Dosage forms and regimens for amino acid compounds

Abstract

To provide αvβ6 integrin inhibitors that are useful for treating fibrosis such as idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP).SOLUTION: The invention provides compounds represented by formula (A) and formula (I), or salts thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 831,060, filed April 8, 2019, U.S. Provisional Patent Application No. 62 / 850,530, filed May 20, 2019, and U.S. Provisional Patent Application No. 62 / 899,071, filed September 11, 2019, 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 leads to extensive tissue scarring that leads to destruction of the renal parenchyma and end-stage renal failure, a devastating condition requiring dialysis or kidney replacement surgery.

[0005] Scleroderma encompasses a complex and diverse range of conditions characterized primarily by fibrosis, vascular alterations, and autoimmunity. Disorders in the scleroderma spectrum share the common feature of fibrosis, resulting in hardening and thickening of the skin. This hardening occurs in limited areas in some patients, but can spread to other major organs in others.

[0006] Cardiac structural remodeling after myocardial infarction is associated with an inflammatory response that results in scar formation at the site of the infarction, which is the result of fibrous tissue deposition that can lead to a decline in cardiac function and disruption of electrical activity within the heart.

[0007] Crohn's disease is a chronic disease of unknown cause that tends to progress despite medical or surgical treatment. Intestinal fibrosis, which results in the formation of strictures in the small intestine and colon, is one of the most common complications of Crohn's disease.

[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 transporting 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 and, eventually, complete respiratory failure.

[0009] Primary biliary cholangitis (PBC), also known as primary biliary cirrhosis, is a chronic disease of the liver that causes liver damage and fibrosis. It results from the slow, 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, this leads to scarring and fibrosis 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 the interstitial cells. The fibrotic form is defined by thickening and scarring of lung tissue. This scarring, known as fibrosis, is irreversible. When lung tissue thickens or scars, it no longer functions effectively. Breathing becomes less efficient, and blood oxygen levels decrease. (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 options are inadequate, with no options on the market proven to impact long-term patient survival or symptom outcomes. For example, drugs such as pirfenidone and nintedanib are being studied for the treatment of fibrosis. While pirfenidone and nintedanib are used to treat IPF, they have demonstrated less than desirable therapeutic efficacy and 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-related peptide of transforming growth factor β1 (TGFβ1), and mediates TGFβ1 activation. Its expression level is significantly increased after injury to lung and bile duct cells, 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 duct. The resulting obstruction of bile flow to the intestine can lead 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 of treating diseases mediated by αvβ6 integrin, such as fibrotic diseases, are disclosed.

[0016] In one aspect, there is provided a compound of Formula (A), or a variation thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), as detailed herein.

[0017] Additionally, there is provided a pharmaceutical composition comprising a compound of Formula (A), or a variant thereof as 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 are methods 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 a variant thereof as described 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 (such as PBC).

[0019] In another aspect, methods are provided for delaying the onset and / or progression 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 a variant thereof as described 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 had 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 a variant thereof as detailed herein, or a pharmaceutical composition thereof, for the treatment of a fibrotic disorder.

[0021] There is also provided the use of a compound of Formula (A), or a variant thereof as detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing, in the manufacture of a medicament for treating a fibrotic disease.

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

[0023] In another aspect, there is provided a method for making a compound of formula (A), or a variant thereof, or a pharmaceutically acceptable salt thereof. Also provided are compound intermediates useful in the synthesis of a compound of formula (A), or a variant thereof.

[0024] In one aspect, there is provided a compound of formula (I), or a variant thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), as detailed herein.

[0025] Additionally, there is provided a pharmaceutical composition comprising a compound of formula (I), a variant thereof as 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 are methods 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 (I), a variant thereof as described 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 psoriasis.

[0027] In another aspect, methods are provided for delaying the onset and / or progression 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 a variant thereof as described 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 had 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] There is also provided a compound of formula (I), or a variant thereof as detailed herein, or a pharmaceutical composition thereof, for the treatment of a fibrotic disease.

[0029] There is also provided the use of a compound of formula (I), or a variant thereof as detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing, in the manufacture of a medicament for treating a fibrotic disease.

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

[0031] In another aspect, there is provided a method for making a compound of formula (I), or a variant thereof, or a pharmaceutically acceptable salt thereof. Also provided are compound intermediates useful in the synthesis of a compound of formula (I), or a variant thereof. [Brief explanation of the drawings]

[0032] [Figure 1] Compounds 1 to 780 disclosed herein are shown. [Figure 2] Table B-3 is provided with biological data for various compounds disclosed herein. [Figure 3A] 1 is a graph showing that in contrast to αVβ1 selective small molecule inhibitors, both compound 5 and the selective antibody αVβ6 inhibitor βα3G9 substantially inhibited normal bronchial epithelial cell adhesion to LAP. [Figure 3B] We show that, in contrast to the selective antibody αVβ6 inhibitor 3G9, both compound 5 and the αVβ1 selective small molecule inhibitor substantially inhibited cell adhesion in IPF-induced lung fibroblasts. [Figure 4A] 1 is a graph of PSMAD3 / SMAD3 in lung tissue from healthy mice dosed with PBS vehicle and various levels of Compound 5 over a 4-day period. [Figure 4B] 1 is a graph of PSMAD3 / SMAD3 in BALF collected from the same healthy mice dosed with PBS vehicle and various levels of Compound 5 over a 4-day period. [Figure 4C] 1 is a graph showing that lung tissue in vehicle-treated mice experienced a substantial increase in SMAD3 phosphorylation compared to healthy mice. [Figure 4D] 1 is a graph showing that lung tissue in vehicle-treated mice experienced a substantial accumulation of new collagen compared to healthy mice, as evidenced by the percentage of lung collagen containing 2H-labeled hydroxyproline. [Figure 4E] Figure 1 shows that vehicle-treated mice experienced a significant increase in total lung collagen compared to healthy mice, as measured by μg hydroxyproline. [Figure 4F] High-resolution second harmonic generation images of fibrillar collagen (collagen types I and III) from formalin-fixed, paraffin-embedded lung tissue sections from healthy mouse lungs. [Figure 4G] High-resolution second harmonic generation images of fibrillar collagen (collagen types I and III) from formalin-fixed, paraffin-embedded lung tissue sections from vehicle-treated mouse lungs. [Figure 4H] High-resolution second harmonic generation images of fibrillar collagen (collagen types I and III) from formalin-fixed, paraffin-embedded lung tissue sections from test article-treated (500 mg / kg of compound 5 twice daily) mouse lungs. [Figure 4I] 4F, 4G, and 4H are graphs showing percent total collagen area in second harmonic generation mouse lung images. [Figure 4J] Graph of serial measurements in bleomycin-treated mice showing a close inverse relationship between pSMAD3 levels in the lungs versus plasma drug exposure. [Figure 4K] Graph of serial measurements in bleomycin-treated mice showing a close inverse relationship between pSMAD3 levels in BALF cells versus plasma drug exposure. [Figure 5A] Bar graph normalized to DMSO-treated control slices showing that all test treatments reduced expression of the type I collagen gene Col1a1. [Figure 5B] Bar graph normalized to DMSO-treated control slices showing that all test treatments reduced lung Col1a1 expression. [Figure 6A] 1 is a bar graph showing that both nintedanib and pirfenidone showed a slight increase in lung Col1a1 expression compared to DMSO vehicle control slices. [Figure 6B] 1 is a bar graph showing the concentration of compound required to reduce lung slice Col1a1 expression by 50% compared to DMSO control slices. [Figure 6C]Bar graph normalized to DMSO-treated control slices showing that all test treatments reduced lung Col1a1 expression. [Figure 6D] 1 is a bar graph showing the relative expression of COL1A1 in precision-cut lung slices (PCLS) derived from 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 a DMSO control. [Figure 6E] 1 is a bar graph showing the dose-dependent decrease in COL1A1 expression in PCLS derived from human IPF lung tissue upon treatment with compound 5 at concentrations ranging from 200 pM to 1 μM. 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 dual selective αVβ6 and αVβ1 inhibition (1.82 μM Compound 5) on the ratio of pSMAD2 / SMAD2 in PCLS derived 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 of Compound 5 at doses of 15, 30, 50, and 75 mg. [Figure 7B] 1 shows multiple ascending dose (MAD) study data for Compound 5 at doses of 10, 20, and 40 mg. [Figures 8A-8F] 8A-8F are a series of graphs depicting data from subjects administered 40 mg / day of a select integrin inhibitor (Compound 5). The data in Figures 8A-8F include the plasma concentration of the administered integrin inhibitor ("PK", round dots) and the relative change in pSMAD2:SMAD2 ratio from baseline (Day -1) in BAL (bronchoalveolar lavage) samples ("pSMAD", square dots) over the indicated time course (hours) following administration of the inhibitor on Day 7. The peak plasma concentration ("PK" curve) is recorded as Cmax. [Figure 8G]Shown is the percent change in BAL SMAD2 phosphorylation levels (pSMAD2:SMAD2 ratio) on day 7 compared to baseline levels recorded on day -1 for placebo-treated subjects and subjects with measured Cmax of integrin inhibitors less than 700 ng / mL, 700 ng / mL to 900 ng / mL, and greater than 900 ng / mL. [Figure 8H] Figure 1 shows the % change in SMAD2 phosphorylation (pSMAD2:SMAD2 ratio) (all time points) correlated with Cmax in subjects administered a 40 mg dose of Compound 5 compared to baseline levels recorded on day -1. 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 diseases.

[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 diseases.

[0035] definition As used herein, unless clearly indicated otherwise, the use of the terms "a," "an," etc. means 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 and includes monovalent saturated, linear (i.e., unbranched) or branched hydrocarbon chains or combinations thereof, having the specified number of carbon atoms (i.e., C1 to C6). 10 means 1 to 10 carbon atoms). Particular alkyl groups are those having 1 to 20 carbon atoms ("C1-C 20 alkyl"), those having 1 to 10 carbon atoms ("C1-C 10 alkyl"), those with 6 to 10 carbon atoms ("C6-C 10 alkyl"), those having 1 to 6 carbon atoms ("C1-C6 alkyl"), those having 2 to 6 carbon atoms ("C2-C6 alkyl"), or those having 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 divalency. Particular alkylene groups are those having 1 to 20 carbon atoms ("C1-C 20 alkylene), those having 1 to 10 carbon atoms ("C1-C 10 alkylene), those with 6 to 10 carbon atoms ("C6-C 10alkylene"), those having 1 to 6 carbon atoms ("C1-C6 alkylene"), those having 1 to 5 carbon atoms ("C1-C5 alkylene"), those having 1 to 4 carbon atoms ("C1-C4 alkylene"), or those 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 specified, "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 a specified number of carbon atoms (i.e., C2-C6). 10 "C" means 2 to 10 carbon atoms), monovalent unsaturated, straight (i.e., unbranched) or branched hydrocarbon chains, or combinations thereof. Alkenyl groups may have the "cis" or "trans" configuration, or alternatively, the "E" or "Z" configuration. Particular alkenyl groups are those having 2 to 20 carbon atoms ("C2-C 20 alkenyl), those with 6 to 10 carbon atoms ("C6-C 10alkenyl"), those having 2 to 8 carbon atoms ("C-C alkenyl"), those having 2 to 6 carbon atoms ("C-C alkenyl"), or those having 2 to 4 carbon atoms ("C-C 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 divalency. Particular alkenylene groups are those having 2 to 20 carbon atoms ("C-C"). 20 alkenylene"), those having 2 to 10 carbon atoms ("C2-C 10 alkenylene"), those having 6 to 10 carbon atoms ("C6-C 10 alkenylene"), those having 2 to 6 carbon atoms ("C-C alkenylene"), those having 2 to 4 carbon atoms ("C-C alkenylene"), or those 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 specified, "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 a specified number of carbon atoms (i.e., C-C). 10"C" means 2 to 10 carbon atoms), monovalent unsaturated straight (i.e., unbranched) or branched hydrocarbon chains, or combinations thereof. Particular alkynyl groups are those having 2 to 20 carbon atoms ("C" means 2 to 10 carbon atoms), 20 alkynyl), those with 6 to 10 carbon atoms ("C6-C 10 alkynyl"), those having 2 to 8 carbon atoms ("C2-C8 alkynyl"), those having 2 to 6 carbon atoms ("C2-C6 alkynyl"), or those having 2 to 4 carbon atoms ("C2-C4 alkynyl"). Examples of alkynyl groups include, but are not limited to, groups such as 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 divalency. Particular alkynylene groups are those having 2 to 20 carbon atoms ("C2-C 20 alkynylene"), those having 2 to 10 carbon atoms ("C2-C 10 alkynylene"), those having 6 to 10 carbon atoms ("C6-C 10 alkynylene"), those having 2 to 6 carbon atoms ("C-C alkynylene"), those having 2 to 4 carbon atoms ("C-C alkynylene"), or those having 2 to 3 carbon atoms ("C-C alkynylene"). Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetylenylene) (-C≡C-), propynylene (-C≡CCH-).

[0044] As used herein, unless otherwise specified, "cycloalkyl" refers to a group having a specified number of carbon atoms (i.e., C3-C6). 10means 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 may be fused, spiro, or bridged, or combinations thereof. Particular 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 residues as cycloalkyl, but with divalency. Cycloalkylene can consist of a single ring or multiple rings that may be fused, spiro, or bridged, or combinations thereof. Particular 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"), 3 to 6 carbon atoms ("C3-C6 cycloalkylene"), or 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 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, cycloalkenyl having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having a specified number of carbon atoms (i.e., C3-C6). 10 "C" refers to and includes monovalent unsaturated, cyclic, non-aromatic hydrocarbon structures ("C" means 3 to 10 carbon atoms). Cycloalkenyls can consist of a single ring, such as cyclohexenyl, or multiple rings, such as norbornenyl. Preferred cycloalkenyls are unsaturated cyclic hydrocarbons having 3 to 8 ring carbon atoms ("C3-C8 cycloalkenyl"). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like.

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

[0048] As used herein, "aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or an unsaturated aromatic carbocyclic group having multiple fused rings (which may or may not be aromatic) (e.g., naphthyl or anthryl). Particular aryl groups are those having 6 to 14 ring carbon atoms ("C6-C6"). 14 Aryl groups having two or more rings, where at least one ring is non-aromatic, can be attached to the parent structure at either an aromatic ring position or a non-aromatic ring position. In one variation, an aryl group having two or more rings, where at least one ring is non-aromatic, is attached to the parent structure at an aromatic ring position.

[0049] As used herein, "arylene" refers to the same residues as aryl, but with divalency. Particular arylene groups are those having 6 to 14 ring carbon atoms ("C6-C 14 arylene).

[0050] As used herein, "heteroaryl" refers to an unsaturated aromatic ring group having 1 to 14 ring carbon atoms and at least one ring heteroatom, including, but not limited to, heteroatoms such as nitrogen, oxygen, and sulfur. Heteroaryl groups can have a single ring (e.g., pyridyl, furyl) or multiple fused rings (which may or may not be aromatic) (e.g., indolizinyl, benzothienyl). Particular heteroaryl groups are 5- to 14-membered rings having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 10-membered rings having 1 to 8 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 5-, 6-, or 7-membered rings having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, certain heteroaryl groups are 5-, 6-, or 7-membered monocyclic aromatic rings having 1 to 6 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, certain 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 attached 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 attached to the parent structure at an aromatic ring position. Heteroaryl groups can be attached to the parent structure at a ring carbon atom or a ring heteroatom.

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

[0052] As used herein, "heterocycle," "heterocyclic," or "heterocyclyl" refers to a saturated or unsaturated non-aromatic ring group having a single ring or multiple fused rings, and having 1 to 14 ring carbon atoms and 1 to 6 ring heteroatoms such as nitrogen, sulfur, or oxygen. Heterocycles having more than one ring may be fused, bridged, or spiro, or combinations thereof, but exclude heteroaryl groups. Heterocyclyl groups are optionally substituted independently with one or more substituents described herein. Particular 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 monocyclic 3-, 4-, 5-, 6-, or 7-membered rings 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 polycyclic non-aromatic rings 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 divalency.

[0054] "Halo" or "halogen" refers to Group 17 elements having atomic numbers 9-85. Preferred halo groups include radicals of fluorine, chlorine, bromine, and iodine. When a residue is substituted with more than one halogen, it may be designated with 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 by a halo group is called 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. An 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 by a deuterium is said to be "perdeuterated." An alkyl group in which each hydrogen is replaced by a tritium is said to be "pertritiated."

[0061] "Optionally substituted" means, unless otherwise specified, that a group is unsubstituted or optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group, which substituents 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 the moiety. For example, a propyl group can be substituted with seven halogen atoms to provide a perhalopropyl group. These substituents can be the same or different.

[0063] As used herein, unless expressly indicated otherwise, the term "individual" refers to 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: reducing one or more symptoms caused by a disease, reducing the severity of the disease, stabilizing the disease (e.g., preventing or slowing the progression 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 condition, providing remission (partial or total) of the disease, reducing the dose of one or more other drugs required to treat the disease, enhancing the effectiveness of another drug, slowing the progression of the disease, improving quality of life, and / or extending 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 treatment regimen.As understood in the art, an effective amount may be in one or more administrations, 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 its pharmaceutically acceptable salt), and a single agent may be considered to be administered in an effective amount when a desired or beneficial result can be achieved or is achieved in conjunction with one or more other agents.The appropriate dose of any of the co-administered compounds may optionally be reduced due to the combined action (e.g., additive or synergistic effect) of the compounds.

[0066] "Therapeutically effective amount" refers to that amount of a compound or salt thereof sufficient to effect the desired therapeutic result.

[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 a 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 fraction 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 an absorption pool. This term encompasses depot formulations designed to gradually release a drug compound over an extended period of time. Controlled-release formulations can encompass a wide variety of drug delivery systems, generally involving mixing a drug compound with a carrier, polymer, or other compound with desired release characteristics (e.g., pH-dependent or non-pH-dependent solubility, different degrees of water solubility, etc.) and formulating this 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 a material that is not biologically or otherwise undesirable; for example, the material can be incorporated into a pharmaceutical composition administered to a patient without producing significant undesirable 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 the required standards of toxicology and manufacturing testing and / or are included in the Inactive Ingredient Guide established by the U.S. Food and Drug Administration.

[0070] "Pharmaceutically acceptable salts" are those salts that retain at least some of the biological activity of the free (non-salt) compound and can be administered to an individual as a drug or pharmaceutical. Such salts include, for example, (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, and the like; and (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth metal ion, or 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 may be prepared in situ during the manufacturing process or by reacting purified compounds of the present invention in their free acid or free base form with a suitable organic or inorganic base or acid, respectively, and then isolating the salt formed during purification.

[0071] As used herein, the term "excipient" refers to an inactive or non-active substance that can be used in the manufacture of a drug or pharmaceutical product, such as a tablet, 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, substances used as binders, disintegrants, coatings, compression / encapsulation aids, creams or lotions, lubricants, parenteral solutions, chewable tablet materials, sweeteners or flavoring agents, suspending / gelling agents, or wet granulation agents. 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 magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable tablet 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" intends a composition containing 10% or less impurities, for example, a composition containing less than 9%, 7%, 5%, 3%, 1%, 0.5% impurities.

[0073] Aspects and embodiments described herein as "comprising" are understood to encompass "consisting of" and "consisting essentially of" embodiments.

[0074] compound In one embodiment, the compound of formula (A): [ka] During the ceremony, R 1 But C6~C 14 aryl or 5-10 membered heteroaryl, C6-C 14 Aryl and 5- to 10-membered heteroaryl are R 1a and optionally replaced by R 2 However, hydrogen, deuterium, and 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 or -S(O)R 2d However, any carbon atom directly bonded to a nitrogen atom is R other than halogen. 2a provided that the moiety is optionally replaced by Each R 1a are independently C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C8 cycloalkyl, C4 to C8 cycloalkenyl, 3 to 12 membered heterocyclyl, 5 to 10 membered heteroaryl, C6 to 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)R3 , -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 may independently be 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; R 2a , R 2b , R 2c , R 2e , and R 2f are each independently oxo or R 1a and R 2d But R 2e C1-C6 alkyl optionally substituted by R 2f C3-C5 cycloalkyl optionally substituted by R3 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; 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; 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; R 4 and R 5 together with the atoms to which they are attached, deuterium, halogen, oxo, -OR 8 , -NR 8 R 9or a 3-6 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; or 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; or 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; R 10 , R 11 , R 12 , and R 13 are each 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; Compounds or salts thereof are provided wherein p is 3, 4, 5, 6, 7, 8, or 9.

[0075] In one variation, it is provided that the compound of Formula A excludes 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]

[0076] In various 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 each 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 each H, p is 3, q ​​is 0, and R 1 The carbon atom to which NH- is bonded is in the S configuration, and the R 1 is one or more of the following separately lettered embodiments (a) through (k): (a) R 1 (b) R is unsubstituted quinazolin-4-yl. 1 But R 1a quinazolin-4-yl substituted by R 1a is methyl. (c)R 1 But R 1a quinazolin-4-yl substituted by R 1a is methyl or ethyl. (d)R 1 But R 1a quinazolin-4-yl substituted by R 1a is C1-C6 alkyl. (e) R 1 But R 1a (f) R is a quinazolin-4-yl substituted by 1 is a 10-membered fused bicyclic heterocycle containing two ring nitrogen atoms, and R 1 is unsubstituted or R 1a (g)R 1 is unsubstituted quinazolinyl. (h) R 1 But R 1a quinazolinyl substituted by R 1a is methyl. (i)R 1 But R 1a quinazolinyl substituted by R 1a is methyl or ethyl. (j)R 1 is substituted by quinazolinyl 1a quinazolinyl substituted by R 1a is C1-C6 alkyl. (k) R 1 But 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 each H, p is 3, q ​​is 0, and R 1 The carbon atom to which NH- is bonded is in the S configuration, and the R 2 is one or more of the following separately lettered embodiments (l) through (p): (l) R 2 But R 2a is ethylene disubstituted by R 2a is methoxy. (m)R 2 But R 2a methylene, ethylene, or propylene substituted by R 2a is methoxy. (n)R 2 But R 2a is ethylene substituted by R 2a is methoxy or ethoxy. (o)R 2 But R 2a is ethylene substituted by R 2a is hydroxy. (p)R 2 But 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 each H, p is 3, q ​​is 0, and R 1 The carbon atom to which NH- is bonded is in the S configuration, and the R 10 , R 11 , R 12 , and R13 together represent one or more of the following separate lettered embodiments (q)-(u): (q) R 10 , R 11 , R 12 , and R 13 are hydrogen. (r)R 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 are deuterium atoms.

[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 each H, p is 3, q ​​is 0, and R 1 The carbon atom to which NH- is bonded is in the S configuration, and the R 15 and R 16 together represent one or more of the following separate lettered embodiments (v) through (aa): (v) R 15 and R 16 are hydrogen. (w)R 15 is hydrogen and R 16 is deuterium or R 15 is deuterium, and R 16 is hydrogen. (x)R 15 and R 16 is deuterium. (y)R15 is hydrogen and R 16 is a halogen, for example, 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, for example, fluorine, or R 15 is a halogen, e.g., fluorine, and R 16 is deuterium. (aa)R 15 and R 16 are each a 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 each 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 lettered embodiments (ab) through (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 each 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 separate lettered embodiments (ae) through (ah): (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 together;R 15 and R 16 together; variable p; and variable q. For example, R 1 ;One of (l)~(p) R 2 ;One of (q)~(u) R 10 , R 11 , R 12 , and R 13 together; (v)~(aa) R 15 and R 16together; one variable p from (ab) through (ad); and one variable q from (ae) through (ah). Exemplary combinations of lettered embodiments may be selected, 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 (a e); (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 with (y); any one of the above combinations in which (v) is replaced with (aa); any one of the above combinations in which (ab) is replaced with (ad); or any one of the above combinations in which (ab) is replaced with (ae);

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

[0085] In one variation, CO2H 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 in which the carbon bearing the moiety is in the "R" configuration. Also encompassed are mixtures of compounds of formula (A), 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 the carbon atom directly bonded to the nitrogen atom is unsubstituted or substituted with deuterium.

[0087] In the description herein, it is understood that every statement, variation, embodiment, or aspect of one moiety can be combined with every statement, variation, embodiment, or aspect of any other moiety as if each and every combination of statements were specifically and individually set forth. For example, R 1All descriptions, variations, embodiments, or aspects provided herein with respect to R are intended to be illustrative and not restrictive, and are not intended to be limiting unless each and every combination is specifically and individually set forth. 2 The present invention may be combined with any and all descriptions, variations, embodiments or aspects of the present invention.

[0088] In one embodiment, the compound of formula (I): [ka] During the ceremony, R 1 But C6~C 14 aryl or 5-10 membered heteroaryl, C6-C 14 Aryl and 5- to 10-membered heteroaryl are R 1a and optionally replaced by R 2 But R 2a C1-C6 alkyl optionally substituted by R 2b C3-C6 cycloalkyl optionally substituted by R 2c or -S(O)R 2d and Each R 1a are independently C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C8 cycloalkyl, C4 to C8 cycloalkenyl, 3 to 12 membered heterocyclyl, 5 to 10 membered heteroaryl, C6 to 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)NR4 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 may independently be 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; R 2a , R 2b , R 2c , R 2e , and R 2f are each independently oxo or R 1a and R 2d But R 2e C1-C6 alkyl optionally substituted by R 2f 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; 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; 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; R 4 and R 5 together with the atoms to which they are attached, deuterium, halogen, oxo, -OR 8 , -NR 8 R 9 or a 3-6 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; or 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; or 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; R 10 , R 11 , R 12 , and R 13 are each independently hydrogen or deuterium; R 14 is deuterium, q is 0, 1, 2, 3, 4, 5, 6, 7, or 8; Compounds or salts thereof are provided wherein p is 3, 4, 5, 6, 7, 8, or 9.

[0089] In one variation, CO2H 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 in which the carbon bearing the moiety is in the "R" configuration. Also encompassed are mixtures of compounds of formula (I), 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 The carbon atom directly bonded to the nitrogen atom is R other than halogen. 2a In one variation of formula (I), R 2 includes the proviso that the carbon atom directly bonded to the nitrogen atom is unsubstituted or substituted with deuterium.

[0091] In the description herein, it is understood that every statement, variation, embodiment, or aspect of one moiety can be combined with every statement, variation, embodiment, or aspect of another moiety as if each and every combination of statements were specifically and individually set forth. For example, R 1 All descriptions, variations, embodiments, or aspects provided herein with respect to R are intended to be illustrative and not restrictive, and are not intended to be limiting unless each and every combination is specifically and individually set forth. 2 The present invention may be combined with any and all descriptions, variations, embodiments or aspects of the present invention.

[0092] In some embodiments of the compounds of Formula (I) or salts 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 , R 11 , R12 , R 13 , R 14 , R 15 , or R 16 At least one of the is deuterium.

[0093] In some embodiments of the compounds of Formula (I) or salts 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). In some embodiments, R 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). In some embodiments, R 1 is pyrimidin-4-yl substituted with both methyl and trifluoromethyl. In some embodiments, R 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 C6~C 14 aryl (e.g., phenyl). In some embodiments, R 1 is R 1a pyrimidin-4-yl optionally substituted by1a is -CN. 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, or C1-C6 alkyl optionally substituted with halogen (e.g., methyl or trifluoromethyl), or —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 R 1a is halogen (e.g., fluoro and chloro), C1-C6 alkyl optionally substituted with halogen (e.g., methyl or trifluoromethyl), or C1-C6 alkoxy (e.g., methoxy). In some embodiments, R 1 is R 1a quinazolin-4-yl optionally substituted by R 1a is a 5-10 membered heteroaryl (e.g., pyridinyl). In some embodiments, R 1 is R 1a In some embodiments, R is a pyrazolopyrimidinyl optionally substituted by 1 is R 1a pyrazolopyrimidinyl optionally substituted by R 1a is C1-C6 alkyl (e.g., methyl). 1 R 1a In some embodiments indicated as optionally substituted by 1 The R moiety is unsubstituted. 1 R 1aIn some embodiments indicated as optionally substituted by 1 The part is one R 1a is replaced by R 1 R 1a In some embodiments indicated as 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 a part.

[0094] Variable Element R 1 In some embodiments of Formula (I), including embodiments that describe 10 , R 11 , R 12 , and R 13 are each hydrogen. 1 , and / or variable R 10 , R 11 , R 12 , and R 13 In some embodiments of Formula (I), including those described below, q is 0. 1 , and / or variable R 10 , R 11 , R 12 , and R 13 and / or in some embodiments, including those recited in variable q, 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] In the formula, R 1 and R 2 is a compound as defined for formula (I) or a salt thereof.

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

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

[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, if applicable, and R 1a In a further embodiment of a compound of formula (IA), m is 0, 1, 2, or 3, and each R 1aare, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl; 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 Formula (IA), m is 1, 2, or 3.

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

[0100] Variable Element R 1a In some embodiments of Formula (IA), including embodiments recited in R 10 , R 11 , R 12 , and R13 are each hydrogen. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (IA), including those embodiments that describe: q is 0. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 and / or p is 3, 4, or 5 in some embodiments of formula (IA), including embodiments recited in variable q.

[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] [In the formula, R 1a and R 2 is as defined for formula (I), m is 0, 1, 2 or 3, and the position on the pyrimidine ring is indicated, or a salt thereof. 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), the compound is a 5-10 membered heteroaryl optionally substituted by [ka] In the formula, R 1a , R 2 , R 10 , R 11 , R 12 , R13 , R 14 , q and p are as defined for formula (I), and m is 0, 1, 2, 3, 4 or 5, and the positions on the quinazoline ring are as shown, or a salt thereof.

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

[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, if applicable, and 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, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl; 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 compounds 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 In some embodiments of compounds of Formula (IB), m is 1 and R 1a 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 position 8. In some embodiments of compounds of Formula (IB), m is 2 and the group R 1a In some embodiments of compounds of formula (IB), m is 2 and the group R 1a are at positions 2 and 6. In some embodiments of compounds of formula (IB), m is 2 and the group R 1a are at positions 2 and 7. In some embodiments of compounds of formula (IB), m is 2 and the group R 1a In some embodiments of compounds of formula (IB), m is 2 and the group R 1a are at positions 5 and 6. In some embodiments of compounds of formula (IB), m is 2 and the group R 1a are at positions 5 and 7. In some embodiments of compounds of formula (IB), m is 2 and the group R 1a are at positions 5 and 8. In some embodiments of compounds of formula (IB), m is 2 and the group R 1a are at positions 6 and 7. In some embodiments of compounds of formula (IB), m is 2 and the group R 1a are at positions 6 and 8. In some embodiments of compounds of formula (IB), m is 2 and the group R 1a are at positions 7 and 8. In some embodiments of compounds of formula (IB), m is 3 and the group R 1a are at positions 2, 5, and 6. In some embodiments of compounds of formula (IB), m is 3 and the groups R1a are at positions 2, 5, and 7. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1a are at positions 2, 5, and 8. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1a are at positions 2, 6, and 7. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1a are at positions 2, 6, and 8. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1a are at positions 2, 7, and 8. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1a are at positions 5, 6 and 7. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1a are at positions 5, 6 and 8. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1a are at positions 5, 7 and 8. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1a are at positions 6, 7, and 8. In some embodiments of compounds of formula (IB), m is 4 and the groups R 1a are at positions 2, 5, 6 and 7. In some embodiments of compounds of formula (IB), m is 4 and the groups R 1a are at positions 2, 5, 6 and 8. In some embodiments of compounds of formula (IB), m is 4 and the groups R 1a are at positions 2, 5, 7 and 8. In some embodiments of compounds of formula (IB), m is 4 and the groups R 1a are at positions 2, 6, 7 and 8. In some embodiments of compounds of formula (IB), m is 4 and the groups R 1a are at positions 5, 6, 7 and 8. In some embodiments of compounds of formula (IB), m is 5 and the groups R 1a are at positions 2, 5, 6, 7 and 8. Two or more groups R 1a Whenever present, the group R 1acan be independently selected. In any of these embodiments of a compound of formula (IB) or a salt thereof, the carbons bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0106] Variable Element R 1a In some embodiments of formula (IB), including embodiments recited in R 10 , R 11 , R 12 , and R 13 are each hydrogen. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (IB), including those embodiments that describe: q is 0. Variable R 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 and / or p is 3, 4, or 5 in some embodiments of formula (IB), including embodiments recited in variable q.

[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] [In the formula, R 1a and R 2 is as defined for formula (I), m is 0, 1, 2, 3, 4 or 5, and the position on the quinazoline ring is indicated, or a salt thereof. 1a , R 2 All descriptions of and m apply equally to formulas (IB) and (II-B).

[0108] R1 R 1a In some embodiments of the compound of Formula (I), the compound is a 5-10 membered heteroaryl optionally substituted by [ka] In the formula, R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 wherein q and p are as defined for formula (I), and m is 0, 1, 2, 3, or 4, and the positions on the pyrido[3,2-d]pyrimidine ring are as indicated. In one embodiment, compounds of formula (IC) or salts thereof are provided in which the carbons bearing the COH and NH moieties are in the "S" configuration. In another embodiment, compounds of formula (IC) or salts thereof are provided in which the carbons bearing the COH and NH moieties are in the "R" configuration. Also encompassed are mixtures of compounds of formula (IC), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0109] 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, if applicable, and R 1a In a further embodiment of a compound of formula (IC), m is 0, 1, 2, 3, or 4, and each R 1a are, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl; R 1awherein 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.

[0110] In some embodiments of the compounds of Formula (IC), m is 0. In some embodiments of the compounds of Formula (IC), m is 1 and R 1a 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 position 8. In some embodiments of compounds of formula (IC), m is 2 and the group R 1a In some embodiments of compounds of formula (IC), m is 2 and the group R 1a are at positions 2 and 7. In some embodiments of compounds of formula (IC), m is 2 and the group R 1a In some embodiments of compounds of formula (IC), m is 2 and the group R 1a are at positions 6 and 7. In some embodiments of compounds of formula (IC), m is 2 and the group R 1a are at positions 6 and 8. In some embodiments of compounds of formula (IC), m is 2 and the group R 1a are at positions 7 and 8. In some embodiments of compounds of formula (IC), m is 3 and the group R 1a are at positions 2, 6, and 7. In some embodiments of compounds of formula (IC), m is 3 and the groups R 1a are at positions 2, 6, and 8. In some embodiments of compounds of formula (IC), m is 3 and the groups R 1a are at positions 2, 7, and 8. In some embodiments of compounds of formula (IC), m is 3 and the groups R1a are at positions 6, 7 and 8. In some embodiments of compounds of formula (IC), m is 4 and the groups R 1a are at positions 2, 6, 7 and 8. Two or more groups R 1a Whenever present, the group R 1a can be independently selected. In any of these embodiments of a compound of formula (IC) or a salt thereof, the carbons bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0111] Variable Element R 1a In some embodiments of formula (IC), including embodiments recited in R 10 , R 11 , R 12 , and R 13 are each hydrogen. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (IC), including those embodiments that describe: q is 0. Variable R 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 and / or in some embodiments of formula (IC), including embodiments reciting variable q, p is 3, 4, or 5.

[0112] In some embodiments of Formula (IC), R 10 , R 11 , R 12 and R 13 is hydrogen, p is 3, and q is 0, and the compound has formula (II-C): [ka] [In the formula, R 1a and R 2is as defined for formula (I), and m is 0, 1, 2, 3, or 4, and the position on the pyrido[3,2-d]pyrimidine ring is indicated, or a salt thereof. 1a , R 2 All descriptions of and m apply equally to formulas (IC) and (II-C).

[0113] R 1 R 1a In some embodiments of the compound of Formula (I), the compound is a 5-10 membered heteroaryl optionally substituted by [ka] In the formula, R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), and m is 0, 1, 2, 3 or 4, and the positions on the pyrido[3,4-d]pyrimidine ring are as shown, or a salt thereof.

[0114] In one embodiment, there is provided a compound of formula (ID), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (ID), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (ID), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0115] 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, if applicable, and R 1aIn a further embodiment of a compound of formula (ID), m is 0, 1, 2, 3, or 4, and each R 1a are, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl; 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.

[0116] In some embodiments of the compounds of Formula (ID), m is 0. In some embodiments of the compounds of Formula (ID), m is 1 and R 1a is at position 2. 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 position 8. In some embodiments of compounds of formula (ID), m is 2 and the group R 1a are at positions 2 and 5. In some embodiments of compounds of formula (ID), m is 2 and the group R 1a are at positions 2 and 6. In some embodiments of compounds of formula (ID), m is 2 and the group R 1a In some embodiments of compounds of formula (ID), m is 2 and the group R 1a are at positions 5 and 6. In some embodiments of compounds of formula (ID), m is 2 and the group R 1a are at positions 5 and 8. In some embodiments of compounds of formula (ID), m is 2 and the group R1a are at positions 6 and 8. In some embodiments of compounds of formula (ID), m is 3 and the group R 1a are at positions 2, 5, and 6. In some embodiments of compounds of formula (ID), m is 3 and the groups R 1a are at positions 2, 5, and 8. In some embodiments of compounds of formula (ID), m is 3 and the groups R 1a are at positions 2, 6, and 8. In some embodiments of compounds of formula (ID), m is 3 and the groups R 1a are at positions 5, 6 and 8. In some embodiments of compounds of formula (ID), m is 4 and the groups R 1a are at positions 2, 5, 6 and 8. Two or more groups R 1a Whenever present, the group R 1a can be independently selected. In any of these embodiments of a compound of formula (ID) or a salt thereof, the carbons bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0117] Variable Element R 1a In some embodiments of formula (ID), including those recited in R 10 , R 11 , R 12 , and R 13 are each hydrogen. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (ID), including those embodiments that describe: q is 0. Variable R 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 and / or in some embodiments of formula (ID), including embodiments reciting variable q, p is 3, 4, or 5.

[0118] In some embodiments of Formula (ID), R 10 , R11 , R 12 , and R 13 is water, p is 3, and q is 0, and the compound has formula (II-D): [ka] [In the formula, R 1a and R 2 is as defined for formula (I), m is 0, 1, 2, 3 or 4, and the position on the pyrido[3,4-d]pyrimidine ring is indicated, or a salt thereof. 1a , R 2 All descriptions of and m apply equally to formulas (ID) and (II-D).

[0119] R 1 R 1a In some embodiments of the compound of Formula (I), the compound is a 5-10 membered heteroaryl optionally substituted by [ka] In the formula, R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), and m is 0, 1, 2, 3 or 4, and the positions on the pyrido[2,3-d]pyrimidine ring are as indicated, or a salt thereof.

[0120] In one embodiment, there is provided a compound of formula (IE), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (IE), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (IE), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0121] 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, if applicable, and 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, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl; 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 compounds of formula (IE), m is 1, 2, 3, or 4.

[0122] In some embodiments of the compounds of Formula (IE), m is 0. In some embodiments of the compounds of Formula (IE), m is 1 and R 1a is at position 2. 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 1a is 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 the group R 1a are at positions 2 and 5. In some embodiments of compounds of formula (IE), m is 2 and the group R 1a are at positions 2 and 6. In some embodiments of compounds of formula (IE), m is 2 and the group R 1aare at positions 2 and 7. In some embodiments of compounds of formula (IE), m is 2 and the group R 1a are at positions 5 and 6. In some embodiments of compounds of formula (IE), m is 2 and the group R 1a are at positions 5 and 7. In some embodiments of compounds of formula (IE), m is 2 and the group R 1a are at positions 6 and 7. In some embodiments of compounds of formula (IE), m is 3 and the group R 1a are at positions 2, 5 and 6. In some embodiments of compounds of formula (IE), m is 3 and the groups R 1a are at positions 2, 5, and 7. In some embodiments of compounds of formula (IE), m is 3 and the groups R 1a are at positions 2, 6, and 7. In some embodiments of compounds of formula (IE), m is 3 and the groups R 1a are at positions 5, 6 and 7. In some embodiments of compounds of formula (IE), m is 4 and the groups R 1a are at positions 2, 5, 6 and 7. Two or more groups R 1a Whenever present, the group R 1a can be independently selected. In any of these embodiments of a compound of formula (IE) or a salt thereof, the carbons bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0123] Variable Element R 1a In some embodiments of formula (IE), including those recited in R 10 , R 11 , R 12 , and R 13 are each hydrogen. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (IE), including those embodiments that describe: q is 0. Variable R 1a and m, and / or variable R 10 , R 11, R 12 and R 13 and / or in some embodiments of formula (IE), including embodiments recited variable q, p is 3, 4, or 5.

[0124] In some embodiments of Formula (IE), R 10 , R 11 , R 12 , and R 13 is water, p is 3, and q is 0, and the compound has formula (II-E): [ka] [In the formula, R 1a and R 2 is as defined for formula (I), m is 0, 1, 2, 3 or 4, and the position on the pyrido[2,3-d]pyrimidine ring is indicated, or a salt thereof. 1a , R 2 All descriptions of and m apply equally to formulas (IE) and (II-E).

[0125] R 1 R 1a In some embodiments of a compound of Formula (I), the compound has the formula (IF): [ka] [In the formula, R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), and m is 0, 1, 2, 3, 4, 5 or 6, and the position on the quinoline ring is indicated; or a salt thereof.

[0126] In one embodiment, there is provided a compound of formula (IF), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (IF), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (IF), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0127] In some embodiments of compounds of Formula (IF), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1a are independently, if applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, and R 1a wherein the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium. 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, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl; 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 (IF), m is 1, 2, 3, 4, 5, or 6.

[0128] In some embodiments of the compounds of Formula (IF), m is 0. In some embodiments of the compounds of Formula (IF), m is 1 and R 1a 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 R1a 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 7-position. In some embodiments of compounds of Formula (IF), m is 1 and R 1a is at position 8. In some embodiments of compounds of formula (IF), m is 2 and the group R 1a In some embodiments of compounds of formula (IF), m is 2 and the group R 1a In some embodiments of compounds of formula (IF), m is 2 and the group R 1a In some embodiments of compounds of formula (IF), m is 2 and the group R 1a In some embodiments of compounds of formula (IF), m is 2 and the group R 1a In some embodiments of compounds of formula (IF), m is 2 and the group R 1a In some embodiments of compounds of formula (IF), m is 2 and the group R 1a are at positions 3 and 6. In some embodiments of compounds of formula (IF), m is 2 and the group R 1a are at positions 3 and 7. In some embodiments of compounds of formula (IF), m is 2 and the group R 1a In some embodiments of compounds of formula (IF), m is 2 and the group R 1a are at positions 5 and 6. In some embodiments of compounds of formula (IF), m is 2 and the group R 1a are at positions 5 and 7. In some embodiments of compounds of formula (IF), m is 2 and the group R 1a are at positions 5 and 8. In some embodiments of compounds of formula (IF), m is 2 and the group R 1a are at positions 6 and 7. In some embodiments of compounds of formula (IF), m is 2 and the group R 1aare at positions 6 and 8. In some embodiments of compounds of formula (IF), m is 2 and the group R 1a are at positions 7 and 8. In some embodiments of compounds of formula (IF), m is 3 and the group R 1a are at positions 2, 3 and 5. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 3 and 6. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 3 and 7. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 3 and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 5 and 6. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 5, and 7. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 5, and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 6, and 7. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 6, and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 7, and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 3, 5 and 6. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 3, 5 and 7. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 3, 5 and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 3, 6 and 7. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1aare at positions 3, 6 and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 3, 7 and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 5, 6 and 7. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 5, 6 and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 5, 7 and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 6, 7 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 3, 5 and 6. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 3, 5 and 7. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 3, 5 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 3, 6 and 7. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 3, 6 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 3, 7 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 5, 6 and 7. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 5, 6 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 5, 7 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1aare at positions 2, 6, 7 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 3, 5, 6 and 7. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 3, 5, 6 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 3, 5, 7 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 3, 6, 7 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 5, 6, 7 and 8. In some embodiments of compounds of formula (IF), m is 5 and the groups R 1a are at positions 2, 3, 5, 6 and 7. In some embodiments of compounds of formula (IF), m is 5 and the groups R 1a are at positions 2, 3, 5, 6 and 8. In some embodiments of compounds of formula (IF), m is 5 and the groups R 1a are at positions 2, 3, 5, 7 and 8. In some embodiments of compounds of formula (IF), m is 5 and the groups R 1a are at positions 2, 3, 6, 7 and 8. In some embodiments of compounds of formula (IF), m is 5 and the groups R 1a are at positions 2, 5, 6, 7 and 8. In some embodiments of compounds of formula (IF), m is 5 and the groups R 1a are at positions 3, 5, 6, 7 and 8. In some embodiments of compounds of formula (IF), m is 6 and the groups R 1a are at positions 2, 3, 5, 6, 7 and 8. Two or more groups R 1a Whenever present, the group R 1a can be independently selected. In any of these embodiments of a compound of formula (IF) or a salt thereof, the carbons bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0129] Variable Element R 1a In some embodiments of Formula (IF), including embodiments recited in R 10 , R 11 , R 12 , and R 13 are each hydrogen. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (IF), including those embodiments that state: 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 and / or in some embodiments of formula (IF), including embodiments reciting variable q, p is 3, 4, or 5.

[0130] 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] [In the formula, R 1a and R 2 is as defined for formula (I), m is 0, 1, 2, 3, 4, 5 or 6, and the position on the quinoline ring is indicated, or a salt thereof. 1a , R 2 All descriptions of and m apply equally to formulas (IF) and (II-F).

[0131] R 1 R 1a In some embodiments of the compound of Formula (I), the compound is a 5-10 membered heteroaryl optionally substituted by [ka] In the formula, R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), and m is 0, 1, 2, 3, 4, 5 or 6, and the positions on the isoquinoline ring are as shown, or salts thereof.

[0132] In one embodiment, there is provided a compound of formula (IG), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (IG), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (IG), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0133] 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, if applicable, and R 1a In a further embodiment of a compound of formula (IG), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1a are, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl; R 1awherein 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 (IG), m is 1, 2, 3, 4, 5, or 6.

[0134] In some embodiments of the compounds of Formula (IG), m is 0. In some embodiments of the compounds 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 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 position 8. In some embodiments of compounds of Formula (IG), m is 2 and the group R 1a are at positions 3 and 4. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 4 and 5. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 4 and 6. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 4 and 7. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 4 and 8. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 3 and 5. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 3 and 6. In some embodiments of compounds of formula (IG), m is 2 and the group R 1aare at positions 3 and 7. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 3 and 8. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 5 and 6. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 5 and 7. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 5 and 8. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 6 and 7. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 6 and 8. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 7 and 8. In some embodiments of compounds of formula (IG), m is 3 and the group R 1a are at positions 3, 4 and 5. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 4 and 6. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 4 and 7. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 4, and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 4, 5 and 6. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 4, 5 and 7. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 4, 5 and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 4, 6, and 7. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1aare at positions 4, 6, and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 4, 7, and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 5 and 6. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 5, and 7. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 5, and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 6, and 7. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 6, and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 7, and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 5, 6 and 7. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 5, 6 and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 5, 7, and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 6, 7 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 4, 5 and 6. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 4, 5 and 7. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 4, 5 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 4, 6 and 7. In some embodiments of compounds of formula (IG), m is 4 and the groups R1a are at positions 4, 3, 6 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 4, 7 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 4, 5, 6 and 7. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 4, 5, 6 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 4, 5, 7 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 4, 6, 7 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 5, 6 and 7. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 5, 6 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 5, 7 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 6, 7 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 5, 6, 7 and 8. In some embodiments of compounds of formula (IG), m is 5 and the groups R 1a are at positions 3, 4, 5, 6 and 7. In some embodiments of compounds of formula (IG), m is 5 and the groups R 1a are at positions 3, 4, 5, 6 and 8. In some embodiments of compounds of formula (IG), m is 5 and the groups R 1a are at positions 3, 4, 5, 7 and 8. In some embodiments of compounds of formula (IG), m is 5 and the groups R 1a are at positions 3, 4, 6, 7 and 8. In some embodiments of compounds of formula (IG), m is 5 and the groups R 1aare at positions 4, 5, 6, 7 and 8. In some embodiments of compounds of formula (IG), m is 5 and the groups R 1a are at positions 3, 5, 6, 7 and 8. In some embodiments of compounds of formula (IG), m is 6 and the groups R 1a are at positions 3, 4, 5, 6, 7 and 8. Two or more groups R 1a Whenever present, the group R 1a can be independently selected. In any of these embodiments, in a compound of formula (IG) or a salt thereof, the carbon bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0135] Variable Element R 1a In some embodiments of Formula (IG), including embodiments recited in R 10 , R 11 , R 12 , and R 13 are each hydrogen. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (IG), including those embodiments that describe: q is 0. Variable R 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 and / or in some embodiments of formula (IG), including embodiments recited variable q, p is 3, 4, or 5.

[0136] 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] [In the formula, R 1a and R2 is as defined for formula (I), m is 0, 1, 2, 3, 4, 5 or 6, and the position on the isoquinoline ring is indicated, or a salt thereof. 1a , R 2 All descriptions of and m apply equally to formulas (IG) and (II-G).

[0137] R 1 R 1a In some embodiments of compounds of Formula (I) that are 5-10 membered heteroaryl optionally substituted by, the compound has the formula (IH): [ka] In the formula, 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, or a salt thereof.

[0138] In one embodiment, there is provided a compound of formula (IH), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (IH), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (IH), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0139] 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, if applicable, and R 1aIn a further embodiment of a compound of formula (IH), m is 0, 1, or 2, and each R 1a are, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl; 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 compounds of Formula (IH), m is 1 or 2.

[0140] In some embodiments of the compounds of Formula (IH), m is 0. In some embodiments of the compounds of Formula (IH), m is 1 and R 1a is at position 3. 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 the group R 1a are at positions 3 and 6. Two or more groups R 1a Whenever present, the group R 1a can be independently selected. In any of these embodiments of a compound of formula (IH) or a salt thereof, the carbons bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0141] Variable Element R 1a In some embodiments of Formula (IH), including embodiments recited in R 10 , R 11 , R 12 , and R 13 are each hydrogen. 1a and m, and / or variable R 10 , R 11 , R 12 and R13 In some embodiments of Formula (IH), including those embodiments that describe: q is 0. Variable R 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 and / or p is 3, 4, or 5 in some embodiments of formula (IH), including embodiments recited in formula (IH) above.

[0142] 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] [In the formula, R 1a and R 2 is as defined for formula (I), m is 0, 1 or 2, and the position on the 1-methyl-1H-pyrazolo[3,4-d]pyrimidine ring is indicated, or a salt thereof. 1a , R 2 All descriptions of and m apply equally to formulas (IH) and (II-H).

[0143] R 1 R 1a Also provided are compounds of Formula (I) or (II) wherein R is a 5- to 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 groups R, which may be the same or different 1aand each R is a 5- to 10-membered heteroaryl substituted by 1a are independently selected from 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 groups R selected from -CH3, -CH2F, -CHF2, and -CF3, which may be the same or different; 1a In some embodiments, R is a 5-membered heteroaryl (e.g., pyrazolyl) substituted by 1 may be the same or different, halogen (e.g., fluoro, chloro, or bromo), C3-C6 cycloalkyl (e.g., cyclopropyl), 5-6 membered heteroaryl (e.g., pyridinyl or pyrazolyl), C6-C 10 Aryl (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) 1a In some embodiments, R is a 6-position heteroaryl (e.g., pyridinyl, pyrimidinyl, or pyrazinyl) substituted by 1 is 1, 2, 3, 4 or 5 groups R selected from -CH3, -CH2F, -CHF2, and -CF3, which may be the same or different; 1aIn some embodiments, R is a 9-membered heteroaryl substituted by (e.g., pyrazolopyrimidinyl, pyrrolopyrimidinyl, thienopyrimidinyl, indalyl, indolyl, or benzimidazolyl). 1 are the same or different and include 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) 1a and 10-membered heteroaryl substituted with (eg, quinazolinyl).

[0144] R 1 but, [ka] Also provided are compounds of formula (I) or (II), or salts thereof, selected from the group consisting of any of the foregoing groups in which any one or more hydrogen atoms are replaced with deuterium atoms. 1 Also provided are compounds of formula (I) or (II) or salts thereof selected from any of the aforementioned groups, wherein one or more hydrogen atoms are replaced with tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon of the aforementioned group can be replaced with a corresponding isotope, such as deuterium or tritium. Each hydrogen bonded to a non-ring carbon of the aforementioned group, such as a methyl or methoxy carbon, can be replaced with a corresponding isotope, such as deuterium or tritium. Also, for example, the aforementioned group can be perdeuterated, in which all hydrogens therein are replaced with deuterium, or part-lithiated, in which all hydrogens therein are replaced with tritium. In some embodiments, one or more ring carbons of the aforementioned group can be 13 For example, in polycyclic rings of the aforementioned groups, one or more ring carbons of the ring directly bonded to the remainder of the compound may be replaced by C. 13In polycyclic rings of the aforementioned groups, one or more ring carbons in the ring substituting or fused to the ring attached to the remainder of the compound may be replaced by C. 13 C. Also, for example, all ring carbons of the above groups can be replaced by 13 It can be replaced by C.

[0145] R 1 but, [ka] Also provided are compounds of formula (I) or (II), or salts thereof, selected from the group consisting of any of the foregoing groups in which any one or more hydrogen atoms are replaced with deuterium atoms. 1 Also provided are compounds of formula (I) or (II) or salts thereof selected from any of the aforementioned groups, wherein one or more hydrogen atoms are replaced with tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon of the aforementioned group can be replaced with a corresponding isotope, such as deuterium or tritium. Each hydrogen bonded to a non-ring carbon of the aforementioned group, such as a methyl or methoxy carbon, can be replaced with a corresponding isotope, such as deuterium or tritium. Also, for example, the aforementioned group can be per-deuterated, where all hydrogens are replaced with deuterium, or per-lithiated, where all hydrogens are replaced with tritium. In some embodiments, one or more ring carbons of the aforementioned group can be 13 For example, in polycyclic rings of the aforementioned groups, one or more ring carbons of the ring directly bonded to the remainder of the compound may be replaced by C. 13 In polycyclic rings of the aforementioned groups, one or more ring carbons in the ring substituting or fused to the ring attached to the remainder of the compound may be replaced by C. 13 C. Also, for example, all ring carbons of the above groups can be replaced by 13 It can be replaced by C.

[0146] R 1 but, [ka] Also provided are compounds of formula (I) or (II), or salts thereof, selected from the group consisting of any of the foregoing groups in which any one or more hydrogen atoms are replaced with deuterium atoms. 1 Also provided are compounds of formula (I) or (II) or salts thereof selected from any of the aforementioned groups, wherein one or more hydrogen atoms are replaced with tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon of the aforementioned group can be replaced with a corresponding isotope, such as deuterium or tritium. Each hydrogen bonded to a non-ring carbon of the aforementioned group, such as a methyl or methoxy carbon, can be replaced with a corresponding isotope, such as deuterium or tritium. Also, for example, the aforementioned group can be per-deuterated, where all hydrogens are replaced with deuterium, or per-lithiated, where all hydrogens are replaced with tritium. In some embodiments, one or more ring carbons of the aforementioned group can be 13 For example, in polycyclic rings of the aforementioned groups, one or more ring carbons of the ring directly bonded to the remainder of the compound may be replaced by C. 13 In polycyclic rings of the aforementioned groups, one or more ring carbons in the ring substituting or fused to the ring attached to the remainder of the compound may be replaced by C. 13 C. Also, for example, all ring carbons of the above groups can be replaced by 13 It can be replaced by C.

[0147] R 1 but, [ka] Also provided are compounds of formula (I) or (II), or salts thereof, selected from the group consisting of any of the foregoing groups in which any one or more hydrogen atoms are replaced with deuterium atoms. 1Also provided are compounds of formula (I) or (II) or salts thereof selected from any of the aforementioned groups, wherein one or more hydrogen atoms are replaced with tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon of the aforementioned group can be replaced with a corresponding isotope, such as deuterium or tritium. Each hydrogen bonded to a non-ring carbon of the aforementioned group, such as a methyl or methoxy carbon, can be replaced with a corresponding isotope, such as deuterium or tritium. Also, for example, the aforementioned group can be per-deuterated, where all hydrogens are replaced with deuterium, or per-lithiated, where all hydrogens are replaced with tritium. In some embodiments, one or more ring carbons of the aforementioned group can be 13 For example, in polycyclic rings of the aforementioned groups, one or more ring carbons of the ring directly bonded to the remainder of the compound may be replaced by C. 13 In polycyclic rings of the aforementioned groups, one or more ring carbons in the ring substituting or fused to the ring attached to the remainder of the compound may be replaced by C. 13 C. Also, for example, all ring carbons of the above groups can be replaced by 13 It can be replaced by C.

[0148] R 1 but, [ka] Also provided are compounds of formula (I) or (II), or salts thereof, selected from the group consisting of any of the foregoing groups in which any one or more hydrogen atoms are replaced with deuterium atoms. 1Also provided are compounds of formula (I) or (II) or salts thereof selected from any of the aforementioned groups, wherein one or more hydrogen atoms are replaced with tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon of the aforementioned group can be replaced with a corresponding isotope, such as deuterium or tritium. Each hydrogen bonded to a non-ring carbon of the aforementioned group, such as a methyl or methoxy carbon, can be replaced with a corresponding isotope, such as deuterium or tritium. Also, for example, the aforementioned group can be per-deuterated, where all hydrogens are replaced with deuterium, or per-lithiated, where all hydrogens are replaced with tritium. In some embodiments, one or more ring carbons of the aforementioned group can be 13 For example, in polycyclic rings of the aforementioned groups, one or more ring carbons of the ring directly bonded to the remainder of the compound may be replaced by C. 13 In polycyclic rings of the aforementioned groups, one or more ring carbons in the ring substituting or fused to the ring attached to the remainder of the compound may be replaced by C. 13 C. Also, for example, all ring carbons of the above groups can be replaced by 13 It can be replaced by C.

[0149] (symbol [ka] The group R described herein as a moiety 1 Although R is shown as being attached at a particular position (e.g., pyrimidin-4-yl, quinazolin-4-yl, isoquinolin-1-yl), they can also be attached through other available valencies (e.g., pyrimidin-2-yl). In some embodiments of a compound of Formula (I) or (II) or a salt thereof, R 1 teeth, [ka] m is 0, 1, 2, or 3, and each R 1aare independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, if applicable, and R 1a In a further embodiment of the compounds of formula (I) or (II) or salts thereof, R 1 teeth, [ka] m is 1, 2, or 3, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl; R 1a The alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl in R are independently optionally substituted with deuterium. 1 teeth, [ka] and m is 0, 1, 2, 3, 4, or 5, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, if applicable, and R 1a In a further embodiment of the compounds of formula (I) or (II) or salts thereof, R 1 teeth, [ka] and m is 1, 2, 3, 4, or 5, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl; R 1aThe alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl in each R are independently optionally substituted with deuterium. 1a are, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl; R 1a wherein C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5-10 membered heteroaryl are independently optionally substituted with deuterium.

[0150] 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 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)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 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 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-C6 alkyl optionally substituted with halogen (e.g., cyclopropyl substituted with fluoro); 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 2 is n-propyl substituted with both halogen and alkoxy (e.g., —CHCH(F)CHOCH). R 2 R 2a In some embodiments indicated as optionally substituted by 2The R moiety is unsubstituted. 2 R 2a In some embodiments indicated as optionally substituted by 2 The part is one R 2a is replaced by R 2 R 2a In some embodiments indicated as optionally substituted by 2 The moieties may be the same or different, and may consist of 2 to 6, or 2 to 5, or 2 to 4, or 2 to 3 R 2a is replaced by a part.

[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 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)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 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 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 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-C6 alkyl optionally substituted with halogen (e.g., cyclopropyl substituted with fluoro); 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 2 is n-propyl substituted with both halogen and alkoxy (e.g., —CHCH(F)CHOCH). R 2 R 2a In some embodiments indicated as optionally substituted by 2 The R moiety is unsubstituted. 2 R 2a In some embodiments indicated as optionally substituted by 2 The part is one R 2a is replaced by R 2 R 2a In some embodiments indicated as optionally substituted by 2 The moieties may be the same or different, and may consist of 2 to 6, or 2 to 5, or 2 to 4, or 2 to 3 R 2a In some embodiments, R 2 is a C1-C6 alkyl substituted with two halogen groups (e.g., two fluoro groups), which may be the same or different. In some embodiments, R 2 is two -ORs which may be the same or different3 In 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) and one -OR, which may be the same or different. 3 In some embodiments, R is a C1-C6 alkyl substituted with a group (e.g., —OH or —OCH3). 2 is 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 (for example, two -OH groups, one -OH group and one -OCH3 group, or two -OCH3 groups).

[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 2b In some embodiments, R 2 is one or two R which may be the same or different 2b In some embodiments, R is a C-C cycloalkyl substituted by a moiety. 2 is a 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 atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon of the aforementioned group can be replaced with a corresponding isotope, e.g., deuterium or tritium. Each hydrogen bonded to a non-ring carbon of the aforementioned group, e.g., a methyl or methoxy carbon, can be replaced with a corresponding isotope, e.g., deuterium or tritium. Also, for example, the aforementioned group can be per-deuterated, where all hydrogens are replaced with deuterium, or per-lithiated, where all hydrogens are replaced with tritium. In some embodiments, one or more ring carbons of the aforementioned group can be 13 For example, in polycyclic rings of the aforementioned groups, one or more ring carbons of the ring directly bonded to the remainder of the compound may be replaced by C. 13 In polycyclic rings of the aforementioned groups, one or more ring carbons in the ring substituting or fused to the ring attached to the remainder of the compound may be replaced by C. 13 C. Additionally, for example, all ring carbons of the aforementioned groups may be replaced by 13 It can be replaced by C.

[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 hydrogen.

[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 R 2a In some embodiments, R 2is -OCH3.

[0155] R 2 but, [ka] and any of the foregoing groups in which any one or more hydrogen atoms are replaced by a tritium atom, or a salt thereof.

[0156] R 2 but, [ka] and any of the foregoing groups in which any one or more hydrogen atoms are replaced by a tritium atom, or a salt thereof.

[0157] R 2 but [ka] [Wherein, R 3 and each R 2a is as defined for formula (I). Also provided are compounds having 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.

[0158] R 2 but [ka] [wherein each R 2a is as defined for formula (I). Also provided are compounds having 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.

[0159] R 2 but [ka] [Wherein, R 3 is as defined for formula (I). Also provided are compounds having 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.

[0160] In one embodiment of formula (I), the tetrahydronaphthyridine group is disubstituted at the 2-position with deuterium.

[0161] In one aspect, there is provided a compound of Formula (I) or a salt thereof (including a pharmaceutically acceptable salt thereof) having any one or more of the following structural features (“SF”): (SFI)p is 3; (SFII)R 10 , R 11 , R 12 , R 13 are each hydrogen; (SFIII)R 1 teeth, (A) unsubstituted 5- to 10-membered heteroaryl; (B) 1, 2, 3, 4 or 5 groups R, which may be the same or different.1a is a 5- to 10-membered heteroaryl substituted by 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) Indalil; or (xviii) is pyrazolyl; (C) unsubstituted naphthalenyl; or (D) 1, 2, 3, 4 or 5 groups R, which may be the same or different. 1a is naphthalenyl substituted by (SFIV)Each R 1a teeth, (A) halogen, such as fluoro, chloro, or bromo; (B) C1-C6 alkyl optionally substituted with halogen, e.g., -CH3, -CHF2, -CF3, or C(CH3)3; (C) C3-C6 cycloalkyl, for example, cyclopropyl; (D) 5-10 membered heteroaryl, such as 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) 1, 2, 3, 4 or 5 groups R, which may be the same or different. 2a C1-C6 alkyl, for example C1-C2 alkyl, substituted by (C) unsubstituted —O—C1-C6 alkyl, for example —O—C1-C2 alkyl; (D) 1, 2, 3, 4 or 5 groups R, which may be the same or different. 2a -O-C1-C6 alkyl, for example -O-C1-C2 alkyl, substituted by (E) unsubstituted C3-C6 cycloalkyl, such as cyclopropyl or cyclobutyl; or (F) 1, 2, 3, 4 or 5 groups R, which may be the same or different 2b C-C cycloalkyl, for example, cyclopropyl or cyclobutyl, substituted by (SFVI)R 2a teeth, (A) halogens, such as fluoro; (B) C3-C8 cycloalkyl, for example, cyclopropyl or cyclobutyl, 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, such as 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 , e.g., -NHC(O)CH3; or (H)-OR 3 , 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.

[0162] It is understood that a compound of formula (I) or a variant thereof described herein, or a salt thereof, in one embodiment, can have any one or more of the structural features described above. For example, a compound of formula (I) or a variant thereof described herein, or a salt thereof, in one embodiment, 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 a variant thereof described herein, or a salt thereof, in one embodiment, can have any one, two, or all of the following structural features: (SFI), and (SFII), (SFIII), and (SFV), or any subembodiment thereof. In one such example, a compound of formula (I) or a variant thereof described herein, or a salt thereof, in one embodiment, can have any one, two, or all of the following structural features: (SFII), and (SFI), (SFIII), and (SFV), or any subembodiment thereof. In one such example, a compound of formula (I) or a variant thereof described herein or a salt thereof, in one embodiment, can have any one, two, or all of the following structural features: (SFIII), and (SFI), (SFII), and (SFV), or any subembodiments thereof. In one such example, a compound of formula (I) or a variant thereof described herein or a salt thereof, in one embodiment, can have any one, two, or all of 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. Although particular combinations of structural features are specifically described below, it is understood that any combination of features is 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 variation, (SFII) and (SFIII) apply. In another variation, (SFII) and (SFV) apply. In another variation, (SFIII) and (SFV) apply. In another variation, (SFI), (SFII), and (SFIII) apply. In another variation, (SFI), (SFII), and (SFV) apply. In another variation, (SFI), (SFIII), and (SFV) apply. In another variation, (SFII), (SFIII), and (SFV) apply. It is understood that each subembodiment of a 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 aspect of this variation, (SFV) is (SFV)(A), (SFV)(B), (SFV)(C), (SFV)(D), (SFV)(E), or (SFV)(F).

[0163] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(A).In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(A). In other variations, (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). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(A). In other variations, (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). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(A).

[0164] 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). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii). 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). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii).In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii).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.

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

[0166] 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). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi).In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi).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.

[0167] 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). In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii). In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii).

[0168] The variations or combinations described herein for compounds of formula (I) may be any of R 15 and R 16 This also applies to formula (A), with the addition of the possible combinations of

[0169] Representative compounds are listed in Figure 1.

[0170] In some embodiments, a compound selected from Compound Nos. 1-66 in FIG. 1, 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. 1-66 in FIG. 1, or a salt of a stereoisomer thereof.

[0171] 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.

[0172] In some embodiments, provided is 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. In some embodiments, the compound is a compound selected from Compound Nos. 1-665, or a salt of a stereoisomer thereof.

[0173] In some embodiments, provided is a compound selected from 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 compound is a compound selected from Compound Nos. 1-780, or a salt of a stereoisomer thereof.

[0174] 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.

[0175] 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.

[0176] In some embodiments, compositions, such as pharmaceutical compositions, are provided that include 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 includes 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 that further includes a pharmaceutically acceptable carrier.

[0177] In some embodiments, compositions, such as pharmaceutical compositions, are provided that include 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 includes 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 that further includes a pharmaceutically acceptable carrier.

[0178] In some embodiments, compositions, such as pharmaceutical compositions, are provided that include 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 includes 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 that further includes a pharmaceutically acceptable carrier.

[0179] In some embodiments, compositions, such as pharmaceutical compositions, are provided that include 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 includes 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 that further includes a pharmaceutically acceptable carrier.

[0180] The present invention also includes all salts of the compounds described herein, such as pharmaceutically acceptable salts. The present invention also includes any or all stereochemical forms, including enantiomeric or diastereomeric forms, and tautomeric or other forms, of the described compounds. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure and name are intended to encompass all possible stereoisomers of the described compound. Furthermore, when a specific stereochemical form is described, it is understood that other stereochemical forms are also described and encompassed by the present invention. All forms of the compounds, including crystalline or amorphous forms of the compounds, are also encompassed by the present invention. Prodrug solvates and metabolites of the compounds are understood to be encompassed by this disclosure. Compositions comprising the compounds of the present invention, such as compositions of substantially pure compounds containing a specific stereochemistry, are also contemplated. Compositions comprising mixtures of the compounds of the present invention in any proportion, including mixtures of two or more stereochemical forms of the compounds of the present invention in any proportion, are also encompassed by the present invention, thereby encompassing racemic, non-racemic, enantioenriched, and scalemic mixtures of the compounds. If one or more tertiary amine moieties are present in the compound, the N-oxides are also provided and described.

[0181] The compounds described herein are αvβ6 integrin inhibitors. In some cases, it is desirable for the compounds to inhibit other integrins in addition to αvβ6 integrin. In some embodiments, the compounds inhibit αvβ6 integrin and one or more of αvβ1 integrin, αvβ3 integrin, αvβ5 integrin, α2β1 integrin, α3β1 integrin, α6β1 integrin, α7β1 integrin, and α11β1 integrin. 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 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 compounds inhibit αvβ6 integrin and α11β1 integrin.

[0182] 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 integrin, αvβ8 integrin, and / or α2β3 integrin. 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.

[0183] The present invention also contemplates isotopically labeled and / or isotopically enriched forms of the compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compounds are isotopically labeled, e.g., isotopically labeled compounds of formula (I) or variations thereof described herein, in which one or more atoms are replaced with an isotope of the same element. Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and chlorine, e.g., 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, can provide certain therapeutic advantages due to improved metabolic stability, e.g., increased in vivo half-life, or reduced dosage requirements, and therefore may be preferred in some cases. As used herein, each example of the replacement of hydrogen with deuterium is also a disclosure of the replacement of that hydrogen with tritium. As used herein, each example of enrichment, substitution, or replacement of an atom with the atom's corresponding isotope encompasses isotopic enrichment levels of one of 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 about 100%, or a range between any two of the foregoing percentages.

[0184] 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 appropriate isotopically labeled reagent for the corresponding unlabeled reagent.

[0185] In various embodiments, for each of the compounds named or described herein, the corresponding isotopically substituted compounds according to the following description are specifically disclosed. For example, the structural variable R 1 and R 1a Corresponding isotopically substituted compounds are disclosed in which groups corresponding to 1 and R 1a can be perdeuterated, such that all hydrogens therein can be independently replaced with deuterium. 1a Structural variable R, not in 1 Corresponding isotopically substituted compounds are disclosed in which one or more hydrogens in the group corresponding to can be independently replaced with deuterium. For example, any substituent R 1a Not in R 1 Corresponding isotopically substituted compounds are disclosed in which all hydrogens attached to the ring in a group corresponding to R can be replaced with deuterium. 1a One or more hydrogens in 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.

[0186] Also, for example, the structural variable R 2 and R 2a can be independently deuterated, e.g., the structural variable R 2 and R 2a The corresponding isotopically substituted compounds are disclosed in which R can be perdeuterated, such that all hydrogens therein can be independently replaced with deuterium. 2a Not in R 2 Also disclosed are corresponding isotopically substituted compounds, where one or more hydrogens in the group corresponding to R can be independently replaced with deuterium. 2 R is the carbon that bonds 2 Corresponding isotopically substituted compounds are disclosed in which each hydrogen at the 1-position of R can be independently replaced with deuterium. For example, R 2For the specified compound having -CH2CH2CH2F corresponding to R 2 Also disclosed are the corresponding isotopically substituted compounds where R is -CD2CH2CH2F; 2 For the designated compound having -CH2-cyclopropyl corresponding to R 2 Also disclosed are the corresponding isotopically substituted compounds where R is -CD2-cyclopropyl, and so on. 2a Corresponding isotopically substituted compounds are disclosed in which each hydrogen in the group corresponding to R can be independently replaced with deuterium. For example, R 2a For each compound where is -OCH3, R 2a Also disclosed are corresponding isotopically substituted compounds where R can be -OCD3; 2a For each compound where is -N(CH3)2, R 2a Also disclosed are corresponding isotopically substituted compounds where R can be -N(CD3)2, and so forth. 2 The 1-position of R can be di-deuterated. 2a Disclosed are compounds in which each hydrogen in a group corresponding to: can be replaced with deuterium.

[0187] 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 in which R 14 is deuterium, and R 14 is substituted with a tetrahydronaphthyridin-2-yl group at the 3-position, the 4-position, or the 3- and 4-positions. 14 is deuterium, and each R 14independently replaces each hydrogen at the 5-position, 6-position, 7-position, 5- and 6-position, 5- and 7-position, 6- and 7-position, or 5-, 6- and 7-position in the tetrahydronaphthyridin-2-yl group, e.g., the 7-position can be substituted with two deuterium atoms.

[0188] In some embodiments, R 1 All ring hydrogens in R can be replaced by deuterium. 2 The 1-position of R can be di-deuterated. 2a The corresponding isotopically substituted compounds are disclosed, where R can be perdeuterated. 1 The corresponding isotopically substituted compounds are disclosed in which all ring hydrogens in R can be replaced by deuterium. 1 All ring hydrogens in R can be replaced by deuterium. 2 The 1-position of R can be di-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 di-deuterated. 1 All ring hydrogens in R can be replaced by deuterium. 2a The corresponding isotopically substituted compounds are disclosed in which each hydrogen in R can be independently replaced by deuterium. 1 All ring hydrogens in R can be replaced by deuterium. 2 The 1-position of R can be di-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 di-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 di-deuterated. 1 All ring hydrogens in R can be replaced by deuterium. 2 The 1-position of R can be di-deuterated.2a can be perdeuterated, R 12 and R 13 Corresponding isotopically substituted compounds are disclosed, wherein can be deuterium.

[0189] 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 The corresponding isotopically substituted compounds are disclosed in which one or more hydrogens in R can be independently replaced by tritium. 1 , R 1a , or R 1 and R 1a The 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 The corresponding isotopically substituted compounds are disclosed in which one or more hydrogens in R can be independently replaced by tritium. 2 , R 2a , or R 2 and R 2a wherein one or more hydrogen atoms 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, e.g., 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, e.g., the 7-position can be ditritiated.

[0190] In some embodiments of the named compounds, one or more carbons 13Corresponding isotopically substituted compounds are disclosed in which R 1 , R 1a , R 2 , R 2a wherein one or more carbons, such as those in the tetrahydronaphthyridin-2-yl ring shown in the structural formulas herein, 13 Corresponding isotopically substituted compounds are disclosed in which R 1 , R 1a , R 2 , R 2a and / or the tetrahydronaphthyridin-2-yl group, one or more ring carbons are 13 C. For example, R 1 , R 1a , R 2 , R 2a and / or tetrahydronaphthyridin-2-yl groups, one or more ring carbons in the ring directly bonded to the remainder of the compound are 13 For example, in the tetrahydronaphthyridin-2-yl group, the ring directly attached to the rest of the compound is an aromatic heterocycle attached at the 2-position. 1 , R 1a , R 2 , R 2a In polycyclic rings in groups corresponding to 13 For example, in a tetrahydronaphthyridin-2-yl ring, the non-aromatic heterocyclyl ring is fused to the ring that is attached to the remainder of the compound. 1 , R 1a , R 2 , R 2a and / or all ring carbons or all carbons in the tetrahydronaphthyridin-2-yl ring are 13 It can be replaced by C.

[0191] The present invention also encompasses any and all metabolites of any of the compounds described. These metabolites may include chemical species produced by the biotransformation of any of the compounds described, such as intermediates and products of metabolism of the compounds.

[0192] 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, preloaded syringe, iv bag, or the like.

[0193] Preferably, the compounds detailed herein are orally bioavailable, however, they may also be formulated for parenteral (e.g., intravenous) administration.

[0194] One or more compounds described herein can be used to prepare medicines by combining one or more of these compounds as active ingredients with pharmacologically acceptable carriers known in the art. Depending on the therapeutic form of the medicine, the carrier can be in various forms.

[0195] General synthesis method The compounds of the present invention can be prepared by several processes, such as the schemes provided in the Examples below, which are generally described below and more specifically described in the Examples. In the process descriptions below, the symbols, when used in the formulae described, should be understood to represent the groups described above in connection with the formulae herein.

[0196] If it is desired to obtain a specific enantiomer of a compound, this can be achieved from the corresponding mixture of enantiomers by using suitable conventional methods for separating or resolving enantiomers.Thus, for example, a mixture of enantiomers, such as a racemate, can be reacted with a suitable chiral compound to produce diastereomeric derivatives.Then, diastereomers can be separated by conventional means, such as crystallization, and the desired enantiomer is recovered.In another resolution process, chiral high performance liquid chromatography can be used to separate racemates.Alternatively, if necessary, a specific enantiomer can be obtained by using suitable chiral intermediates in one of the processes described.

[0197] Chromatography, recrystallization, and other conventional separation methods may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify the product of a reaction.

[0198] Solvates and / or polymorphs of the compounds provided herein or their pharmaceutically acceptable salts are also contemplated. Solvates contain 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 include different crystalline packing arrangements of a compound with the same elemental composition. Polymorphs typically 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 result in the predominance of a single crystal.

[0199] 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.

[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, P, Q, R, S, T, and U, and the Examples herein.

[0201] Compounds of formula 11A can be prepared according to general scheme A, where R 1 and R 2 can be prepared according to formula (I) or as defined for formula (I) or as applicable variations detailed herein). [ka]

[0202] Coupling of 1A with a compound of formula 2A in the presence of a suitable coupling agent gives a compound of formula 3A, which is reduced to give a compound of formula 4A. Reductive amination of a compound of formula 4A with compound 5A gives a compound of formula 6A. Removal of the N-Boc protecting group on a compound of formula 6A by exposure to a suitable acid gives a compound of formula 7A, which can be coupled with a compound of formula 8A to give a compound of formula 10A. Hydrolysis of a compound of formula 10A in the presence of a suitable hydroxide source gives a compound of formula 11A.

[0203] Reaction conditions for the transformations of General Scheme A are provided in the general procedures below, particularly General Procedures A, D, E, F, G, H and P.

[0204] General Scheme A may be modified to include the group R 2Variants of the compound of formula 11A can be prepared by starting with variants of 1A having five and six carbon linkers between the nitrogen bearing the .alpha. and the tetrahydronaphthyridine group. These variants of the compound of formula 11A can be synthesized by replacing 1A with 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. 6-Oxoheptanoic acid and 7-oxooctanoic acid can be converted to 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid and 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid, respectively, by condensation with 2-aminonicotinaldehyde in the presence of a suitable catalyst, followed by hydrogenation of the resulting naphthyridine ring to the 5,6,7,8-tetrahydronaphthyridine ring using procedures known in the chemical literature.

[0205] Compounds of formula 11A can alternatively be prepared according to general scheme B, where R 1 and R 2 can be prepared according to formula (I) or as defined for formula (I) or as applicable variations detailed herein). [ka]

[0206] 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 on compound of formula 7B by exposure to a suitable acid gives a compound of formula 7A, which can be 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.

[0207] Reaction conditions for the transformations of General Scheme B are provided in the general procedures below, particularly General Procedures B, D, F, G, H and P.

[0208] General Scheme B may be modified to include the group R 2 Variants of the compound of formula 11A can be prepared by starting with variants of 1B having five and six carbon linkers between the nitrogen bearing the methyl group and the tetrahydronaphthyridine group. These variants of the compound of formula 11A can be synthesized by replacing 1B with 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. Ethyl 6-oxoheptanoate and ethyl 7-oxooctanoate can be converted to 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, by condensation with 2-aminonicotinaldehyde in the presence of a suitable catalyst, followed by hydrogenation of the resulting naphthyridine ring to the 5,6,7,8-tetrahydronaphthyridin ring using procedures known in the chemical literature.

[0209] 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 can be prepared according to formula (I) or as defined for formula (I) or as applicable variations detailed herein). [ka]

[0210] Coupling of 1C with a compound of formula 4C in the presence of a suitable coupling agent provides a compound of formula 2C, which is reduced to provide a compound of formula 3C. Reductive amination of a compound of formula 3C with compound 5A provides a compound of formula 5C. Global removal of the N-Boc protecting group from a compound of formula 5C by exposure to a suitable acid provides a compound of formula 6C, which can be coupled with a compound of formula 8A to provide a compound of formula 9C. Hydrolysis of a compound of formula 9C in the presence of a suitable hydroxide source provides a compound of formula 10C.

[0211] 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.

[0212] By modifying General Scheme C to start with variants of 1C having five and six carbon linkers between the nitrogen bearing the -CHR group and the tetrahydronaphthyridine group, variants of the compound of Formula 10C can be prepared. These variants of the compound of Formula 10C can be synthesized by replacing 1C with 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. 6-Oxoheptanoic acid and 7-oxooctanoic acid can be converted to 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid and 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid, respectively, by condensation with 2-aminonicotinaldehyde in the presence of a suitable catalyst, followed by hydrogenation of the resulting naphthyridine ring to the 5,6,7,8-tetrahydronaphthyridine ring using procedures known in the chemical literature. The resulting carboxylic acids can be converted to primary amines by a two-step process involving coupling the carboxylic acid with a suitable ammonia source in the presence of a suitable coupling reagent, followed by reduction.

[0213] Compounds of formula 10C can alternatively be prepared according to general scheme D, where R is R 2aC1-C5 alkyl optionally substituted by R 1 and R 2a can be prepared according to formula (I) or as defined for formula (I) or as applicable variations detailed herein). [ka]

[0214] 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. Removal of the N-Boc protecting group on a compound of formula 5C by exposure to a suitable acid provides a compound of formula 6C, which can be 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.

[0215] 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.

[0216] By modifying General Scheme D to start with variants of 1C having five and six carbon linkers between the nitrogen bearing the -CHR group and the tetrahydronaphthyridine group, compounds of Formula 10C can be prepared. These variants of the compound of Formula 10C can be synthesized by replacing 1C with 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. 6-Oxoheptanoic acid and 7-oxooctanoic acid can be converted to 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid and 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid, respectively, by condensation with 2-aminonicotinaldehyde in the presence of a suitable catalyst, followed by hydrogenation of the resulting naphthyridine ring to the 5,6,7,8-tetrahydronaphthyridine ring using procedures known in the chemical literature. The resulting carboxylic acids can be converted to primary amines by a two-step process involving coupling the carboxylic acid with a suitable ammonia source in the presence of a suitable coupling reagent, followed by reduction.

[0217] Compounds of formula 1f can be prepared according to general scheme E. It is understood that the ring bearing the Het designation can be an aromatic heterocycle. [ka]

[0218] Compounds of formula 1a can be hydrolyzed to give compounds of formula 1b, which can be alkylated with a suitable electrophile to give compounds of formula 1c. Compounds of formula 1c can be deprotected under reducing conditions to give compounds of formula 1d. Metal-catalyzed cross-coupling of halogenated arenes with compounds of formula 1d gives compounds of formula 1e, which can be hydrolyzed under acidic conditions to give compounds of formula 1f.

[0219] 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.

[0220] It is understood that the above scheme 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, 4th edition, Wiley-Interscience, New York, 2006.

[0221] Further methods for preparing compounds according to formula (I) and salts thereof are provided in the Examples. As one skilled in the art will recognize, the preparation methods taught herein can be adapted to provide additional compounds within the scope of formula (I), for example, by selecting starting materials that provide the desired compound.

[0222] 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) and (II-H) or a salt thereof, or any of the compounds of Figure 1 or a salt thereof, or mixtures 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), and (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 encompasses pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions of the 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, hi one embodiment, the pharmaceutical composition is a controlled release composition of any of the compounds detailed herein.

[0223] 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 or salts thereof that make up the majority of the composition. For example, a composition of a compound selected from the compounds of Figure 1 can contain 35% or less impurities, where impurities refer to compounds other than the compound or salts thereof that make up the majority of the composition. For example, a composition comprising a compound selected from the compounds of Figure 1 can have 35% or less impurities, where impurities refer to compounds other than the compound or salts thereof that make up the majority of the composition. For example, a composition comprising a compound selected from the compounds of Figure 1 can have 35% or less impurities, where impurities refer to compounds other than the compound or salts thereof that make up the majority of the composition. In one embodiment, the composition can contain 25% or less impurities. In one embodiment, the composition can contain 20% or less impurities. In a further embodiment, a composition comprising a compound detailed herein or a salt thereof 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 comprising a compound or salt thereof detailed herein is in substantially pure form. In yet another variation, a substantially pure composition of the compound or salt thereof is provided, the composition containing 10% or less impurities. In a further variation, a substantially pure composition of the compound or salt thereof is provided, the composition containing 9% or less impurities. In a further variation, a substantially pure composition of the compound or salt thereof is provided, the composition containing 7% or less impurities. In a further variation, a substantially pure composition of the compound or salt thereof is provided, the composition containing 5% or less impurities. In another variation, a substantially pure composition of the compound or salt thereof is provided, the composition containing 3% or less impurities. In yet another variation, a substantially pure composition of the compound or salt thereof is provided, the composition containing 1% or less impurities. In a further variation, a substantially pure composition of the compound or salt thereof is provided, the composition containing 0.5% or less impurities.In yet another variation, a composition of a substantially pure compound means that the composition contains no more than 10%, or preferably no more than 5%, or more preferably no more than 3%, or even more preferably no more than 1%, or most preferably no more than 0.5%, 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 no more than 10%, or no more than 5%, or no more than 3%, or no more than 1%, or no more than 0.5% of the (R) form of the compound.

[0224] 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. Purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for the compounds or forms detailed herein.

[0225] The compounds or salts thereof detailed herein can be formulated for available delivery routes, including oral, mucosal (e.g., intranasal, 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 (e.g., hard or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, poultices, pastes, powders, dressings, creams, liquids, patches, aerosols (e.g., nasal sprays or inhalants), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, or elixirs.

[0226] One or more compounds or salts thereof described herein can be used to prepare formulations, e.g., pharmaceutical preparations, by combining one or more compounds or salts thereof as active ingredients with pharmaceutically acceptable carriers, e.g., those described above. Depending on the therapeutic dosage form of the system (e.g., transdermal patch vs. 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. Preparations containing compounds can also contain other substances with useful 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.

[0227] The compounds described herein can be administered to individuals (e.g., humans) in the form of commonly accepted oral compositions, such as tablets, coated tablets, and hard or soft-shelled gel capsules, emulsions, or suspensions. Examples of carriers that can be used to prepare such compositions include lactose, corn starch or its derivatives, talc, stearates or their salts, etc. Acceptable carriers for soft-shelled gel capsules include vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. In addition, pharmaceutical formulations can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, colorants, regulators, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants.

[0228] In one embodiment, the compound can be administered in the liquid vehicle ORA-SWEET® (a syrup vehicle having the ingredients 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%)) manufactured by PERRIGO® (Allegan, Michigan), or in a mixture of ORA-SWEET® and water in any ratio, for example, a 50:50 ORA-SWEET®:water mixture. The water used should be of pharmaceutically acceptable grade, e.g., sterile water.

[0229] Any of the compounds described herein can be formulated into tablets in the dosage forms described, for example, a compound described herein or a pharmaceutically acceptable salt thereof can be formulated as a 10 mg tablet.

[0230] 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 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 the methods described herein. In some embodiments, the composition is for use in treating a disease or disorder described herein.

[0231] How to use The compounds and compositions of the invention, e.g., pharmaceutical compositions containing a compound of the formula provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, can be used in methods of administration and treatment as 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.

[0232] In one aspect, there is provided a method of treating a fibrotic disorder in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a 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. 1-66 of FIG. 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, there is provided a method of treating a fibrotic disorder in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a 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. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, there is provided a method of treating a fibrotic disorder in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a 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. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.In one aspect, a method of treating a fibrotic disorder in an individual in need thereof is provided, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a 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 aspect, a method of treating a fibrotic disorder in an individual in need thereof is provided, comprising administering to the individual a therapeutically effective amount of a compound of Formula (A), or a variant thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, the individual is a human. The individual, eg, a human, can be one in need of treatment, such as a human having or suspected of having a fibrotic disease.

[0233] In another embodiment, 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 understood that delaying onset can include prevention if the individual does not have a fibrotic disease. In one embodiment, an individual at risk of developing a fibrotic disease has or is suspected of having one or more risk factors for developing a fibrotic disease. Risk factors for fibrotic disease can include the individual's age (e.g., middle-aged or older adult), 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 method (e.g., radiology) believed to be associated with an increased susceptibility to fibrosis or a medical condition believed to be associated with fibrosis, a smoking history, and the presence of occupational and / or environmental factors such as exposure to pollutants associated with the development of a fibrotic disease. 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 had 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.

[0234] In some embodiments, the fibrotic disorder is fibrosis of a tissue such as the lung (pulmonary fibrosis), liver, skin, heart (cardiac fibrosis), kidney (renal fibrosis), or gastrointestinal tract (gastrointestinal fibrosis).

[0235] 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 (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.

[0236] 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 systemic sclerosis-associated interstitial lung disease.

[0237] 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.

[0238] In some embodiments, the fibrotic disease is fibrotic nonspecific interstitial pneumonia (NSIP).

[0239] In some embodiments, fibrotic disease is liver fibrosis, for example infectious liver fibrosis (caused by pathogens such as HCV, HBV or parasites such as schistosomiasis), NASH, alcoholic fatty liver-induced liver fibrosis and liver cirrhosis.In some embodiments, liver fibrosis is non-alcoholic fatty liver disease (NAFLD).In some embodiments, liver fibrosis is NASH.

[0240] In some embodiments, the fibrotic disease is biliary fibrosis.

[0241] In some embodiments, the fibrotic disease is renal fibrosis, such as 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.

[0242] 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.

[0243] In some embodiments, the fibrotic disorder is systemic or localized sclerosis or scleroderma, keloids and hypertrophic scars, or post-surgical adhesions. In some embodiments, the fibrotic disorder is scleroderma or systemic sclerosis.

[0244] In some embodiments, the fibrotic disease is atherosclerosis or restenosis.

[0245] In some embodiments, the fibrotic disease is gastrointestinal fibrosis, eg, Crohn's disease.

[0246] In some embodiments, the fibrotic disease is cardiac fibrosis, such as post-myocardial infarction-induced fibrosis and hereditary cardiomyopathies.

[0247] In some embodiments, the fibrotic disorder is psoriasis.

[0248] 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 at least one integrin in a subject in need thereof. V The method may include modulating the activity of α6. V The method may include modulating the activity of α1. V β1 and α V The method may include modulating the activity of β6. Modulating the activity of at least one integrin may include, for example, inhibiting at least one integrin. The method may include administering to a subject at least one integrin, such as α6, in the subject. V β1 and α VThe method may include administering an amount of the compound or a pharmaceutically acceptable salt thereof effective to modulate the activity of at least one of β6. The subject in need of modulating 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, systemic sclerosis-related interstitial lung disease, 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 also include administering to a subject in need of treatment for NASH at least one integrin, such as α V β1 and α V The method may include administering to a subject an amount of the compound or a pharmaceutically acceptable salt thereof effective to modulate the activity of at least one integrin, such as αβ, in a subject in need of treatment for IPF. V β1 and α V The method may comprise administering the compound or a pharmaceutically acceptable salt thereof in an amount effective to modulate the activity of at least one of β6.

[0249] Fibrotic diseases are primarily caused by α V β6, for example, the fibrotic disease can include idiopathic pulmonary fibrosis or renal fibrosis. V It regulates the activity of β6, mainly α V Fibrotic diseases can include treating conditions mediated by β6. V For example, the fibrotic disease may be mediated by β1, such as NASH. V Regulating the activity of β1, mainly α VFibrotic diseases may include treating conditions mediated by β1, such as NASH. V β1 and α V β6, for example, the fibrotic disease may include PSC or biliary atresia. V β1 and α V Regulating the activity of β6 and α V β1 and α V The present invention may include treating a condition mediated by both β6 and β7.

[0250] This 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 α V β1 and α V The compound may be a dual modulator, e.g., a dual inhibitor, e.g., a dual selective inhibitor, of β6. For example, Table B-3 shows that some exemplary compounds are primarily selective for α V Alpha over Beta6 V Inhibiting β1; some exemplary compounds inhibit primarily α V α rather than β1 V β6; and some exemplary compounds inhibit α V β1 and α V It inhibits β6 equally well, e.g., "α V β1 / α V This indicates that it can be considered a "dual β6 inhibitor."

[0251] α V β1 integrin and α V Treating patients with fibrotic diseases by modulating or inhibiting the activity of one or both of the β6 integrins is a method of treating fibrotic disease. V β1 integrin, α V β6 integrin, or α V β1 integrin and α V It is shown that the β6 integrin is modulated or inhibited sufficiently to treat a fibrotic disease in a subject.

[0252] In one aspect, there is provided a compound of Formula (A), a compound of Formula (I), or a 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 to 66 in FIG. 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a fibrotic disease.

[0253] In one aspect, there is provided a compound of Formula (A), a compound of Formula (I), or a 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 to 147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a fibrotic disease.

[0254] In one aspect, there is provided a compound of Formula (A), a compound of Formula (I), or a 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 to 665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a fibrotic disease.

[0255] In one aspect, there is provided a compound of Formula (A), a compound of Formula (I), or a 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 to 780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a fibrotic disease.

[0256] Also provided is the use of a compound of Formula (A), a compound of Formula (I), or a variant thereof, such as 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 to 66 in Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a fibrotic disease.

[0257] Also provided is the use of a compound of Formula (A), a compound of Formula (I), or a variant thereof, such as 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 treating a fibrotic disease.

[0258] Also provided is the use of a compound of Formula (A), a compound of Formula (I), or a variant thereof, such as 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 treating a fibrotic disease.

[0259] Also provided is the use of a compound of Formula (A), a compound of Formula (I), or a variant thereof, such as 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 treating a fibrotic disease.

[0260] In another aspect, there is provided a method of treating a subject in need thereof, comprising administering to the subject 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. 1-66 of FIG. 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Provided herein are methods comprising administering a therapeutically effective amount of a salt or a dosage form disclosed herein to a subject having at least one tissue in need of therapy, wherein the tissue has 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 a healthy state of the tissue. In some embodiments, the at least one tissue in the subject comprises one or more of lung tissue, liver tissue, skin tissue, heart tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue. In some embodiments, the tissue has elevated pSMAD2 / SMAD2 levels or elevated pSMAD3 / SMAD3 levels compared to a healthy state of the tissue.

[0261] 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.

[0262] In some embodiments, the method comprises administering to the subject α V α compared with β6 integrin activity and / or expression V In some embodiments, the method selectively reduces β1 integrin activity and / or expression in a subject. Vα compared with β1 integrin activity and / or expression V In some embodiments, the method selectively reduces β6 integrin activity and / or expression in a subject. V Compared to containing integrins, α V β1 integrin and α V In some embodiments, the subject's β6 integrin activity and / or expression is reduced in one or more fibroblasts in the subject. V In some embodiments, the activity of β1 integrin is reduced in one or more epithelial cells in the subject. V The activity of β6 integrin is reduced.

[0263] In another aspect, there is provided a method of treating a subject in need thereof, comprising administering to the subject 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. 1-66 of FIG. 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. or a therapeutically effective amount of a dosage form disclosed herein, wherein the subject has at least one tissue in need of therapy, and the tissue has 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, wherein the levels are elevated compared to a healthy state of the tissue. In some embodiments, the at least one tissue in the subject comprises one or more of lung tissue, liver tissue, skin tissue, heart tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue. In some embodiments, the tissue has elevated pSMAD2 / SMAD2 levels or elevated pSMAD3 / SMAD3 levels compared to a healthy state of the tissue.

[0264] 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.

[0265] In some embodiments, the method comprises administering to the subject α V α compared with β6 integrin activity and / or expression V In some embodiments, the method selectively reduces β1 integrin activity and / or expression in a subject. V α compared with β1 integrin activity and / or expression V In some embodiments, the method selectively reduces β6 integrin activity and / or expression in a subject. V Compared to containing integrins, α V β1 integrin and α V In some embodiments, the subject's β6 integrin activity and / or expression is reduced in one or more fibroblasts in the subject. V In some embodiments, the activity of β1 integrin is reduced in one or more epithelial cells in the subject. V The activity of β6 integrin is reduced.

[0266] Also provided herein are methods for characterizing the antifibrotic activity of a small molecule in a subject, the methods 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 latency-associated peptide-TGF-β; determining a first pSMAD / SMAD value in 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 in the subject as the first live cell sample; determining a second pSMAD / SMAD value in the second live cell sample; and characterizing the antifibrotic activity of the small molecule in the subject by comparing the second pSMAD / SMAD value with the first pSMAD / SMAD value. In some embodiments, the small molecule is a compound disclosed herein, optionally in a dosage form disclosed herein.

[0267] In some embodiments, each live cell sample is a plurality of cells obtained 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 is a plurality of alveolar macrophages obtained from bronchoalveolar lavage fluid of the subject.

[0268] 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 the plurality of alveolar macrophages.

[0269] 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.

[0270] In some embodiments, at least one integrin is α V In some embodiments, at least one integrin is α V In some embodiments, at least one integrin is α V Contains β6.

[0271] In some embodiments, determining a first pSMAD / SMAD value in the at least one living cell comprises determining a pSMAD2 / SMAD2 value or a pSMAD3 / SMAD3 value, and determining a second pSMAD / SMAD value in 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.

[0272] Also provided herein 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 beta (TGF-β) from latency-associated peptide-TGF-β; determining a first pSMAD / SMAD value in 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 in the subject as the first live cell sample; determining a second pSMAD / SMAD value in 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 disclosed herein or a salt thereof, optionally in a dosage form disclosed herein. In some embodiments, the first live cell sample is obtained from the subject prior to treatment with the small molecule.

[0273] In some embodiments, each live cell sample is a plurality of cells obtained 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 is a plurality of alveolar macrophages obtained 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 produce bronchoalveolar lavage fluid containing a plurality of macrophages as the plurality of alveolar macrophages.

[0274] 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.

[0275] In some embodiments, at least one integrin is α V In some embodiments, at least one integrin is α V In some embodiments, at least one integrin is α V Contains β6.

[0276] In some embodiments, determining a first pSMAD / SMAD value in a first live cell sample comprises determining a pSMAD2 / SMAD2 value or a pSMAD3 / SMAD3 value, and determining a second pSMAD / SMAD value in 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.

[0277] In another aspect, there is provided a method of inhibiting αvβ6 integrin in an individual, comprising administering a compound of Formula (A), a compound of Formula (I), or a variant thereof, such as 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 FIG. 1, or a pharmaceutically acceptable salt thereof.

[0278] In another aspect, there is provided a method of inhibiting αvβ6 integrin in an individual, comprising administering a compound of Formula (A), a compound of Formula (I), or a variant thereof, such as 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.

[0279] In another aspect, there is provided a method of inhibiting αvβ6 integrin in an individual, comprising administering a compound of Formula (A), a compound of Formula (I), or a variant thereof, such as 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.

[0280] In another aspect, there is provided a method of inhibiting αvβ6 integrin in an individual, comprising administering a compound of Formula (A), a compound of Formula (I), or a 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 stereoisomer thereof, or a compound selected from Compound Nos. 1-780, or a pharmaceutically acceptable salt thereof.

[0281] Also provided is a method of inhibiting TGFβ activation in a cell, comprising administering to the cell a compound of Formula (A), a compound of Formula (I), or a 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. 1-66 in FIG. 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0282] Also provided is a method of inhibiting TGFβ activation in a cell, comprising administering to the cell a compound of Formula (A), a compound of Formula (I), or a 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. 1-147, 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 to the cell a compound of Formula (A), a compound of Formula (I), or a 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. 1-665, 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 to the cell a compound of Formula (A), a compound of Formula (I), or a 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.

[0285] 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), a compound of Formula (I), or a 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 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), a compound of Formula (I), or a 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. 1-147, 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), a compound of Formula (I), or a 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. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.Also provided are methods for inhibiting αvβ6 integrin in an individual in need thereof, comprising administering to the individual a compound of Formula (A), a compound of Formula (I), or a 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 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 a subject 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 for inhibiting αvβ6 integrin and α6β1 integrin is provided. In another embodiment, a method for inhibiting αvβ6 integrin and α7β1 integrin is provided. In another embodiment, a method for inhibiting αvβ6 integrin and α11β1 integrin is provided.In one aspect, in all such embodiments, the method of inhibiting is for an individual in need of inhibition, 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), a compound of Formula (I), or a 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 numbers 1-66 in FIG. 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, in all such embodiments, the method of inhibiting is for an individual in need of inhibition, 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), a compound of Formula (I), or a 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. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, in all such embodiments, the method of inhibiting is for an individual in need of inhibition, 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), a compound of Formula (I), or a 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. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.In one aspect, in all such embodiments, the method of inhibiting is for an individual in need of inhibition, 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), a compound of Formula (I), or a 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.

[0286] Compounds of formula (A) can be used in the compositions, methods, and uses described herein for formula (I) and variations of formula (I).

[0287] In any of the described methods, in one embodiment, the individual is a human, e.g., a human in need of the method. 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.

[0288] Also provided herein are dosage forms configured for daily administration comprising a pharmaceutically acceptable carrier or excipient and a unit dose of a compound of Formula (A), a compound of Formula (I), or a 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.

[0289] A unit dose, such as a unit dose for daily administration, may 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, 15-30 , 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, 60-85, 70-90, 70-100, 80-125, 90-125, or 100-125 mg of the compound.

[0290] A unit dose, such as a unit dose for daily administration, may 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~ The dosages may include 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, the unit dose may be 10 mg, the unit dose may be 15 mg, the unit dose may be 20 mg, the unit dose may be 30 mg, the unit dose may be 40 mg, the unit dose may be 50 mg, the unit dose may be 60 mg, the unit dose may be 70 mg, the unit dose may be 75 mg, the unit dose may be 80 mg, the unit dose may be 90 mg, the unit dose may be 100 mg, or the unit dose may 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.

[0291] A unit dose, such as a unit dose for daily administration, may have a concentration of at least about one of or greater than 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 ng / mL, or a range between any two of the foregoing concentrations, e.g., 7 Individual plasma C levels of 00-1500, 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. max For example, C max can be about 700 ng / mL or more. max can be about 750 ng / mL or more. max can be about 800 ng / mL or more. max can be about 850 ng / mL or greater. max can be 900 ng / mL or more. max can be about 950 ng / mL or more. max can be about 1000 ng / mL or more. max can be about 1050 ng / mL or greater. max can be about 1100 ng / mL or more. max can be about 1200 ng / mL or more. max can be about 1300 ng / mL or more. max can be about 1400 ng / mL or more. max can be about 1500 ng / mL or greater.

[0292] A unit dose, such as a unit dose for daily administration, may be 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, e.g., 50-100, 60-90, 70-90, 75-95, etc., of the alpha-glucan in an individual. V β6 or α V Individual plasma C corresponding to the plasma conditioning concentration effective for β1 inhibition max In some embodiments, the compound can be a double alpha V β6 / α V It may be a β1 inhibitor, max is a percentage of individuals each independently selected from the aforementioned percentages or ranges between any two of the aforementioned percentages. V β6 and α V For example, the plasma concentration can correspond to a plasma concentration effective to inhibit α 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 In addition, for example, the plasma adjusted concentration may be effective to inhibit α by at least about 90%. 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 in each independently selected percentage of subjects.V β6 and / or α V The specification "β1" instead refers to a single α V β6 inhibitors and corresponding percentages, single α V β1 inhibitors and corresponding percentages, or dual α V β6 / α V β6 inhibitors and corresponding independently selected percentages.

[0293] The dosage form for daily administration can be administered once a day to an individual in need thereof. That is, the total amount of the compound of formula (A), the compound of formula (I), or a variant thereof, such as 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 to 780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, to be administered daily can be administered at once. Alternatively, when it is desired to administer the total amount of a compound of Formula (A), a compound of Formula (I), or a variant thereof, such as 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 to 780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in two or more divided doses per day, a dosage form containing an appropriate amount of the compound can be administered two or more times per day, for example, twice, three times, or four times per day.

[0294] kit The present invention further provides a kit for carrying out the method of the present invention, comprising one or more compounds or salts thereof as described herein, or pharmaceutical compositions comprising the compounds as described herein.The kit can use any of the compounds disclosed herein.In one variation, the kit uses the compounds described herein or their pharmaceutically acceptable salts.The kit can be used for any one or more of the uses described herein, and therefore can contain instructions for use in treating fibrotic diseases.

[0295] The kit generally includes a suitable package. The kit may include one or more containers containing the compounds described herein. Each component (if there are two or more components) may be packaged in a separate container, or several components may be combined into one container if cross-reactivity and shelf life permit. One or more components of the kit may be sterile and / or may be contained in a sterile package.

[0296] The kits may be in unit dosage form, bulk packages (e.g., multi-dose packages), or sub-unit doses. For example, kits may be provided that contain a sufficient dosage of a compound disclosed herein (e.g., a therapeutically effective amount) and / or a second pharmaceutically active compound useful for a disease detailed herein (e.g., fibrosis) to effectively treat an individual for an extended period of time, e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or longer. The kits may also include multiple unit doses of the compound and instructions for use, and may be packaged in a quantity sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0297] The kit may optionally include a set of instructions, typically written instructions, although electronic storage media (e.g., magnetic or optical disks) containing instructions are also acceptable, regarding the use of the components of the methods of the invention. The instructions included with the kit generally include information regarding the components and their administration to an individual.

[0298] The kit may optionally further comprise instructions for administering the dosage form to an individual in need thereof, e.g., instructions for administering the dosage form to an individual in need thereof once, twice, three times, or four times daily, e.g., instructions for administering the dosage form to an individual in need thereof once daily.

[0299] General Procedure The compounds provided herein can be prepared according to general schemes, as illustrated by the general procedures and examples. Even when these general procedures are followed, slight variations in temperature, concentration, reaction time, and other parameters can occur that do not substantially affect the outcome of the procedures.

[0300] In the following general procedures, where a specific stereoisomer, or an unspecified stereoisomer, or a mixture of stereoisomers is shown, it is understood that analogous chemical transformations can be carried out on other specific stereoisomers, or an unspecified stereoisomer, or a mixture thereof. For example, the hydrolysis reaction of methyl (S)-4-amino-butanoate to (S)-4-amino-butanoic acid can be carried out on methyl (R)-4-amino-butanoate to prepare (R)-4-amino-butanoic acid, or on a mixture of methyl (S)-4-amino-butanoate and methyl (R)-4-amino-butanoate to prepare a mixture of (S)-4-amino-butanoic acid and (R)-4-amino-butanoic acid.

[0301] Some of the following general procedures use specific compounds to illustrate the general reaction (e.g., deprotection of a compound having a Boc-protected amine to a compound having a deprotected amine using an acid). The general reaction can be performed on other specific compounds having the same functional group (e.g., a different compound having a protected amine where the Boc-protecting group can be removed using an acid in the same manner) only if such other specific compounds do not contain additional functional groups susceptible to the general reaction (i.e., such other specific compounds do not contain acid-sensitive functional groups), or if the effect of the general reaction on these additional functional groups is desired (e.g., such other specific compounds have another group susceptible to acid, and the effect of acid on this other group is the desired reaction).

[0302] Where a particular reagent or solvent is specifically described for a reaction in a general procedure, one skilled in the art will recognize that other reagents or solvents can be substituted as needed. For example, where hydrochloric acid is used to remove the Boc group, trifluoroacetic acid can be used instead. As another example, where HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) is used as a coupling reagent, BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate) or PyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) can be used instead. [ka]

[0303] N-Cyclopropyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide. To a mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanoic acid hydrochloride (5.0 g, 19.48 mmol) and cyclopropanamine (1.51 mL, 21.42 mmol) in CHCl (80 mL) was added DIPEA (13.57 mL, 77.9 mmol) at room temperature. HATU (8.1 g, 21.42 mmol) was then added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified by normal-phase silica gel chromatography to give N-cyclopropyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide. [ka]

[0304] N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide. To a mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (351 mg, 1.71 mmol) and formic acid (0.09 mL, 2.22 mmol) in THF / DMF (4:1) (5 mL) was added HATU (844 mg, 2.22 mmol), followed by DIPEA (0.89 mL, 5.13 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified by normal phase silica gel chromatography to give N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide. [ka]

[0305] N-(2-Methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. A mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (300 mg, 1.46 mmol), 1-bromo-2-methoxyethane (0.11 mL, 1.17 mmol), and DIPEA (0.25 mL, 1.46 mmol) in i-PrOH (3 mL) was heated to 70° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, then concentrated in vacuo and purified by normal phase silica gel chromatography to give N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. [ka]

[0306] N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. To a solution of N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide (200 mg, 0.86 mmol) in THF (2 mL) at room temperature was added dropwise a borane-tetrahydrofuran complex solution (1.0 M in THF, 4.0 mL, 4.0 mmol). The resulting mixture was then heated to 60° C. for 2 hours and then allowed to cool to room temperature. The reaction mixture was diluted with MeOH and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. [ka]

[0307] N-(2-Methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (5). To a solution of N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide (15.5 g, 1.0 equiv.) in 1,4-dioxane (124 mL) at room temperature was slowly added LiAlH (1.0 M in THF, 123 mL, 2.2 equiv.), and the resulting mixture was heated to reflux for 20 hours and then cooled to 0° C. To this solution was added HO (4.7 mL), followed by 1 M NaOH (4.7 mL), followed by HO (4.7 mL), warmed to room temperature, and stirred for 30 minutes, at which point solid MgSO was added and stirred for an additional 30 minutes. The resulting mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated in vacuo to give N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. [ka]

[0308] Methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. To a mixture of N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (5) (187 mg, 0.85 mmol) in MeOH (5 mL) at room temperature was added acetic acid (0.12 mL, 2.05 mmol), followed by the addition of methyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (217 mg, 0.94 mmol). The resulting mixture was stirred at room temperature for 15 minutes, at which time sodium cyanoborohydride (80 mg, 1.28 mmol) was added to the reaction mixture, which was stirred for 30 minutes and then concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. [ka]

[0309] Methyl (S)-2-amino-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (152 mg, 0.35 mmol) in 2 mL of CHCl at room temperature was added 4 N HCl in 1,4-dioxane (1 mL, 4 mmol), and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo to give methyl (S)-2-amino-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate as the trihydrochloride salt. [ka]

[0310] A solution of (S)-methyl 2-amino-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate trihydrochloride (80 mg, 0.16 mmol), 4-chloro-2-methyl-6-(trifluoromethyl)pyrimidine (64 mg, 0.33 mmol), and DIPEA (0.23 mL, 1.31 mmol) in i-PrOH (1 mL) was heated at 60 °C overnight. The reaction was allowed to cool to room temperature and then concentrated in vacuo. The resulting crude residue was purified by normal phase silica gel chromatography to give methyl (S)-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)butanoate. [ka]

[0311] (S)-2-((2-chloro-3-fluorophenyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a solution of methyl (S)-2-((2-chloro-3-fluorophenyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate in THF / MeOH / HO (4:1:1) at room temperature was added lithium hydroxide (about 4 equivalents), and the resulting mixture was stirred for 30 minutes. The reaction mixture was concentrated in vacuo and the resulting crude residue was purified by reverse-phase HPLC to afford (S)-2-((2-chloro-3-fluorophenyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid as the trifluoroacetate salt. [ka]

[0312] (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a mixture of methyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (1 g, 1.90 mmol) in HO (3 mL), THF (3 mL), and MeOH (3 mL) was added LiOH·HO (159.36 mg, 3.80 mmol), and the mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo. The mixture was adjusted to pH=6 with AcOH (2 mL) and the residue was concentrated in vacuo to give the compound (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. LCMS (ESI+): m / z=513.5 (M+H). + . 11H NMR (400 MHz, DMSO-d6): δ ppm 7.25 - 7.37 (m, 5H), 7.00 (d, J = 7.28 Hz, 1H), 6.81 (br d, J = 7.50 Hz, 1H), 6.22 (d, J = 7.28 Hz, 1H), 4.93 - 5.05 (m, 2H), 3.68 - 3.77 (m, 1H), 3.25 - 3.34 (m, 1H), 3.15 - 3.24 (m, 5H), 2.58 (br t, J = 6.06 Hz, 2H), 2.29 - 2.49 (m, 8H), 2.16 (br dd, J = 12.90, 6.06 Hz, 1H), 1.69 - 1.78 (m, 2H), 1.58 - 1.68 (m, 1H), 1.53 (quin, J = 7.39 Hz, 2H), 1.28 - 1.40 (m, 2H), 1.00 (d, J = 5.95 Hz, 3H). [Chemical formula]

[0313] (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate tert-Butyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8 To a solution of N-naphthyridin-2-yl)butyl)amino)butanoic acid (300 mg, 523.84 μmol, HOAc salt) in DMA (4 mL) was added N-benzyl-N,N-diethylethanaminium chloride (119.32 mg, 523.84 μmol), K2CO3 (1.88 g, 13.62 mmol), and 2-bromo-2-methylpropane (3.45 g, 25.14 mmol). The mixture was stirred at 55 °C for 18 hours and then allowed to cool to room temperature. The reaction mixture was concentrated in vacuo, and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative TLC to give tert-butyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. LCMS (ESI+): m / z=569.3 (M+H). + . [ka]

[0314] tert-Butyl (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. To a solution of tert-butyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (107 mg, 188.13 μmol) in i-PrOH (2 mL) was added Pd(OH) (26 mg) under a N atmosphere. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (15 psi) at room temperature for 15 h. The mixture was filtered and concentrated in vacuo to give tert-butyl (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. LCMS (ESI+): m / z=435.5 (M+H). + . 1 H NMR(400MHz,CDCl3):δ ppm 7.06(d,J=7.34Hz,1H)6.34(d,J=7.34Hz,1H)4.98(br s,1H)3.38-3.44(m,4H)3.34(s,3H)2.69(t,J=6.30Hz,2H)2.51-2.59(m,5H)2.31(dd,J=1 3.39,5.56Hz,1H)1.86-1.94(m,5H)1.49-1.69(m,6H)1.47(s,9H)1.13(d,J=6.11Hz,3H). [ka]

[0315] (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate tert-butyl (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate tert-butyl (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate tert-butyl (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (100 mg, 230.09 μmol) and 2-chloro-5-methyl- To a solution of pyrimidine (24.65 mg, 191.74 μmol) in 2-methyl-2-butanol (2 mL) was added t-BuONa (2 M in THF, 191.74 μL) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (15.23 mg, 19.17 μmol), and the resulting mixture was stirred at 100° C. for 14 hours. The mixture was concentrated in vacuo to give tert-butyl (S)-4-(((S)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate. LCMS (ESI+): m / z = 527.3 (M+H). + . [ka]

[0316] (S)-4-(((R)-2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid. To a solution of tert-butyl (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate (80 mg, 151.89 μmol) in DCM (2 mL) was added TFA (254.14 mg, 2.23 mmol) at 0° C. The mixture was stirred at room temperature for 6 hours. The mixture was concentrated in vacuo and the resulting crude residue was purified by preparative HPLC to give the compound (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid. LCMS (ESI+): m / z=471.2 (M+H). + . 1 H NMR (400MHz, methanol-d4) δ ppm 8.57(br s,2H)7.60(d,J=7.28Hz,1H)6.67(d,J=7.28Hz,1H)4.81-4.86(m,1H)3.86(br s,1H)3.41-3.59(m,4H)3.39(s,3H)3.33-3.38(m,1H)3.12-3.30(m,3H)2.76-2.86(m,4H)2.54(br s,1H)2.39(br d,J=8.82Hz,1H)2.30(s,3H)1.76-1.99(m,6H)1.22(d,J=5.95Hz,3H).

[0317] List of embodiments The embodiments listed below are representative of some aspects of the present invention. Embodiment 1. Formula (I): [ka] During the ceremony, R 1 But C6~C 14 aryl or 5-10 membered heteroaryl, C6-C 14Aryl and 5- to 10-membered heteroaryl are R 1a and optionally replaced by R 2 But R 2a C1-C6 alkyl optionally substituted by R 2b C3-C6 cycloalkyl optionally substituted by R 2c or -S(O)R 2d and Each R 1a are independently C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C8 cycloalkyl, C4 to C8 cycloalkenyl, 3 to 12 membered heterocyclyl, 5 to 10 membered heteroaryl, C6 to 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 may independently be deuterium, halogen, oxo, -OR, if possible. 6 , -NR6 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; R 2a , R 2b , R 2c , R 2e , and R 2f are each independently oxo or R 1a and R 2d But R 2e C1-C6 alkyl optionally substituted by R f 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; 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 5are 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; 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; R 4 and R 5 together with the atoms to which they are attached, deuterium, halogen, oxo, -OR 8 , -NR 8 R 9 or a 3-6 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; or 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 9are 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; or 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; R 10 , R 11 , R 12 , and R 13 are each independently hydrogen or deuterium; R 14 is deuterium, q is 0, 1, 2, 3, 4, 5, 6, 7, or 8; A compound or a salt thereof, wherein p is 3, 4, 5, 6, 7, 8, or 9. Embodiment 2.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 , R 11 , R 12 , R 13 , or R 14 or a salt thereof, wherein at least one of: is deuterium. Embodiment 3.R 10 , R 11 , R 12 , R 13 , and R 14is hydrogen, and p is 3, represented by a compound of formula (II): or a salt thereof. [ka] Embodiment 4.R 1 But R 1a or a salt thereof. Embodiment 5.R 1 But R 1a or a salt thereof. Embodiment 6.R 1 But R 1a pyrimidin-4-yl optionally substituted by 1a is 5-10 membered heteroaryl, or C1-C6 alkyl optionally substituted with halogen; or a salt thereof. Embodiment 7.R 1 is pyrimidin-4-yl optionally substituted with pyrazolyl, methyl, difluoromethyl, or trifluoromethyl; or a salt thereof. Embodiment 8.R 1 is pyrimidin-4-yl substituted with both methyl and trifluoromethyl; or a salt thereof. Embodiment 9.R 1 But R 1a or a salt thereof. Embodiment 10.R 1 is quinazolin-4-yl optionally substituted with halogen, C1-C6 alkyl optionally substituted with halogen, or C1-C6 alkoxy; or a salt thereof. Embodiment 11.R 1is quinazolin-4-yl optionally substituted with fluoro, chloro, methyl, trifluoromethyl, or methoxy; or a salt thereof. Embodiment 12.R 2 But R 2a or a salt thereof. Embodiment 13.R 2 But R 2a C1-C6 alkyl optionally substituted by R 2a is halogen, C3-C8 cycloalkyl optionally substituted with halogen, 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl, -NR 4 R 5 , -NR 3 C(O)R 4 , -S(O)2R 3 or oxo. Embodiment 14.R 2 But R 2a C1-C6 alkyl optionally substituted by R 2a 12. The compound according to any one of embodiments 1 to 11, wherein is fluoro, cyclobutyl substituted with fluoro, pyrazolyl substituted with methyl, or -S(O)2CH3, or a salt thereof. Embodiment 15.R 2 But, -OR 3 or a salt thereof. Embodiment 16.R 2 But, -OR 3 C1-C6 alkyl optionally substituted by R 3 is hydrogen, C1-C6 alkyl optionally substituted with halogen, C3-C6 cycloalkyl optionally substituted with halogen, C6-C 1412. The compound according to any one of embodiments 1 to 11, or a salt thereof, which is aryl, or 5-6 membered heteroaryl optionally substituted with halogen or C1-C6 alkyl. Embodiment 17.R 2 But, -OR 3 C1-C6 alkyl optionally substituted by R 3 or a salt thereof. Embodiment 18.R 2 12. The compound according to any one of embodiments 1 to 11, or a salt thereof, wherein is —CH 2 CH 2 OCH 3 . Embodiment 19.R 2 However, halogens and OR 3 and R is a C1-C6 alkyl substituted with both 3 is C1-C6 alkyl; or a salt thereof. Embodiment 20.R 2 But R 2b or a salt thereof. Embodiment 21.R 2 12. The compound according to any one of embodiments 1 to 11, or a salt thereof, wherein is cyclopropyl. Embodiment 22.R 1 but [ka] wherein m is 0, 1, 2, or 3; and each R 1a are, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R 1aor a salt thereof. 4. The compound of embodiment 1, 2, or 3, wherein alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium; Embodiment 23.R 1 but, [ka] where each R 1a is independently deuterium, alkyl, haloalkyl, or heteroaryl; or a salt thereof. Embodiment 24.R 1 but [ka] wherein m is 0, 1, 2, or 3; and each R 1a are, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R 1a or a salt thereof. 4. The compound of embodiment 1, 2, or 3, wherein alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium; Embodiment 25.R 1 but [ka] wherein m is 0, 1, 2, 3, 4, or 5; and each R 1a are, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R 1a or a salt thereof. 4. The compound of embodiment 1, 2, or 3, wherein alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium; Embodiment 26.R 1 but, [ka] where each R 1a is independently deuterium, halogen, alkyl, haloalkyl, or alkoxy; or a salt thereof. Embodiment 27.R 1 but, [ka] wherein m is 0, 1, 2, 3, 4, or 5; and each R 1a are, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R 1a or a salt thereof. 4. The compound of embodiment 1, 2, or 3, wherein alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium; Embodiment 28.R 1 but [ka] wherein m is 0, 1, 2, 3, or 4, and each R 1a are, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R 1a or a salt thereof. 4. The compound of embodiment 1, 2, or 3, wherein alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium; Embodiment 29.R 1 but, [ka] or a salt thereof. Embodiment 30.R 1 but [ka] wherein m is 0, 1, 2, 3, or 4, and each R 1aare, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R 1a or a salt thereof. 4. The compound of embodiment 1, 2, or 3, wherein alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium; Embodiment 31.R 1 but, [ka] or a salt thereof. Embodiment 32.R 1 but [ka] wherein m is 0, 1, 2, 3, or 4, and each R 1a are, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R 1a or a salt thereof. 4. The compound of embodiment 1, 2, or 3, wherein alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium; Embodiment 33.R 1 but, [ka] or a salt thereof. Embodiment 34.R 1 but [ka] wherein m is 0, 1, 2, 3, 4, 5, or 6; and each R 1a are, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R 1aor a salt thereof. 4. The compound of embodiment 1, 2, or 3, wherein alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium; Embodiment 35.R 1 but [ka] wherein m is 0, 1, 2, 3, 4, 5, or 6; and each R 1a are, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R 1a or a salt thereof. 4. The compound of embodiment 1, 2, or 3, wherein alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium; Embodiment 36.R 1 but [ka] wherein m is 0, 1, or 2, and each R 1a is, if applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a or a salt thereof. 4. The compound of embodiment 1, 2, or 3, wherein alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium; Embodiment 37.R 1 but, [ka] and any of the foregoing groups in which any one or more hydrogen atoms are replaced by deuterium atoms; or a salt thereof. Embodiment 38.R 1 but, [ka] and any of the foregoing groups in which any one or more hydrogen atoms are replaced by deuterium atoms; or a salt thereof. Embodiment 39.R 1 but, [ka] and any of the foregoing groups in which any one or more hydrogen atoms are replaced by deuterium atoms; or a salt thereof. Embodiment 40.R 2 but [ka] wherein n is 1, 2, 3, 4, 5, or 6; and R 3 is C1-C2 alkyl optionally substituted with fluoro, phenyl optionally substituted with fluoro, pyridinyl optionally substituted with fluoro or methyl, or cyclopropyl optionally substituted with fluoro; or a salt thereof. Embodiment 41.R 2 but, [ka] and any of the foregoing groups in which any one or more hydrogen atoms are replaced by deuterium atoms; or a salt thereof. Embodiment 42. A compound selected from compound numbers 1 to 66 in FIG. 1, or a salt thereof. Embodiment 43. A compound selected from compound numbers 1 to 147, or a salt thereof. Embodiment 44. A compound selected from compound numbers 1 to 665, or a salt thereof. Embodiment 45. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 44 or a salt thereof, and a pharmaceutically acceptable carrier or excipient. Embodiment 46. A method of treating a fibrotic disorder in an individual in need thereof, comprising administering a compound according to any one of embodiments 1 to 44, or a pharmaceutically acceptable salt thereof. Embodiment 47. The method of embodiment 46, wherein the fibrotic disease is pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis. Embodiment 48. A kit comprising a compound according to any one of embodiments 1 to 44, or a pharmaceutically acceptable salt thereof. Embodiment 49. The kit of embodiment 48, further comprising instructions for treating a fibrotic disorder. Embodiment 50. A method for inhibiting αvβ6 integrin in an individual, comprising administering a compound according to any one of embodiments 1 to 44, or a pharmaceutically acceptable salt thereof. Embodiment 51. A method for inhibiting TGFβ activation in a cell, comprising administering to the cell a compound described in any one of embodiments 1 to 44 or a pharmaceutically acceptable salt thereof. Embodiment 52. Use of a compound according to any one of embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a fibrotic disease. Embodiment 53.R 2 12. The compound according to any one of embodiments 1 to 11, wherein is C3-C5 alkyl substituted with both fluorine and -OCH3; or a salt thereof. Embodiment 54.R 2 But, -OR 3 C1-C6 alkyl optionally substituted by R 3 12. The compound according to any one of embodiments 1-11, wherein is phenyl optionally substituted with fluorine; or a salt thereof. Embodiment 55.R 2 But, -OR 3 C1-C6 alkyl optionally substituted by R 312. The compound according to any one of embodiments 1-11, wherein is pyridinyl optionally substituted with fluorine or methyl; or a salt thereof. Embodiment 56.R 2 But R 2a C1-C6 alkyl substituted by R 2a 12. The compound according to any one of embodiments 1 to 11, or a salt thereof, wherein is halogen. Embodiment 57.R 2 But R 2a C1-C6 alkyl substituted by R 2a 12. The compound or salt thereof according to any one of embodiments 1 to 11, wherein is deuterium. Embodiment 58.R 2 But R 2a C1-C6 alkyl substituted by R 2a 12. The compound according to any one of embodiments 1 to 11, wherein is 3- to 12-membered heterocyclyl optionally substituted by oxo; or a salt thereof. Embodiment 59.R 2 But R 2a C1-C6 alkyl substituted by R 2a 12. The compound according to any one of embodiments 1 to 11, wherein is 4-5 membered heterocyclyl optionally substituted by oxo; or a salt thereof. Embodiment 60.R 2 But R 2a C1-C6 alkyl substituted by R 2a But halogen or -OR 6 C6 to C optionally substituted by 14 12. The compound according to any one of embodiments 1 to 11, or a salt thereof, wherein: Embodiment 61.R 2 But R 2a C1-C6 alkyl substituted by R 2a But halogen or -OR 6 or a salt thereof. Embodiment 62.R2 But R 2a C1-C6 alkyl substituted by R 2a is 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl; or a salt thereof. Embodiment 63.R 2 But R 2a C1-C6 alkyl substituted by R 2a is pyrazolyl optionally substituted with methyl; or a salt thereof. Embodiment 64.R 2 But R 2a C1-C6 alkyl substituted by R 2a is -CN, halogen, or -OR 6 or a salt thereof. Embodiment 65.R 2 But R 2a C1-C6 alkyl substituted by R 2a -S(O)2R 3 or a salt thereof. Embodiment 66.R 1 But R 1a or a salt thereof. Embodiment 67.R 1 But R 1a or a salt thereof. Embodiment 68.R 1 But R 1a or a salt thereof. 4. The compound according to embodiment 1, 2, or 3, wherein R is 1H-pyrrolopyridyl optionally substituted by: Embodiment 69.R 1 But R 1aor a salt thereof. Embodiment 70.R 1 But R 1a or a salt thereof. Embodiment 71.R 1 But R 1a or a salt thereof.

[0318] Synthesis Example The chemical reactions in the described synthetic examples can be easily adapted to prepare some other compounds of the present invention, and alternative methods for preparing compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds of the present invention can be successfully carried out by modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups or by utilizing other suitable reagents known in the art other than those described, or by routine modification of reaction conditions. Alternative...

Claims

1. A dosage form adapted for daily administration, A pharma- ceutically acceptable carrier or excipient; Formula (A): 【Chemistry 1】 During the ceremony, R １ But, C ６ ~C １４ aryl or 5- to 10-membered heteroaryl, ６ ~C １４ Aryl and 5- to 10-membered heteroaryl are R １ａ is optionally replaced by R ２ is hydrogen, deuterium, R ２ａ C optionally substituted by １ ~C ６ Alkyl, -OH, R ２ａ -OC optionally substituted １ ~C ６ Alkyl, R ２ｂ C optionally substituted by ３ ~C ６ Cycloalkyl, R ２ｂ -OC optionally substituted ３ ~C ６ Cycloalkyl, R ２ｃ or -S(O) ２ R ２ｄ with the proviso that any carbon atom directly bonded to a nitrogen atom is R other than a halogen. ２ａ provided that the moiety is optionally replaced by Each R １ａ became independent and C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ８ Cycloalkyl, C ４ ~C ８ Cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C ６ ~C １４ Aryl, deuterium, halogen, -CN, -OR ３ , -SR ３ , -NR ４ R ５ , -NO ２ , -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) ２ R ３ , -NR ３ S(O)R ４ , -NR ３ S (O) ２ R ４ , -S(O)NR ４ R ５ , -S(O) ２ N.R. ４ R ５ or -P(O)(OR ４ ) (OR ５ ) wherein each R １ａ are each independently, if possible, deuterium, halogen, oxo, -OR ６ , -NR ６ R ７ , -C(O)R ６ , -CN, -S(O)R ６ , -S(O) ２ R ６ , -P(O)(OR ６ ) (OR ７ ), C ３ ~C ８ cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C ６ ~C １４ Aryl or C optionally substituted with deuterium, oxo, —OH, or halogen １ ~C ６ is optionally substituted with alkyl; Each R ２ａ , R ２ｂ , R ２ｃ , R ２ｅ , and R ２ｆ are independently oxo or R １ａ and R ２ｄ But, R ２ｅ C optionally substituted by １ ~C ６ Alkyl or R ２ｆ C optionally substituted by ３ ~C ５ is cycloalkyl, R ３ are independently hydrogen, deuterium, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, C ６ ~C １４ aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; R ３ The above C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, C ６ ~C １４ Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are independently selected from halogen, deuterium, oxo, —CN, —OR ８ , -NR ８ R ９ , -P(O)(OR ８ ) (OR ９ ), or C optionally substituted by deuterium, halogen, —OH, or oxo １ ~C ６ is optionally substituted with alkyl; R ４ and R ５ are each independently hydrogen, deuterium, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, C ６ ~C １４ aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl; R ４ and R ５ The above C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, C ６ ~C １４ Aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from deuterium, halogen, oxo, —CN, —OR ８ , -NR ８ R ９ or C optionally substituted by deuterium, halogen, —OH, or oxo １ ~C ６ optionally substituted with alkyl, or R ４ and R ５ together with the atom to which they are attached, deuterium, halogen, oxo, -OR ８ , -NR ８ R ９ or C optionally substituted by deuterium, halogen, oxo, or -OH １ ~C ６ forming a 3- to 6-membered heterocyclyl optionally substituted by alkyl; R ６ and R ７ are each independently optionally substituted by hydrogen, deuterium, halogen, or oxo. １ ~C ６ C optionally substituted with alkyl, deuterium, halogen, or oxo ２ ~C ６ alkenyl, or C optionally substituted with deuterium, halogen, or oxo ２ ~C ６ alkynyl, or R ６ and R ７ are optionally substituted with deuterium, halogen, oxo, or deuterium, halogen, or oxo, together with the atom to which they are attached; １ ~C ６ forming a 3- to 6-membered heterocyclyl optionally substituted by alkyl; R ８ and R ９ are each independently optionally substituted by hydrogen, deuterium, halogen, or oxo. １ ~C ６ C optionally substituted with alkyl, deuterium, halogen, or oxo ２ ~C ６ alkenyl, or C optionally substituted with deuterium, halogen, or oxo ２ ~C ６ alkynyl, or R ８ and R ９ are optionally substituted, together with the atom to which they are attached, by deuterium, halogen, oxo, or deuterium, oxo, or halogen; １ ~C ６ forming a 3- to 6-membered heterocyclyl optionally substituted by alkyl; 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 １５ are independently selected from hydrogen, deuterium, or a halogen; Each R １６ are independently selected from hydrogen, deuterium, or a halogen; and a unit dose of a compound, or a salt thereof, wherein p is 3, 4, 5, 6, 7, 8, or 9.

2. R ２ But, R ２ａ C optionally substituted by １ ~C ６ Alkyl, R ２ｂ C optionally substituted by ３ ~C ６ Cycloalkyl, R ２ｃ or -S(O) ２ R ２ｄ and R ３ are independently hydrogen, deuterium, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, C ６ ~C １４ aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl; R ３ The above C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, C ６ ~C １４ Aryl, 5- to 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 C optionally substituted by deuterium, halogen, —OH, or oxo １ ~C ６ is optionally substituted with alkyl; Each R １５ is hydrogen, Each R １６ is hydrogen, 2. The dosage form of claim 1, wherein said compound of formula (A) is represented by formula (I): 【Chemistry 2】

3. 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 , R １１ , R １２ , R １３ , or R １４ 3. The dosage form of claim 1 or claim 2, or a salt thereof, wherein at least one of:

4. R １０ , R １１ , R １２ , R １３ , and R １４ 3. The dosage form of claim 1 or claim 2, wherein: is hydrogen; p is 3; and said compound of formula (A) is represented by a compound of formula (II): 【Chemistry 3】

5. R １ But, R １ａ 5. The dosage form of claim 1, wherein R is 5 to 10 membered heteroaryl optionally substituted by R, ...

6. R １ but, pyrimidinyl, quinazolinyl, pyrazolopyrimidinyl, pyrazinyl, quinolinyl, pyridopyrimidinyl, thienopyrimidinyl, pyridinyl, pyrrolopyrimidinyl, quinoxalinyl, indazolyl, benzothiazolyl, naphthalenyl, purinyl, or isoquinolinyl, and Deuterium, hydroxyl, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Perhaloalkyl, C １ ~C ６ Alkoxyl, C ３ ~C ８ Cycloalkyl, C ３ ~C ８ Halocycloalkyl, C ３ ~C ８ Cycloalkoxyl, 5-10 membered heteroaryl, C ６ ~C １４ 5. The dosage form of any one of claims 1 to 4, optionally substituted with aryl, cyano, amino, alkylamino, or dialkylamino, or a salt thereof.

7. R １ but, Pyrimidin-2-yl, pyrimidin-4-yl, quinazolin-4-yl, 1H-pyrazolo[3,4-d]pyrimidin-4-yl, 1H-pyrazolo[4,3-d]pyrimidin-7-yl, pyrazin-2-yl, quinolin-4-yl, pyrido[2,3-d]pyrimidin-4-yl, pyrido[3,2-d]pyrimidin-4-yl, pyrido[3,4-d]pyrimidin-4-yl, thieno[2,3-d] pyrimidin-4-yl, thieno[3,2-d]pyrimidin-4-yl, thienopyrimidin-4-yl, pyridin-2-yl, pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, quinoxalin-2-yl, 1H-indazol-3-yl, benzo[d]thiazol-2-yl, naphthalen-1-yl, 9H-purin-6-yl, or isoquinolin-1-yl; and 5. The dosage form of any one of claims 1 to 4, optionally substituted with one or more deuterium, methyl, cyclopropyl, fluoro, chloro, bromo, difluoromethyl, trifluoromethyl, methyl and fluoro, methyl and trifluoromethyl, methoxy, cyano, dimethylamino, phenyl, pyridin-3-yl, or pyridin-4-yl, or a salt thereof.

8. R １ But, R １ａ 5. The dosage form of any one of claims 1 to 4, wherein R is pyrimidin-4-yl optionally substituted by:

9. R １ But, R １ａ pyrimidin-4-yl optionally substituted by １ａ is a 5-10 membered heteroaryl optionally substituted with halogen or C １ ~C ６ 5. The dosage form of any one of claims 1 to 4, or a salt thereof, wherein:

10. R １ 5. The dosage form of any one of claims 1 to 4, wherein is pyrimidin-4-yl optionally substituted by pyrazolyl, methyl, difluoromethyl, or trifluoromethyl, or a salt thereof.

11. R １ 5. The dosage form of any one of claims 1 to 4, wherein is pyrimidin-4-yl substituted by both methyl and trifluoromethyl, or a salt thereof.

12. R １ But, R １ａ 5. The dosage form of any one of claims 1 to 4, wherein R is quinazolin-4-yl optionally substituted by:

13. R １ is halogen, C optionally substituted by halogen １ ~C ６ Alkyl, or C １ ~C ６ 5. The dosage form of any one of claims 1 to 4, which is quinazolin-4-yl optionally substituted by alkoxy, or a salt thereof.

14. R １ The dosage form of any one of claims 1 to 4, wherein is quinazolin-4-yl optionally substituted with fluoro, chloro, methyl, trifluoromethyl, or methoxy, or a salt thereof.

15. R ２ but, hydrogen, deuterium, Hydroxy, or Deuterium, halogens, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Alkoxyl, C ３ ~C ８ Cycloalkyl, C ３ ~C ８ Halocycloalkyl, C ３ ~C ８ Cycloalkoxyl, C ６ ~C １４ Aryl, C ６ ~C １４ aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy, 3- to 12-membered heterocyclyl optionally substituted with oxo, —C(O)NR ４ R ５ , -NR ３ C(O)R ４ or -S(O) ２ R ３ C optionally substituted with １ ~C ６ Alkyl or C １ ~C ６ 15. The dosage form of any one of claims 1 or 3 to 14, or a salt thereof, which is alkoxyl.

16. R ２ but, methyl, methoxy, ethyl, ethoxy, propyl, cyclopropyl, or cyclobutyl; each of which is optionally substituted by one or more of hydroxy, methoxy, ethoxy, acetamido, fluoro, fluoroalkyl, phenoxy, dimethylamido, methylsulfonyl, cyclopropoxyl, pyridin-2-yloxy, optionally methylated or fluorinated pyridin-3-yloxy, N-morpholinyl, N-pyrrolidin-2-onyl, dimethylpyrazol-1-yl, dioxiran-2-yl, morpholin-2-yl, oxetan-3-yl, phenyl, tetrahydrofuran-2-yl, thiazol-2-yl; 15. The dosage form of any one of claims 1 or 3-14, or a salt thereof, each of which is substituted with 0, 1, 2, or 3 of deuterium, hydroxy, methyl, fluoro, cyano, or oxo.

17. R ２ But, R ２ａ C optionally substituted by １ ~C ６ 15. The dosage form of any one of claims 1 to 14, or a salt thereof, wherein:

18. R ２ But, R ２ａ C optionally substituted by １ ~C ６ alkyl, R ２ａ is halogen, C optionally substituted by halogen ３ ~C ８ Cycloalkyl, C １ ~C ６ 5-10 membered heteroaryl optionally substituted with alkyl, -NR ４ R ５ , -NR ３ C(O)R ４ , -S(O) ２ R ３ 15. The dosage form of any one of claims 1 to 14, wherein said compound is oxo, or oxo, or a salt thereof.

19. R ２ But, R ２ａ C optionally substituted by １ ~C ６ alkyl, R ２ａ is fluoro, cyclobutyl substituted by fluoro, pyrazolyl substituted by methyl, or -S(O) ２ CH ３ 15. The dosage form according to any one of claims 1 to 14, wherein:

20. R ２ But, -OR ３ C optionally substituted by １ ~C ６ 15. The dosage form of any one of claims 1 to 14, or a salt thereof, wherein:

21. R ２ But, -OR ３ C optionally substituted by １ ~C ６ alkyl, R ３ is optionally substituted by hydrogen, halogen １ ~C ６ C optionally substituted with alkyl, halogen ３ ~C ６ Cycloalkyl, C optionally substituted with halogen ６ ~C １４ Aryl, or halogen or C １ ~C ６ 15. The dosage form of any one of claims 1 to 14, wherein is 5-6 membered heteroaryl optionally substituted with alkyl, or a salt thereof.

22. R ２ But, OR ３ C optionally substituted by １ ~C ６ alkyl, R ３ is hydrogen, methyl, ethyl, difluoromethyl, -CH ２ CHF ２ , -CH ２ CF ３ , cyclopropyl substituted by fluoro, phenyl optionally substituted by fluoro, or pyridinyl optionally substituted by fluoro or methyl, or a salt thereof.

23. R ２ Ga-CH ２ CH ２ OCH ３ 15. The dosage form according to any one of claims 1 to 14, wherein:

24. R ２ is halogen and OR ３ C is substituted by both １ ~C ６ alkyl, R ３ C １ ~C ６ 15. The dosage form of any one of claims 1 to 14, or a salt thereof, wherein:

25. R ２ But, R ２ｂ C optionally substituted by ３ ~C ６ 15. The dosage form of any one of claims 1 to 14, or a salt thereof, wherein the aryl group is cycloalkyl.

26. R ２ The dosage form of any one of claims 1 to 14, wherein is cyclopropyl, or a salt thereof.

27. R １ but 【Chemistry 4】 wherein m is 0, 1, 2, or 3; １ａ is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R １ａ 5. The dosage form of any one of claims 1 to 4, wherein said alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium, or a salt thereof.

28. R １ but, 【Chemistry 5】 wherein each R １ａ 28. The dosage form of claim 27, or a salt thereof, wherein is independently deuterium, alkyl, haloalkyl, or heteroaryl.

29. R １ but 【Chemistry 6】 wherein m is 0, 1, 2, or 3; １ａ is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R １ａ 5. The dosage form of any one of claims 1 to 4, wherein said alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium, or a salt thereof.

30. R １ but 【Chemistry 7】 wherein m is 0, 1, 2, 3, 4, or 5; and each R １ａ is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R １ａ 5. The dosage form of any one of claims 1 to 4, wherein said alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium, or a salt thereof.

31. R １ but, 【Chemistry 8】 wherein each R １ａ 31. The dosage form of claim 30, or a salt thereof, wherein is independently deuterium, halogen, alkyl, haloalkyl, or alkoxy.

32. R １ but, 【Chemistry 9】 wherein m is 0, 1, 2, 3, 4, or 5; and each R １ａ is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R １ａ 5. The dosage form of any one of claims 1 to 4, wherein said alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium, or a salt thereof.

33. R １ but 【Chemistry 10】 wherein m is 0, 1, 2, 3, or 4; １ａ is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R １ａ 5. The dosage form of any one of claims 1 to 4, wherein said alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium, or a salt thereof.

34. R １ but, 【Chemistry 11】 34. The dosage form of claim 33, selected from the group consisting of:

35. R １ but 【Chemistry 12】 wherein m is 0, 1, 2, 3, or 4; １ａ is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R １ａ 5. The dosage form of any one of claims 1 to 4, wherein said alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium, or a salt thereof.

36. R １ but, 【Chemistry 13】 36. The dosage form of claim 35, selected from the group consisting of:

37. R １ but 【Chemistry 14】 wherein m is 0, 1, 2, 3, or 4; １ａ is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R １ａ 5. The dosage form of any one of claims 1 to 4, wherein said alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium, or a salt thereof.

38. R １ but, 【Chemistry 15】 38. The dosage form of claim 37, selected from the group consisting of:

39. R １ but 【Chemistry 16】 wherein m is 0, 1, 2, 3, 4, 5, or 6; and each R １ａ is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R １ａ 5. The dosage form of any one of claims 1 to 4, wherein said alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium, or a salt thereof.

40. R １ but 【Chemistry 17】 wherein m is 0, 1, 2, 3, 4, 5, or 6; and each R １ａ is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R １ａ 5. The dosage form of any one of claims 1 to 4, wherein said alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium, or a salt thereof.

41. R １ but 【Chemistry 18】 wherein m is 0, 1, or 2; １ａ is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl; R １ａ 5. The dosage form of any one of claims 1 to 4, wherein said alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium, or a salt thereof.

42. R １ but, 【Chemistry 19】 and any of the preceding groups in which any one or more hydrogen atoms are replaced with a deuterium atom, or a salt thereof.

43. R １ but, 【Chemistry 20】 and any of the preceding groups in which any one or more hydrogen atoms are replaced with a deuterium atom, or a salt thereof.

44. R １ but, 【Chemistry 21】 and any of the preceding groups in which any one or more hydrogen atoms are replaced with a deuterium atom, or a salt thereof.

45. R １ but, 【Chemical 22】 and any of the preceding groups in which any one or more hydrogen atoms are replaced with a deuterium atom, or a salt thereof.

46. R ２ but 【Chemistry 23】 where n is 1, 2, 3, 4, 5, or 6; R ３ is optionally substituted by fluoro １ ~C ２ 46. ​​The dosage form of any one of claims 1-14 or 27-45, wherein R is alkyl, phenyl optionally substituted with fluoro, pyridinyl optionally substituted with fluoro or methyl, or cyclopropyl optionally substituted with fluoro, or a salt thereof.

47. R ２ but, 【Chemistry 24】 and any of the preceding groups in which any one or more hydrogen atoms are replaced with a deuterium atom, or a salt thereof.

48. R ２ but, 【Chemistry 25】 and any of the preceding groups in which any one or more hydrogen atoms are replaced with a deuterium atom, or a salt thereof.

49. R ２ Fluorine and -OCH ３ C is substituted by both ３ ~C ５ 12. The dosage form of any one of claims 1 to 11, or a salt thereof, wherein:

50. R ２ But, -OR ３ C optionally substituted by １ ~C ６ alkyl, R ３ 46. ​​The dosage form of any one of claims 1-14 or 27-45, or a salt thereof, wherein is phenyl optionally substituted with fluorine.

51. R ２ But, -OR ３ C optionally substituted by １ ~C ６ alkyl, R ３ 46. ​​The dosage form of any one of claims 1-14 or 27-45, wherein is pyridinyl optionally substituted with fluorine or methyl, or a salt thereof.

52. R ２ But, R ２ａ C substituted by １ ~C ６ alkyl, R ２ａ 46. ​​The dosage form of any one of claims 1-14 or 27-45, or a salt thereof, wherein is a halogen.

53. R ２ But, R ２ａ C substituted by １ ~C ６ alkyl, R ２ａ 46. ​​The dosage form of any one of claims 1-14 or 27-45, or a salt thereof, wherein is deuterium.

54. R ２ But, R ２ａ C substituted by １ ~C ６ alkyl, R ２ａ is 3-12 membered heterocyclyl optionally substituted by oxo, or a salt thereof.

55. R ２ But, R ２ａ C substituted by １ ~C ６ alkyl, R ２ａ is 4-5 membered heterocyclyl optionally substituted by oxo, or a salt thereof.

56. R ２ But, R ２ａ C substituted by １ ~C ６ alkyl, R ２ａ is halogen or -OR ６ C optionally substituted by ６ ~C １４ 46. ​​The dosage form of any one of claims 1 to 14 or 27 to 45, or a salt thereof, wherein

57. R ２ But, R ２ａ C substituted by １ ~C ６ alkyl, R ２ａ is halogen or -OR ６ 46. ​​The dosage form of any one of claims 1-14 or 27-45, wherein R is phenyl optionally substituted by, or a salt thereof.

58. R ２ But, R ２ａ C substituted by １ ~C ６ alkyl, R ２ａ But, C １ ~C ６ 46. ​​The dosage form of any one of claims 1-14 or 27-45, or a salt thereof, wherein is 5-10 membered heteroaryl optionally substituted with alkyl.

59. R ２ But, R ２ａ C substituted by １ ~C ６ alkyl, R ２ａ 46. ​​The dosage form of any one of claims 1-14 or 27-45, or a salt thereof, wherein is pyrazolyl optionally substituted with methyl.

60. R ２ But, R ２ａ C substituted by １ ~C ６ alkyl, R ２ａ is -CN, halogen, or -OR ６ C optionally substituted by ３ ~C ８ 46. ​​The dosage form of any one of claims 1 to 14 or 27 to 45, or a salt thereof, wherein:

61. R ２ But, R ２ａ C substituted by １ ~C ６ alkyl, R ２ａ Ga-S (O) ２ R ３ 46. ​​The dosage form of any one of claims 1 to 14 or 27 to 45, or a salt thereof.

62. R １ But, R １ａ 5. The dosage form of any one of claims 1 to 4, wherein R is pyridyl optionally substituted by:

63. R １ But, R １ａ 5. The dosage form of any one of claims 1 to 4, wherein R is indazolyl optionally substituted by:

64. R １ But, R １ａ 5. The dosage form of any one of claims 1 to 4, wherein R is 1H-pyrrolopyridyl optionally substituted by:

65. R １ But, R １ａ 5. The dosage form of any one of claims 1 to 4, wherein R is quinolinyl optionally substituted by:

66. R １ But, R １ａ 5. The dosage form of any one of claims 1 to 4, wherein R is phenyl optionally substituted by, or a salt thereof.

67. R １ But, R １ａ 5. The dosage form of any one of claims 1 to 4, wherein R is indanyl optionally substituted by:

68. A dosage form adapted for daily administration, comprising a pharma- ceutically acceptable carrier or excipient and a unit dose of a compound selected from compound numbers 1-66 of FIG. 1, or a salt thereof.

69. A dosage form adapted for daily administration, comprising a pharma- ceutically acceptable carrier or excipient and a unit dose of a compound selected from Compound Nos. 1-147, or a salt thereof.

70. A dosage form adapted for daily administration, comprising a pharma- ceutically acceptable carrier or excipient and a unit dose of a compound selected from Compound Nos. 1-665, or a salt thereof.

71. A dosage form adapted for daily administration, comprising a pharma- ceutically acceptable carrier or excipient and a unit dose of a compound selected from Compound Nos. 1-780, or a salt thereof.

72. The compound is (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, 【Chemistry 26】 or a salt thereof.

73. 73. The dosage form of any one of claims 1-72, comprising 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 of the compound, or a range between any two of the preceding values.

74. 73. The dosage form of any one of claims 1-72, comprising one of 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 of the compound, or a range between any two of the preceding amounts.

75. C in the plasma of the individual of at least about one of 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 ng / mL, or a range between any two of the foregoing concentrations. ｍａｘ 73. The dosage form of any one of claims 1 to 72, comprising an amount of said compound effective for administration to said individual to provide.

76. 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, of individuals Ｖ β ６ or α Ｖ β １ C in the individual's plasma corresponding to a plasma conditioning concentration effective to inhibit ｍａｘ 73. The dosage form of any one of claims 1 to 72, comprising an amount of said compound effective for administration to said individual to result in a naive ...

77. 77. A method of treating a fibrotic disease in an individual in need thereof, comprising administering to said individual daily a dosage form according to any one of claims 1 to 76, or a pharma- ceutically acceptable salt thereof.

78. 78. The method of claim 77, wherein the fibrotic disease is pulmonary fibrosis, hepatic fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis.

79. 79. The method of claim 78, wherein the fibrotic disease is hepatic fibrosis, cardiac fibrosis, primary sclerosing cholangitis, or biliary fibrosis.

80. 80. The method of any one of claims 77-79, wherein said daily administration occurs once, twice, three times, or four times daily.

81. 80. The method of any one of claims 77-79, wherein said daily administration occurs once a day.

82. The individual is administered a C of the compound in the plasma of the individual of at least about one of 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 ng / mL, or a range between any two of the foregoing concentrations. ｍａｘ 78. The method of claim 77, comprising administering the dosage form effective to produce:

83. In said individual, 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, of α in said individual. Ｖ β ６ or α Ｖ β １ C in the individual's plasma corresponding to a plasma conditioning concentration effective to inhibit ｍａｘ 78. The method of claim 77, comprising administering the dosage form effective to produce (ng / mL).

84. A kit comprising a dosage form according to any one of claims 1 to 76.

85. 85. The kit of claim 84, further comprising instructions for said treating a fibrotic disorder.

86. 85. The kit of claim 84, further comprising instructions for daily administration of said dosage form to an individual in need thereof.

87. 85. The kit of claim 84, further comprising instructions for administration of the dosage form to an individual in need thereof one, two, three, or four times daily.

88. 85. The kit of claim 84, further comprising instructions for administration of said dosage form to an individual in need thereof once daily.

89. C in the plasma of the individual of at least about one of 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, or 1400 ng / mL, or a range between any two of the foregoing concentrations. ｍａｘ 85. The kit of claim 84, further comprising instructions for administering the dosage form to the individual in need thereof so as to result in

90. 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, of individuals Ｖ β ６ or α Ｖ β １ C in the individual's plasma corresponding to a plasma conditioning concentration effective to inhibit ｍａｘ 85. The kit of claim 84, further comprising instructions for administering said dosage form to said individual in need thereof to result in (ng / mL).

91. Alpha in an individual Ｖ β ６ or α Ｖ β １ 77. A method of inhibiting an integrin comprising administering a dosage form according to any one of claims 1 to 76, or a pharma- ceutically acceptable salt thereof.

92. The individual is administered a C of the compound in the plasma of the individual of at least about one of 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, or 1400 ng / mL, or a range between any two of the foregoing concentrations. ｍａｘ 92. The method of claim 91, comprising administering the dosage form effective to produce:

93. In said individual, 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, of α in said individual. Ｖ β ６ or α Ｖ β １ C in the individual's plasma corresponding to a plasma conditioning concentration effective to inhibit ｍａｘ 92. The method of claim 91, comprising administering the dosage form effective to produce (ng / mL).

94. 77. A method of inhibiting TGFβ activation in a cell, comprising administering to said cell a dosage form according to any one of claims 1 to 76, or a pharma- ceutically acceptable salt thereof.

95. The cells are administered a C of the compound in the cells of at least about one of 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, or 1400 ng / mL, or a range between any two of the foregoing concentrations. ｍａｘ 95. The method of claim 94, comprising administering the dosage form effective to produce:

96. In the cells, 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, of the α Ｖ β ６ or α Ｖ β １ C in the cells corresponding to a concentration effective to inhibit ｍａｘ 95. The method of claim 94, comprising administering the dosage form effective to produce (ng / mL).

97. α Ｖ β ６ or α Ｖ β １ integrin, said use comprising administering to an individual in need thereof said alpha Ｖ β ６ or α Ｖ β １ 77. The dosage form of any of claims 1 to 76, or a salt thereof, comprising administering an amount of said dosage form effective to inhibit an integrin.

98. The use comprises administering to the individual a C of the compound in the plasma of the individual of at least about one of 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 ng / mL, or a range between any two of the foregoing concentrations. ｍａｘ 98. The dosage form of claim 97, comprising administering the dosage form effective to produce:

99. The use provides the individual with 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, of α in the individual. Ｖ β ６ or α Ｖ β １ C in the individual's plasma corresponding to a plasma conditioning concentration effective to inhibit ｍａｘ 98. The dosage form of claim 97, comprising administering the dosage form effective to produce (ng / mL).

100. A method of modulating the activity of at least one integrin in a subject in need of modulation of the activity of at least one integrin, comprising administering to the subject a dosage form according to any one of claims 1 to 76, or a pharma- ceutical acceptable salt thereof, in an amount effective to modulate the activity of the at least one integrin in the subject, wherein the at least one integrin is α Ｖ β １ Integrins and α Ｖ β ６ The method comprises at least one of the following integrins:

101. α in the subject Ｖ β １ Integrins and α Ｖ β ６ 101. The method of claim 100, comprising inhibiting the activity of one or both of the integrins.

102. the subject has or is at risk for 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; The method comprises administering to the subject Ｖ β １ Integrins and α Ｖ β ６ 102. The method of claim 100 or claim 101, comprising treating the fibrotic disease in the subject by inhibiting the activity of one or both of the integrins.

103. The subject has or is at risk for psoriasis, and the method comprises: Ｖ β １ Integrins and α Ｖ β ６ 102. The method of claim 100 or claim 101, comprising treating the fibrotic disease in the subject by inhibiting the activity of one or both of the integrins.

104. The subject is in need of treatment for NASH, and the amount of the dosage form administered to the subject is at least Ｖ β １ 102. The method of claim 100 or claim 101, which is effective to treat NASH in the subject by inhibiting integrin activity.

105. The subject is in need of treatment for IPF, and the amount of the dosage form administered to the subject is at least α Ｖ β ６ 102. The method of claim 100 or claim 101, which is effective to treat IPF in the subject by inhibiting integrin activity.

106. the subject is in need of treatment for PSC, and the amount of the dosage form administered to the subject is Ｖ β ６ Integrins and α Ｖ β １ The method of claim 100 or claim 101, which is effective to treat PSC in the subject by inhibiting the activity of at least one integrin.

107. The individual is administered a C of the compound in the plasma of the individual of at least about one of 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 ng / mL, or a range between any two of the foregoing concentrations. ｍａｘ 102. The method of claim 100 or 101, comprising administering the dosage form effective to provide.

108. In said individual, 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, of α in said individual. Ｖ β ６ or α Ｖ β １ C in the individual's plasma corresponding to a plasma conditioning concentration effective to inhibit ｍａｘ 102. The method of claim 100 or 101, comprising administering the dosage form effective to provide (ng / mL).

109. A method of treating a subject in need of treatment comprising administering to the subject a therapeutically effective amount of the dosage form of any one of claims 1 to 76, wherein the subject has at least one tissue in need of therapy, and the tissue is α Ｖ β １ integrin activity and / or expression, α Ｖ β ６ integrin activity and / or expression, pSMAD / SMAD value, New collagen formation or deposition, Total collagen, and have an elevated level of at least one of type I collagen gene Col1a1 expression, wherein said level is elevated as compared to a healthy state of said tissue.

110. The method further comprises administering to the subject α Ｖ β ６ α compared to integrin activity and / or expression Ｖ β １ The method of claim 109, which selectively reduces integrin activity and / or expression.

111. The method further comprises administering to the subject α Ｖ β １ α compared to integrin activity and / or expression Ｖ β ６ The method of claim 109, which selectively reduces integrin activity and / or expression.

112. The method further comprises administering to the subject at least one other α Ｖ Compared to integrin-containing α Ｖ β １ Integrins and α Ｖ β ６ The method of claim 109, wherein both integrin activity and / or expression are reduced.

113. α in one or more fibroblasts in the subject Ｖ β １ 112. The method of claim 110 or 111, wherein the activity of an integrin is reduced.

114. α in one or more epithelial cells in the subject Ｖ β ６ 112. The method of claim 110 or 111, wherein the activity of an integrin is reduced.

115. 115. The method of any one of claims 109-114, wherein the at least one tissue in the subject comprises one or more of lung tissue, liver tissue, skin tissue, cardiac tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue.

116. 116. The method of any one of claims 109 to 115, wherein the tissue has elevated pSMAD2 / SMAD2 values ​​or elevated pSMAD3 / SMAD3 values ​​compared to the healthy state of the tissue.

117. The subject is administered a C of the compound in the plasma of the subject of at least about one of 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 ng / mL, or a range between any two of the foregoing concentrations. ｍａｘ 116. The method of any one of claims 109 to 115, comprising administering said dosage form effective to produce:

118. In said individual, each percentage independently selected from one of at least about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 percentages, or a range between any two of the foregoing percentages, of α in said subject. Ｖ β ６ and / or α Ｖ β １ The plasma C of the subject corresponding to a plasma conditioning concentration effective to inhibit ｍａｘ 92. The method of claim 91, comprising administering the dosage form effective to produce (ng / mL).

119. 1. A method for characterizing anti-fibrotic activity of a small molecule in a subject, comprising: providing a first live cell sample from the subject, the first live cell sample being characterized by the presence of at least one integrin capable of activating transforming growth factor beta (TGF-β) from latency associated peptide-TGF-β; determining a first pSMAD / SMAD value in the first live cell sample; administering said small molecule to said subject; providing a second live cell sample from the subject, the second live cell sample being taken from the same tissue in the subject as the first live cell sample; determining a second pSMAD / SMAD value in the second live cell sample; and characterizing an antifibrotic activity of the small molecule in the subject by comparing the second pSMAD / SMAD value to the first pSMAD / SMAD value.

120. 120. The method of claim 119, wherein each live cell sample is a plurality of cells obtained from a tissue of the subject or a plurality of macrophages associated with the tissue of the subject.

121. 121. The method of claim 120, wherein the tissue comprises one of lung tissue, liver tissue, skin tissue, cardiac tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue.

122. 121. The method of claim 120, wherein each live cell sample comprises a plurality of alveolar macrophages obtained from bronchoalveolar lavage fluid of the subject.

123. 121. The method of claim 120, wherein the method further comprises performing a bronchoalveolar lavage on the subject's lungs effective to provide a bronchoalveolar lavage fluid containing the plurality of macrophages as a plurality of alveolar macrophages.

124. The method of claim 120, wherein 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.

125. 121. The method of claim 120, wherein the subject has psoriasis.

126. The at least one integrin is α Ｖ 120. The method of claim 119, comprising:

127. The at least one integrin is α Ｖ β １ 120. The method of claim 119, comprising:

128. The at least one integrin is α Ｖ β ６ 120. The method of claim 119, comprising:

129. determining the first pSMAD / SMAD value in the at least one living cell comprises determining a pSMAD2 / SMAD2 value or a pSMAD3 / SMAD3 value; 120. The method of claim 119, wherein determining the second pSMAD / SMAD value in the at least one living cell after contacting the at least one living cell with the small molecule comprises determining a pSMAD2 / SMAD2 value or a pSMAD3 / SMAD3 value.

130. The administering of the small molecule to the subject increases the C of the small molecule in the subject to at least about one of 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 ng / mL, or a range between any two of the foregoing concentrations. ｍａｘ 129. The method of any one of claims 119 to 128, which is effective to produce

131. said administering to said subject reduces α in said subject to a percentage each independently selected from one of at least about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100, or a range between any two of the aforesaid percentages. Ｖ β ６ and / or α Ｖ β １ C in the subject corresponding to a concentration effective to inhibit ｍａｘ 129. The method of any one of claims 119 to 128, effective to provide (ng / mL).

132. 132. The method of any one of claims 119 to 131, wherein said administering to said subject said small molecule comprises administering to said subject a dosage form of any one of claims 1 to 76.

133. 1. A method of treating a fibrotic disease in a subject in need thereof, 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 beta (TGF-β) from latency associated peptide-TGF-β; determining a first pSMAD / SMAD value in the first live cell sample; administering to the subject a small molecule; providing a second live cell sample from the subject, the second live cell sample being taken from the same tissue in the subject as the first live cell sample; determining a second pSMAD / SMAD value in the second live cell sample; comparing the second pSMAD / SMAD value to the first pSMAD / SMAD value; and if the second pSMAD / SMAD value is lower than the first pSMAD / SMAD value, administering the small molecule to the subject.

134. 134. The method of claim 133, wherein each live cell sample is a plurality of cells obtained from a tissue of the subject or a plurality of macrophages associated with the tissue of the subject.

135. 135. The method of claim 134, wherein the tissue comprises one of lung tissue, liver tissue, skin tissue, cardiac tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue.

136. 135. The method of claim 134, wherein each live cell sample comprises a plurality of alveolar macrophages obtained from bronchoalveolar lavage fluid of the subject.

137. 135. The method of claim 134, wherein the method further comprises performing a bronchoalveolar lavage on the subject's lungs effective to provide a bronchoalveolar lavage fluid containing the plurality of macrophages as a plurality of alveolar macrophages.

138. The method of claim 134, wherein 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.

139. 135. The method of claim 134, wherein the subject has psoriasis.

140. The at least one integrin is α Ｖ 135. The method of claim 134, comprising:

141. The at least one integrin is α Ｖ β １ 134. The method of claim 133, comprising:

142. The at least one integrin is α Ｖ β ６ 134. The method of claim 133, comprising:

143. determining the first pSMAD / SMAD value in the first live cell sample comprises determining a pSMAD2 / SMAD2 value or a pSMAD3 / SMAD3 value; 134. The method of claim 133, wherein determining the second pSMAD / SMAD value in the at least one living cell after contacting the first living cell sample with the small molecule comprises determining a pSMAD2 / SMAD2 value or a pSMAD3 / SMAD3 value.

144. The administering of the small molecule to the subject increases the C of the small molecule in the subject to at least about one of 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 ng / mL, or a range between any two of the foregoing concentrations. ｍａｘ 144. The method of any one of claims 133 to 143, which is effective to produce

145. said administering to said subject reduces α in said subject to a percentage each independently selected from one of at least about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100, or a range between any two of the aforesaid percentages. Ｖ β ６ and / or α Ｖ β １ C in the subject corresponding to a concentration effective to inhibit ｍａｘ 144. The method of any one of claims 133 to 143, effective to provide (ng / mL).

146. 146. The method of any one of claims 133-145, wherein said administering to said subject said small molecule comprises administering to said subject a dosage form of any one of claims 1-76.

147. 103. A method of treating a fibrotic disease in an individual in need thereof comprising administering to said individual an amount of 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 of a compound, or a range between any two of the preceding amounts, wherein said compound is a compound according to any of claims 1-76.

148. 1. A method of treating a fibrotic disease in an individual in need thereof, comprising administering to the individual a C of at least about one of 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 ng / mL in the individual's plasma, or a range between any two of the aforesaid concentrations. ｍａｘ 77. A method comprising administering to a subject a subject in need thereof a compound according to any one of claims 1 to 76, comprising administering to said subject a compound in an amount effective to produce said compound.

149. 1. A method of treating a fibrotic disorder in an individual in need thereof, comprising administering to said individual a fibrotic disorder treatment comprising administering to said individual a fibrotic disorder treatment to said individual, each independently at least about one of 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 percentage, or each percentage selected from a range between any two of the foregoing percentages, of α in said subject. Ｖ β ６ and / or α Ｖ β １ C in the individual's plasma corresponding to a plasma conditioning concentration effective to inhibit ｍａｘ (ng / mL), wherein the compound is a compound according to any one of claims 1 to 76.

Images