apply.In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply.

[0168] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(H)(vii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply.

[0169] Any variation or combination recited herein for compounds of formula (I) may be R 15 and R 16 also applies to formula (A), in addition to any possible combination of

[0170] Representative compounds are listed in FIG.

[0171] In some embodiments, provided is a compound selected from compound numbers 1-66 in Figure 1, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the compound is a compound selected from compound numbers 1-66 in Figure 1, or a salt of a stereoisomer thereof.

[0172] In some embodiments, a compound selected from Compound Nos. 1-147, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof is provided. In some embodiments, the compound is a compound selected from Compound Nos. 1-147, or a salt of a stereoisomer thereof.

[0173] In some embodiments, a compound selected from Compound Nos. 1-665, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof is provided. In some embodiments, the compound is a compound selected from Compound Nos. 1-665, or a salt of a stereoisomer thereof.

[0174] In some embodiments, provided is a compound selected from Compound Nos. 1-780, or a stereoisomer thereof (including a mixture of two or more thereof), or a salt thereof. In some embodiments, the compound is a compound selected from Compound Nos. 1-780, or a salt of a stereoisomer thereof.

[0175] In one variation, the compounds detailed herein are selected from the group consisting of: 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-(difluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-hydroxy-2-methylpropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((3,3-Difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)butanoic acid; 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-(trifluoromethyl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((8-(trifluoromethyl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,4-d]pyrimidin-4-ylamino)butanoic acid; 2-((5-fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6-fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((8-fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6,7-difluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((6-(difluoromethyl)pyrimidin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methyl-2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-(((3,3-difluorocyclobutyl)methyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-fluoro-2-methylquinazolin-4-yl)amino)butanoic acid; 2-(Isoquinolin-1-ylamino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(Difluoromethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinolin-4-ylamino)butanoic acid; 2-((7-chloroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((8-chloroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-(quinazolin-4-ylamino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid; 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-methoxyquinazolin-4-yl)amino)butanoic acid; 4-((2-(2,2-difluorocyclopropoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-fluoro-2-methylquinazolin-4-yl)amino)butanoic acid; 4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((8-methoxyquinazolin-4-yl)amino)butanoic acid; 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-(((S)-2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid; 4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((8-chloroquinazolin-4-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-(pyrido[3,2-d]pyrimidin-4-ylamino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid; 4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butanoic acid; 4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butanoic acid; 4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butanoic acid; 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-(((R)-2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; and 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid.

[0176] In another variation, the compounds detailed herein are selected from the group consisting of: 2-((3-cyanopyrazin-2-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-cyanopyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-bromopyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-hydroxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((3-cyanopyrazin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-fluoropyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((1H-pyrazolo[4,3-d]pyrimidin-7-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid; 2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-bromopyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-cyanopyrimidin-2-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-bromopyrimidin-2-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-bromopyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-bromopyrimidin-2-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid; 2-((5-cyanopyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-cyanopyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-fluoropyrimidin-2-yl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((Oxetan-2-ylmethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((3-hydroxy-2-(hydroxymethyl)propyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((5-bromopyrimidin-2-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-cyanopyrimidin-2-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid; 2-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-bromopyrimidin-2-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; and 4-(((3-fluorooxetan-3-yl)methyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid.

[0177] In some embodiments, a composition, such as a pharmaceutical composition, is provided, the composition comprising a compound selected from the group consisting of one or more of Compound Nos. 1-66 in Figure 1, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of one or more salts of Compound Nos. 1-66. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0178] In some embodiments, compositions, such as pharmaceutical compositions, are provided, comprising a compound selected from the group consisting of one or more of Compound Nos. 1-147, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of one or more salts of Compound Nos. 1-147. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0179] In some embodiments, compositions, such as pharmaceutical compositions, are provided, comprising a compound selected from the group consisting of one or more of Compound Nos. 1-665, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of one or more salts of Compound Nos. 1-665. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0180] In some embodiments, compositions, such as pharmaceutical compositions, are provided, comprising a compound selected from the group consisting of one or more of Compound Nos. 1-780, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of one or more salts of Compound Nos. 1-780. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0181] The present invention also includes all salts of the compounds referred to herein, such as pharmaceutically acceptable salts. The present invention also includes any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomeric or other forms, of the described compounds. Unless stereochemistry is explicitly stated in a chemical structure or name, the structure or name is intended to encompass all possible stereoisomers of the depicted compound. Additionally, when a specific stereochemical form is depicted, it is understood that other stereochemical forms are also described and encompassed by the present invention. All forms of the compounds, such as crystalline or amorphous forms of the compounds, are encompassed by the present invention. It is also understood that prodrugs, solvates, and metabolites of the compounds are encompassed by the present disclosure. Compositions comprising the compounds of the present invention, for example, compositions of substantially pure compounds comprising a specific stereochemical form thereof, are also contemplated. Compositions comprising mixtures of the compounds of the present invention in any ratio are also encompassed by the present invention, including mixtures of two or more stereochemical forms of the compounds of the present invention in any ratio, including racemic, non-racemic, enantiomerically enriched, and scameric mixtures of the compounds. If one or more tertiary amine moieties are present in the compound, the N-oxides are also provided and described.

[0182] The compounds described herein are αvβ6 integrin inhibitors. In some cases, it is desirable that the compounds inhibit other integrins in addition to αvβ6 integrin. In some embodiments, the compounds inhibit αvβ6 integrin and one or more of αvβ1, αvβ3, αvβ5, α2β1, α3β1, α6β1, α7β1, and α11β1 integrins. In some embodiments, the compounds inhibit αvβ6 integrin and αvβ1 integrin. In some embodiments, the compounds inhibit αvβ6 integrin, αvβ3 integrin, and αvβ5 integrin. In some embodiments, the compounds inhibit αvβ6 integrin and α2β1 integrin. In some embodiments, the compounds inhibit αvβ6 integrin, α2β1 integrin, and α3β1 integrin. In some embodiments, the compounds inhibit αvβ6 integrin and α6β1 integrin. In some embodiments, the compounds inhibit αvβ6 integrin and α7β1 integrin. In some embodiments, the compound inhibits αvβ6 integrin and α11β1 integrin.

[0183] In some cases, it is desirable to avoid inhibition of other integrins. In some embodiments, the compound is a selective αvβ6 integrin inhibitor. In some embodiments, the compound does not substantially inhibit α4β1, αvβ8, and / or α2β3 integrins. In some embodiments, the compound inhibits αvβ6 integrin but does not substantially inhibit α4β1 integrin. In some embodiments, the compound inhibits αvβ6 integrin but does not substantially inhibit αvβ8 integrin. In some embodiments, the compound inhibits αvβ6 integrin but does not substantially inhibit αvβ3 integrin. In some embodiments, the compound inhibits αvβ6 integrin but does not substantially inhibit αvβ8 integrin and α4β1 integrin.

[0184] The present invention also contemplates isotopically labeled and / or isotopically enriched forms of the compounds described herein.The compounds herein may also contain unconventional proportions of atomic isotopes in one or more of the atoms constituting such compounds.In some embodiments, the compounds are isotopically labeled, for example, isotopically labeled compounds of formula (I) or its variants described herein, in which one or more atoms are replaced by isotopes of the same element.Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and chlorine, for example, 2 H, 3 H, 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, e.g., increased in vivo half-life or reduced dosage requirements. As used herein, each example of replacement of hydrogen with deuterium is also a disclosure of replacing that hydrogen with tritium. As used herein, each example of enrichment, substitution, or replacement of an atom with the atom's corresponding isotope encompasses one of the following isotopic enrichment levels: about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or 100%, or a range between any two of the foregoing percentages.

[0185] Isotopically labeled compounds of the present invention 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.

[0186] In various embodiments, for each compound named or depicted herein, the corresponding isotopically substituted compound is specifically disclosed in accordance with the following description. For example, the structural variable R 1 and R 1a The corresponding isotopically substituted compounds, e.g., the structural variable R 1 and R 1a The corresponding isotopically substituted compounds are disclosed in which the structural variable R can be perdeuterated, whereby all hydrogens can be independently replaced with deuterium. 1 One or more hydrogens in the group corresponding to 1a Further disclosed are corresponding isotopically substituted compounds in which there is no replacement in R 1 All hydrogen atoms bonded to the ring of the group corresponding to 1a The corresponding isotopically substituted compounds are disclosed in which R 1a and the corresponding isotopically substituted compounds, in which one or more hydrogens in R may be independently replaced by deuterium, e.g., R 1a Also disclosed are corresponding isotopically substituted compounds in which all hydrogens in the group corresponding to may be replaced with deuterium.

[0187] For example, the structural variable R 2 and R 2a The corresponding isotopically substituted compounds, e.g., the structural variable R 2 and R 2a Further disclosed are the corresponding isotopically substituted compounds where R can be perdeuterated, whereby all hydrogens can be independently replaced with deuterium. 2 One or more hydrogens in the group corresponding to 2a Also disclosed are corresponding isotopically substituted compounds in which there is no replacement of R. 2 R is the carbon that bonds 2Also disclosed are the corresponding isotopically substituted compounds, in which each hydrogen at the 1-position of R can be independently replaced with deuterium. 2 For compounds named as having -CH2CH2CH2F corresponding to R 2 Also disclosed are the corresponding isotopically substituted compounds where R is -CD2CH2CH2F; 2 For compounds named to have the -CH2-cyclopropyl corresponding to R 2 Also disclosed are the corresponding isotopically substituted compounds where R is -CD2-cyclopropyl. 2a Corresponding isotopically substituted compounds are disclosed in which all hydrogens in the group corresponding to R can be independently replaced with deuterium. 2a For each compound where is -OCH3, R 2a Also disclosed are the corresponding isotopically substituted compounds, where R can be -OCD3; 2a For each compound where is -N(CH3)2, R 2a Also disclosed are the corresponding isotopically substituted compounds, where R can be —N(CD3)2. 2 The 1-position of R can be deuterated. 2a Further disclosed are compounds wherein hydrogen in a group corresponding to: can be replaced with deuterium.

[0188] Also, R 10 , R 11 , R 12 , R 13 , and each R 14 Also disclosed are the corresponding isotopically substituted compounds where R is independently deuterated. 10 , R 11 is deuterium or R 12 , R 13 is deuterium or R 10 , R 11 , R 12 , and R 13 The corresponding isotopically substituted compounds are disclosed where R is all deuterium. 14 is deuterium, and R 14 Further disclosed are compounds in which R is substituted at the 3-, 4-, or 3- and 4-positions of the tetrahydronaphthyridin-2-yl group. 14 is deuterium, and each R14 independently replace hydrogen atoms at the 5-, 6-, 7-, 5- and 6-, 5- and 7-, 6- and 7-positions, or 5-, 6- and 7-positions in the tetrahydronaphthyridin-2-yl group, e.g., compounds in which the 7-position can be substituted with two deuterium atoms are also disclosed.

[0189] In some embodiments, R 1 All ring hydrogens in R can be replaced with deuterium. 2 The 1-position of R can be deuterated. 2a The corresponding isotopically substituted compounds are disclosed in which R can be perdeuterated. 1 The corresponding isotopically substituted compounds are disclosed in which all ring hydrogens in R can be replaced with deuterium. 1 All ring hydrogens in R can be replaced with deuterium. 2 The 1-position of R can be deuterated. 2a can be perdeuterated, R 12 and R 13 The corresponding isotopically substituted compounds are disclosed in which R can be deuterium and the 7-position of the tetrahydronaphthyridin-2-yl group can be deuterated. 1 All ring hydrogens in R can be replaced with deuterium. 2a The corresponding isotopically substituted compounds are disclosed in which each hydrogen in R can be independently replaced with deuterium. 1 All ring hydrogens in R can be replaced with deuterium. 2 The 1-position of R can be deuterated. 2a can be perdeuterated, R 12 and R 13 Corresponding isotopically substituted compounds are disclosed where R can be deuterium. 1 and R 1a can be perdeuterated, R 2 The 1-position of R can be deuterated. 2a can be perdeuterated, R 12 and R 13 The corresponding isotopically substituted compounds are disclosed in which R can be deuterium and the 7-position of the tetrahydronaphthyridin-2-yl group can be deuterated. 1 All ring hydrogens in R can be replaced with deuterium. 2 The 1-position of R can be deuterated.2a can be perdeuterated, R 12 and R 13 Corresponding isotopically substituted compounds are disclosed, wherein can be deuterium.

[0190] In some embodiments of the named compounds, R 1 , R 1a , R 2 , R 2a , R 10 , R 11 , R 12 , R 13 , and R 14 Each hydrogen represented in may independently be tritium. For example, R 1 , R 1a , or R 1 and R 1a Corresponding isotopically substituted compounds are disclosed in which one or more hydrogen atoms in R can be independently replaced by tritium. 1 , R 1a , or R 1 and R 1a Corresponding isotopically substituted compounds are disclosed in which one or more ring hydrogens in R can be independently replaced by tritium. 2 , R 2a , or R 2 and R 2a Corresponding isotopically substituted compounds are disclosed in which one or more hydrogen atoms in R can be independently replaced by tritium. 2 , R 2a , or R 2 and R 2a Corresponding isotopically substituted compounds are disclosed in which one or more hydrogen atoms in the tetrahydronaphthyridin-2-yl group can be independently replaced by tritium. Corresponding isotopically substituted compounds are disclosed in which one of the 3- or 4-positions of the tetrahydronaphthyridin-2-yl group, for example, the 3-position, can be tritiated. Corresponding isotopically substituted compounds are disclosed in which one of the 5-, 6-, or 7-positions of the tetrahydronaphthyridin-2-yl group can be monotritiated or ditritiated, for example, the 7-position can be ditritiated.

[0191] In some embodiments of the named compounds, one or more carbons 13Corresponding isotopically substituted compounds are disclosed in which R C can be substituted. For example, R C shown in the structural formulas herein is 1 , R 1a , R 2 , R 2a , one or more carbons such as the carbons in the tetrahydronaphthyridin-2-yl ring 13 Corresponding isotopically substituted compounds are disclosed in which R 1 , R 1a , R 2 , R 2a and / or in the ring represented by the tetrahydronaphthyridin-2-yl group, one or more ring carbons may be 13 C. For example, R 1 , R 1a , R 2 , R 2a and / or in the polycyclic ring represented by the tetrahydronaphthyridin-2-yl group, one or more ring carbons in the ring directly bonded to the remainder of the compound is 13 C, for example, in a tetrahydronaphthyridin-2-yl group, the ring directly attached to the remainder of the compound is an aromatic heterocycle attached at the 2-position. 1 , R 1a , R 2 , R 2a and / or in polycyclic rings in the group corresponding to the tetrahydronaphthyridin-2-yl group, one or more ring carbons in the ring substituting or fused to the ring attached to the remainder of the compound is 13 For example, in a tetrahydronaphthyridin-2-yl ring, the non-aromatic heterocyclyl ring is fused to a ring that is bonded to the remainder of the compound. 1 , R 1a , R 2 , R 2a and / or all ring carbons or all carbons in the group corresponding to the tetrahydronaphthyridin-2-yl ring are 13 It can be replaced by C.

[0192] The present invention also includes any or all of the metabolites of the described compounds. Metabolites can include any chemical species produced by the biotransformation of any of the described compounds, for example, intermediates and products of metabolism of the compounds.

[0193] An article of manufacture is provided comprising a compound of the invention, or a salt or solvate thereof, in a suitable container, which may be a vial, jar, ampoule, pre-filled syringe, or intravenous bag.

[0194] Preferably, the compounds detailed herein are orally bioavailable. However, the compounds can also be formulated for parenteral (e.g., intravenous) administration.

[0195] 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. General synthesis method

[0196] The compounds of the present invention can be prepared by a number of processes, such as the schemes provided in the Examples below, as 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.

[0197] If it is desired to obtain a specific enantiomer of a compound, this can be achieved by using any conventional procedure suitable for separating or resolving enantiomers from the corresponding enantiomeric 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 racemates.Alternatively, if desired, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the processes described.

[0198] Where it is desired to obtain a particular isomer of a compound or otherwise refine a reaction product, chromatography, recrystallization, and other conventional separation procedures may be used on intermediates or final products.

[0199] 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.

[0200] The compounds provided herein can be prepared according to general Schemes A, B, C, and D, general procedures A, B, C, D, E, F, G, H, and P, and the Examples herein.

[0201] The compounds provided herein can be prepared according to general Schemes A, B, C, and D, general procedures A, B, C, D, E, F, G, H, P, Q, R, S, T, and U, and the Examples herein.

[0202] Compounds of formula 11A can be prepared according to general scheme A, where R 1 and R 2 is as defined for formula (I) or any applicable variation detailed herein. General Scheme A [ka]

[0203] Coupling of 1A with compound of formula 2A in the presence of a suitable coupling agent gives compound of formula 3A, which is reduced to give compound of formula 4A. Reductive amination of compound of formula 4A with compound 5A gives compound of formula 6A. Removal of the N-Boc protecting group from compound of formula 6A by exposure to a suitable acid gives compound of formula 7A, which is coupled with compound of formula 8A to give compound of formula 10A. Hydrolysis of compound of formula 10A in the presence of a suitable hydroxide source gives compound of formula 11A.

[0204] Reaction conditions for the transformations of General Scheme A are provided in the general procedures below, specifically General Procedures A, D, E, F, G, H, and P.

[0205] Modifying the general scheme A to include R 2Starting with variants of 1A containing five and six carbon linkers between the group-bearing nitrogen and the tetrahydronaphthyridine group, variants of the compound of formula 11A can be prepared. These variants of the compound of formula 11A can be synthesized by replacing 1A with either 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid or 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid and using the route described in general Scheme A. Condensation of 6-oxoheptanoic acid and 7-oxooctanoic acid with 2-aminonicotinaldehyde in the presence of a suitable catalyst to give 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid and 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid, respectively, followed by hydrogenation of the resulting naphthyridine ring using procedures known in the chemical literature, gives the 5,6,7,8-tetrahydronaphthyridine ring.

[0206] Alternatively, compounds of formula 11A can be prepared according to general scheme B, where R 1 and R 2 is as defined for formula (I) or any applicable variation detailed herein. General Scheme B [ka]

[0207] Introduction of the N-Boc group of 1B in the presence of a suitable base and di-tert-butyl dicarbonate gives a compound of formula 2B, which is reduced to give a compound of formula 3B. Oxidation of the compound of formula 3B with a suitable oxidizing agent gives a compound of formula 4B. Reductive amination of the compound of formula 4B with compound 2A gives a compound of formula 5B. Reductive amination of the compound of formula 5B with compound 5A gives a compound of formula 7B. Removal of the N-Boc protecting group of the compound of formula 7B by exposure to a suitable acid gives a compound of formula 7A, which is coupled with a compound of formula 8A to give a compound of formula 10A. Hydrolysis of the compound of formula 10A in the presence of a suitable hydroxide source gives a compound of formula 11A.

[0208] Reaction conditions for the transformations of General Scheme B are provided in the general procedures below, specifically General Procedures B, D, F, G, H, and P.

[0209] Modifying general scheme B to include R 2 Starting with variants of 1B containing five and six carbon linkers between the group-bearing nitrogen and the tetrahydronaphthyridine group, variants of the compound of formula 11A can be prepared. These variants of the compound of formula 11A can be synthesized by replacing 1B with either ethyl 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentanoate or ethyl 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexanoate and using the route described in general scheme B. Condensation of ethyl 6-oxoheptanoate and ethyl 7-oxooctanoate with 2-aminonicotinaldehyde in the presence of a suitable catalyst to give ethyl 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentanoate and ethyl 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexanoate, respectively, followed by hydrogenation of the resulting naphthyridine ring using procedures known in the chemical literature, affords the 5,6,7,8-tetrahydronaphthyridine ring.

[0210] Compounds of formula 10C can be prepared according to general scheme C, where R is R 2a C1-C5 alkyl optionally substituted by R 1 and R 2a is as defined for formula (I) or any applicable variation detailed herein. General Scheme C [ka]

[0211] Coupling of 1C with compound of formula 4C in the presence of a suitable coupling agent gives compound of formula 2C, which is reduced to give compound of formula 3C. Reductive amination of compound of formula 3C with compound 5A gives compound of formula 5C. Exposure of compound of formula 5C to a suitable acid for global removal of the N-Boc protecting group gives compound of formula 6C, which is coupled with compound of formula 8A to give compound of formula 9C. Hydrolysis of compound of formula 9C in the presence of a suitable hydroxide source gives compound of formula 10C.

[0212] Reaction conditions for the transformations of General Scheme C are provided in the general procedures below, particularly General Procedures B, D, F, G, H, and P.

[0213] General Scheme C can be modified to prepare variants of the compound of Formula 10C, starting with variants of 1C containing five and six carbon linkers between the nitrogen bearing the -CHR group and the tetrahydronaphthyridine group. These variants of the compound of Formula 10C can be synthesized by replacing 1C with either 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentan-1-amine or 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexan-1-amine and using the route described in General Scheme C. Condensation of 6-oxoheptanoic acid and 7-oxooctanoic acid with 2-aminonicotinaldehyde in the presence of a suitable catalyst to give 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid and 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid, respectively, followed by hydrogenation of the resulting naphthyridine ring using procedures known in the chemical literature, affords the 5,6,7,8-tetrahydronaphthyridine ring. The resulting carboxylic acids can be converted to primary amines by a two-step procedure involving coupling the carboxylic acid with a suitable ammonia source in the presence of a suitable coupling reagent, followed by reduction.

[0214] Alternatively, compounds of formula 10C can be prepared according to general scheme D, where R is R 2a C1-C5 alkyl optionally substituted by R 1 and R 2a is as defined for formula (I) or any applicable variation detailed herein. General Scheme D [ka]

[0215] Alkylation of 1C with a compound of formula 2D in the presence of a suitable alkyl halide provides a compound of formula 3C. Reductive amination of a compound of formula 3C with compound 5A provides a compound of formula 5C. Exposure of a compound of formula 5C to a suitable acid to remove the N-Boc protecting group provides a compound of formula 6C, which is coupled with a compound of formula 9A to provide a compound of formula 9C. Hydrolysis of a compound of formula 8A in the presence of a suitable hydroxide source provides a compound of formula 10C.

[0216] Reaction conditions for the transformations of General Scheme D are provided in the general procedures below, particularly General Procedures C, F, G, H, and P.

[0217] General Scheme D can be modified to prepare variants of the compound of Formula 10C, starting with variants of 1C containing five and six carbon linkers between the nitrogen bearing the -CHR group and the tetrahydronaphthyridine group. These variants of the compound of Formula 10C can be synthesized by replacing 1C with either 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentan-1-amine or 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexan-1-amine and using the route described in General Scheme D. Condensation of 6-oxoheptanoic acid and 7-oxooctanoic acid with 2-aminonicotinaldehyde in the presence of a suitable catalyst to give 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid and 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid, respectively, followed by hydrogenation of the resulting naphthyridine ring using procedures known in the chemical literature, affords the 5,6,7,8-tetrahydronaphthyridine ring. The resulting carboxylic acids can be converted to primary amines by a two-step procedure involving coupling the carboxylic acid with a suitable ammonia source in the presence of a suitable coupling reagent, followed by reduction.

[0218] Compounds of formula 1f can be prepared according to general scheme E. It is understood that the ring bearing the Het designation can be any aromatic heterocycle. General Scheme E [ka]

[0219] Hydrolysis of compounds of formula 1a gives compounds of formula 1b, which can be alkylated with a suitable electrophile to give compounds of formula 1c. Deprotection of compounds of formula 1c under reductive conditions gives compounds of formula 1d. Metal-catalyzed cross-coupling of compounds of formula 1d with halogenated arenes gives compounds of formula 1e, which can be hydrolyzed under acidic conditions to give compounds of formula 1f.

[0220] Reaction conditions for the transformations of general Scheme E are provided in the general procedures below, particularly general procedures Q, R, S, T, and U.

[0221] It will be appreciated that the above schemes can be modified to arrive at a variety of compounds of the present invention 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" th See, e.g., Wiley-Interscience, New York, 2006.

[0222] Additional methods for preparing compounds according to 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 (I), for example, by selecting starting materials that will provide the desired compound.

[0223] Pharmaceutical Compositions and Formulations Pharmaceutical compositions of any of the compounds detailed herein, including compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), or a salt thereof, or any of the compounds in Figure 1, or a salt thereof, or a mixture thereof, are encompassed by the present invention. Pharmaceutical compositions of any of the compounds detailed herein, including compounds of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), or salts thereof, or any of the compounds in Figure 1, or salts thereof, or mixtures thereof, are encompassed by the present invention. Pharmaceutical compositions of compounds of Formula (A), or salts thereof, or mixtures thereof, are encompassed by the present invention. Accordingly, the present invention includes pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one embodiment, 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 invention 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 one embodiment, the pharmaceutical composition is a controlled release composition of any of the compounds detailed herein.

[0224] In one aspect, the compounds detailed herein can be in purified form, and compositions comprising the compounds in purified form are described herein. In one embodiment, the composition can have 35% or less impurities, where impurities refer to compounds other than the compound that makes up the majority of the composition or its salt. For example, a composition of a compound selected from the compounds of FIG. 1 can contain 35% or less impurities, where impurities refer to compounds other than the compound of FIG. 1 or its salt. In one embodiment, the composition can have 35% or less impurities, where impurities refer to compounds other than the compound that makes up the majority of the composition or its salt. For example, a composition of a compound selected from the compounds of FIG. 1 can contain 35% or less impurities, where impurities refer to compounds other than the compound of FIG. 1 or its salt. In one embodiment, the composition can contain 25% or less impurities. In one embodiment, the composition can contain 20% or less impurities. In yet a further embodiment, a composition comprising a compound detailed herein or its salt is provided as a composition of substantially pure compound. A "substantially pure" composition is one that contains 10% or less impurities, e.g., less than 9%, 7%, 5%, 3%, 1%, or 0.5% impurities. In some embodiments, a composition containing a compound or salt thereof detailed herein is in substantially pure form. In yet another variation, a substantially pure composition of a compound or salt thereof is provided, wherein the composition contains 10% or less impurities. In a further variation, a substantially pure composition of a compound or salt thereof is provided, wherein the composition contains 9% or less impurities. In a further variation, a substantially pure composition of a compound or salt thereof is provided, wherein the composition contains 7% or less impurities. In a further variation, a substantially pure composition of a compound or salt thereof is provided, wherein the composition contains 5% or less impurities. In another variation, a substantially pure composition of a compound or salt thereof is provided, wherein the composition contains 3% or less impurities. In yet another variation, a substantially pure composition of a compound or salt thereof is provided, wherein the composition contains 1% or less impurities.In a further variation, a composition of a substantially pure compound or salt thereof is provided, wherein the composition contains 0.5% or less of impurities. In yet another variation, a composition of a substantially pure compound means that the composition contains 10% or less, or preferably 5% or less, or more preferably 3% or less, or even more preferably 1% or less of impurities, or most preferably 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 10% or less, or 5% or less, or 3% or less, or 1% or less, or 0.5% or less of the (R) form of the compound.

[0225] 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, the invention encompasses pharmaceutical compositions comprising the compounds detailed herein and a pharmaceutically acceptable carrier or excipient. In another variation, methods of administering the compounds are provided. The purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for any of the compounds or forms thereof detailed herein.

[0226] The compounds or salts thereof detailed herein 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 salts thereof can be formulated with suitable carriers to provide delivery forms, 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, liquids, 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.

[0227] One or more compounds described herein or their salts can be used to prepare formulations such as pharmaceutical preparations by combining one or more compounds or their salts 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, and 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.

[0228] The compounds described herein can be administered to individuals (e.g., humans) in the form of commonly accepted oral compositions, such as tablets, coatings, and hard or soft-shell gel capsules, emulsions, or suspensions. Examples of carriers that can be used to prepare such compositions include lactose, corn starch or derivatives thereof, talc, stearates or salts thereof, etc. Acceptable carriers for soft-shell gel capsules include 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.

[0229] In one embodiment, the compound can be administered in the liquid vehicle ORA-SWEET® from PERRIGO® (Allegan, Michigan), which is a syrupy vehicle containing purified water, glycerin, sorbitol, sodium saccharin, xanthan gum, and flavorings, buffered with citric acid and sodium citrate, and preserved with methylparaben (0.03%), potassium sorbate (0.1%), and propylparaben (0.008%), or in a mixture of ORA-SWEET® and water in any ratio, for example, a 50:50 mixture of ORA-SWEET® and water. The water used should be of pharmaceutically acceptable grade, for example, sterile water.

[0230] Any of the compounds described herein can be formulated into tablets in any of the dosage forms described, for example, a compound described herein or a pharmaceutically acceptable salt thereof can be formulated as a 10 mg tablet.

[0231] 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. How to use

[0232] The compounds and compositions of the invention, e.g., pharmaceutical compositions containing a compound of any formula provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, can be used in the methods of administration and treatment provided herein. The compounds and compositions can also be 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.

[0233] In one 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 (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compound numbers 1-66 in Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one 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 (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one 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 (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.In one embodiment, 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 (I), or any variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, 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 any variant thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the individual is a human. An individual, such as a human, may be in need of treatment, such as a human having or suspected of having a fibrotic disease.

[0234] 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 thought to be associated with an increased susceptibility to fibrosis (e.g., radiation) or a medical condition thought 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, or PBC, or has suffered or is suspected of having a myocardial infarction. In some embodiments, the individual at risk for developing a fibrotic disease has or is suspected of having psoriasis.

[0235] 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).

[0236] 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). In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skin fibrosis, psoriasis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis (such as PBC). In some embodiments, the fibrotic disease is psoriasis.

[0237] In some embodiments, the fibrotic disease is pulmonary fibrosis, e.g., idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis is, for example, interstitial lung disease, radiation-induced pulmonary fibrosis, or interstitial lung disease associated with systemic sclerosis.

[0238] 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) or biliary atresia.

[0239] In some embodiments, the fibrotic disease is fibrotic nonspecific interstitial pneumonia (NSIP).

[0240] 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 steatosis-induced liver fibrosis, and liver cirrhosis.In some embodiments, the liver fibrosis is non-alcoholic fatty liver disease (NAFLD).In some embodiments, the liver fibrosis is NASH.

[0241] In some embodiments, the fibrotic disease is biliary fibrosis.

[0242] In some embodiments, the fibrotic disease is renal fibrosis, e.g., diabetic nephrosclerosis, hypertensive nephrosclerosis, focal segmental glomerulosclerosis ("FSGS"), and acute kidney injury due to contrast-induced nephropathy. In some embodiments, the fibrotic disease is diabetic nephropathy, diabetic kidney disease, or chronic kidney disease.

[0243] In some embodiments, the fibrotic disease is characterized by one or more of glomerulonephritis, end-stage renal disease, hearing loss, changes in the lens of the eye, hematuria, or proteinuria. In some embodiments, the fibrotic disease is Alport syndrome.

[0244] In some embodiments, the fibrotic disorder is systemic and localized sclerosis or scleroderma, keloids and hypertrophic scars, or post-surgical adhesions, hi some embodiments, the fibrotic disorder is scleroderma or systemic sclerosis.

[0245] In some embodiments, the fibrotic disease is atherosclerosis or restenosis.

[0246] In some embodiments, the fibrotic disease is gastrointestinal fibrosis, for example, Crohn's disease.

[0247] In some embodiments, the fibrotic disease is cardiac fibrosis, for example, induced fibrosis after myocardial infarction and hereditary cardiomyopathies.

[0248] In some embodiments, the fibrotic disease is psoriasis.

[0249] In some embodiments, the method can include modulating the activity of at least one integrin in a subject in need thereof. For example, the method can include modulating the activity of α V The method may include modulating the activity of αβ. V The method may include modulating the activity of α1. V β1 and α V The method may include modulating the activity of at least one integrin in a subject. The method may include modulating the activity of at least one integrin, for example, β6. Modulating the activity of at least one integrin may include, for example, inhibiting at least one integrin. The method may include modulating the activity of at least one integrin in a subject, for example, α V β1 and α VThe method may include administering to a subject an amount of a compound or a pharmaceutically acceptable salt thereof effective to modulate at least one activity of β6. The subject requiring modulation of the activity of at least one integrin may have any of the fibrotic diseases or conditions described herein. For example, the fibrotic disease or condition may include idiopathic pulmonary fibrosis, interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease-induced fibrosis, Alport syndrome, primary sclerosing cholangitis, primary biliary cholangitis (also known as primary biliary cirrhosis), biliary atresia, interstitial lung disease associated with systemic sclerosis, scleroderma (also known as systemic sclerosis), diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, or Crohn's disease. The fibrotic disease or condition may include psoriasis. The method may include administering to a subject at least one integrin, such as α V β1 and α V The method may include administering to a subject an amount of a compound or a pharmaceutically acceptable salt thereof effective to modulate at least one activity of β6, wherein the subject is a subject in need of treatment for NASH. The method may also ... V β1 and α V The method may include administering to a subject an amount of a compound or a pharmaceutically acceptable salt thereof effective to modulate at least one activity of β6, wherein the subject is in need of treatment for IPF.

[0250] Fibrotic diseases are primarily α V For example, the fibrotic disease may include idiopathic pulmonary fibrosis or renal fibrosis. V To treat conditions mediated by β6, such as IPF, V Fibrotic diseases may involve modulating the activity of β6. V For example, the fibrotic disease may include NASH. V To treat β1-mediated conditions, such as NASH, VFibrotic diseases may involve modulating the activity of α V β1 and α V β6, for example, the fibrotic disease may include PSC or biliary atresia. V β1 and α V To treat conditions mediated by both β6 V β1 and α V This may involve modulating the activity of β6.

[0251] The compound is α V The compound may be a modulator, e.g., an inhibitor, of α V The compound may be a modulator, e.g., an inhibitor, of β6. The compound may be a dual modulator, e.g., a dual inhibitor, e.g., an inhibitor of α V β1 and α V For example, Table B-3 shows that some exemplary compounds are primarily α V Alpha over Beta6 V β1, and several exemplary compounds were shown to inhibit primarily α V α rather than β1 V β6, and several exemplary compounds inhibit α V β1 and α V Since it inhibits β6 equally, for example, "double α V β1 / α V This indicates that it can be considered a "β6 inhibitor."

[0252] α V β1 integrin and α V Treating a subject with a fibrotic disease by modulating or inhibiting the activity of one or both of the β6 integrins is an effective treatment for α V β1 integrin, α V β6 integrin, or α V β1 integrin and α V It is shown that β6 integrin is modulated or inhibited to a degree sufficient to treat the fibrotic disease in the subject.

[0253] In one aspect, there is provided a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compound numbers 1-66 in Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating a fibrotic disease.

[0254] In one aspect, there is provided a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating a fibrotic disease.

[0255] In one aspect, there is provided a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a fibrotic disease.

[0256] In one aspect, there is provided a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating a fibrotic disease.

[0257] Also provided is the use of a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compound numbers 1-66 in Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.

[0258] Also provided is the use of a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.

[0259] Also provided is the use of a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.

[0260] Also provided is the use of a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.

[0261] In another aspect, provided herein is a method of treating in an individual in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compound numbers 1-66 in FIG. 1 , or a stereoisomer thereof. The present invention also provides a method for treating a subject having at least one tissue in need of treatment, the method comprising administering an isomer, or a pharmaceutically acceptable salt thereof, or a dosage form disclosed herein, to a subject having at least one tissue in need of treatment, the tissue having elevated levels of at least one of αVβ1 integrin activity and / or expression; αVβ6 integrin activity and / or expression; pSMAD / SMAD levels; new collagen formation or accumulation; total collagen; and type I collagen gene Col1a1 expression, the levels being elevated compared to healthy tissue. In some embodiments, the subject's at least one tissue comprises one or more of lung tissue, liver tissue, skin tissue, heart tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue. In some embodiments, the tissue has elevated pSMAD2 / SMAD2 levels or elevated pSMAD3 / SMAD3 levels compared to healthy tissue.

[0262] Methods for determining levels of αVβ1 integrin activity and / or expression; αVβ6 integrin activity and / or expression; pSMAD / SMAD levels; new collagen formation or accumulation; total collagen; and type I collagen gene Col1a1 expression are known in the art, and exemplary methods, such as antibody assays of tissue samples such as biopsy samples, are disclosed in the Examples.

[0263] In some embodiments, the method selectively reduces αVβ1 integrin activity and / or expression in the subject relative to αVβ6 integrin activity and / or expression. Vβ6 integrin activity and / or expression, V In some embodiments, the method selectively reduces α1 integrin activity and / or expression in a subject. V β1 integrin and α V The activity and / or expression of both β6 integrins and at least one other α V In some embodiments, the activity of αVβ1 integrin in one or more fibroblast cells in the subject is reduced. In some embodiments, the activity of αVβ6 integrin in one or more epithelial cells in the subject is reduced.

[0264] In another aspect, provided herein is a method of treating in an individual in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compound numbers 1-66 in FIG. 1 , or a stereoisomer thereof. The present invention also provides a method for treating a subject having at least one tissue in need of treatment, the method comprising administering an isomer, or a pharmaceutically acceptable salt thereof, or a dosage form disclosed herein, to a subject having at least one tissue in need of treatment, the tissue having elevated levels of at least one of αVβ1 integrin activity and / or expression; αVβ6 integrin activity and / or expression; pSMAD / SMAD levels; new collagen formation or accumulation; total collagen; and type I collagen gene Col1a1 expression, the levels being elevated compared to healthy tissue. In some embodiments, the subject's at least one tissue comprises one or more of lung tissue, liver tissue, skin tissue, heart tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue. In some embodiments, the tissue has elevated pSMAD2 / SMAD2 levels or elevated pSMAD3 / SMAD3 levels compared to healthy tissue.

[0265] Methods for determining levels of αVβ1 integrin activity and / or expression; αVβ6 integrin activity and / or expression; pSMAD / SMAD levels; new collagen formation or accumulation; total collagen; and type I collagen gene Col1a1 expression are known in the art, and exemplary methods, such as antibody assays of tissue samples such as biopsy samples, are disclosed in the Examples.

[0266] In some embodiments, the method selectively reduces αVβ1 integrin activity and / or expression in the subject relative to αVβ6 integrin activity and / or expression. V β6 integrin activity and / or expression, V In some embodiments, the method selectively reduces α1 integrin activity and / or expression in a subject. V β1 integrin and α V The activity and / or expression of both β6 integrins and at least one other α V In some embodiments, the activity of αVβ1 integrin in one or more fibroblast cells in the subject is reduced. In some embodiments, the activity of αVβ6 integrin in one or more epithelial cells in the subject is reduced.

[0267] Also provided is a method for characterizing the antifibrotic activity of a small molecule in a subject, the method comprising: providing a first live cell sample from the subject, the first live cell sample characterized by the presence of at least one integrin capable of activating transforming growth factor β (TGF-β) from latent peptide TGF-β; determining a first pSMAD / SMAD value for the first live cell sample; administering the small molecule to the subject; providing a second live cell sample from the subject, the second live cell sample obtained from the same tissue as the first live cell sample; determining a second pSMAD / SMAD value for the second live cell sample; and comparing the second pSMAD / SMAD value to the first pSMAD / SMAD value, thereby characterizing the antifibrotic activity of the small molecule in the subject. In some embodiments, the small molecule is a compound disclosed herein, optionally in a dosage form disclosed herein.

[0268] In some embodiments, each live cell sample is a plurality of cells derived from a tissue of the subject or a plurality of macrophages associated with the tissue of the subject. In some embodiments, the tissue comprises one of lung tissue, liver tissue, skin tissue, heart tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue. In some embodiments, each live cell sample comprises a plurality of alveolar macrophages derived from bronchoalveolar lavage fluid of the subject.

[0269] In some embodiments, the method further comprises performing a bronchoalveolar lavage on the subject's lungs effective to provide a bronchoalveolar lavage fluid comprising a plurality of macrophages as a plurality of alveolar macrophages.

[0270] In some embodiments, the subject has a fibrotic disease selected from the group consisting of idiopathic pulmonary fibrosis (IPF), interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease-induced fibrosis, Alport syndrome, primary sclerosing cholangitis (PSC), primary biliary cholangitis, biliary atresia, systemic sclerosis-associated interstitial lung disease, scleroderma, diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn's disease. In some embodiments, the subject has the fibrotic disease psoriasis.

[0271] 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 six integrins include α V Contains β6.

[0272] In some embodiments, determining a first pSMAD / SMAD value of the at least one living cell comprises determining a pSMAD2 / SMAD2 value or a pSMAD3 / SMAD3 value, and determining a second pSMAD / SMAD value of the at least one living cell after contacting the at least one living cell with a small molecule comprises determining a pSMAD2 / SMAD2 value or a pSMAD3 / SMAD3 value.

[0273] Also provided is a method of treating a fibrotic disease in a subject in need thereof, the method comprising: providing a first live cell sample from the subject, the first live cell sample having at least one integrin capable of activating transforming growth factor β (TGF-β) from latent peptide TGF-β; determining a first pSMAD / SMAD value for the first live cell sample; administering a small molecule to the subject; providing a second live cell sample from the subject, the second live cell sample being obtained from the same tissue as the first live cell sample; determining a second pSMAD / SMAD value for the second live cell sample; comparing the second pSMAD / SMAD value with the first pSMAD / SMAD value; and administering the small molecule to the subject if the second pSMAD / SMAD value is lower than the first pSMAD / SMAD value. In some embodiments, the small molecule is a compound or salt thereof disclosed herein, optionally in a dosage form disclosed herein. In some embodiments, the first live cell sample is obtained from the subject prior to treatment with a small molecule.

[0274] In some embodiments, each live cell sample is a plurality of cells derived from a tissue of the subject or a plurality of macrophages associated with the tissue of the subject. In some embodiments, the tissue comprises one of lung tissue, liver tissue, skin tissue, heart tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue. In some embodiments, each live cell sample comprises a plurality of alveolar macrophages derived from bronchoalveolar lavage fluid of the subject. In some embodiments, the method further comprises performing bronchoalveolar lavage on the lungs of the subject effective to provide bronchoalveolar lavage fluid comprising the plurality of macrophages as a plurality of alveolar macrophages.

[0275] In some embodiments, the subject is characterized by having a fibrotic disease selected from the group consisting of idiopathic pulmonary fibrosis (IPF), interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease-induced fibrosis, Alport syndrome, primary sclerosing cholangitis (PSC), primary biliary cholangitis, biliary atresia, systemic sclerosis-associated interstitial lung disease, scleroderma, diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn's disease. In some embodiments, the subject is characterized by having psoriasis.

[0276] 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 six integrins include α V Contains β6.

[0277] In some embodiments, determining a first pSMAD / SMAD value of a first live cell sample comprises determining a pSMAD2 / SMAD2 value or a pSMAD3 / SMAD3 value, and determining a second pSMAD / SMAD value of at least one live cell after contacting the first live cell sample with a small molecule comprises determining a pSMAD2 / SMAD2 value or a pSMAD3 / SMAD3 value.

[0278] In another aspect, provided is a method of inhibiting αβ integrin in an individual, comprising administering a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a stereoisomer thereof, or a compound selected from compound numbers 1-66 in Figure 1, or a pharmaceutically acceptable salt thereof.

[0279] In another aspect, provided is a method of inhibiting αβ integrin in an individual, comprising administering a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a stereoisomer thereof, or a compound selected from Compound Nos. 1-147, or a pharmaceutically acceptable salt thereof.

[0280] In another aspect, a method of inhibiting αβ integrin in an individual is provided, comprising administering a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a stereoisomer thereof, or a compound selected from Compound Nos. 1-665, or a pharmaceutically acceptable salt thereof.

[0281] In another aspect, a method of inhibiting αβ integrin in an individual is provided, comprising administering a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a stereoisomer thereof, or a compound selected from Compound Nos. 1-780, or a pharmaceutically acceptable salt thereof.

[0282] Also provided is a method of inhibiting TGFβ activation in a cell, comprising administering a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compound numbers 1-66 in FIG. 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0283] Also provided is a method of inhibiting TGFβ activation in a cell, comprising administering a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0284] Also provided is a method of inhibiting TGFβ activation in a cell, comprising administering a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0285] Also provided is a method of inhibiting TGFβ activation in a cell, comprising administering a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0286] Also provided is a method of inhibiting αvβ6 integrin in an individual in need thereof, comprising administering to the individual a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compound numbers 1-66 in Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Also provided is a method of inhibiting αvβ6 integrin in an individual in need thereof, comprising administering to the individual a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Also provided is a method of inhibiting αvβ6 integrin in an individual in need thereof, comprising administering to the individual a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.Also provided are methods of inhibiting αvβ6 integrin in an individual in need thereof, comprising administering to the individual a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one such method, the compound is a selective αvβ6 integrin inhibitor. In another such method, the compound does not substantially inhibit α4β1, αvβ8, and / or α2β3 integrins. In yet another such method, the compound inhibits αvβ6 integrin but does not substantially inhibit α4β1 integrin. In yet another such method, the compound inhibits αvβ6 integrin but does not substantially inhibit αvβ8 integrin. In a further such method, the compound inhibits αvβ6 integrin but does not substantially inhibit α2β3 integrin. In one embodiment, a method is provided for inhibiting αvβ6 integrin and one or more of αvβ1, αvβ3, αvβ5, α2β1, α3β1, α6β1, α7β1, and α11β1 integrin in an individual in need thereof. In another embodiment, a method is provided for inhibiting αvβ6 integrin and αvβ1 integrin. In another embodiment, a method is provided for inhibiting αvβ6 integrin, αvβ3 integrin, and αvβ5 integrin. In another embodiment, a method is provided for inhibiting αvβ6 integrin and α2β1 integrin. In another embodiment, a method is provided for inhibiting αvβ6 integrin, α2β1 integrin, and α3β1 integrin. In another embodiment, a method is provided for inhibiting αvβ6 integrin and α6β1 integrin. In another embodiment, a method of inhibiting αvβ6 integrin and α7β1 integrin is provided.In another embodiment, a method of inhibiting αvβ6 integrin and α11β1 integrin is provided.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), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compound numbers 1-66 in FIG. 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 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), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 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), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.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), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0287] Compounds of formula (A) may be used in any of the compositions, methods, and uses recited herein for formula (I) and variations of formula (I).

[0288] In any of the methods described, in one embodiment, the individual is a human, a human in need of the method, etc. The individual may be a human diagnosed with or suspected of having a fibrotic disease. The individual may be a human without detectable disease but with one or more risk factors for developing a fibrotic disease.

[0289] Also provided is a dosage form configured for daily administration comprising a pharmaceutically acceptable carrier or excipient and a unit dose of a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0290] A unit dose, e.g., a unit dose for daily administration, can be about 1, 2.5, 5, 7.5, 10, 15, 20, 25, 30, 35, 40, 50, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, or 125 mg, or a range between any two of the foregoing values, e.g., about 1-125, 1-5, 2.5-7.5, 5-15, 10-15, 10-20, 10-25, 10-30, 10-35, 10-40, 10-50, 10-75, 15-20, 15-25, 15 The dosage form may contain between 30, 15 and 35, 15 and 40, 15 and 50, 15 and 75, 20 and 25, 20 and 30, 20 and 35, 20 and 40, 20 and 50, 20 and 75, 25 and 30, 25 and 35, 25 and 40, 25 and 50, 25 and 75, 30 and 35, 30 and 40, 30 and 50, 30 and 75, 35 and 40, 35 and 50, 35 and 75, 40 and 50, 40 and 75, 50 and 75, 50 and 100, 60 and 85, 70 and 90, 70 and 100, 80 and 125, 90 and 125, or 100 and 125 mg of the compound.

[0291] A unit dose, e.g., a unit dose for daily administration, can be about 1, 2.5, 5, 7.5, 10, 15, 20, 25, 30, 35, 40, 50, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 150, 175, 200, 225, or 250 mg, or a range between any two of the foregoing values, e.g., about 1-125, 1-250, 1-5, 2.5-7.5, 5-15, 10-15, 10-20, 10-25, 10-30, 10-35, 10-40, 10-50, 10-75, 15-20, 15-25, 15-30, 15-35, 15-40, 15 ~50, 15~75, 20~25, 20~30, 20~35, 20~40, 20~50, 20~75, 25~30, 25~35, 25~40, 25~50, 25~75, 30~35, 30~40, 30~50, 30~75, 35~40, 35~50, 35~75, 40~50, 40~75 , 50-75, 50-100, 50-150, 50-250, 60-85, 70-90, 70-100, 80-125, 90-125, 100-125, 100-150, 100-200, 125-175, 100-225, 100-250, and 150-250 mg of the compound. For example, a unit dose can be 10 mg. A unit dose can be 15 mg. A unit dose can be 20 mg. A unit dose can be 30 mg. A unit dose can be 40 mg. A unit dose can be 50 mg. A unit dose can be 60 mg. A unit dose can be 70 mg. A unit dose can be 75 mg. A unit dose can be 80 mg. A unit dose can be 90 mg. A unit dose can be 100 mg. The unit dose can be 110 mg. The unit dose can be 120 mg. The unit dose can be 125 mg. The unit dose can be 150 mg. The unit dose can be 175 mg. The unit dose can be 200 mg. The unit dose can be 225 mg. The unit dose can be 250 mg.

[0292] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may have a concentration of at least about one of 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 or more; or a range between any two of the foregoing concentrations, e.g., 700-1500. , 700-900, 800-1300, 750-950, 800-1000, 850-950, 850-1050, 900-1400, 900-1300, 900-1200, 900-1100, 950-1050, 950-1400, 950-1150, 1000-1400, 1000-1300, 1000-1200, etc. Individual plasma C in ng / mL max For example, C max may be about 700 ng / mL or greater. max may be about 750 ng / mL or greater. max may be about 800 ng / mL or greater. max may be about 850 ng / mL or greater. max may be about 900 ng / mL or greater. max may be about 950 ng / mL or greater. max may be about 1000 ng / mL or greater. max may be about 1050 ng / mL or greater. max may be about 1100 ng / mL or greater. max may be about 1200 ng / mL or greater. max may be about 1300 ng / mL or greater. max may be about 1400 ng / mL or greater. max can be about 1500 ng / mL or greater.

[0293] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may be a dose that provides a C in ng / mL in the individual's plasma. max and C maxis an α in an individual of at least about one of 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 percent, or a range between any two of the foregoing percentages (e.g., 50-100, 60-90, 70-90, 75-95 percent, etc.). V β6 or α V In some embodiments, the compound corresponds to a plasma adjusted concentration effective to inhibit β1. V β6 and α V It may be a dual inhibitor of β1 and C max is the α V β6 and α V Each of the above percentages can correspond to a plasma-adjusted concentration effective to inhibit a certain percentage of each of β1, where each percentage is independently selected from the aforementioned percentages or a range between any two of the aforementioned percentages. For example, the plasma-adjusted concentration can be V It may be effective to inhibit β6 by at least about 50%. V It may be effective to inhibit β6 by at least about 60%. V It may be effective to inhibit β6 by at least about 70%. V It may be effective to inhibit β6 by at least about 80%. V It can be effective to inhibit β6 by at least about 90%. Furthermore, for example, the plasma adjusted concentration can be V It may be effective to inhibit β1 by at least about 50%. V It may be effective to inhibit β1 by at least about 60%. V It may be effective to inhibit β1 by at least about 70%. V It may be effective to inhibit β1 by at least about 80%. V β1 by at least about 90%. V β6 and / or α V The phrase "each percentage of β1, each percentage being independently selected" may alternatively be used to refer to a single α Vβ6 inhibitors and corresponding percentages, single α V β1 inhibitors and corresponding percentages, or α V β6 / α V β6 dual inhibitors and the corresponding percentages selected independently.

[0294] Also provided is a dosage form configured for daily administration comprising a pharmaceutically acceptable carrier or excipient and a unit dose of a compound of Formula (A), Formula (I), or any variation thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0295] In various embodiments, the dose, e.g., unit dose, e.g., unit dose for daily administration, may be 1, 2.5, 5, 7.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 225, 240, 250, 275, 300, 320, 325, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 465, 475, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 93 0, 375, 400, 425, 450, 475, 480, 500, 525, 550, 560, 575, 600, 625, 640, 650, 675, 700, 720, 725, 750, 775, 800, 825, 850, 875, 880, 900, 925, 950, 960, 975, 1000, 1025, 1040, 1050, 1075, 1100, 1125, 1150, 1175, 1200, 1225, 1250, 1275, 1 280, 1300, 1325, 1350, 1375, 1400, 1425, 1450, 1475, 1480, 1500, 1525, 1550, 1575, 1600, 1625, 1650, 1675, 1700, 1725, 1750, 1775, 1800, 1825, 1850, 1875, 1880, 1900, 1925, 1950, 1975, 2000, 2025, 2040, 2050, 2075, 2100, 2125, 215 0, 2175, 2200, 2225, 2250, 2275, 2280, 2300, 2325, 2350, 2375, 2400, 2425, 2450, 2475, 2480, 2500, 2525, 2550, 2560, 2575, 2600, 2625, 2650, 2675, 2700, 2725, 2750, 2775, 2800, 2825, 2850, 2875, 2880, 2900, 2925, 2950, ​​2975, or 3,000 milligrams, or about 1, about 2.5, about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 140, about 150, about 160, about 170, about 175, about 180, about 190, about 200, about 225, about 240, about 250, about 275, about 300, about 320, about 325, about 350, about 375, about 400, about 425 , about 450, about 475, about 480, about 500, about 525, about 550, about 560, about 575, about 600, about 625, about 640, about 650, about 675, about 700, about 720, about 725, about 750, about 775, about 800, about 825, about 850, about 875, about 880, about 900, about 925, about 950, about 960, about 975, about 1000, about 1025, about 1040, about 1050, about 1075, about 1100, about 1125, about 1150, about 1175, about 1200, about 1225, about 1250, about 1275, about 1280, about 1 300, about 1325, about 1350, about 1375, about 1400, about 1425, about 1450, about 1475, about 1480, about 1500, about 1525, about 1550, about 1575, about 1600, about 1625, about 1650, about 1675, about 1700, about 1725, about 1750, about 1775, about 1800, about 1825, about 1850, about 1875, about 1880, about 1900, about 1925, about 1950, about 1975, about 2000, about 2025, about 2040, about 2050, about 2075, about 2100, about 2125, about 2150, about 2175, about 2200, about 2225, about 2250, about 2275, about 2280, about 2300, about 2325, about 2350, about 2375, about 2400, about 2425, about 2450, about 2475, about 2480, about 2500, about 2525, about 2550, about 2560, about 2575, about 2600, about 2625, about 2650, about 2675, about 2700, about 2725, about 2750, about 2775, about 2800, about 2825, about 2850, about 2875, about 2880, about 2900, about 2925, about 2950, ​​about 2975, or about 3,The dose may contain the compound in an amount of 1,000 milligrams. For example, a dose may contain the compound in an amount of 10 mg or about 10 mg. A dose may contain the compound in an amount of 15 mg or about 15 mg. A dose may contain the compound in an amount of 20 mg or about 20 mg. A dose may contain the compound in an amount of 30 mg or about 30 mg. A dose may contain the compound in an amount of 40 mg or about 40 mg. A dose may contain the compound in an amount of 50 mg or about 50 mg. A dose may contain the compound in an amount of 75 mg or about 75 mg. A dose may contain the compound in an amount of 80 mg or about 80 mg. A dose may contain the compound in an amount of 100 mg or about 100 mg. A dose may contain the compound in an amount of 120 mg or about 120 mg. A dose may contain the compound in an amount of 160 mg or about 160 mg. A dose may contain the compound in an amount of 240 mg or about 240 mg. A dose may contain the compound in an amount of 320 mg or about 320 mg. A dose may contain the compound in an amount of 400 mg or about 400 mg. A dose may contain the compound in an amount of 480 mg or about 480 mg. A dose may contain the compound in an amount of 560 mg or about 560 mg. A dose may contain the compound in an amount of 640 mg or about 640 mg. A dose may contain the compound in an amount of 720 mg or about 720 mg. A dose may contain the compound in an amount of 800 mg or about 800 mg. A dose may contain the compound in an amount of 880 mg or about 880 mg. A dose may contain the compound in an amount of 960 mg or about 960 mg. A dose may contain the compound in an amount of 1040 mg or about 1040 mg. A dose may contain the compound in an amount of 1280 mg or about 1280 mg. A dose may contain the compound in an amount of 1500 mg or about 1500 mg. A dose may contain the compound in an amount of 1750 mg or about 1750 mg. A dose may contain the compound in an amount of 2000 mg or about 2000 mg. A dose may contain the compound in an amount of 2560 mg or about 2560 mg. A dose may contain the compound in an amount of 3000 mg or about 3000 mg.

[0296] In various embodiments, a dose, e.g., a unit dose, e.g., a unit dose for daily administration, may comprise an amount of compound comprising about one of about 320, about 400, about 480, about 560, about 640, about 720, about 800, about 880, about 960, or about 1040, or an amount of compound in mg in a range between any two of the foregoing values.

[0297] In various embodiments, a dose, e.g., a unit dose, e.g., a unit dose for daily administration, can contain an amount of compound that includes about 1 of about 400, about 480, about 560, about 640, about 720, about 800, about 880, about 960, or about 1040 mg of compound.

[0298] In various embodiments, a dose, e.g., a unit dose, e.g., a unit dose for daily administration, can include an amount of compound in mg ranging from about 320 to any one of about 400, about 480, about 560, about 640, about 720, about 800, about 880, about 960, or about 1040 mg of compound.

[0299] In various embodiments, a dose, e.g., a unit dose, e.g., a unit dose for daily administration, may comprise an amount of compound comprising about one of 400, 480, 560, 640, 720, 800, 880, 960, or 1040 mg of compound, or an amount of compound in mg ranging between any two of the foregoing values.

[0300] In various embodiments, the dose, e.g., unit dose, e.g., unit dose for daily administration, is about 300, about 320, about 325, about 350, about 375, about 400, about 425, about 450, about 475, about 480, about 500, about 525, about 550, about 560, about 575, about 600, about 625, about 640, about 650, about 675, about 700, about 720, about 725, about 750, about 775, about 800, about 825, about 850, about 875, about 880, about 900, about 925, about 950, about 960, about 975, about 1000, about 1025, about 1040, about 1050, about 1075, about 1100, about 1125, about 1150, about 1175, about 1200, about 1225, about 1250, about 1275, about 1280, about 1300, about 1325, about 1350, about 1375, about 1400, about 1425, about 1450, about 1475, about 1480, about 1500, about 1525, about 1550, about 1575, about 1600, about 1625, about 1650, about 1675, about 1700 00, about 1725, about 1750, about 1775, about 1800, about 1825, about 1850, about 1875, about 1880, about 1900, about 1925, about 1950, about 1975, about 2000, about 2025, about 2040, about 2050, about 2075, about 2100, about 2125, about 2150, about 2175, about 2200, about 2225, about 2250, about 2275, about 2280, about 2300, about 2325, about 2350, about 2375, about 2400, about 2425, about 2450, about 2 The compound may comprise an amount of compound in mg that is about one of about 475, about 2480, about 2500, about 2525, about 2550, about 2560, about 2575, about 2600, about 2625, about 2650, about 2675, about 2700, about 2725, about 2750, about 2775, about 2800, about 2825, about 2850, about 2875, about 2880, about 2900, about 2925, about 2950, ​​about 2975, or about 3,000, or an amount of compound in mg that ranges between any two of the foregoing values.

[0301] In various embodiments, the dose, e.g., unit dose, e.g., unit dose for daily administration, is about 1250, about 1275, about 1280, about 1300, about 1325, about 1350, about 1375, about 1400, about 1425, about 1450, about 1475, about 1480, about 1500, about 1525, about 1550, about 1575 , about 1600, about 1625, about 1650, about 1675, about 1700, about 1725, about 1750, about 1775, about 1800, about 1825, about 1850, about 1875, about 1880, about 1900, about 1925, about 1950, about 1975, about 2000, about 2025, about 2040, about 2050, about 2075, about 2100 , about 2125, about 2150, about 2175, about 2200, about 2225, about 2250, about 2275, about 2280, about 2300, about 2325, about 2350, about 2375, about 2400, about 2425, about 2450, about 2475, about 2480, about 2500, about 2525, about 2550, about 2560, about 2575, about 2600 , about 2625, about 2650, about 2675, about 2700, about 2725, about 2750, about 2775, about 2800, about 2825, about 2850, about 2875, about 2880, about 2900, about 2925, about 2950, ​​about 2975, or about 3,000 mg of compound.

[0302] In various embodiments, the dose, e.g., unit dose, e.g., unit dose for daily administration, is about 320, about 1250, about 1275, about 1280, about 1300, about 1325, about 1350, about 1375, about 1400, about 1425, about 1450, about 1475, about 1480, about 1500, about 1525, about 1550, about 1560, about 1570, about 1580, about 1590, about 2000, about 2010, about 2020, about 2030, about 2040, about 2050, about 2060, about 2070, about 2080, about 2100, about 2110, about 2125, about 2130, about 2140, about 2150, about 2160, about 2170, about 2180, about 2190, about 2210, about 2225, about 2230, about 2240, about 2250, about 2260, about 2275, about 2280, about 2290, about 2300, about 2310, about 2320, about 2330, about 2340, about 2350, about 2375, about 2380, about 2390, about 2410, about 2425, about 2450, about 2475, about 2480, about 2500, about 2525, about 2550, about 2560, about 2570, about 2580, about 2590, about 575, approximately 1600, approximately 1625, approximately 1650, approximately 1675, approximately 1700, approximately 1725, approximately 1750, approximately 1775, approximately 1800, approximately 1825, approximately 1850, approximately 1875, approximately 1880, approximately 1900, approximately 1925, approximately 1950, approximately 1975, approximately 2000, approximately 2025, approximately 2040, approximately 2050, approximately 2075, approximately 2100 , about 2125, about 2150, about 2175, about 2200, about 2225, about 2250, about 2275, about 2280, about 2300, about 2325, about 2350, about 2375, about 2400, about 2425, about 2450, about 2475, about 2480, about 2500, about 2525, about 2550, about 2560, about 2575, about 2600, about 2625, about 2645, about 2660, about 2685, about 2690, about 2700, about 2715, about 2725, about 2730, about 2740, about 2750, about 2765, about 2775, about 2780, about 2790, about 2800, about 2815, about 2825, about 2850, about 2865, about 2875, about 2880, about 280 ... The compound may comprise an amount of compound in mg ranging between any one of about 625, about 2650, about 2675, about 2700, about 2725, about 2750, about 2775, about 2800, about 2825, about 2850, about 2875, about 2880, about 2900, about 2925, about 2950, ​​about 2975, or about 3,000.

[0303] In various embodiments, doses, e.g., unit doses, e.g., unit doses for daily administration, are 1280, 1300, 1325, 1350, 1375, 1400, 1425, 1450, 1475, 1480, 1500, 1525, 1550, 1575, 1600, 1625, 1650, 1675, 1700, 1725, 1750, 1775, 1800, 1825, 1850, 1875, 1880, 1900, 1925, 1950, 1975, 2000, 2025, 2040, 2050, 2075, 2100, 2125, 2150, 2175 , 2200, 2225, 2250, 2275, 2280, 2300, 2325, 2350, 2375, 2400, 2425, 2450, 2475, 2480, 2500, 2525, 2550, 2560, 2575, 2600, 2625, 2650, 2675, 2700, 2725, 2750, 2775, 2800, 2825, 2850, 2875, 2880, 2900, 2925, 2950, ​​2975, or 3,000 mg of compound, or an amount of compound in mg ranging between any two of the foregoing values.

[0304] In various embodiments, a dose, e.g., a unit dose, e.g., a unit dose for daily administration, may comprise an amount of compound comprising about one of 320, 400, 480, 560, 640, 720, 800, 880, 960, 1040, 1280, 1500, 2000, 2460, or 3000 mg of compound, or an amount of compound in mg ranging between any two of the foregoing values.

[0305] In various embodiments, a dose, e.g., a unit dose, e.g., a unit dose for daily administration, may comprise an amount of compound comprising about one of 480, 560, 640, 720, 800, 880, 960, 1040, 1280, 1500, 2000, or 2460 mg of compound, or an amount of compound in mg ranging between any two of the foregoing values.

[0306] In various embodiments, a dose, e.g., a unit dose, e.g., a unit dose for daily administration, may comprise an amount of compound comprising about one of 320, 400, 480, 560, or 640 mg of compound, or an amount of compound in mg ranging between any two of the foregoing values.

[0307] In various embodiments, a dose, e.g., a unit dose, e.g., a unit dose for daily administration, can include an amount of compound in mg ranging from about 320 to any one of about 400, about 480, about 560, about 640, about 720, about 800, about 880, about 960, about 1040, about 1280, about 1500, about 2000, about 2460, or about 3000 mg of compound.

[0308] In various embodiments, a dose, e.g., a unit dose, e.g., a unit dose for daily administration, may comprise an amount of compound comprising about one of 400, 480, 560, 640, 720, 800, 880, 960, 1040, 1280, 1500, 2000, 2460, or 3000 mg of compound, or an amount of compound in mg ranging between any two of the foregoing values.

[0309] In some embodiments, the unit dose may contain a compound within any percentage range independently selected from any of the individual milligram values ​​listed in the preceding paragraph, such as ±1%, ±2%, ±2.5%, ±5%, ±7.5%, ±10%, ±15%, ±20%, ±25%, ±30%, ±40%, or ±50%, or from ±about 1%, ±about 2%, ±about 2.5%, ±about 5%, ±about 7.5%, ±about 10%, ±about 15%, ±about 20%, ±about 25%, ±about 30%, ±about 40%, or ±about 50%. For example, the range may be ±1% or ±about 1%. The range may be ±2% or ±about 2%. The range may be ±2.5% or ±about 2.5%. The range may be ±5%, or ±about 5%. The range may be ±7.5%, or ±about 7.5%. The range may be ±10%, or ±about 10%. The range may be ±15%, or ±about 15%. The range may be ±20%, or ±about 20%. The range may be ±25%, or ±about 25%. The range may be ±30%, or ±about 30%. The range may be ±40%, or ±about 40%. The range may be ±50%, or ±about 50%.

[0310] Further, for example, a unit dose may contain the compound in one of the following amounts: 10 mg ± 1%, 10 mg ± 2%, 10 mg ± 2.5%, 10 mg ± 5%, 10 mg ± 7.5%, 10 mg ± 10%, 10 mg ± 15%, 10 mg ± 20%, 10 mg ± 25%, 10 mg ± 30%, 10 mg ± 40%, or 10 mg ± 50%. A unit dose may contain the compound in one of the following amounts: 15 mg ± 1%, 15 mg ± 2%, 15 mg ± 2.5%, 15 mg ± 5%, 15 mg ± 7.5%, 15 mg ± 10%, 15 mg ± 15%, 15 mg ± 20%, 15 mg ± 25%, 15 mg ± 30%, 15 mg ± 40%, or 15 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 20 mg ± 1%, 20 mg ± 2%, 20 mg ± 2.5%, 20 mg ± 5%, 20 mg ± 7.5%, 20 mg ± 10%, 20 mg ± 15%, 20 mg ± 20%, 20 mg ± 25%, 20 mg ± 30%, 20 mg ± 40%, or 20 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 30 mg ± 1%, 30 mg ± 2%, 30 mg ± 2.5%, 30 mg ± 5%, 30 mg ± 7.5%, 30 mg ± 10%, 30 mg ± 15%, 30 mg ± 20%, 30 mg ± 25%, 30 mg ± 30%, 30 mg ± 40%, or 30 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 40 mg ± 1%, 40 mg ± 2%, 40 mg ± 2.5%, 40 mg ± 5%, 40 mg ± 7.5%, 40 mg ± 10%, 40 mg ± 15%, 40 mg ± 20%, 40 mg ± 25%, 40 mg ± 30%, 40 mg ± 40%, or 40 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 50 mg ± 1%, 50 mg ± 2%, 50 mg ± 2.5%, 50 mg ± 5%, 50 mg ± 7.5%, 50 mg ± 10%, 50 mg ± 15%, 50 mg ± 20%, 50 mg ± 25%, 50 mg ± 30%, 50 mg ± 40%, or 50 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 60 mg ± 1%; 60 mg ± 2%; 60 mg ± 2.5%; 60 mg ± 5%; 60 mg ± 7.5%; 60 mg ± 10%; 60 mg ± 15%; 60 mg ± 20%; 60 mg ± 25%; 60 mg ± 30%; 60 mg ± 40%; or 60 mg ± 50%.The unit dose may contain the compound in one of the following amounts: 75 mg ± 1%, 75 mg ± 2%, 75 mg ± 2.5%, 75 mg ± 5%, 75 mg ± 7.5%, 75 mg ± 10%, 75 mg ± 15%, 75 mg ± 20%, 75 mg ± 25%, 75 mg ± 30%, 75 mg ± 40%, or 75 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 80 mg ± 1%, 80 mg ± 2%, 80 mg ± 2.5%, 80 mg ± 5%, 80 mg ± 7.5%, 80 mg ± 10%, 80 mg ± 15%, 80 mg ± 20%, 80 mg ± 25%, 80 mg ± 30%, 80 mg ± 40%, or 80 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 100 mg ± 1%, 100 mg ± 2%, 100 mg ± 2.5%, 100 mg ± 5%, 100 mg ± 7.5%, 100 mg ± 10%, 100 mg ± 15%, 100 mg ± 20%, 100 mg ± 25%, 100 mg ± 30%, 100 mg ± 40%, or 100 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 120 mg ± 1%, 120 mg ± 2%, 120 mg ± 2.5%, 120 mg ± 5%, 120 mg ± 7.5%, 120 mg ± 10%, 120 mg ± 15%, 120 mg ± 20%, 120 mg ± 25%, 120 mg ± 30%, 120 mg ± 40%, or 120 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 160 mg ± 1%, 160 mg ± 2%, 160 mg ± 2.5%, 160 mg ± 5%, 160 mg ± 7.5%, 160 mg ± 10%, 160 mg ± 15%, 160 mg ± 20%, 160 mg ± 25%, 160 mg ± 30%, 160 mg ± 40%, or 160 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 240 mg ± 1%, 240 mg ± 2%, 240 mg ± 2.5%, 240 mg ± 5%, 240 mg ± 7.5%, 240 mg ± 10%, 240 mg ± 15%, 240 mg ± 20%, 240 mg ± 25%, 240 mg ± 30%, 240 mg ± 40%, or 240 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 320 mg ± 1%; 320 mg ± 2%; 320 mg ± 2.5%; 320 mg ± 5%; 320 mg ± 7.5%; 320 mg ± 10%; 320 mg ± 15%; 320 mg ± 20%; 320 mg ± 25%; 320 mg ± 30%; 320 mg ± 40%; or 320 mg ± 50%.The unit dose may contain the compound in one of the following amounts: 400 mg ± 1%, 400 mg ± 2%, 400 mg ± 2.5%, 400 mg ± 5%, 400 mg ± 7.5%, 400 mg ± 10%, 400 mg ± 15%, 400 mg ± 20%, 400 mg ± 25%, 400 mg ± 30%, 400 mg ± 40%, or 400 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 480 mg ± 1%, 480 mg ± 2%, 480 mg ± 2.5%, 480 mg ± 5%, 480 mg ± 7.5%, 480 mg ± 10%, 480 mg ± 15%, 480 mg ± 20%, 480 mg ± 25%, 480 mg ± 30%, 480 mg ± 40%, or 480 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 560 mg ± 1%, 560 mg ± 2%, 560 mg ± 2.5%, 560 mg ± 5%, 560 mg ± 7.5%, 560 mg ± 10%, 560 mg ± 15%, 560 mg ± 20%, 560 mg ± 25%, 560 mg ± 30%, 560 mg ± 40%, or 560 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 640 mg ± 1%, 640 mg ± 2%, 640 mg ± 2.5%, 640 mg ± 5%, 640 mg ± 7.5%, 640 mg ± 10%, 640 mg ± 15%, 640 mg ± 20%, 640 mg ± 25%, 640 mg ± 30%, 640 mg ± 40%, or 640 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 720 mg ± 1%, 720 mg ± 2%, 720 mg ± 2.5%, 720 mg ± 5%, 720 mg ± 7.5%, 720 mg ± 10%, 720 mg ± 15%, 720 mg ± 20%, 720 mg ± 25%, 720 mg ± 30%, 720 mg ± 40%, or 720 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 800 mg ± 1%, 800 mg ± 2%, 800 mg ± 2.5%, 800 mg ± 5%, 800 mg ± 7.5%, 800 mg ± 10%, 800 mg ± 15%, 800 mg ± 20%, 800 mg ± 25%, 800 mg ± 30%, 800 mg ± 40%, or 800 mg ± 50%.The unit dose may contain the compound in one of the following amounts: 880 mg ± 1%, 880 mg ± 2%, 880 mg ± 2.5%, 880 mg ± 5%, 880 mg ± 7.5%, 880 mg ± 10%, 880 mg ± 15%, 880 mg ± 20%, 880 mg ± 25%, 880 mg ± 30%, 880 mg ± 40%, or 880 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 960 mg ± 1%, 960 mg ± 2%, 960 mg ± 2.5%, 960 mg ± 5%, 960 mg ± 7.5%, 960 mg ± 10%, 960 mg ± 15%, 960 mg ± 20%, 960 mg ± 25%, 960 mg ± 30%, 960 mg ± 40%, or 960 mg ± 50%. The unit dose may contain the compound in one of the following amounts: 1040 mg ± 1%; 1040 mg ± 2%; 1040 mg ± 2.5%; 1040 mg ± 5%; 1040 mg ± 7.5%; 1040 mg ± 10%; 1040 mg ± 15%; 1040 mg ± 20%; 1040 mg ± 25%; 1040 mg ± 30%; 1040 mg ± 40%; or 1040 mg ± 50%.

[0311] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may have a concentration of at least about one of 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, or 2500 or more; or a range between any two of the foregoing concentrations, e.g., 700-1500, 700-1600, 750-1800, 700-1900, or more; Individual plasma C in ng / mL, such as ~900, 800-1300, 750-950, 800-1000, 850-950, 850-1050, 900-1400, 900-1300, 900-1200, 900-1100, 950-1050, 950-1400, 950-1150, 1000-1400, 1000-1300, 1000-1200, 700-2500, 1000-2500, 1500-2500, 1500-2000, 1500-2500, and 2000-2500 max For example, C maxmay be 700 ng / mL or about 700 ng / mL or more. max may be 750 ng / mL or about 750 ng / mL or more. max may be 800 ng / mL or about 800 ng / mL or more. max may be 850 ng / mL or about 850 ng / mL or more. max may be 900 ng / mL or may be about 900 ng / mL or higher. max may be 950 ng / mL or about 950 ng / mL or higher. max may be 1000 ng / mL or may be about 1000 ng / mL or more. max may be 1050 ng / mL or may be about 1050 ng / mL or higher. max may be 1100 ng / mL or about 1100 ng / mL or more. max may be 1200 ng / mL or may be about 1200 ng / mL or higher. max may be 1300 ng / mL or may be about 1300 ng / mL or higher. max may be 1400 ng / mL or may be about 1400 ng / mL or higher. max may be 1500 ng / mL or about 1500 ng / mL or more. max may be 1600 ng / mL or may be about 1600 ng / mL or higher. max may be 1700 ng / mL or may be about 1700 ng / mL or higher. max may be 1800 ng / mL or may be about 1800 ng / mL or higher. max may be 1900 ng / mL or may be about 1900 ng / mL or higher. maxmay be 2000 ng / mL or may be about 2000 ng / mL or higher. max may be 2100 ng / mL or may be about 2100 ng / mL or higher. max may be 2200 ng / mL or may be about 2200 ng / mL or higher. max may be 2300 ng / mL or may be about 2300 ng / mL or higher. max may be 2400 ng / mL or may be about 2400 ng / mL or higher. max may be 2500 ng / mL or may be about 2500 ng / mL or higher.

[0312] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may have a C in the individual's plasma in ng / mL of at least about one of 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500, or a range between any two of the foregoing concentrations. max The compound may be present in an amount effective to provide:

[0313] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may provide a C in the individual's plasma in ng / mL ranging between at least about one of a lower limit of any of 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, or 1450 and an upper limit of 1500. max The compound may be present in an amount effective to provide:

[0314] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may have a C in the individual's plasma in ng / mL of at least about one of 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, or 2500, or a range between any two of the foregoing concentrations. maxThe compound may be present in an amount effective to provide:

[0315] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may have a C in the individual's plasma in ng / mL of at least about one of 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, or 2500, or a range between any two of the foregoing concentrations. max The compound may be present in an amount effective to provide:

[0316] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may provide a C in the individual's plasma in ng / mL ranging from at least 1500 to any one of 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, or 2500. max The compound may be present in an amount effective to provide:

[0317] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may be at least about 1500 to 10000 ng / mL of C in the individual's plasma. max The compound may be present in an amount effective to provide:

[0318] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may have a C concentration in the individual's plasma in ng / mL of at least about one of 5000, 5500, 6000, 6500, or 7000, or a range between any two of the foregoing concentrations. max The compound may be present in an amount effective to provide:

[0319] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may be configured to produce a C in the individual's plasma in ng / mL ranging between at least about one of a lower limit of 5000, 5500, 6000, 6500, or 7000 and an upper limit of 10000. max The compound may be present in an amount effective to provide:

[0320] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may be a dose that provides a C in ng / mL in the individual's plasma. max and C max is an alpha of at least one of, or at least about one of, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 97, 98, 99, or 100 percent, in an individual, or a range between any two of the foregoing percentages (e.g., 50-100, 60-90, 70-90, 75-95, 90-95, 90-98, 90-99 percent, etc.). V β6 or α V In some embodiments, the compound corresponds to a plasma adjusted concentration effective to inhibit β1. V β6 and α V It may be a dual inhibitor of β1 and C max is the α V β6 and α V Each of the above percentages can correspond to a plasma-adjusted concentration effective to inhibit a certain percentage of each of β1, where each percentage is independently selected from the aforementioned percentages or a range between any two of the aforementioned percentages. For example, the plasma-adjusted concentration can be V It may be effective to inhibit β6 by at least about 50%. V It may be effective to inhibit β6 by at least about 60%. V It may be effective to inhibit β6 by at least about 70%. V It may be effective to inhibit β6 by at least about 80%. V It may be effective to inhibit β6 by at least about 90%. V It may be effective to inhibit β6 by at least about 95%. V It may be effective to inhibit β6 by at least about 97%. V It may be effective to inhibit β6 by at least about 98%. VIt may be effective to inhibit β6 by at least about 99%. V It can be effective to inhibit β6 by 100%. Furthermore, for example, the plasma adjusted concentration can be V It may be effective to inhibit β1 by at least about 50%. V It may be effective to inhibit β1 by at least about 60%. V It may be effective to inhibit β1 by at least about 70%. V It may be effective to inhibit β1 by at least about 80%. V It may be effective to inhibit β1 by at least about 90%. V It may be effective to inhibit β1 by at least about 95%. V It may be effective to inhibit β1 by at least about 97%. V It may be effective to inhibit β1 by at least about 98%. V It may be effective to inhibit β1 by at least about 99%. V It can be effective in blocking 100% of β1 in a subject. V β6 and / or α V The phrase "each percentage of β1, each percentage being independently selected" may alternatively be used to refer to a single α V β6 inhibitors and corresponding percentages, single α V β1 inhibitors and corresponding percentages, or α V β6 / α V β6 dual inhibitors and the corresponding percentages selected independently.

[0321] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may have an AUC in the individual's plasma in ng×h / mL of at least about one of 50,000, 60,000, 70,000, 80,000, 90,000, 100,000, 110,000, 120,000, 130,000, or 135,000 or more. 0-24hFor example, the compound may be present in an amount effective to provide an AUC 0-24h AUC may be 50,000 ng×h / mL or may be about 50,000 ng×h / mL or more. 0-24h AUC may be 60,000 ng×h / mL or may be about 60,000 ng×h / mL or greater. 0-24h AUC may be 70,000 ng×h / mL or may be about 70,000 ng×h / mL or greater. 0-24h AUC may be 80,000 ng×h / mL or may be about 80,000 ng×h / mL or greater. 0-24h AUC may be 90,000 ng×h / mL or may be about 90,000 ng×h / mL or greater. 0-24h AUC can be 100,000 ng×h / mL or can be about 100,000 ng×h / mL or more. 0-24h AUC may be 110,000 ng×h / mL or may be about 110,000 ng×h / mL or greater. 0-24h AUC may be 120,000 ng×h / mL or may be about 120,000 ng×h / mL or greater. 0-24h AUC may be 130,000 ng×h / mL or may be about 130,000 ng×h / mL or greater. 0-24h may be 135,000 ng×h / mL or may be about 135,000 ng×h / mL or more.

[0322] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may have an AUC in the individual's plasma of at least about 50,000 to 135,000 ng×h / mL. 0-24h For example, the compound may be present in an amount effective to provide an AUC 0-24h AUC may be 50,000 ng×h / mL or about 50,000 ng×h / mL. 0-24h AUC may be 60,000 ng×h / mL or about 60,000 ng×h / mL.0-24h AUC may be 70,000 ng×h / mL or about 70,000 ng×h / mL. 0-24h AUC may be 80,000 ng×h / mL or about 80,000 ng×h / mL. 0-24h AUC may be 90,000 ng×h / mL or may be about 90,000 ng×h / mL. 0-24h AUC may be 100,000 ng×h / mL or about 100,000 ng×h / mL. 0-24h AUC may be or may be about 105,000 ng×h / mL. 0-24h AUC may be 110,000 ng×h / mL or may be about 110,000 ng×h / mL. 0-24h AUC may be 120,000 ng×h / mL or about 120,000 ng×h / mL. 0-24h AUC may be 130,000 ng×h / mL or about 130,000 ng×h / mL. 0-24h may be 135,000 ng×h / mL or may be about 135,000 ng×h / mL.

[0323] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may have an AUC in the individual's plasma in ng×h / mL of at least about one of 50,000, 60,000, 70,000, 80,000, 90,000, 100,000, 110,000, 120,000, 130,000, or 135,000, or a range between any two of the foregoing concentrations. 0-24h The compound may be present in an amount effective to provide:

[0324] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may have an AUC in the individual's plasma in ng×h / mL ranging between at least about one of a lower limit of 50,000, 60,000, 70,000, 80,000, 90,000, 100,000, 110,000, 120,000, or 130,000 and an upper limit of 135,000.0-24h The compound may be present in an amount effective to provide:

[0325] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may have an AUC in the individual's plasma in ng×h / mL of at least about 90,000, 100,000, 110,000, 120,000, 130,000, or 135,000, or a range between any two of the foregoing concentrations. 0-24h The compound may be present in an amount effective to provide:

[0326] A unit dose, e.g., a unit dose for daily administration, upon administration to an individual, may have an AUC in the individual's plasma in ng×h / mL ranging between at least about one of a lower limit of 90,000, 100,000, 110,000, 120,000, or 130,000 and an upper limit of 135,000. 0-24h The compound may be present in an amount effective to provide:

[0327] A unit dose, for example a unit dose for daily administration, when administered to an individual, may have an AUC of about ng×h / mL in the individual's plasma. 0-24 and the compound may be present in an amount effective to provide an AUC 0-24h is an alpha of at least one of, or at least about one of, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 97, 98, 99, or 100 percent, in an individual, or a range between any two of the foregoing percentages (e.g., 50-100, 60-90, 70-90, 75-95, 90-95, 90-98, 90-99 percent, etc.). V β6 or α V In some embodiments, the compound corresponds to a plasma adjusted concentration effective to inhibit β1. V β6 and α V It can be a dual inhibitor of β1, and AUC 0-24h is the α V β6 and α VEach of the above percentages can correspond to a plasma-adjusted concentration effective to inhibit a certain percentage of each of β1, where each percentage is independently selected from the aforementioned percentages or a range between any two of the aforementioned percentages. For example, the plasma-adjusted concentration can be V It may be effective to inhibit β6 by at least about 50%. V It may be effective to inhibit β6 by at least about 60%. V It may be effective to inhibit β6 by at least about 70%. V It may be effective to inhibit β6 by at least about 80%. V It may be effective to inhibit β6 by at least about 90%. V It may be effective to inhibit β6 by at least about 95%. V It may be effective to inhibit β6 by at least about 97%. V It may be effective to inhibit β6 by at least about 98%. V It may be effective to inhibit β6 by at least about 99%. V It can be effective to inhibit β6 by 100%. Furthermore, for example, the plasma adjusted concentration can be V It may be effective to inhibit β1 by at least about 50%. V It may be effective to inhibit β1 by at least about 60%. V It may be effective to inhibit β1 by at least about 70%. V It may be effective to inhibit β1 by at least about 80%. V It may be effective to inhibit β1 by at least about 90%. V It may be effective to inhibit β1 by at least about 95%. V It may be effective to inhibit β1 by at least about 97%. V It may be effective to inhibit β1 by at least about 98%. VIt may be effective to inhibit β1 by at least about 99%. V It can be effective in blocking 100% of β1 in a subject. V β6 and / or α V The phrase "each percentage of β1, each percentage being independently selected" may alternatively be used to refer to a single α V β6 inhibitors...

Claims

1. A pharmaceutical composition comprising a medicament comprising a medicament comprising: a medicament comprising a medicament for use in treating or treating a disease; and about 320 mg to about 640 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1, comprising about 320 mg, about 400 mg, about 480 mg, about 560 mg, or about 640 mg of the compound.

3. The pharmaceutical composition of claim 1, comprising approximately 320 mg of the compound.

4. The pharmaceutical composition of claim 1, comprising approximately 480 mg of the compound.

5. The pharmaceutical composition of claim 1, comprising approximately 640 mg of the compound.

6. A kit comprising the pharmaceutical composition according to any one of claims 1 to 5, (i) instructions for the treatment of a fibrotic disorder; (ii) instructions for administering the pharmaceutical composition daily to an individual in need thereof; (iii) instructions for administering the pharmaceutical composition to an individual in need thereof once, twice, three times, or four times daily; (iv) administering the pharmaceutical composition to an individual in need thereof to increase the C in plasma of the individual in ng / mL to at least about one of 5000, 5500, 6000, 6500, or 7000, or a range between any two of the foregoing concentrations. ｍａｘ or (v) administering said pharmaceutical composition to an individual in need thereof, said individual's plasma AUC ０－２４ｈ instructions for administering to provide the AUC ０－２４ｈ is at least about one of 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 percentages, or a range between any two of the foregoing percentages, in said individual. Ｖ β ６ Or α Ｖ β １ or (vi) administering the pharmaceutical composition to an individual in need thereof for about 3, 3.5, or 4 hours, or a range between any two of the aforementioned times, to the individual's plasma T ｍａｘ Instructions for administration to effect The kit may further comprise one or more of:

7. A daily dose of about 320 mg to about 640 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof for treating a fibrotic disease in an individual in need thereof. (i) about 320 mg, about 400 mg, about 480 mg, about 560 mg, or about 640 mg of the compound; and / or (ii) is administered to said individual to result in a C max in said individual's plasma in ng / mL of at least about one of 5000, 5500, 6000, 6500, or 7000, or a range between any two of the foregoing concentrations; and / or (iii) administered to an individual to provide an AUC 0-24h in the plasma of said individual, said AUC 0-24h corresponding to a plasma adjusted concentration effective to inhibit α v β 6 or α v β 1 in said individual by at least about one of 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 percentage, or a range between any two of the foregoing percentages; and / or (iv) is administered to said individual to result in a T max in said individual's plasma of about 3, 3.5, or 4 hours, or a range between any two of the foregoing times; The pharmaceutical composition according to claim 7.

9. A pharmaceutical composition according to claim 7 or 8, comprising a pharmaceutical composition according to any one of claims 1 to 5.

10. The pharmaceutical composition according to claim 7 or 8, wherein the fibrotic disease is pulmonary fibrosis, hepatic fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or bile duct fibrosis.

11. The pharmaceutical composition of claim 10, wherein the fibrotic disease is hepatic fibrosis, cardiac fibrosis, primary sclerosing cholangitis, or bile duct fibrosis.

12. The pharmaceutical composition described in claim 7 or 8, wherein the fibrotic disease is idiopathic pulmonary fibrosis.

13. The pharmaceutical composition described in claim 7 or 8, wherein the fibrotic disease is primary sclerosing cholangitis.

14. The pharmaceutical composition of claim 9, administered once, twice, three times, or four times daily.

15. The pharmaceutical composition described in claim 14, which is administered once a day.

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