Integrin inhibitors and their use in combination with other agents

Abstract

In particular, the present invention relates to methods of (i) treating a disease in a subject, (ii) ameliorating a decrease in forced vital capacity in a subject in need thereof, (iii) modulating an avf36 integrin, an avf31 integrin, or both an avf36 integrin and an avf31 integrin in a subject in need thereof, (iv) increasing expression of one or more genes in a subject in need thereof, (v) reducing the expression of one or more genes in a subject in need thereof, and (vi) modulating the activity of at least one gene that affects fibrosis activity in a subject in need thereof, comprising administering a compound of Formula (A), Formula (I), Formula (II) as described herein or (S)-4-((2-methoxyethyl) (4-(5, 6, 7, 8-tetrahydro-1, 3, 4, 5, 6, 7, 8-tetrahydro-1, 3, 4, 5, 6, 7, 8-tetrahydro-1, 3, 4, 5, 6, 7, 8-tetrahydro-1, 3, 4-tetrahydro-1, 3, 4-tetrahydro-1, 3, 4-tetrahydro-1, 3, 4-tetrahydro-1, 3, 4-tetrahydro-1, 3-tetrahydro-1, 3 The present invention relates to a pharmaceutically acceptable salt of 2-(5, 8-naphthyridine-2-yl) butyl) amino)-2-(quinazoline-4-ylamino) butyric acid or a pharmaceutically acceptable salt thereof; and administering to the subject a second drug selected from at least pirfenidone and nintedanib or a salt thereof.

Description

[0001] Cross - Reference to Related Applications

[0002] This patent application claims the priority benefits of U.S. Provisional Patent Application No. 63 / 416,453, filed on October 14, 2022; U.S. Provisional Patent Application No. 63 / 440,406, filed on January 21, 2023; U.S. Provisional Patent Application No. 63 / 463,006, filed on April 29, 2023; U.S. Provisional Patent Application No. 63 / 359,835, filed on July 9, 2022; and U.S. Provisional Patent Application No. 63 / 359,875, filed on July 10, 2022. The entire contents of these patent applications are hereby incorporated by reference into this text. Background Art

[0003] Fibrosis is a pathological feature of many diseases and is caused by a malfunction in the body's natural ability to repair damaged tissues. If left untreated, fibrosis can lead to scarring of vital organs, causing irreparable damage and ultimately organ failure.

[0004] Patients with non - alcoholic fatty liver disease (NAFLD) can progress from simple steatosis to non - alcoholic steatohepatitis (NASH) and then to fibrosis. Although liver fibrosis is reversible in its early stages, progressive liver fibrosis can lead to cirrhosis.

[0005] Kidney fibrosis, characterized by glomerulosclerosis and tubulointerstitial fibrosis, is the final common manifestation of many chronic kidney diseases (CKD). Regardless of the initial cause, progressive CKD often leads to extensive tissue scarring, causing destruction of the renal parenchyma and end - stage renal failure, a devastating condition that requires dialysis or kidney transplantation.

[0006] Scleroderma encompasses a complex and variable spectrum of conditions characterized by fibrosis, vascular changes, and autoimmunity. Conditions within the scleroderma spectrum share the common feature of fibrosis, resulting in hardening or thickening of the skin. For some patients, this hardening occurs only in limited areas, but for others, it can spread to other major organs.

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

[0008] Crohn's disease is a chronic disease of unknown etiology that often progresses even with medical or surgical treatment. Intestinal fibrosis is one of the most common complications of Crohn's disease and leads to the formation of strictures in the small intestine and colon.

[0009] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic disease of unknown etiology that occurs in adults and is limited to the lungs. In IPF, the lung tissue becomes thickened, stiffened, and scarred. As pulmonary fibrosis progresses, it becomes increasingly difficult for the lungs to deliver oxygen into the bloodstream, and the organs do not receive the oxygen needed to function properly. IPF currently affects approximately 200,000 people in the United States and causes 40,000 deaths each year. Patients diagnosed with IPF experience progressive shortness of breath and eventually complete respiratory failure.

[0010] Primary biliary cholangitis (PBC), also known as primary biliary cirrhosis, is a chronic liver disease that causes liver damage and fibrosis. It is caused by the slow, progressive destruction of the small bile ducts in the liver, leading to the accumulation of bile and other toxins in the liver, a condition known as cholestasis. Over time, this results in scarring and fibrosis in the liver and bile ducts.

[0011] Nonspecific interstitial pneumonia (NSIP) is a rare condition that affects the tissue surrounding and separating the tiny air sacs in the lungs. These air sacs are called alveoli, where the exchange of oxygen and carbon dioxide occurs between the lungs and the bloodstream. Interstitial pneumonia is a disease in which the reticular walls of the alveoli become inflamed. The pleura (the thin covering that protects and cushions the lungs and the individual lung lobes) may also become inflamed. NSIP has two main forms, cellular and fibrotic. The cellular form is defined mainly by the inflammation of the cells in the interstitium. The fibrotic form is defined by the thickening and scarring of the lung tissue. This scarring is called fibrosis and is irreversible. When the lung tissue thickens or scars, it cannot function effectively. Respiratory efficiency is reduced, and the oxygen level in the blood is low. (Kim et al., Proc. Am. Thorac. Soc. (2006) 3:285 - 292; Lynch, D., Radiology (2001) 221:583 - 584; Kinder et al., Am. J. Respir. Crit. Care Med. (2007) 176:691 - 697)

[0012] There are few available treatment processes because there are currently no market options that have proven to have an impact on long - term patient survival or symptomatology. For example, agents such as pirfenidone and nintedanib have been studied for the treatment of fibrosis. In the treatment of IPF, pirfenidone and nintedanib have been used, but have shown treatment efficacy lower than expected and have also exhibited many side effects. There is still a need for the treatment of fibrotic diseases.

[0013] alpha V beta 6Integrins are expressed in epithelial cells, bind to the latency-associated peptide of transforming growth factor-β1 (TGFβ1), and mediate TGFβ1 activation. After lung and bile duct cell injury, their expression levels increase significantly and play a key in vivo role in tissue fibrosis. Increased levels are also associated with increased mortality in patients with IPF and NSIP.

[0014] Primary sclerosing cholangitis (PSC) involves bile duct inflammation and fibrosis of the occluded bile ducts. The obstruction to bile flow into the intestine can lead to cirrhosis and subsequent complications such as liver failure and liver cancer. The expression of α V β 6 is elevated in the liver and bile ducts of patients with PSC.

[0015] The present disclosure provides α V β 6 integrin inhibitors that can be used to treat fibrosis. SUMMARY OF THE INVENTION

[0016] Disclosed herein are amino acid compounds as α V β 6 integrin inhibitors, compositions containing these compounds, and methods of treating α V β 6 integrin-mediated diseases such as fibrotic diseases.

[0017] In one aspect, there is provided a compound of formula (A) as detailed herein or any variant thereof or a salt thereof (e.g., a pharmaceutically acceptable salt thereof).

[0018] Further provided is a pharmaceutical composition comprising a compound of formula (A) as detailed herein or any variant thereof or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier or excipient.

[0019] In another aspect, there is provided a method of treating a fibrotic disease in an individual (such as a human) in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (A) as detailed herein or any variant thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skin fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis or biliary fibrosis (such as PBC). In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skin fibrosis, psoriasis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis or biliary fibrosis (such as PBC). In some embodiments, the fibrotic disease is pulmonary fibrosis (such as 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).

[0020] In another aspect, there is provided a method of delaying the onset and / or development of a fibrotic disease in an individual (such as a human) at risk of developing a fibrotic disease, comprising administering to the individual a therapeutically effective amount of a compound of formula (A) as detailed herein or any variant thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skin fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis or 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. 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 is an individual who has had or is suspected of having a myocardial infarction. In some embodiments, the individual at risk of developing a fibrotic disease has or is suspected of having psoriasis.

[0021] There is also provided a compound of formula (A) as detailed herein or any variant thereof or a pharmaceutical composition thereof for treating a fibrotic disease.

[0022] Also provided is the use of a compound of formula (A) as detailed herein, or any variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing, in the preparation of a medicament for treating fibrotic diseases.

[0023] Further provided is a kit comprising a compound of formula (A) as detailed herein, or any variant thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises instructions for use according to the methods described herein (such as a method of treating a fibrotic disease in an individual).

[0024] In another aspect, a method for preparing a compound of formula (A), or any variant thereof, or a pharmaceutically acceptable salt thereof is provided. Compound intermediates useful for synthesizing a compound of formula (A) or any variant thereof are also provided.

[0025] In one aspect, a compound of formula (I) as detailed herein, or any variant thereof, or a salt thereof (such as a pharmaceutically acceptable salt thereof) is provided.

[0026] Further provided is a pharmaceutical composition comprising a compound of formula (I) as detailed herein, or any variant thereof, or a salt thereof (such as a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient.

[0027] In another aspect, a method for treating a fibrotic disease in an individual (such as a human) in need thereof is provided, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) as detailed herein, or any variant thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skin fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis (such as PBC). In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skin fibrosis, psoriasis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis (such as PBC). In some embodiments, the fibrotic disease is psoriasis.

[0028] On the other hand, there is provided a method for delaying the onset and / or development of a fibrotic disease in an individual (such as a human) at risk of developing a fibrotic disease, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) as detailed herein or any variant thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skin fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis or 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. 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 is an individual who has had or is suspected of having a myocardial infarction. In some embodiments, the individual at risk of developing a fibrotic disease has or is suspected of having psoriasis.

[0029] There is also provided a compound of formula (I) as detailed herein or any variant thereof or a pharmaceutical composition thereof for treating a fibrotic disease.

[0030] There is also provided the use of a compound of formula (I) as detailed herein or any variant thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising any of the foregoing in the preparation of a medicament for treating a fibrotic disease.

[0031] There is further provided a kit comprising a compound of formula (I) as detailed herein or any variant thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises instructions for use according to the methods described herein (such as a method for treating a fibrotic disease in an individual).

[0032] On the other hand, there is provided a method for preparing a compound of formula (I) or any variant thereof or a pharmaceutically acceptable salt thereof. There are also provided compound intermediates useful for synthesizing a compound of formula (I) or any variant thereof.

[0033] On the other hand, there is provided a method for treating a disease in a subject, comprising: administering to the subject a first medicament comprising a compound of formula (A) or a salt thereof; and administering to the subject at least one second medicament selected from the group consisting of pirfenidone and nintedanib or a salt thereof, thereby treating the disease in the subject.

[0034] In another aspect, there is provided a method of ameliorating the decline in forced vital capacity (FVC) in a subject in need thereof, comprising administering to the subject (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof, thereby ameliorating the decline in forced vital capacity (FVC) in the subject.

[0035] In another aspect, there is provided a method of modulating α V β 6 integrin, α V β 1 integrin or α V β 6 integrin and α V β 1 integrin in a subject in need thereof, comprising:

[0036] administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof, wherein the administration is not accompanied by serious adverse events.

[0037] In another aspect, there is provided a method of increasing the expression of one or more genes in a subject in need thereof, comprising administering to the subject (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof, wherein the one or more genes are selected from ACACA, AKR1B10, APOB, BCL2L1, C3, C6, CCL2, CXCL8, CYP4A11 / 22, DAPK1, DLL1, EGFR, ELOVL6, EPHX2, F11R, FASN, FLNB, FZD5, GCNT1, GPC4, HADH, IL1RAP, IL20RB, JAG2, KIR2DL3, KLRB1, LYN, MS4A1, MUC5B, PLIN4, PPARGC1A, PTGER4, SAA1, SCD, SCIN, SLC25A10, SLC2A2, SPIB, SREBF1 or VAMP8.

[0038] In another aspect, there is provided a method of increasing the expression of one or more genes in a subject in need thereof, comprising administering to the subject (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and pirfenidone, wherein the one or more genes are selected from the group consisting of BCL2L1, C3, CCL4, CD209, CYP2J2, EGFR, FLNB, GPC4, GZMA, HCAR2, HDC, IL1B, JAG2, LYN, MAPK10, MMP12, MUC5B, SLC25A10, SPIB, SREBF1, TJP2, TNF or VAMP8.

[0039] In another aspect, there is provided a method of decreasing the expression of one or more genes in a subject in need thereof, comprising administering to the subject (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof, wherein the one or more genes are selected from the group consisting of APOC2, CDH2, COL1A1, COL4A2, FCGR3A / B, ITGB3, LOXL2, NID1, SERPINH1, SPP1, TGFB1, THBS2, FAP, LOX, PDGFRB, POSTN or SERPINE1.

[0040] In another aspect, there is provided a method of decreasing the expression of one or more genes in a subject in need thereof, comprising administering to the subject (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and pirfenidone, wherein the one or more genes are selected from the group consisting of CDH2, COL1A1, COL5A3, ITGA5 or THBS2.

[0041] In another aspect, there is provided a method of increasing the expression of one or more genes in a subject in need thereof, comprising administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof, wherein the one or more genes are selected from the group consisting of CCL13, IFI6, CXCL2, MET, NOS1, APOA2, OAS1, CIITA, WWC1, TTN, ALDH7A1, CD19, LTA, GPC4, TNF, XAF1, SMAD3, FZD5, IFI35 and PTGER4.

[0042] In another aspect, there is provided a method for reducing the expression of one or more genes in a subject in need thereof, comprising administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof, wherein the one or more genes are selected from COL10A1, POSTN, COL5A1, MARCO, MMP8, COL6A3, GREM1, PECAM1, COL1A2, CXCR4, COL3A1, LOX, MMP11, FAP, PDGFRB, FN1, SERPINE1, PLPP4, LOXL1 and TIMP1.

[0043] In another aspect, there is provided a method for modulating the activity of at least one gene that affects fibrotic activity in a subject in need thereof, comprising (i) administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof, or (ii) administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and pirfenidone, wherein the at least one gene is modulated substantially by administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof or by administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and pirfenidone, but not substantially by administering only (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof, only nintedanib or a pharmaceutically acceptable salt thereof or only pirfenidone.

[0044] In any embodiment disclosed herein, the compound for use in any method (including a method of treating a disease or a method of treating a subject in need thereof) can be a compound, salt, or polymorph disclosed in International Patent Application No. WO 2022 / 109598, U.S. Patent Application Publication No. US2022 / 0177468, U.S. Patent No. 10,793,564, U.S. Patent No. 11,419,869, or U.S. Patent Application Publication No. US2023 / 0028658. The entire content of each of the foregoing patent documents is incorporated herein by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 Showing Compounds 1-780 as disclosed herein.

[0046] Figure 2 Showing Table B-3 with biological data of various compounds as disclosed herein.

[0047] Figure 3A Is a graph showing Compound 5 and the selective antibody α V β 6 inhibitor 3G9, in contrast to the α V β 1 selective small molecule inhibitor, both of which substantially inhibit the adhesion of normal bronchial epithelial cells to LAP.

[0048] Figure 3B Showing in contrast to the selective antibody α V β 6 inhibitor 3G9, that both Compound 5 and the α V β 1 selective small molecule inhibitor substantially inhibit cell adhesion in lung fibroblasts derived from IPF.

[0049] Figure 4A Is a graph of PSMAD3 / SMAD3 in lung tissue from healthy mice administered PBS vehicle and different levels of Compound 5 for 4 days.

[0050] Figure 4B Is a graph of PSMAD3 / SMAD3 in BALF from the same healthy mice administered PBS vehicle and different levels of Compound 5 for 4 days.

[0051] Figure 4C Is a graph showing that lung tissue in mice treated with vehicle undergoes a significant increase in SMAD3 phosphorylation compared to healthy mice.

[0052] Figure 4D Is a graph showing that compared to healthy mice, as determined by containing 2Graph showing the percentage of lung collagen of H-labeled hydroxyproline, where lung tissue in vehicle-treated mice undergoes significant accumulation of new collagen.

[0053] Figure 4E Showing that vehicle-treated mice experienced a significant increase in total lung collagen compared to healthy mice, as measured by the number of micrograms of hydroxyproline.

[0054] Figure 4F High-resolution second harmonic generation images of fibrillar collagen (type I and type III collagen) obtained from formalin-fixed paraffin-embedded lung tissue sections from the lungs of healthy mice.

[0055] Figure 4G High-resolution second harmonic generation images of fibrillar collagen (type I and type III collagen) obtained from formalin-fixed paraffin-embedded lung tissue sections from the lungs of vehicle-treated mice.

[0056] Figure 4H High-resolution second harmonic generation images of fibrillar collagen (type I and type III collagen) obtained from formalin-fixed paraffin-embedded lung tissue sections from the lungs of mice treated with the test substance (compound 5 at 500 mg / kg BID).

[0057] Figure 4I Shows Figure 4F 、 4G and the percentage of total collagen area in second harmonic generation images of the mouse lungs at 4H.

[0058] Figure 4J Graph showing continuous measurements in bleomycin-treated mice, demonstrating a close inverse relationship between pSMAD3 levels in the lung and plasma drug exposure.

[0059] Figure 4K Graph showing continuous measurements in bleomycin-treated mice, demonstrating a close inverse relationship between pSMAD3 levels in BALF cells and plasma drug exposure.

[0060] Figure 5A Bar graph normalized to control sections treated with DMSO, showing that all test treatments reduced the expression of the type I collagen gene Col1a1.

[0061] Figure 5B Bar graph normalized to control sections treated with DMSO, showing that all test treatments reduced lung Col1a1 expression.

[0062] Figure 6Ais a bar graph that shows that both nintedanib and pirfenidone show a slight increase in lung Col1a1 expression compared to DMSO vehicle control sections.

[0063] Figure 6B is a bar graph that shows the concentration of compounds required to reduce lung section Col1a1 expression by 50% compared to DMSO control sections.

[0064] Figure 6C is a bar graph normalized to control sections treated with DMSO that shows that all test treatments reduce lung Col1a1 expression.

[0065] Figure 6D is a bar graph showing the relative expression of COL1A1 in precision-cut lung slices (PCLS) from idiopathic pulmonary fibrosis (IPF) lung tissue after exposure to compound 5, the clinical standard of care compounds nintedanib (Nin) and pirfenidone (Pirf), and an ALK5 inhibitor, all compared to DMSO control.

[0066] Figure 6E is a bar graph that shows a dose-dependent decrease in COL1A1 expression in PCLS from human IPF lung tissue after treatment with compound 5 in a concentration range of 200 pM to 1 μM. The COL1A1 expression of PCLS in the presence of 0.1% DMSO control and 1 μM of the ALK5 inhibitor was also plotted.

[0067] Figure 6F is a bar graph that shows dual-selective α V β 6 and α V β 1 inhibition (1.82 μM of compound 5) on the ratio of pSMAD2 / SMAD2 in PCLS from human IPF lung tissue samples. The ratio of pSMAD2 / SMAD2 of PCLS in the presence of 0.1% DMSO control and 1 μM of the ALK5 inhibitor was also plotted.

[0068] Figure 7A Shows single ascending dose (SAD) study data for the administration of 15, 30, 50, and 75 mg of compound 5.

[0069] Figure 7B Shows multiple ascending dose (MAD) study data for the administration of 10, 20, and 40 mg of compound 5.

[0070] Figure 8AData are shown for subjects receiving the selected integrin inhibitor (Compound 5) at 40 mg / day. The data include the plasma concentration of the integrin inhibitor administered (“PK”, dots) and the relative change in the pSMAD2:SMAD2 ratio in BAL (bronchoalveolar lavage) samples relative to baseline (Day -1) in the time course (hours) shown following the dose of inhibitor administered on Day 7. The peak of the plasma concentration (“PK” curve) was recorded as C max . C was shown to be max > 900 ng / mL with a sustained PD effect.

[0071] Figure 8B Data are shown for subjects receiving the selected integrin inhibitor (Compound 5) at 40 mg / day. The data include the plasma concentration of the integrin inhibitor administered (“PK”, dots) and the relative change in the pSMAD2:SMAD2 ratio in BAL (bronchoalveolar lavage) samples relative to baseline (Day -1) in the time course (hours) shown following the dose of inhibitor administered on Day 7. The peak of the plasma concentration (“PK” curve) was recorded as C max . C was shown to be max > 900 ng / mL with a sustained PD effect.

[0072] Figure 8C Data are shown for subjects receiving the selected integrin inhibitor (Compound 5) at 40 mg / day. The data include the plasma concentration of the integrin inhibitor administered (“PK”, dots) and the relative change in the pSMAD2:SMAD2 ratio in BAL (bronchoalveolar lavage) samples relative to baseline (Day -1) in the time course (hours) shown following the dose of inhibitor administered on Day 7. The peak of the plasma concentration (“PK” curve) was recorded as C max . C was shown to be max = 700 - 900 ng / mL with a transient PD effect.

[0073] Figure 8D Data are shown for subjects receiving the selected integrin inhibitor (Compound 5) at 40 mg / day. The data include the plasma concentration of the integrin inhibitor administered (“PK”, dots) and the relative change in the pSMAD2:SMAD2 ratio in BAL (bronchoalveolar lavage) samples relative to baseline (Day -1) in the time course (hours) shown following the dose of inhibitor administered on Day 7. The peak of the plasma concentration (“PK” curve) was recorded as C max . C was shown to be max = 700 - 900 ng / mL with a transient PD effect.

[0074] Figure 8E Data are shown for subjects receiving the selected integrin inhibitor (Compound 5) at 40 mg / day. The data include the plasma concentration of the integrin inhibitor administered ("PK", dots) and the relative change in the pSMAD2:SMAD2 ratio in BAL (bronchoalveolar lavage) samples relative to baseline (Day -1) in the time course (hours) shown following the dose of inhibitor administered on Day 7. The peak of the plasma concentration ("PK" curve) was recorded as C max . It was shown that C max < 700 ng / mL and there was no PD effect.

[0075] Figure 8F Data are shown for subjects receiving the selected integrin inhibitor (Compound 5) at 40 mg / day. The data include the plasma concentration of the integrin inhibitor administered ("PK", dots) and the relative change in the pSMAD2:SMAD2 ratio in BAL (bronchoalveolar lavage) samples relative to baseline (Day -1) in the time course (hours) shown following the dose of inhibitor administered on Day 7. The peak of the plasma concentration ("PK" curve) was recorded as C max , showing that C max < 700 ng / mL and there was no PD effect.

[0076] Figure 8G Shows the change % in the BAL SMAD2 phosphorylation level (pSMAD2:SMAD2 ratio) on Day 7 compared to the baseline level recorded on Day -1 for subjects receiving placebo treatment and for subjects with a measured C max of less than 700 ng / mL, 700 ng / mL to 900 ng / mL, and greater than 900 ng / mL of the integrin inhibitor. Asterisks refer to p < 0.05 compared to placebo and C max < 700 ng / mL group.

[0077] Figure 8H Shows the change % in SMAD2 phosphorylation (pSMAD2:SMAD2 ratio) associated with C max in subjects receiving a 40 mg dose of Compound 5 compared to the baseline level recorded on Day -1 (at all time points).

[0078] Figure 9 Is a plot of unbound plasma concentration (X-axis) against Vt (Y-axis) for baseline Vt at each dose, Vt measured after each dose, and the fitted line.

[0079] Figure 10 Is a plot of unbound plasma concentration (X-axis) against % receptor occupancy (Y-axis).

[0080] Figure 11 It is a bar graph showing the percentage of target engagement for each subject and dose.

[0081] Figure 12 Describes the dose-dependent effect of Compound 5.

[0082] Figure 13 Shows the change in FVC (forced vital capacity) from baseline to week 12.

[0083] Figure 14 Shows the change in FVC over time in the combined Compound 5 group.

[0084] Figure 15 Shows the change in FVC over time in the 40 mg Compound 5 group.

[0085] Figure 16 Shows the change in FVC over time in the 80 mg Compound 5 group.

[0086] Figure 17 Shows the change in FVC over time in the 160 mg Compound 5 group.

[0087] Figure 18 Shows the change in FVC from baseline to week 12 in the standard of care subgroup.

[0088] Figure 19 Shows the change in FVC from baseline to week 12 in the subgroup that is not the standard of care.

[0089] Figure 20 Shows the proportion of participants with a decline in forced vital capacity - predicted value % (FVCpp) of greater than or equal to 10%.

[0090] Figure 21 Compares the serum biomarkers of collagen synthesis in the Compound 5 group versus the placebo group.

[0091] Figure 22 Shows the mean percent change in quantitative lung fibrosis measured by high-resolution computed tomography (HRCT)-based quantitative lung fibrosis (QLF) imaging (range from baseline to week 12 in the CT protocol population).

[0092] Figure 23 Shows the mean percent change in quantitative lung fibrosis in the CT protocol population within the screening window measured by high-resolution computed tomography (HRCT)-based quantitative lung fibrosis (QLF) imaging (range from baseline to week 12).

[0093] Figure 24Shows the overlap of genes significantly altered by compound 5 alone and in combination with nintedanib or pirfenidone (adjusted p < 0.05, |log 2 FC| > 0.5). As indicated in the legend, regions A to G of the Venn diagram show the number of genes as follows, where compound X is pirfenidone or nintedanib: A: genes significantly altered only by the combination of compound 5 + compound X; B: genes significantly altered by compound 5 alone and in combination; C: genes significantly altered by compound X alone and in combination; D: genes significantly altered by compound 5 and compound X alone and in combination; E: genes significantly altered by compound 5 only in the absence of compound X; F: genes significantly altered by compound 5 and compound X alone but not in combination; G: genes significantly altered by compound X only in the absence of compound 5. In Figure 24 the top row refers to the legend, the middle row refers to downregulated, and the bottom row refers to upregulated.

[0094] Figure 25 Shows the log2 fold change of a subset of genes reduced more by the combination of compound 5 with nintedanib or pirfenidone (striped bars) than by individual treatment (solid bars). Significant changes (adjusted p < 0.05) are marked with *.

[0095] Figure 26 Shows the incidence of diarrhea in a randomized clinical trial of IPF.

[0096] Figure 27 Shows the change in FVC relative to the baseline at week 12 in the ITT population – SoC subgroup.

[0097] Figure 28 Shows the change in FVC relative to the baseline at 12 weeks in the mITT population.

[0098] Figure 29 Shows the proportion of participants in the ITT population with an FVCpp decline ≥ 10%.

[0099] Figure 30 Shows the change in FVC relative to the baseline at week 12 in the ITT population – not in the SoC subgroup.

[0100] Figure 31 Shows the proportion of participants in the ITT population with an absolute FVCpp decline ≥ 10%.

[0101] Figure 32 Shows the mean percentage change in QLF relative to the baseline at week 12 in the CT protocol population.

[0102] Figure 33Show the serum biomarkers of reduced collagen synthesis by Compound 5 (change relative to baseline at Week 4 and Week 12 compared to placebo).

[0103] Figure 34 Show the change in forced vital capacity (FVC) relative to baseline in the intention-to-treat (ITT) population over 24 weeks.

[0104] Figure 35 Show the change in forced vital capacity (FVC) relative to baseline in a subgroup of patients receiving standard care for idiopathic pulmonary fibrosis over 24 weeks.

[0105] Figure 36 Show that patients treated with Compound 5 showed a sustained improvement in FVC at Week 24. Approximately 89% of patients treated with Compound 5 who had an improvement in FVC at Week 12 maintained the improvement in FVC at Week 24.

[0106] Figure 37 Show the change in the predicted percentage of FVC (FVCpp) relative to baseline at Week 24 for the 320 mg cohort of Compound 5 and for the placebo group.

[0107] Figure 38 Show the percentage change in quantitative lung fibrosis (QLF) relative to baseline at Week 24 for the 320 mg cohort of Compound 5 and for the placebo group.

[0108] Figure 39 Show the change in cough severity relative to baseline on a visual analog scale (VAS) at Week 24 for the 320 mg cohort of Compound 5 and for the placebo group.

[0109] Figure 40 Show that treatment with Compound 5 reduced the levels of the circulating biomarkers integrin β-6 (ITGB6) and the neo-epitope of type III collagen synthesis (PRO-C3) relative to the placebo group. Detailed Description

[0110] The present disclosure particularly provides compounds of formula (A) and variants or salts thereof, pharmaceutical compositions comprising a compound of formula (A) or a salt thereof, and methods of using such compounds and compositions to treat fibrotic diseases.

[0111] The present disclosure particularly provides compounds of formula (I) and variants or salts thereof, pharmaceutical compositions comprising a compound of formula (I) or a salt thereof, and methods of using such compounds and compositions to treat fibrotic diseases.

[0112] Definitions

[0113] For use in this text, unless otherwise specified, the terms “a,” “an,” etc. refer to one or more.

[0114] As used herein, “about” a value or parameter includes (and describes) embodiments that are directed to that value or parameter itself. For example, a description of “about X” includes a description of “X.”

[0115] As used herein, “small molecule” refers to an organic molecule characterized by a mass of less than 900 daltons. Non-limiting examples of small molecules include Figure 1 the compounds or salts thereof described in

[0116] Unless otherwise stated, as used herein “alkyl” refers to and includes saturated straight-chain (i.e., unbranched) or branched monovalent hydrocarbon chains having the specified number of carbon atoms (i.e., C 1 -C 10 meaning one to ten carbon atoms) or combinations thereof. Specific alkyls have 1 to 20 carbon atoms (“C 1 -C 20 alkyl”), 1 to 10 carbon atoms (“C 1 -C 10 alkyl”), 6 to 10 carbon atoms (“C 6 -C 10 alkyl”), 1 to 6 carbon atoms (“C 1 -C 6 alkyl”), 2 to 6 carbon atoms (“C 2 -C 6 alkyl”) or 1 to 4 carbon atoms (“C 1 -C 4 alkyl”). Examples of alkyls include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0117] As used herein, “alkylene” refers to the same as alkyl but with a divalent residue. Specific alkylenes have 1 to 20 carbon atoms (“C 1 -C 20 alkylene”), 1 to 10 carbon atoms (“C 1 -C 10 alkylene”), 6 to 10 carbon atoms (“C 6 -C 10 alkylene”), 1 to 6 carbon atoms (“C 1 -C 6 alkylene”), 1 to 5 carbon atoms (“C 1 -C 5 alkylene”), 1 to 4 carbon atoms (“C1 -C 4 “alkylene”) or 1 to 3 carbon atoms (“C 1 -C 3 “alkylene”). Examples of alkylene include, but are not limited to, groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), isopropylidene (-CH 2 CH(CH 3 )-), butylene (-CH 2 (CH 2 ) 2 CH 2 -), isobutylene (-CH 2 CH(CH 3 )CH 2 -), pentylene (-CH 2 (CH 2 ) 3 CH 2 -), hexylene (-CH 2 (CH 2 ) 4 CH 2 -), heptylene (-CH 2 (CH 2 ) 5 CH 2 -), octylene (-CH 2 (CH 2 ) 6 CH 2 -), etc.

[0118] Unless otherwise specified, as used herein, “alkenyl” means and includes an unsaturated straight-chain (i.e., non-branched) or branched monovalent hydrocarbon chain having at least one ethylenic unsaturation site (i.e., having at least one moiety of the formula C═C) and having a specified number of carbon atoms (i.e., C 2 -C 10 means 2 to 10 carbon atoms). The alkenyl can have a “cis” or “trans” configuration, or have an “E” or “Z” configuration. Specific alkenyls have 2 to 20 carbon atoms (“C 2 -C 20 “alkenyl”), 6 to 10 carbon atoms (“C 6 -C 10 “alkenyl”), 2 to 8 carbon atoms (“C 2 -C 8 “alkenyl”), 2 to 6 carbon atoms (“C 2-C 6 alkenyl”) or having 2 to 4 carbon atoms (“C 2 -C 4 alkenyl”). Examples of alkenyl include, but are not limited to, groups such as ethenyl / 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-methylbuta-1,3-dienyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, and the like.

[0119] As used herein, “alkenylene” refers to a residue that is the same as alkenyl but divalent. Specific alkenylene groups have 2 to 20 carbon atoms (“C 2 -C 20 alkenylene”), having 2 to 10 carbon atoms (“C 2 -C 10 alkenylene”), having 6 to 10 carbon atoms (“C 6 -C 10 alkenylene”), having 2 to 6 carbon atoms (“C 2 -C 6 alkenylene”), 2 to 4 carbon atoms (“C 2 -C 4 alkenylene”) or 2 to 3 carbon atoms (“C 2 -C 3 alkenylene”). Examples of alkenylene include, but are not limited to, groups such as ethenylene / vinylene (-CH=CH-), propenylene (-CH=CHCH 2 -), 1,4-but-1-enylene (-CH=CH-CH 2 CH 2 -), 1,4-but-2-enylene (-CH 2 CH=CHCH 2 -), 1,6-hex-1-enylene (-CH=CH-(CH 2 ) 3 CH 2 -), and the like.

[0120] Unless otherwise specified, as used herein, “alkynyl” refers to and includes an unsaturated straight-chain (i.e., non-branched) or branched monovalent hydrocarbon chain or a combination thereof having at least one acetylenic unsaturation site (i.e., having at least one moiety of the formula C≡C) and having a specified number of carbon atoms (i.e., C 2 -C 10 means two to ten carbon atoms). Specific alkynyl groups have 2 to 20 carbon atoms (“C 2 -C 20"alkynyl"), having 6 to 10 carbon atoms ("C 6 -C 10 alkynyl"), having 2 to 8 carbon atoms ("C 2 -C 8 alkynyl"), having 2 to 6 carbon atoms ("C 2 -C 6 alkynyl") or having 2 to 4 carbon atoms ("C 2 -C 4 alkynyl"). Examples of alkynyl groups include, but are not limited to, groups such as ethynyl / acetylenyl, prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, etc.

[0121] As used herein, "alkynylene" refers to a residue that is the same as alkynyl but divalent. Specific alkynylene groups have 2 to 20 carbon atoms ("C 2 -C 20 alkynylene"), having 2 to 10 carbon atoms ("C 2 -C 10 alkynylene"), having 6 to 10 carbon atoms ("C 6 -C 10 alkynylene"), having 2 to 6 carbon atoms ("C 2 -C 6 alkynylene"), 2 to 4 carbon atoms ("C 2 -C 4 alkynylene") or 2 to 3 carbon atoms ("C 2 -C 3 alkynylene"). Examples of alkynylene groups include, but are not limited to, groups such as ethynylene / acetylenylene (-C≡C-), propynylene (-C≡CCH 2 -), etc.

[0122] Unless otherwise specified, as used herein, "cycloalkyl" refers to and includes a saturated cyclic monovalent hydrocarbon structure having the specified number of carbon atoms (i.e., C 3 -C 10 means three to ten carbon atoms). A cycloalkyl group can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl group containing more than one ring can be fused, spiro, bridged, or a combination thereof. Specific cycloalkyl groups have 3 to 12 ring carbon atoms. Preferred cycloalkyl groups are those having 3 to 8 ring carbon atoms ("C 3 -C 8 cycloalkyl"), having 3 to 6 ring carbon atoms ("C 3 -C 6 cycloalkyl") or having 3 to 4 ring carbon atoms ("C 3-C 4 a cyclic hydrocarbon of “cycloalkyl”). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, etc.

[0123] As used herein, “cycloalkylene” refers to a residue that is the same as cycloalkyl but divalent. Cycloalkylene can consist of one ring or multiple rings, and the multiple rings can be fused, spiro, bridged, or a combination thereof. Specific cycloalkylenes have 3 to 12 ring carbon atoms. Preferred cycloalkylenes are those having 3 to 8 ring carbon atoms (“C 3 -C 8 cycloalkylene”), those having 3 to 6 carbon atoms (“C 3 -C 6 cycloalkylene”), or those having 3 to 4 ring carbon atoms (“C 3 -C 4 cycloalkylene”) cyclic hydrocarbons. Examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, etc. Cycloalkylene can be linked to the rest of the structure via the same ring carbon atom or different ring carbon atoms. When cycloalkylene is linked to the rest of the structure via two different ring carbon atoms, the linking 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 a mixture thereof.

[0124] Unless otherwise specified, “cycloalkenyl” means and includes an unsaturated cyclic non-aromatic monovalent hydrocarbon structure having at least one ethylenic unsaturation site (i.e., having at least one moiety of the formula C═C) and having a specified number of carbon atoms (i.e., C 3 -C 10 meaning three to ten carbon atoms). Cycloalkenyl can consist of one ring, such as cyclohexenyl, or multiple rings, such as norbornenyl. Preferred cycloalkenyls are unsaturated cyclic hydrocarbons having 3 to 8 ring carbon atoms (“C 3 -C 8 cycloalkenyl”). Examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, etc.

[0125] As used herein, “cycloalkenylene” refers to a residue that is the same as cycloalkenyl but divalent.

[0126] As used herein, “aryl” or “Ar” refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracenyl), where the fused rings can be aromatic or non-aromatic. Specific aryls have 6 to 14 ring carbon atoms (“C 6 -C 14"Aryl"). An aryl having more than one ring, at least one of which is non-aromatic, can be attached to the parent structure at an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl having more than one ring, at least one of which is non-aromatic, is attached to the parent structure at an aromatic ring position.

[0127] As used herein, "arylene" refers to a residue that is the same as aryl but divalent. A particular arylene has 6 to 14 ring carbon atoms ("C 6 -C 14 arylene").

[0128] As used herein, "heteroaryl" refers to an unsaturated aromatic cyclic group having 1 to 14 ring carbon atoms and at least one ring heteroatom, where the ring heteroatoms include, but are not limited to, heteroatoms such as nitrogen, oxygen, and sulfur. A heteroaryl can have a single ring (e.g., pyridyl, furyl) or multiple fused rings (e.g., indolizinyl, benzothienyl), where the fused rings can be aromatic or non-aromatic. A particular heteroaryl has a 5- to 14-membered ring having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered ring having 1 to 8 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-, 6-, or 7-membered ring having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, a particular heteroaryl is a monocyclic aromatic 5-, 6-, or 7-membered ring having 1 to 6 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, a particular heteroaryl is a polycyclic aromatic ring having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. A heteroaryl having more than one ring, at least one of which is non-aromatic, can be attached to the parent structure at an aromatic ring position or at a non-aromatic ring position. In one variation, a heteroaryl having more than one ring, at least one of which is non-aromatic, is attached to the parent structure at an aromatic ring position. A heteroaryl can be attached to the parent structure at a ring carbon atom or at a ring heteroatom.

[0129] As used herein, "heteroarylene" refers to a residue that is the same as heteroaryl but divalent.

[0130] As used herein, "heterocyclic", "heterocyclic ring", or "heterocyclic group" refers to a saturated or unsaturated non-aromatic cyclic 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, etc.). The heterocyclic ring containing more than one ring can be fused, bridged, spiro, or any combination thereof, but does not include heteroaryl. The heterocyclic group may optionally and independently be substituted by one or more substituents described herein. Specific heterocyclic groups include 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, the heterocyclic group 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, the heterocyclic group 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.

[0131] As used herein, "heterocyclylene" refers to a divalent residue identical to the heterocyclic group.

[0132] "Halogenated" or "halogen" refers to an element of Group 17 series with atomic numbers from 9 to 85. Preferred halogenated groups include fluorine, chlorine, bromine, and iodine groups. In the case where a residue is substituted by more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached, for example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl groups substituted by two ("di") or three ("tri") halogenated groups which may or may not be the same halogen; thus 4-chloro-3-fluorophenyl falls within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced by a halogenated group is called a "perhaloalkyl". Preferred perhaloalkyl is trifluoromethyl (-CF 3 ). Similarly, "perhaloalkoxy" refers to an alkoxy group in which each H in the hydrocarbon of the alkyl moiety constituting the alkoxy is replaced by a halogen. Examples of perhaloalkoxy are trifluoromethoxy (–OCF 3 ).

[0133] "Carbonyl" refers to the group C=O.

[0134] "Thiocarbonyl" refers to the group C=S.

[0135] "Oxo" refers to the moiety =O.

[0136] “D” refers to deuterium ( 2 H).

[0137] “T” refers to tritium ( 3 H).

[0138] An alkyl group in which every hydrogen is replaced by deuterium is referred to as “perdeuterated”. An alkyl group in which every hydrogen is replaced by tritium is referred to as “pertritiated”.

[0139] Unless otherwise specified, “optionally substituted” means that the group may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents listed for the group, where the substituents may be the same or different. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In another embodiment, the optionally substituted group has four substituents. In some embodiments, the 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, the optionally substituted group is unsubstituted.

[0140] It is to be understood that, if the valency available for substitution permits in part, the optionally substituted moiety may be substituted with more than five substituents. For example, propyl may be substituted with seven halogen atoms to give a perhalogenated propyl. The substituents may be the same or different.

[0141] Unless expressly indicated otherwise, as used herein, “subject” is intended to be a mammal, including but not limited to a primate, human, bovine, equine, feline, canine, or rodent. In one variation, the subject is a human.

[0142] As used herein, “treatment / treating” is a method of obtaining a beneficial or desired result, including a clinical result. Beneficial or desired results include, but are not limited to, one or more of the following: reducing one or more symptoms produced by a disease, alleviating the degree of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, delaying the onset or recurrence of the disease, delaying or slowing the progression of the disease, improving the disease state, alleviating the disease (either partially or completely), reducing the dose of one or more other drugs required to treat the disease, enhancing the effect of another drug, delaying the progression of the disease, improving the quality of life, and / or extending the survival period. “Treatment” also encompasses alleviating the pathological consequences of fibrosis. The methods of the present invention encompass any one or more of these treatment aspects.

[0143] As used herein, the term "effective amount" is intended to mean an amount of a compound of the present invention that should be effective in a given therapeutic form. As understood in the art, an effective amount can be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. An effective amount can be considered in the context of administering one or more therapeutic agents (e.g., a compound or a pharmaceutically acceptable salt thereof), and a single agent can be considered to be administered in an effective amount if the desired or beneficial result can be achieved or realized in combination with one or more other agents. Due to the combined action (e.g., additive or synergistic effect) of the compounds, the appropriate dose of any co-administered compound can optionally be reduced.

[0144] A "therapeutically effective amount" means an amount of a compound or a salt thereof sufficient to produce the desired therapeutic result.

[0145] As used herein, a "unit dosage form" refers to physically discrete units suitable as a unit dose, each unit containing a predetermined quantity of an active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0146] As used herein, the term "controlled release" refers to a formulation containing a drug or a portion thereof, wherein the release of the drug is not immediate, i.e., with a "controlled release" formulation, administration does not result in an immediate release of the drug into the absorption pool. The term encompasses depot formulations designed to gradually release the drug compound over an extended period of time. Controlled release formulations can include many types of drug delivery systems and generally involve mixing the drug compound with a carrier, polymer, or other compound having the desired release characteristics (e.g., pH-dependent or non-pH-dependent solubility, varying degrees of water solubility, etc.) and formulating the mixture according to the desired route of delivery (e.g., coated capsules, implantable depots, injectable solutions containing biodegradable capsules, etc.).

[0147] As used herein, "pharmaceutically acceptable" or "pharmacologically acceptable" means a substance that is not biologically or otherwise adverse, e.g., the substance can be incorporated into a pharmaceutical composition administered to a patient without causing any significant adverse biological effects or interacting in a harmful manner with any other component of the composition containing it. A pharmaceutically acceptable carrier or excipient preferably meets the required standards of toxicological and manufacturing tests, and / or is included in the Inactive Ingredient Guides prepared by the U.S. Food and Drug Administration.

[0148] "Pharmaceutically acceptable salts" are those salts that retain at least some of the biological activity of the free (non-salt) compound and are administrable to an individual as a medicament or drug product. Such salts include, for example: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, etc.; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion); or coordinated with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc. Pharmaceutically acceptable salts can be prepared in situ during the manufacturing process, or by reacting the purified compound of the present invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.

[0149] As used herein, the term "excipient" means an inert or inactive substance that can be used in the production of a medicament or drug product (such as a tablet containing the compound of the present invention as an active ingredient). The term "excipient" can encompass a variety of substances, including but not limited to any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solution for parenteral administration, substance for chewable tablets, sweetening or flavoring agent, suspending / gelling agent, or wet granulating agent. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coatings include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coating, 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, sodium croscarmellose, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; substances for chewable tablets include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweetening agents include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0150] Unless otherwise specified, "substantially pure" is intended to mean a composition containing no more than 10% impurities, such as a composition containing less than 9%, 7%, 5%, 3%, 1%, 0.5% impurities.

[0151] It is to be understood that aspects and embodiments described herein as "comprising" include embodiments "consisting of" and "consisting essentially of".

[0152] The blood level concentration of a drug substance and other substances in a subject can be measured in plasma or serum depending on the circumstances. In cases where measurement of the level of a substance in plasma is indicated, the level can also be measured in serum, provided that such measurement is suitably accurate. In cases where measurement of the level of a substance in serum is indicated, the level can also be measured in plasma, provided that such measurement is suitably accurate.

[0153] Compound

[0154] In one aspect, there is provided a compound of formula (A):

[0155]

[0156] or a salt thereof, wherein:

[0157] R 1 is C 6 -C 14 aryl or 5- to 10-membered heteroaryl, wherein C 6 -C 14 aryl and 5- to 10-membered heteroaryl are optionally substituted with R 1a ;

[0158] R 2 is hydrogen; deuterium; C 2a -C 1 -alkyl optionally substituted with R 6 ; OH; -O-C 2a -C 1 -alkyl optionally substituted with R 6 ; C 2b -C 3 -cycloalkyl optionally substituted with R 6 ; -O-C 2b -C 3 -cycloalkyl optionally substituted with R 6 ; 3- to 12-membered heterocyclic group optionally substituted with R 2c ; or -S(O) 2 R 2d ; provided that any carbon atom directly bonded to the nitrogen atom is optionally substituted with an R 2a moiety other than halogen;

[0159] Each R 1a is independently C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6Alkynyl, C 3 -C 8 Cycloalkyl, C 4 -C 8 Cycloalkenyl, 3- to 12-membered heterocyclic group, 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 , -NR 4 R 5 or -P(O)(OR 4 )(OR 5 ), where each R 1a is independently optionally substituted, where possible, by 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 heterocyclic group, 5- to 10-membered heteroaryl, C 6 -C 14An aryl or a C substituted optionally with deuterium, oxo, -OH or halogen 1 -C 6 substituted with an alkyl;

[0160] Each R 2a 、R 2b 、R 2c 、R 2e and R 2f is independently oxo or R 1a ;

[0161] R 2d is an optionally R 2e -substituted C 1 -C 6 alkyl or an optionally R 2f -substituted C 3 -C 5 cycloalkyl;

[0162] R 3 is 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, a 5- to 6-membered heteroaryl or a 3- to 6-membered heterocyclic group, wherein the C 3 of R 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, a 5- to 6-membered heteroaryl and a 3- to 6-membered heterocyclic group are independently optionally substituted with halogen, deuterium, oxo, -CN, -OR 8 、-NR 8 R 9 、-P(O)(OR 8 )(OR 9 ) or an optionally deuterium-, halogen-, -OH- or oxo-substituted C 1 -C 6 alkyl;

[0163] R 4 and R 5 are each independently hydrogen, deuterium, C 1 -C 6 alkyl, C2 -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 heterocyclic group, wherein R 4 and R 5 's 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 heterocyclic group are each independently optionally substituted by deuterium, halogen, oxo, -CN, -OR 8 , -NR 8 R 9 or C optionally substituted by deuterium, halogen, -OH or oxo 1 -C 6 alkyl substitution;

[0164] Or R 4 and R 5 together with the atoms to which they are attached form a 3- to 6-membered heterocyclic group optionally substituted by deuterium, halogen, oxo, -OR 8 , -NR 8 R 9 or C optionally substituted by deuterium, halogen, oxo or -OH 1 -C 6 alkyl substitution;

[0165] R 6 and R 7 are each independently hydrogen, deuterium; C optionally substituted by deuterium, halogen or oxo 1 -C 6 alkyl; C optionally substituted by deuterium, halogen or oxo 2 -C 6 alkenyl; or C optionally substituted by deuterium, halogen or oxo 2 -C 6 alkynyl;

[0166] Or R 6 and R 7 together with the atoms to which they are attached form a 3- to 6-membered heterocyclic group optionally substituted by deuterium, halogen, oxo or C optionally substituted by deuterium, halogen or oxo 1 -C 6 alkyl substitution;

[0167] R 8 and R 9 each independently is hydrogen, deuterium; C 1 -C 6 alkyl optionally substituted with deuterium, halogen or oxo; C 2 -C 6 alkenyl optionally substituted with deuterium, halogen or oxo; or C 2 -C 6 alkynyl;

[0168] or R 8 and R 9 together with the atoms to which they are attached form a 3- to 6-membered heterocyclic group optionally substituted with deuterium, halogen, oxo or C 1 -C 6 alkyl substituted with deuterium, oxo or halogen;

[0169] each R 10 , R 11 , R 12 and R 13 is independently hydrogen or deuterium;

[0170] R 14 is deuterium;

[0171] q is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0172] each R 15 is independently selected from hydrogen, deuterium or halogen;

[0173] each R 16 is independently selected from hydrogen, deuterium or halogen; and

[0174] p is 3, 4, 5, 6, 7, 8 or 9.

[0175] In one variation, the provided compound of formula A does not include 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)butyric acid:

[0176]

[0177] In various embodiments, the compound does not include the free base of the compound represented by formula A, wherein: R 1 is unsubstituted quinazolin-4-yl; R 2 is -CH 2 CH 2 OCH 3 ; R 10 , R11 , R 12 , R 13 , R 15 and R 16 are each H; p is 3; q is 0; and the carbon to which R 1 NH- is bonded has the S configuration. For example, in some embodiments, the compound of formula A does not include 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)butyric acid:

[0178]

[0179] In some embodiments, the compound does not include the free base of the compound represented by formula A, wherein R 2 is -CH 2 CH 2 OCH 3 ; R 10 , R 11 , R 12 , R 13 , R 15 and R 16 are each H; p is 3; q is 0; the carbon to which R 1 NH- is bonded has the S configuration, and R 1 is one or more of the following individually lettered embodiments (a)-(k). (a) R 1 is unsubstituted quinazolin-4-yl. (b) R 1 is quinazolin-4-yl substituted with R 1a , where R 1a is methyl. (c) R 1 is quinazolin-4-yl substituted with R 1a , where R 1a is methyl or ethyl. (d) R 1 is quinazolin-4-yl substituted with R 1a , where R 1a is C 1 -C 6 alkyl. (e) R 1 is quinazolin-4-yl substituted with R 1a . (f) R 1 is a 10-membered fused bicyclic heterocycle containing two ring nitrogen atoms, and R 1 is unsubstituted or substituted with R 1a . (g) R 1 is unsubstituted quinazolinyl. (h) R 1 is quinazolinyl substituted with R 1a , where R 1ais methyl. (i) R 1 is quinazolinyl substituted by R 1a wherein R 1a is methyl or ethyl. (j) R 1 is quinazolinyl substituted by R 1a wherein R 1a is C 1 -C 6 alkyl. (k) R 1 is quinazolinyl substituted by R 1a .

[0180] In some embodiments, the compound does not include the free base of the compound represented by formula A, wherein R 1 is unsubstituted quinazolin-4-yl; R 10 , R 11 , R 12 , R 13 , R 15 , and R 16 are each H; p is 3; q is 0; the carbon to which R 1 NH- is bonded has the S configuration, and R 2 is one or more of the following individually lettered embodiments (l)-(p). (l) R 2 is 2-substituted ethylene by R 2a and R 2a is methoxy. (m) R 2 is methylene, ethylene or propylene substituted by R 2a and R 2a is methoxy. (n) R 2 is ethylene substituted by R 2a and R 2a is methoxy or ethoxy. (o) R 2 is ethylene substituted by R 2a and R 2a is hydroxy. (p) R 2 is methylene, ethylene or propylene substituted by R 2a and R 2a is hydroxy, methoxy or ethoxy.

[0181] In some embodiments, the compound does not include the free base of the compound represented by formula A, wherein R 1 is unsubstituted quinazolin-4-yl; R 2 is -CH 2 CH 2 OCH 3 ; R 15 and R 16 are each H; p is 3; q is 0; R 1The carbon to which NH- is bonded has the S configuration, and R 10 , R 11 , R 12 and R 13 together represent one or more of the following individually lettered embodiments (q)-(u). (q) Each of R 10 , R 11 , R 12 and R 13 is hydrogen. (r) One of R 10 , R 11 , R 12 and R 13 is deuterium and the remainder are hydrogen. (s) Two of R 10 , R 11 , R 12 and R 13 are deuterium and the remainder are hydrogen. (t) Three of R 10 , R 11 , R 12 and R 13 are deuterium and the remainder are hydrogen. (u) Each of R 10 , R 11 , R 12 and R 13 is deuterium.

[0182] In some embodiments, the compound does not include the free base of the compound represented by formula A, wherein R 1 is unsubstituted quinazolin-4-yl; R 2 is -CH 2 CH 2 OCH 3 ; R 10 , R 11 , R 12 and R 13 are each H; p is 3; q is 0; the carbon to which R 1 NH- is bonded has the S configuration, and R 15 and R 16 together represent one or more of the following individually lettered embodiments (v)-(aa). v) Each of R 15 and R 16 is 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 are deuterium. (y) R 15 is hydrogen and R 16 is a halogen (e.g., fluorine), or R 15 is a halogen (e.g., fluorine) and R16 is hydrogen. (z)R 15 is deuterium, and R 16 is a halogen (e.g., fluorine), or R 15 is a halogen (e.g., fluorine), and R 16 is deuterium. (aa)R 15 and R 16 are each a halogen (e.g., fluorine).

[0183] In some embodiments, the compound does not include the free base of the compound represented by formula A, wherein R 1 is an unsubstituted quinazolin-4-yl; R 2 is -CH 2 CH 2 OCH 3 ; R 10 、R 11 、R 12 、R 13 、R 15 and R 16 are each H; q is 0; the carbon to which NH- is bonded has the S configuration; and p is one of the following individually lettered embodiments (ab)-(ad). (ab) p is 3. (ac) p is 4. (ad) p is 5. 1 NH- is bonded to the carbon in the S configuration; and p is one of the following individually lettered embodiments (ab)-(ad). (ab) p is 3. (ac) p is 4. (ad) p is 5.

[0184] In some embodiments, the compound does not include the free base of the compound represented by formula A, wherein R 1 is an unsubstituted quinazolin-4-yl; R 2 is -CH 2 CH 2 OCH 3 ; R 10 、R 11 、R 12 、R 13 、R 15 and R 16 are each H; p is 3; the carbon to which NH- is bonded has the S configuration; and q is one of the following individually lettered embodiments (ae)-(ah). (ae) q is 0. (af) q is 1. (ag) q is 2. (ah) q is 3. 1 NH- is bonded to the carbon in the S configuration; and q is one of the following individually lettered embodiments (ae)-(ah). (ae) q is 0. (af) q is 1. (ag) q is 2. (ah) q is 3.

[0185] In some embodiments, it does not include R 1 ; R 2 ; R 10 、R 11 、R 12 and R 13 together; R 15 and R 16The free base of a compound of any combination of the lettered embodiments selected for each of together; variable p; and variable q. For example, the following combinations may be selected: R 1 selected from one of (a)-(k); R 2 selected from one of (l)-(p); R 10 R 11 R 12 and R 13 together selected from one of (q)-(u); R 15 and R 16selected from one of (v)-(aa); variable p is selected from one of (ab)-(ad); and variable q is selected from one of (ae)-(ah). Exemplary combinations of the lettered embodiments may include, for example: (a), (l), (q), (v), (ab) and (ae); (b), (l), (q), (v), (ab) and (ae); (c), (l), (q), (v), (ab) and (ae); (d), (l), (q), (v), (ab) and (ae); (e), (l), (q), (v), (ab) and (ae); (f), (l), (q), (v), (ab) and (ae); (g), (l), (q), (v), (ab) and (ae); (h), (l), (q), (v), (ab) and (ae); (i), (l), (q), (v), (ab) and (ae); (j), (l), (q), (v), (ab) and (ae); (k), (l), (q), (v), (ab) and (ae); (a), (m), (q), (v), (ab) and (ae); (b), (m), (q), (v), (ab) and (ae); (c), (m), (q), (v), (ab) and (ae); (d), (m), (q), (v), (ab) and (ae); (e), (m), (q), (v), (ab) and (ae); (f), (m), (q), (v), (ab) and (ae); (g), (m), (q), (v), (ab) and (ae); (h), (m), (q), (v), (ab) and (ae); (i), (m), (q), (v), (ab) and (ae); (j), (m), (q), (v), (ab) and (ae); (k), (m), (q), (v), (ab) and (ae); (a), (n), (q), (v), (ab) and (ae); (b), (n), (q), (v), (ab) and (ae); (c), (n), (q), (v), (ab) and (ae); (d), (n), (q), (v), (ab) and (ae); (e), (n), (q), (v), (ab) and (ae); (f), (n), (q), (v), (ab) and (ae); (g), (n), (q), (v), (ab) and (ae); (h), (n), (q), (v), (ab) and (ae); (i), (n), (q), (v), (ab) and (ae); (j), (n), (q), (v), (ab) and (ae); (k), (n), (q), (v), (ab) and (ae); (a), (o), (q), (v), (ab) and (ae); (b), (o), (q), (v), (ab) and (ae);(c), (o), (q), (v), (ab) and (ae); (d), (o), (q), (v), (ab) and (ae); (e), (o), (q), (v), (ab) and (ae); (f), (o), (q), (v), (ab) and (ae); (g), (o), (q), (v), (ab) and (ae); (h), (o), (q), (v), (ab) and (ae); (i), (o), (q), (v), (ab) and (ae); (j), (o), (q), (v), (ab) and (ae); (k), (o), (q), (v), (ab) and (ae); (a), (p), (q), (v), (ab) and (ae); (b), (p), (q), (v), (ab) and (ae); (c), (p), (q), (v), (ab) and (ae); (d), (p), (q), (v), (ab) and (ae); (e), (p), (q), (v), (ab) and (ae); (f), (p), (q), (v), (ab) and (ae); (g), (p), (q), (v), (ab) and (ae); (h), (p), (q), (v), (ab) and (ae); (i), (p), (q), (v), (ab) and (ae); (j), (p), (q), (v), (ab) and (ae); (k), (p), (q), (v), (ab) and (ae); any of the foregoing combinations wherein (v) is replaced by (y); any of the foregoing combinations wherein (v) is replaced by (aa); any of the foregoing combinations wherein (ab) is replaced by (ad); or any of the foregoing combinations wherein (ab) is replaced by (ae);

[0186] In some embodiments, salts of compounds that do not include any one or any combination of the lettered embodiments (a)-(ah) as described above are excluded. In some embodiments, pharmaceutical compositions that do not include compounds or their salts that include any one or any combination of the lettered embodiments (a)-(ah) as described above are excluded. In some embodiments, kits that do not include compounds or their salts that include any one or any combination of the lettered embodiments (a)-(ah) as described above are excluded. In some embodiments, dosage forms that do not include compounds that include any one or any combination of the lettered embodiments (a)-(ah) as described above are excluded. In some embodiments, methods that do not include compounds or their salts that include any one or any combination of the lettered embodiments (a)-(ah) as described above are excluded.

[0187] In one variation, a compound of formula (A) or a salt thereof is provided, wherein with CO 2 H and NHR 1Part of the carbon is in the "S" configuration. In another variation, a compound of formula (A) or a salt thereof is provided, wherein the carbon bearing CO 2 H and NHR 1 Part of the carbon is in the "R" configuration. Mixtures of compounds of formula (A) are also encompassed, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0188] In one variation of formula (A), R 2 is such that any carbon atom directly bonded to the nitrogen atom is unsubstituted or substituted with deuterium.

[0189] In the description herein, it is to be understood that each description, variation, embodiment or aspect of one part can be combined with each description, variation, embodiment or aspect of other parts, as if each combination were specifically and individually listed. For example, each description, variation, embodiment or aspect provided herein regarding R of formula (A) 1 can be combined with each description, variation, embodiment or aspect of R 2 as if each combination were specifically and individually listed.

[0190] In one aspect, a compound of formula (I) is provided

[0191]

[0192] or a salt thereof, wherein:

[0193] R 1 is C 6 -C 14 aryl or 5- to 10-membered heteroaryl, wherein C 6 -C 14 aryl and 5- to 10-membered heteroaryl are optionally substituted with R 1a ;

[0194] R 2 is C 2a -C 1 alkyl optionally substituted with R 6 ; C 2b -C 3 cycloalkyl optionally substituted with R 6 ; a 3- to 12-membered heterocyclic group optionally substituted with R 2c ; or -S(O) 2 R 2d ;

[0195] Each R 1a is independently 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 heterocyclic group, 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 , -NR 2 R 4 , -S(O)NR 4 R 5 , -S(O) 2 NR 4 R 5 or -P(O)(OR 4 )(OR 5 ), where each R 1a is independently optionally substituted, where possible, by 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 8Cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14 Aryl or C optionally substituted by deuterium, oxo, -OH or halogen 1 -C 6 Alkyl substitution;

[0196] Each R 2a , R 2b , R 2c , R 2e and R 2f are independently oxo or R 1a ;

[0197] R 2d Is optional 2e Substituted C 1 -C 6 Alkyl or optionally R 2f Substituted C 3 -C 5 Cycloalkyl;

[0198] 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 heterocyclic group, wherein R 3 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 optionally substituted with 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 Alkyl substitution;

[0199] R 4 and R5 Each independently is 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 heterocyclic group, wherein R 4 and R 5 's 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 heterocyclic group are independently optionally substituted by deuterium, halogen, oxo, -CN, -OR 8 , -NR 8 R 9 or C 1 -C 6 alkyl optionally substituted by deuterium, halogen, -OH or oxo;

[0200] Or R 4 and R 5 together with the atoms to which they are attached form a 3- to 6-membered heterocyclic group optionally substituted by deuterium, halogen, oxo, -OR 8 , -NR 8 R 9 or C 1 -C 6 alkyl optionally substituted by deuterium, halogen, oxo or -OH;

[0201] R 6 and R 7 Each independently is hydrogen, deuterium; C 1 -C 6 alkyl optionally substituted by deuterium, halogen or oxo; C 2 -C 6 alkenyl optionally substituted by deuterium, halogen or oxo; or C 2 -C 6 alkynyl;

[0202] Or R 6 and R 7Combined with the atoms to which they are attached to form a 3- to 6-membered heterocyclic group optionally substituted with deuterium, halogen, oxo, or C 1 -C 6 alkyl substituted;

[0203] R 8 and R 9 are each independently hydrogen, deuterium; C optionally substituted with deuterium, halogen, or oxo 1 -C 6 alkyl; C optionally substituted with deuterium, halogen, or oxo 2 -C 6 alkenyl; or C optionally substituted with deuterium, halogen, or oxo 2 -C 6 alkynyl;

[0204] Or R 8 and R 9 Combined with the atoms to which they are attached to form a 3- to 6-membered heterocyclic group optionally substituted with deuterium, halogen, oxo, or C 1 -C 6 alkyl substituted;

[0205] Each R 10 , R 11 , R 12 and R 13 is independently hydrogen or deuterium;

[0206] R 14 is deuterium;

[0207] q is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and

[0208] p is 3, 4, 5, 6, 7, 8, or 9.

[0209] In one variant, there is provided a compound of formula (I) or a salt thereof, wherein the carbon bearing the CO 2 H and NHR 1 moiety is in the "S" configuration. In another variant, there is provided a compound of formula (I) or a salt thereof, wherein the carbon bearing the CO 2 H and NHR 1 moiety is in the "R" configuration. Also covered 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.

[0210] In one variant of formula (I), R 2 includes the condition that any carbon atom directly bonded to the nitrogen atom is optionally substituted with an R 2a moiety other than halogen. In one variant of formula (I), R 2Includes the following conditions: Any carbon atom directly bonded to a nitrogen atom is unsubstituted or substituted with deuterium.

[0211] In the description herein, it is to be understood that each description, variation, embodiment or aspect of one part can be combined with each description, variation, embodiment or aspect of other parts, as if each combination were specifically and individually listed. For example, herein with respect to R of formula (I) 1 Each description, variation, embodiment or aspect provided can be combined with each description, variation, embodiment or aspect of R 2 as if each combination were specifically and individually listed.

[0212] In some embodiments of the compound of formula (I) or a salt thereof, R 1a 、R 2a 、R 2b 、R 2c 、R 2e 、R 2f 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 or at least one of R

[0213] In some embodiments of the compound of formula (I) or a salt thereof, R 1 is a 5- to 10-membered heteroaryl optionally substituted with R 1a . In some embodiments, R 1 is a pyrimidin-4-yl optionally substituted with R 1a . In some embodiments, R 1 is a pyrimidin-4-yl optionally substituted with R 1a , wherein R 1a is a 5- to 10-membered heteroaryl (e.g., pyrazolyl) or a C 1 -C 6 alkyl optionally substituted with halogen (e.g., methyl, difluoromethyl and trifluoromethyl). In some embodiments, R 1 is a pyrimidin-4-yl optionally substituted with R 1a , wherein R 1a is a 5- to 10-membered heteroaryl (e.g., pyrazolyl or pyridyl) or a C 1 -C6 Alkyl (e.g., methyl, difluoromethyl, and trifluoromethyl). In some embodiments, R 1 is a pyrimidin-4-yl substituted with both methyl and trifluoromethyl. In some embodiments, R 1 is a pyrimidin-4-yl substituted with both methyl and pyridyl. In some embodiments, R 1 is a pyrimidin-4-yl optionally substituted with R 1a , where R 1a is C 6 -C 14 aryl (e.g., phenyl). In some embodiments, R 1 is a pyrimidin-4-yl optionally substituted with R 1a , where R 1a is -CN. In some embodiments, R 1 is a pyrimidin-2-yl optionally substituted with R 1a . In some embodiments, R 1 is a pyrimidin-2-yl optionally substituted with R 1a , where R 1a is halogen, C 1 -C 6 alkyl optionally substituted with halogen (e.g., methyl or trifluoromethyl), -CN, or C 3 -C 8 cycloalkyl (e.g., cyclopropyl). In some embodiments of the compound of formula (I) or its salt, R 1 is a quinazolin-4-yl optionally substituted with R 1a . In some embodiments, R 1 is a quinazolin-4-yl optionally substituted with R 1a , where R 1a is halogen (e.g., fluoro and chloro), C 1 -C 6 alkyl optionally substituted with halogen (e.g., methyl or trifluoromethyl), or C 1 -C 6 alkoxy (e.g., methoxy). In some embodiments, R 1 is a quinazolin-4-yl optionally substituted with R 1a , where R 1a is a 5- to 10-membered heteroaryl (e.g., pyridyl). In some embodiments, R 1 is a pyrazolopyrimidinyl optionally substituted with R 1a . In some embodiments, R 1 is a pyrazolopyrimidinyl optionally substituted with R 1a , where R 1a is C 1 -C 6An alkyl group (e.g., methyl). In those indicating R 1 optionally substituted by R 1a in some embodiments, the R 1 moiety is unsubstituted. In those indicating R 1 optionally substituted by R 1a in some embodiments, the R 1 moiety is substituted by one R 1a substituent. In those indicating R 1 optionally substituted by R 1a in some embodiments, the R 1 moiety is substituted by 2 to 6 or 2 to 5 or 2 to 4 or 2 to 3 R 1a moieties which may be the same or different.

[0214] In some embodiments of formula (I) (including those embodiments describing the R 1 variable), each of R 10 , R 11 , R 12 and R 13 is hydrogen. In some embodiments of formula (I) (including those embodiments describing the R 1 variable and / or the R 10 , R 11 , R 12 and R 13 variables), q is 0. In some embodiments (including those embodiments describing the R 1 variable and / or the R 10 , R 11 , R 12 and R 13 variables and / or the q variable), p is 3, 4 or 5.

[0215] In some embodiments of formula (I), R 10 , R 11 , R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound has formula (II):

[0216] or a salt thereof, wherein R 1 and R 2 are as defined for formula (I).

[0217] In some embodiments of a compound of formula (I) in which R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a , the compound has formula (I-A):

[0218]

[0219] or a salt thereof, wherein R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), m is 0, 1, 2 or 3, and the positions on the pyrimidine ring and the tetrahydronaphthyridine ring are as indicated.

[0220] In one embodiment, there is provided a compound of formula (I-A) or a salt thereof, wherein the carbon bearing the CO 2 H and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-A) or a salt thereof, wherein the carbon bearing the CO 2 H and NH moieties is in the "R" configuration. Also embraced are mixtures of compounds of formula (I-A), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0221] In some embodiments of the compounds of formula (I-A), m is 0, 1, 2 or 3, and each R 1a is independently, where applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium. In further embodiments of the compounds of formula (I-A), m is 0, 1, 2 or 3, and each R 1a is independently, where applicable, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl (which in one variation may be C 1 -C 6 perhaloalkyl), C 1 -C 6 alkoxy, hydroxy, -CN or a 5- to 10-membered heteroaryl, wherein the C 1a of R 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy and 5- to 10-membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of formula (I-A), m is 1, 2 or 3.

[0222] In some embodiments of the compounds of formula (I-A), m is 0. In some embodiments of the compounds of formula (I-A), m is 1, and R1a at the 2-position. In some embodiments of the compounds of formula (I-A), m is 1, and R 1a at the 5-position. In some embodiments of the compounds of formula (I-A), m is 1, and R 1a at the 6-position. In some embodiments of the compounds of formula (I-A), m is 2, and R 1a groups are at the 2-position and the 5-position. In some embodiments of the compounds of formula (I-A), m is 2, and R 1a groups are at the 2-position and the 6-position. In some embodiments of the compounds of formula (I-A), m is 2, and R 1a groups are at the 5-position and the 6-position. In some embodiments of the compounds of formula (I-A), m is 3, and R 1a groups are at the 2-position, the 5-position and the 6-position. Whenever there is more than one R 1a group, the R 1a groups can be independently selected. In any of these embodiments of the compounds of formula (I-A) or their salts, the carbon bearing the CO 2 H and NH moieties can be in the "S" configuration or the "R" configuration.

[0223] In some embodiments of formula (I-A) (including the embodiments describing the R 1a and m variables), each of R 10 , R 11 , R 12 and R 13 is hydrogen. In some embodiments of formula (I-A) (including the embodiments describing the R 1a and m variables and / or the R 10 , R 11 , R 12 and R 13 variables), q is 0. In some embodiments of formula (I-A) (including the embodiments describing the R 1a and m variables and / or the R 10 , R 11 , R 12 and R 13 variables and / or the q variable), p is 3, 4 or 5.

[0224] In some embodiments of formula (I-A), R 10 , R 11 , R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound has formula (II-A):

[0225]

[0226] or a salt thereof, wherein R 1a and R 2 As defined for formula (I), m is 0, 1, 2 or 3, and the positions on the pyrimidine ring are as indicated. Regarding R 1a 、R 2 and all descriptions of m in formula (I) apply equally to formula (I-A) and (II-A).

[0227] In some embodiments of the compounds of formula (I) in which R 1 is an optionally R 1a substituted 5- to 10-membered heteroaryl, the compound has formula (I-B):

[0228]

[0229] or a salt thereof, wherein R 1a 、R 2 、R 10 、R 11 、R 12 、R 13 、R 14 、q and p are as defined for formula (I), m is 0, 1, 2, 3, 4 or 5, and the positions on the quinazoline ring are as indicated.

[0230] In one embodiment, there is provided a compound of formula (I-B) or a salt thereof, wherein the carbon bearing the CO 2 H and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-B) or a salt thereof, wherein the carbon bearing the CO 2 H and NH moieties is in the "R" configuration. Also covered are mixtures of compounds of formula (I-B), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0231] In some embodiments of the compounds of formula (I-B), m is 0, 1, 2, 3, 4 or 5, and each R 1a is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium. In further embodiments of the compounds of formula (I-B), m is 0, 1, 2, 3, 4 or 5, and each R 1a is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl (which in one variation can be C 1 -C 6 perhaloalkyl), C1 -C 6 an alkoxy group, a hydroxyl group, -CN, or a 5- to 10-membered heteroaryl group, wherein R 1a the C of 1 -C 6 an alkyl group, C 1 -C 6 a haloalkyl group, C 1 -C 6 the alkoxy group, the hydroxyl group, and the 5- to 10-membered heteroaryl group are each independently optionally substituted with deuterium. In some embodiments of the compounds of formula (I-B), m is 1, 2, 3, 4, or 5.

[0232] In some embodiments of the compounds of formula (I-B), m is 0. In some embodiments of the compounds of formula (I-B), m is 1, and R 1a is at the 2-position. In some embodiments of the compounds of formula (I-B), m is 1, and R 1a is at the 5-position. In some embodiments of the compounds of formula (I-B), m is 1, and R 1a is at the 6-position. In some embodiments of the compounds of formula (I-B), m is 1, and R 1a is at the 7-position. In some embodiments of the compounds of formula (I-B), m is 1, and R 1a is at the 8-position. In some embodiments of the compounds of formula (I-B), m is 2, and R 1a the group is at the 2-position and the 5-position. In some embodiments of the compounds of formula (I-B), m is 2, and R 1a the group is at the 2-position and the 6-position. In some embodiments of the compounds of formula (I-B), m is 2, and R 1a the group is at the 2-position and the 7-position. In some embodiments of the compounds of formula (I-B), m is 2, and R 1a the group is at the 2-position and the 8-position. In some embodiments of the compounds of formula (I-B), m is 2, and R 1a the group is at the 5-position and the 6-position. In some embodiments of the compounds of formula (I-B), m is 2, and R 1a the group is at the 5-position and the 7-position. In some embodiments of the compounds of formula (I-B), m is 2, and R 1a the group is at the 5-position and the 8-position. In some embodiments of the compounds of formula (I-B), m is 2, and R 1a the group is at the 6-position and the 7-position. In some embodiments of the compounds of formula (I-B), m is 2, and R 1a the group is at the 6-position and the 8-position. In some embodiments of the compounds of formula (I-B), m is 2, and R 1aThe group is at the 7-position and 8-position. In some embodiments of the compounds of formula (I-B), m is 3, and R 1a The group is at the 2-position, 5-position and 6-position. In some embodiments of the compounds of formula (I-B), m is 3, and R 1a The group is at the 2-position, 5-position and 7-position. In some embodiments of the compounds of formula (I-B), m is 3, and R 1a The group is at the 2-position, 5-position and 8-position. In some embodiments of the compounds of formula (I-B), m is 3, and R 1a The group is at the 2-position, 6-position and 7-position. In some embodiments of the compounds of formula (I-B), m is 3, and R 1a The group is at the 2-position, 6-position and 8-position. In some embodiments of the compounds of formula (I-B), m is 3, and R 1a The group is at the 2-position, 7-position and 8-position. In some embodiments of the compounds of formula (I-B), m is 3, and R 1a The group is at the 5-position, 6-position and 7-position. In some embodiments of the compounds of formula (I-B), m is 3, and R 1a The group is at the 5-position, 6-position and 8-position. In some embodiments of the compounds of formula (I-B), m is 3, and R 1a The group is at the 5-position, 7-position and 8-position. In some embodiments of the compounds of formula (I-B), m is 3, and R 1a The group is at the 6-position, 7-position and 8-position. In some embodiments of the compounds of formula (I-B), m is 4, and R 1a The group is at the 2-position, 5-position, 6-position and 7-position. In some embodiments of the compounds of formula (I-B), m is 4, and R 1a The group is at the 2-position, 5-position, 6-position and 8-position. In some embodiments of the compounds of formula (I-B), m is 4, and R 1a The group is at the 2-position, 5-position, 7-position and 8-position. In some embodiments of the compounds of formula (I-B), m is 4, and R 1a The group is at the 2-position, 6-position, 7-position and 8-position. In some embodiments of the compounds of formula (I-B), m is 4, and R 1a The group is at the 5-position, 6-position, 7-position and 8-position. In some embodiments of the compounds of formula (I-B), m is 5, and R 1a The group is at the 2-position, 5-position, 6-position, 7-position and 8-position. Whenever there is more than one R 1a group, R can be selected independently1a group. In any of these embodiments of the compound of formula (I-B) or its salt, the carbon bearing the CO 2 H and NH moieties can be in the "S" configuration or the "R" configuration.

[0233] In some embodiments of formula (I-B) (including those embodiments that describe the R 1a and m variables), each of R 10 、R 11 、R 12 and R 13 is hydrogen. In some embodiments of formula (I-B) (including those embodiments that describe the R 1a and m variables and / or R 10 、R 11 、R 12 and R 13 variables), q is 0. In some embodiments of formula (I-B) (including those embodiments that describe the R 1a and m variables and / or R 10 、R 11 、R 12 and R 13 variables and / or the q variable), p is 3, 4 or 5.

[0234] In some embodiments of formula (I-B), R 10 、R 11 、R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound has formula (II-B):

[0235]

[0236] or its salt, wherein R 1a and R 2 are as defined for formula (I), m is 0, 1, 2, 3, 4 or 5, and the positions on the quinazoline ring are as indicated. All descriptions of R 1a 、R 2 and m for formula (I) apply equally to formula (I-B) and (II-B).

[0237] In some embodiments of the compound of formula (I) in which R 1 is a 5- to 10-membered heteroaryl optionally substituted with R 1a , the compound has formula (I-C):

[0238]

[0239] or its salt, wherein R 1a 、R 2 、R 10 、R11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), m is 0, 1, 2, 3 or 4, and the positions on the pyrido[3,2-d]pyrimidine ring are as indicated.

[0240] In one embodiment, there is provided a compound of formula (I-C) or a salt thereof, wherein the carbon bearing the CO 2 H and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-C) or a salt thereof, wherein the carbon bearing the CO 2 H and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (I-C), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0241] In some embodiments of the compounds of formula (I-C), m is 0, 1, 2, 3 or 4, and each R 1a is independently, where applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium. In further embodiments of the compounds of formula (I-C), m is 0, 1, 2, 3 or 4, and each R 1a is independently, where applicable, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl (which in one variation can be C 1 -C 6 perhaloalkyl), C 1 -C 6 alkoxy, hydroxy, -CN or a 5- to 10-membered heteroaryl, wherein the C 1a of R 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy and 5- to 10-membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of the compounds of formula (I-C), m is 1, 2, 3 or 4.

[0242] In some embodiments of the compounds of formula (I-C), m is 0. In some embodiments of the compounds of formula (I-C), m is 1, and R 1a is in the 2-position. In some embodiments of the compounds of formula (I-C), m is 1, and R 1aAt the 6-position. In some embodiments of the compounds of formula (I-C), m is 1, and R 1a At the 7-position. In some embodiments of the compounds of formula (I-C), m is 1, and R 1a At the 8-position. In some embodiments of the compounds of formula (I-C), m is 2, and R 1a Groups are at the 2- and 6-positions. In some embodiments of the compounds of formula (I-C), m is 2, and R 1a Groups are at the 2- and 7-positions. In some embodiments of the compounds of formula (I-C), m is 2, and R 1a Groups are at the 2- and 8-positions. In some embodiments of the compounds of formula (I-C), m is 2, and R 1a Groups are at the 6- and 7-positions. In some embodiments of the compounds of formula (I-C), m is 2, and R 1a Groups are at the 6- and 8-positions. In some embodiments of the compounds of formula (I-C), m is 2, and R 1a Groups are at the 7- and 8-positions. In some embodiments of the compounds of formula (I-C), m is 3, and R 1a Groups are at the 2-, 6- and 7-positions. In some embodiments of the compounds of formula (I-C), m is 3, and R 1a Groups are at the 2-, 6- and 8-positions. In some embodiments of the compounds of formula (I-C), m is 3, and R 1a Groups are at the 2-, 7- and 8-positions. In some embodiments of the compounds of formula (I-C), m is 3, and R 1a Groups are at the 6-, 7- and 8-positions. In some embodiments of the compounds of formula (I-C), m is 4, and R 1a Groups are at the 2-, 6-, 7- and 8-positions. Whenever there is more than one R 1a group, the R 1a groups can be selected independently. In any of these embodiments of the compounds of formula (I-C) or their salts, the carbon bearing the CO 2 H and NH moieties can be in the "S" configuration or the "R" configuration.

[0243] In some embodiments of formula (I-C) (including those describing the R 1a and m variables), each of R 10 , R 11 , R 12 and R 13 is hydrogen. In some embodiments of formula (I-C) (including those describing the R 1a and m variables and / or R10 , R 11 , R 12 and R 13 In some embodiments of the variables, q is 0. In some embodiments of formula (I-C) (including those describing the R 1a and m variables and / or the R 10 , R 11 , R 12 and R 13 variables and / or the q variable), p is 3, 4, or 5.

[0244] In some embodiments of formula (I-C), R 10 , R 11 , R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound has formula (II-C):

[0245]

[0246] or a salt thereof, wherein R 1a and R 2 are as defined for formula (I), m is 0, 1, 2, 3, or 4, and the positions on the pyrido[3,2-d]pyrimidine ring are as indicated. All descriptions of R 1a , R 2 and m for formula (I) apply equally to formula (I-C) and (II-C).

[0247] In some embodiments of the compounds of formula (I) in which R 1 is an optionally R 1a -substituted 5- to 10-membered heteroaryl, the compound has formula (I-D):

[0248]

[0249] or a salt thereof, wherein R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q, and p are as defined for formula (I), m is 0, 1, 2, 3, or 4, and the positions on the pyrido[3,4-d]pyrimidine ring are as indicated.

[0250] In one embodiment, there is provided a compound of formula (I-D) or a salt thereof, wherein the carbon bearing the CO 2 H and NH moieties has an "S" configuration. In another embodiment, there is provided a compound of formula (I-D) or a salt thereof, wherein the carbon bearing the CO 2The carbon of the H and NH moieties is in the “R” configuration. Also covered are mixtures of compounds of formula (I-D), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0251] In some embodiments of the compounds of formula (I-D), m is 0, 1, 2, 3, or 4, and each R 1a is independently, where applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, where the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R 1a are independently optionally substituted with deuterium. In further embodiments of the compounds of formula (I-D), m is 0, 1, 2, 3, or 4, and each R 1a is independently, where applicable, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl (which in one variation can be C 1 -C 6 perhaloalkyl), C 1 -C 6 alkoxy, hydroxy, -CN, or a 5- to 10-membered heteroaryl, where the C 1a of R 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of the compounds of formula (I-D), m is 1, 2, 3, or 4.

[0252] In some embodiments of the compounds of formula (I-D), m is 0. In some embodiments of the compounds of formula (I-D), m is 1, and R 1a is in the 2-position. In some embodiments of the compounds of formula (I-D), m is 1, and R 1a is in the 5-position. In some embodiments of the compounds of formula (I-D), m is 1, and R 1a is in the 6-position. In some embodiments of the compounds of formula (I-D), m is 1, and R 1a is in the 8-position. In some embodiments of the compounds of formula (I-D), m is 2, and the R 1a groups are in the 2- and 5-positions. In some embodiments of the compounds of formula (I-D), m is 2, and the R 1a groups are in the 2- and 6-positions. In some embodiments of the compounds of formula (I-D), m is 2, and R1a The group is at the 2-position and the 8-position. In some embodiments of the compounds of formula (I-D), m is 2, and R 1a The group is at the 5-position and the 6-position. In some embodiments of the compounds of formula (I-D), m is 2, and R 1a The group is at the 5-position and the 8-position. In some embodiments of the compounds of formula (I-D), m is 2, and R 1a The group is at the 6-position and the 8-position. In some embodiments of the compounds of formula (I-D), m is 3, and R 1a The group is at the 2-position, the 5-position and the 6-position. In some embodiments of the compounds of formula (I-D), m is 3, and R 1a The group is at the 2-position, the 5-position and the 8-position. In some embodiments of the compounds of formula (I-D), m is 3, and R 1a The group is at the 2-position, the 6-position and the 8-position. In some embodiments of the compounds of formula (I-D), m is 3, and R 1a The group is at the 5-position, the 6-position and the 8-position. In some embodiments of the compounds of formula (I-D), m is 4, and R 1a The group is at the 2-position, the 5-position, the 6-position and the 8-position. Whenever there is more than one R 1a group, the R 1a groups can be selected independently. In any of these embodiments of the compounds of formula (I-D) or their salts, the carbon bearing the CO 2 H and NH moieties can be in the "S" configuration or the "R" configuration.

[0253] In some embodiments of formula (I-D) (including those describing the R 1a and m variables), each of R 10 , R 11 , R 12 and R 13 is hydrogen. In some embodiments of formula (I-D) (including those describing the R 1a and m variables and / or the R 10 , R 11 , R 12 and R 13 variables), q is 0. In some embodiments of formula (I-D) (including those describing the R 1a and m variables and / or the R 10 , R 11 , R 12 and R 13 variables and / or the q variable), p is 3, 4 or 5.

[0254] In some embodiments of formula (I-D), R 10 , R 11 , R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound has formula (II-D):

[0255]

[0256] or a salt thereof, wherein R 1a and R 2 are as defined for formula (I), m is 0, 1, 2, 3, or 4, and the positions on the pyrido[3,4-d]pyrimidine ring are as indicated. All descriptions of R 1a , R 2 and m for formula (I) apply equally to formula (I-D) and (II-D).

[0257] In some embodiments of compounds of formula (I) wherein R 1 is a 5- to 10-membered heteroaryl optionally substituted with R 1a , the compound has formula (I-E):

[0258]

[0259] or a salt thereof, wherein R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), m is 0, 1, 2, 3, or 4, and the positions on the pyrido[2,3-d]pyrimidine ring are as indicated.

[0260] In one embodiment, there is provided a compound of formula (I-E) or a salt thereof, wherein the carbon bearing the CO 2 H and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-E) or a salt thereof, wherein the carbon bearing the CO 2 H and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (I-E), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0261] In some embodiments of the compounds of formula (I-E), m is 0, 1, 2, 3, or 4, and each R 1a is independently, where applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, wherein R 1aThe alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl groups are each independently optionally substituted with deuterium. In a further embodiment of the compound of formula (I-E), m is 0, 1, 2, 3 or 4, and each R 1a is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl (which in one variation may be C 1 -C 6 perhaloalkyl), C 1 -C 6 alkoxy, hydroxy, -CN or a 5- to 10-membered heteroaryl group, where the C 1a of R 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy and 5- to 10-membered heteroaryl groups are each independently optionally substituted with deuterium. In some embodiments of the compound of formula (I-E), m is 1, 2, 3 or 4.

[0262] In some embodiments of the compound of formula (I-E), m is 0. In some embodiments of the compound of formula (I-E), m is 1 and R 1a is in the 2-position. In some embodiments of the compound of formula (I-E), m is 1 and R 1a is in the 5-position. In some embodiments of the compound of formula (I-E), m is 1 and R 1a is in the 6-position. In some embodiments of the compound of formula (I-E), m is 1 and R 1a is in the 7-position. In some embodiments of the compound of formula (I-E), m is 2 and the R 1a groups are in the 2- and 5-positions. In some embodiments of the compound of formula (I-E), m is 2 and the R 1a groups are in the 2- and 6-positions. In some embodiments of the compound of formula (I-E), m is 2 and the R 1a groups are in the 2- and 7-positions. In some embodiments of the compound of formula (I-E), m is 2 and the R 1a groups are in the 5- and 6-positions. In some embodiments of the compound of formula (I-E), m is 2 and the R 1a groups are in the 5- and 7-positions. In some embodiments of the compound of formula (I-E), m is 2 and the R 1a groups are in the 6- and 7-positions. In some embodiments of the compound of formula (I-E), m is 3 and R1a The group is at the 2-position, 5-position, and 6-position. In some embodiments of the compound of formula (I-E), m is 3, and R 1a The group is at the 2-position, 5-position, and 7-position. In some embodiments of the compound of formula (I-E), m is 3, and R 1a The group is at the 2-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-E), m is 3, and R 1a The group is at the 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-E), m is 4, and R 1a The group is at the 2-position, 5-position, 6-position, and 7-position. Whenever there is more than one R 1a group, the R 1a groups can be independently selected. In any of these embodiments of the compound of formula (I-E) or its salt, the carbon bearing the CO 2 H and NH moieties can be in the "S" configuration or the "R" configuration.

[0263] In some embodiments of formula (I-E) (including those embodiments describing the R 1a and m variables), each of R 10 , R 11 , R 12 , and R 13 is hydrogen. In some embodiments of formula (I-E) (including those embodiments describing the R 1a and m variables and / or the R 10 , R 11 , R 12 , and R 13 variables), q is 0. In some embodiments of formula (I-E) (including those embodiments describing the R 1a and m variables and / or the R 10 , R 11 , R 12 , and R 13 variables and / or the q variable), p is 3, 4, or 5.

[0264] In some embodiments of formula (I-E), R 10 , R 11 , R 12 , and R 13 are hydrogen, p is 3, q is 0, and the compound has the formula (II-E):

[0265]

[0266] or its salt, wherein R 1a and R 2As defined for formula (I), m is 0, 1, 2, 3 or 4, and the positions on the pyrido[2,3-d]pyrimidine ring are as indicated. Regarding R of formula (I) 1a , R 2 and all descriptions of m apply equally to formulas (I-E) and (II-E).

[0267] In some embodiments of the compounds of formula (I) in which R 1 is an optionally R 1a -substituted 5- to 10-membered heteroaryl, the compound has formula (I-F):

[0268]

[0269] or a salt thereof, wherein R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), m is 0, 1, 2, 3, 4, 5, or 6, and the positions on the quinoline ring are as indicated.

[0270] In one embodiment, a compound of formula (I-F) or a salt thereof is provided, wherein the carbon bearing the CO 2 H and NH moieties is in the "S" configuration. In another embodiment, a compound of formula (I-F) or a salt thereof is provided, wherein the carbon bearing the CO 2 H and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (I-F), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0271] In some embodiments of the compounds of formula (I-F), m is 0, 1, 2, 3, 4, 5 or 6, and each R 1a is independently, where applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium. In further embodiments of the compounds of formula (I-F), m is 0, 1, 2, 3, 4, 5 or 6, and each R 1a is independently, where applicable, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl (which in one variation can be C 1 -C 6 perhaloalkyl), C 1 -C6 an alkoxy group, a hydroxyl group, -CN, or a 5- to 10-membered heteroaryl group, wherein R 1a of C 1 -C 6 alkyl group, C 1 -C 6 haloalkyl group, C 1 -C 6 the alkoxy group, the hydroxyl group, and the 5- to 10-membered heteroaryl group are each independently optionally substituted with deuterium. In some embodiments of the compounds of formula (I-F), m is 1, 2, 3, 4, 5, or 6.

[0272] In some embodiments of the compounds of formula (I-F), m is 0. In some embodiments of the compounds of formula (I-F), m is 1, and R 1a is at the 2-position. In some embodiments of the compounds of formula (I-F), m is 1, and R 1a is at the 3-position. In some embodiments of the compounds of formula (I-F), m is 1, and R 1a is at the 5-position. In some embodiments of the compounds of formula (I-F), m is 1, and R 1a is at the 6-position. In some embodiments of the compounds of formula (I-F), m is 1, and R 1a is at the 7-position. In some embodiments of the compounds of formula (I-F), m is 1, and R 1a is at the 8-position. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a groups are at the 2-position and the 3-position. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a groups are at the 2-position and the 5-position. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a groups are at the 2-position and the 6-position. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a groups are at the 2-position and the 7-position. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a groups are at the 2-position and the 8-position. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a groups are at the 3-position and the 5-position. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a groups are at the 3-position and the 6-position. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a groups are at the 3-position and the 7-position. In some embodiments of the compounds of formula (I-F), m is 2, and R 1aThe group is at the 3-position and the 8-position. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a The group is at the 5-position and the 6-position. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a The group is at the 5-position and the 7-position. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a The group is at the 5-position and the 8-position. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a The group is at the 6-position and the 7-position. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a The group is at the 6-position and the 8-position. In some embodiments of the compounds of formula (I-F), m is 2, and R 1a The group is at the 7-position and the 8-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 2-position, 3-position and 5-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 2-position, 3-position and 6-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 2-position, 3-position and 7-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 2-position, 3-position and 8-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 2-position, 5-position and 6-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 2-position, 5-position and 7-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 2-position, 5-position and 8-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 2-position, 6-position and 7-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 2-position, 6-position and 8-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 2-position, 7-position and 8-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 3-position, 5-position and 6-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1aThe group is at the 3-position, 5-position, and 7-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 3-position, 5-position, and 8-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 3-position, 6-position, and 7-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 3-position, 6-position, and 8-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 3-position, 7-position, and 8-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 5-position, 6-position, and 7-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 5-position, 6-position, and 8-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 5-position, 7-position, and 8-position. In some embodiments of the compounds of formula (I-F), m is 3, and R 1a The group is at the 6-position, 7-position, and 8-position. In some embodiments of the compounds of formula (I-F), m is 4, and R 1a The group is at the 2-position, 3-position, 5-position, and 6-position. In some embodiments of the compounds of formula (I-F), m is 4, and R 1a The group is at the 2-position, 3-position, 5-position, and 7-position. In some embodiments of the compounds of formula (I-F), m is 4, and R 1a The group is at the 2-position, 3-position, 5-position, and 8-position. In some embodiments of the compounds of formula (I-F), m is 4, and R 1a The group is at the 2-position, 3-position, 6-position, and 7-position. In some embodiments of the compounds of formula (I-F), m is 4, and R 1a The group is at the 2-position, 3-position, 6-position, and 8-position. In some embodiments of the compounds of formula (I-F), m is 4, and R 1a The group is at the 2-position, 3-position, 7-position, and 8-position. In some embodiments of the compounds of formula (I-F), m is 4, and R 1a The group is at the 2-position, 5-position, 6-position, and 7-position. In some embodiments of the compounds of formula (I-F), m is 4, and R 1a The group is at the 2-position, 5-position, 6-position, and 8-position. In some embodiments of the compounds of formula (I-F), m is 4, and R1a The group is at the 2-position, 5-position, 7-position and 8-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is at the 2-position, 6-position, 7-position and 8-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is at the 3-position, 5-position, 6-position and 7-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is at the 3-position, 5-position, 6-position and 8-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is at the 3-position, 5-position, 7-position and 8-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is at the 3-position, 6-position, 7-position and 8-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is at the 5-position, 6-position, 7-position and 8-position. In some embodiments of the compound of formula (I-F), m is 5, and R 1a The group is at the 2-position, 3-position, 5-position, 6-position and 7-position. In some embodiments of the compound of formula (I-F), m is 5, and R 1a The group is at the 2-position, 3-position, 5-position, 6-position and 8-position. In some embodiments of the compound of formula (I-F), m is 5, and R 1a The group is at the 2-position, 3-position, 5-position, 7-position and 8-position. In some embodiments of the compound of formula (I-F), m is 5, and R 1a The group is at the 2-position, 3-position, 6-position, 7-position and 8-position. In some embodiments of the compound of formula (I-F), m is 5, and R 1a The group is at the 2-position, 5-position, 6-position, 7-position and 8-position. In some embodiments of the compound of formula (I-F), m is 5, and R 1a The group is at the 3-position, 5-position, 6-position, 7-position and 8-position. In some embodiments of the compound of formula (I-F), m is 6, and R 1a The group is at the 2-position, 3-position, 5-position, 6-position, 7-position and 8-position. Whenever there is more than one R 1a group, R 1a groups can be independently selected. In any of these embodiments of the compound of formula (I-F) or its salt, the carbon bearing the CO 2 H and NH moieties can be in the "S" configuration or the "R" configuration.

[0273] In some embodiments of formula (I-F), including embodiments that describe the R 1a and m variables, each of R 10 、R 11 、R 12 and R 13 is hydrogen. In some embodiments of formula (I-F), including embodiments that describe the R 1a and m variables and / or the R 10 、R 11 、R 12 and R 13 variables, q is 0. In some embodiments of formula (I-F), including embodiments that describe the R 1a and m variables and / or the R 10 、R 11 、R 12 and R 13 variables and / or the q variable, p is 3, 4, or 5.

[0274] In some embodiments of formula (I-F), R 10 、R 11 、R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound has formula (II-F):

[0275]

[0276] or a salt thereof, wherein R 1a and R 2 are as defined for formula (I), m is 0, 1, 2, 3, 4, 5, or 6, and the positions on the quinoline ring are as indicated. All descriptions of R 1a 、R 2 and m for formula (I) apply equally to formula (I-F) and (II-F).

[0277] In some embodiments of the compounds of formula (I) in which R 1 is a 5- to 10-membered heteroaryl optionally substituted with R 1a , the compound has formula (I-G):

[0278]

[0279] or a salt thereof, wherein R 1a 、R 2 、R 10 、R 11 、R 12 、R 13 、R 14, q, and p are as defined for formula (I), m is 0, 1, 2, 3, 4, 5, or 6, and the positions on the isoquinoline ring are as indicated.

[0280] In one embodiment, a compound of formula (I-G) or a salt thereof is provided, wherein the carbon bearing the CO 2 and the carbon of the H and NH moieties are in the "S" configuration. In another embodiment, a compound of formula (I-G) or a salt thereof is provided, wherein the carbon bearing the CO 2 and the carbon of the H and NH moieties are in the "R" configuration. Also encompassed are mixtures of compounds of formula (I-G), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0281] In some embodiments of the compounds of formula (I-G), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1a is independently, where applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R 1a are independently optionally substituted with deuterium. In further embodiments of the compounds of formula (I-G), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1a is independently, where applicable, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl (which in one variation can be C 1 -C 6 perhaloalkyl), C 1 -C 6 alkoxy, hydroxy, -CN, or a 5- to 10-membered heteroaryl, wherein the C 1a -C 1 alkyl, C 6 -C 1 haloalkyl, C 6 -C 1 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R 6 are independently optionally substituted with deuterium. In some embodiments of the compounds of formula (I-G), m is 1, 2, 3, 4, 5, or 6.

[0282] In some embodiments of the compounds of formula (I-G), m is 0. In some embodiments of the compounds of formula (I-G), m is 1, and R 1a is in the 3-position. In some embodiments of the compounds of formula (I-G), m is 1, and R 1a is in the 4-position. In some embodiments of the compounds of formula (I-G), m is 1, and R 1aAt the 5-position. In some embodiments of the compounds of formula (I-G), m is 1, and R 1a At the 6-position. In some embodiments of the compounds of formula (I-G), m is 1, and R 1a At the 7-position. In some embodiments of the compounds of formula (I-G), m is 1, and R 1a At the 8-position. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The group is at the 3-position and 4-position. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The group is at the 4-position and 5-position. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The group is at the 4-position and 6-position. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The group is at the 4-position and 7-position. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The group is at the 4-position and 8-position. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The group is at the 3-position and 5-position. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The group is at the 3-position and 6-position. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The group is at the 3-position and 7-position. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The group is at the 3-position and 8-position. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The group is at the 5-position and 6-position. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The group is at the 5-position and 7-position. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The group is at the 5-position and 8-position. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The group is at the 6-position and 7-position. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The group is at the 6-position and 8-position. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The group is at the 7-position and 8-position. In some embodiments of the compounds of formula (I-G), m is 3, and R 1aThe group is at the 3-position, 4-position, and 5-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 3-position, 4-position, and 6-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 3-position, 4-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 3-position, 4-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 4-position, 5-position, and 6-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 4-position, 5-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 4-position, 5-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 4-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 4-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 4-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 3-position, 5-position, and 6-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 3-position, 5-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 3-position, 5-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 3-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 3-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 3-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is at the 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1aThe group is at the 5-position, 6-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 3, and R 1a The group is at the 5-position, 7-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 3, and R 1a The group is at the 6-position, 7-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 4, and R 1a The group is at the 3-position, 4-position, 5-position, and 6-position. In some embodiments of the compounds of formula (I-G), m is 4, and R 1a The group is at the 3-position, 4-position, 5-position, and 7-position. In some embodiments of the compounds of formula (I-G), m is 4, and R 1a The group is at the 3-position, 4-position, 5-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 4, and R 1a The group is at the 3-position, 4-position, 6-position, and 7-position. In some embodiments of the compounds of formula (I-G), m is 4, and R 1a The group is at the 4-position, 3-position, 6-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 4, and R 1a The group is at the 3-position, 4-position, 7-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 4, and R 1a The group is at the 4-position, 5-position, 6-position, and 7-position. In some embodiments of the compounds of formula (I-G), m is 4, and R 1a The group is at the 4-position, 5-position, 6-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 4, and R 1a The group is at the 4-position, 5-position, 7-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 4, and R 1a The group is at the 4-position, 6-position, 7-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 4, and R 1a The group is at the 3-position, 5-position, 6-position, and 7-position. In some embodiments of the compounds of formula (I-G), m is 4, and R 1a The group is at the 3-position, 5-position, 6-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 4, and R 1a The group is at the 3-position, 5-position, 7-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 4, and R 1aThe group is at the 3-position, 6-position, 7-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 4, and R 1a The group is at the 5-position, 6-position, 7-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 5, and R 1a The group is at the 3-position, 4-position, 5-position, 6-position, and 7-position. In some embodiments of the compounds of formula (I-G), m is 5, and R 1a The group is at the 3-position, 4-position, 5-position, 6-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 5, and R 1a The group is at the 3-position, 4-position, 5-position, 7-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 5, and R 1a The group is at the 3-position, 4-position, 6-position, 7-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 5, and R 1a The group is at the 4-position, 5-position, 6-position, 7-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 5, and R 1a The group is at the 3-position, 5-position, 6-position, 7-position, and 8-position. In some embodiments of the compounds of formula (I-G), m is 6, and R 1a The group is at the 3-position, 4-position, 5-position, 6-position, 7-position, and 8-position. Whenever there is more than one R 1a group, the R 1a groups can be independently selected. In any of these embodiments of the compounds of formula (I-G) or their salts, the carbon bearing the CO 2 H and NH moieties can be in the "S" configuration or the "R" configuration.

[0283] In some embodiments of formula (I-G) (including those embodiments that describe the R 1a and m variables), each of R 10 , R 11 , R 12 , and R 13 is hydrogen. In some embodiments of formula (I-G) (including those embodiments that describe the R 1a and m variables and / or the R 10 , R 11 , R 12 , and R 13 variables), q is 0. In some embodiments of formula (I-G) (including those embodiments that describe the R 1a and m variables and / or the R 10 , R 11 , R12 and R 13 In embodiments of the p, q variables and / or the q variable, p is 3, 4, or 5.

[0284] In some embodiments of formula (I-G), R 10 , R 11 , R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound has formula (II-G):

[0285]

[0286] or a salt thereof, wherein R 1a and R 2 are as defined for formula (I), m is 0, 1, 2, 3, 4, 5, or 6, and the positions on the isoquinoline ring are as indicated. All descriptions of R 1a , R 2 and m for formula (I) apply equally to formula (I-G) and (II-G).

[0287] In some embodiments of the compounds of formula (I) in which R 1 is a 5- to 10-membered heteroaryl optionally substituted with R 1a , the compound has formula (I-H):

[0288]

[0289] or a salt thereof, wherein R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), m is 0, 1, or 2, and the positions on the 1-methyl-1H-pyrazolo[3,4-d]pyrimidine ring are as indicated.

[0290] In one embodiment, there is provided a compound of formula (I-H) or a salt thereof, wherein the carbon bearing the CO 2 H and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-H) or a salt thereof, wherein the carbon bearing the CO 2 H and NH moieties is in the "R" configuration. Also embraced are mixtures of compounds of formula (I-H), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0291] In some embodiments of the compounds of formula (I-H), m is 0, 1, or 2, and each R 1aIndependently, when applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, where R 1a The alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are independently optionally substituted with deuterium. In a further embodiment of the compound of formula (I-H), m is 0, 1, or 2, and each R 1a Independently, when applicable, is deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl (which in one variation can be C 1 -C 6 perhaloalkyl), C 1 -C 6 alkoxy, hydroxy, -CN, or a 5- to 10-membered heteroaryl, where R 1a The C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of the compound of formula (I-H), m is 1 or 2.

[0292] In some embodiments of the compound of formula (I-H), m is 0. In some embodiments of the compound of formula (I-H), m is 1, and R 1a Is in the 3-position. In some embodiments of the compound of formula (I-H), m is 1, and R 1a Is in the 6-position. In some embodiments of the compound of formula (I-H), m is 2, and the R 1a Groups are in the 3-position and 6-position. Whenever there is more than one R 1a Group, the R 1a Groups can be independently selected. In any of these embodiments of the compound of formula (I-H) or its salt, the carbon bearing the CO 2 H and NH moieties can be in the "S" configuration or the "R" configuration.

[0293] In some embodiments of formula (I-H) (including those embodiments that describe the R 1a And m variables), each of R 10 , R 11 , R 12 And R 13 Is hydrogen. In some embodiments of formula (I-H) (including those embodiments that describe the R 1a And m variables and / or R 10 , R 11 , R 12and R 13 In some embodiments of the variable embodiments), q is 0. In some embodiments of formula (I-H) including those describing R 1a and the m variable and / or R 10 、R 11 、R 12 and R 13 variable embodiments and / or q variable embodiments), p is 3, 4 or 5.

[0294] In some embodiments of formula (I-H), R 10 、R 11 、R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound has the formula (II-H):

[0295]

[0296] or a salt thereof, wherein R 1a and R 2 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 indicated. All descriptions of R 1a 、R 2 and m for formula (I) apply equally to formula (I-H) and (II-H).

[0297] Also provided are compounds of formula (I) or (II) or salts thereof, wherein R 1 is a 5- to 10-membered heteroaryl optionally substituted with R 1a . In some embodiments, R 1 is an unsubstituted 5- to 10-membered heteroaryl (e.g., pyridyl, pyrimidinyl, quinoxalinyl, quinazolinyl, pyrazolopyrimidinyl, quinolinyl, pyridopyrimidinyl, thienopyrimidinyl, pyridyl, pyrrolopyrimidinyl, benzothiazolyl, isoquinolinyl, purinyl or benzoxazolyl). In some embodiments, R 1 is a 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4 or 5 R 1a groups which may be the same or different, wherein each R 1a is independently selected from halogen (e.g., fluoro, chloro or bromo), C 1 -C 6 alkyl optionally substituted with halogen (e.g., -CH 3 、-CHF 2 、-CF 3 or C(CH 3 ) 3 ), C 3 -C 6Cycloalkyl (e.g., cyclopropyl), 5- to 10-membered heteroaryl (e.g., pyridyl or pyrazolyl), C 6 -C 14 Aryl (e.g., phenyl), -CN, -OR 3 (e.g., -OCH 3 ) and -NR 4 R 5 (e.g., -N(CH 3 ) 2 ). In some embodiments, R 1 is a 5-membered heteroaryl (e.g., pyrazolyl) substituted with 1, 2, 3, or 4 R 3 groups that may be the same or different and are selected from -CH 2 F, -CHF 2 and -CF 3 . In some embodiments, R 1a is a 6-membered heteroaryl (e.g., pyridyl, pyrimidinyl, or pyrazinyl) substituted with 1, 2, 3, 4, or 5 R 1 groups that may be the same or different and are selected from the following: halogen (e.g., fluoro, chloro, or bromo), C 1a -C 3 Cycloalkyl (e.g., cyclopropyl), 5- to 6-membered heteroaryl (e.g., pyridyl or pyrazolyl), C 6 -C 6 Aryl (e.g., phenyl), C 10 -C 1 alkyl optionally substituted with halogen (e.g., -CH 4 , -CF 3 , or C(CH 3 ) 3 ), -CN, -OR 3 (e.g., -OCH 3 ), and -NR 3 R 4 R 5 (e.g., -N(CH 3 ) 2 ). In some embodiments, R 1 is a 9-membered heteroaryl (e.g., pyrazolopyrimidinyl, pyrrolopyrimidinyl, thiophenopyrimidinyl, indazolyl, indolyl, or benzimidazolyl) substituted with 1, 2, 3, 4, or 5 R 3 groups that may be the same or different and are selected from -CH 2 F, -CHF 2 and -CF 3 . In some embodiments, R 1a is a 9-membered heteroaryl (e.g., pyrazolopyrimidinyl, pyrrolopyrimidinyl, thiophenopyrimidinyl, indazolyl, indolyl, or benzimidazolyl) substituted with 1, 2, 3, 4, or 5 R 1 groups that may be the same or different and are selected from the following:1a Group-substituted 10-membered heteroaryl (e.g., quinazolinyl): halogen (e.g., fluoro or chloro), 5- to 6-membered heteroaryl (e.g., pyridyl), C 1 alkyl (e.g., -CH 3 or -CF 3 ) and -OR 3 (e.g., -OCH 3 ).

[0298] Also provided are compounds of formula (I) or (II) or salts thereof, wherein R 1 is selected from the group consisting of:

[0299] and any of the foregoing groups in which any one or more hydrogen atoms are replaced by deuterium atoms. Also provided are compounds of formula (I) or (II) or salts thereof, wherein R 1 is selected from any of the foregoing groups in which any one or more hydrogen atoms are replaced by tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon in the foregoing groups can be replaced by the corresponding isotope (e.g., deuterium or tritium). Each hydrogen bonded to a non-ring carbon (e.g., methyl or methoxy carbon) in the foregoing groups can be replaced by the corresponding isotope (e.g., deuterium or tritium). Further, for example, the foregoing groups can be fully deuterated, in which each hydrogen is replaced by deuterium, or fully tritiated, in which each hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the foregoing groups can be 13 replaced by C. For example, in a polycyclic ring among the foregoing groups, one or more ring carbons directly bonded to the remainder of the compound in the ring can be 13 replaced by C. In a polycyclic ring among the foregoing groups, in a ring that is substituted with or fused to a ring bonded to the remainder of the compound, one or more ring carbons can be 13 replaced by C. Further, for example, each ring carbon in the foregoing groups can be 13 replaced by C.

[0300] Also provided are compounds of formula (I) or (II) or salts thereof, wherein R 1 is selected from the group consisting of:

[0301] and any of the foregoing groups in which any one or more hydrogen atoms are replaced by deuterium atoms. Also provided are compounds of formula (I) or (II) or salts thereof, wherein R 1Any of the foregoing groups in which any one or more hydrogen atoms are replaced by tritium atoms. For example, in some embodiments, each hydrogen atom bonded to a ring carbon in the foregoing group may be replaced by a corresponding isotope (e.g., deuterium or tritium). Each hydrogen atom bonded to an acyclic carbon (e.g., methyl or methoxy carbon) in the foregoing group may be replaced by a corresponding isotope (e.g., deuterium or tritium). Further, for example, the foregoing group may be fully deuterated, in which each hydrogen is replaced by deuterium, or fully tritiated, in which each hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the foregoing group may be 13 replaced by C. For example, in a polycyclic ring among the foregoing groups, one or more ring carbons directly bonded to the remainder of the compound in the ring may be 13 replaced by C. In a polycyclic ring among the foregoing groups, in a ring that is substituted with or fused to a ring bonded to the remainder of the compound, one or more ring carbons may be 13 replaced by C. Further, for example, each ring carbon in the foregoing group may be 13 replaced by C.

[0302] There is also provided a compound of formula (I) or (II) or a salt thereof, wherein R 1 is selected from the group consisting of: and any of the foregoing groups in which any one or more hydrogen atoms are replaced by deuterium atoms. There is also provided a compound of formula (I) or (II) or a salt thereof, wherein R 1 is selected from any of the foregoing groups in which any one or more hydrogen atoms are replaced by tritium atoms. For example, in some embodiments, each hydrogen atom bonded to a ring carbon in the foregoing group may be replaced by a corresponding isotope (e.g., deuterium or tritium). Each hydrogen atom bonded to an acyclic carbon (e.g., methyl or methoxy carbon) in the foregoing group may be replaced by a corresponding isotope (e.g., deuterium or tritium). Further, for example, the foregoing group may be fully deuterated, in which each hydrogen is replaced by deuterium, or fully tritiated, in which each hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the foregoing group may be 13 replaced by C. For example, in a polycyclic ring among the foregoing groups, one or more ring carbons directly bonded to the remainder of the compound in the ring may be 13 replaced by C. In a polycyclic ring among the foregoing groups, in a ring that is substituted with or fused to a ring bonded to the remainder of the compound, one or more ring carbons may be 13 replaced by C. Further, for example, each ring carbon in the foregoing group may be 13 replaced by C.

[0303] There is also provided a compound of formula (I) or (II) or a salt thereof, wherein R 1Selected from the group consisting of:

[0304] And any of the foregoing groups in which any one or more hydrogen atoms are replaced by deuterium atoms. Also provided are compounds of formula (I) or (II) or salts thereof, wherein R 1 Selected from any of the foregoing groups in which any one or more hydrogen atoms are replaced by tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon in the foregoing group may be replaced by the corresponding isotope (e.g., deuterium or tritium). Each hydrogen bonded to an acyclic carbon (e.g., methyl or methoxy carbon) in the foregoing group may be replaced by the corresponding isotope (e.g., deuterium or tritium). Further, for example, the foregoing group may be fully deuterated, in which each hydrogen is replaced by deuterium, or fully tritiated, in which each hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the foregoing group may be 13 Replaced by C. For example, in a polycyclic ring among the foregoing groups, one or more ring carbons directly bonded to the remainder of the compound in the ring may be 13 Replaced by C. In a polycyclic ring among the foregoing groups, in a ring that is substituted or fused to a ring bonded to the remainder of the compound, one or more ring carbons may be 13 Replaced by C. Further, for example, each ring carbon in the foregoing group may be 13 Replaced by C.

[0305] Also provided are compounds of formula (I) or (II) or salts thereof, wherein R 1 Selected from the group consisting of:

[0306] And any of the foregoing groups in which any one or more hydrogen atoms are replaced by deuterium atoms. Also provided are compounds of formula (I) or (II) or salts thereof, wherein R 1 Selected from any of the foregoing groups in which any one or more hydrogen atoms are replaced by tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon in the foregoing group may be replaced by the corresponding isotope (e.g., deuterium or tritium). Each hydrogen bonded to an acyclic carbon (e.g., methyl or methoxy carbon) in the foregoing group may be replaced by the corresponding isotope (e.g., deuterium or tritium). Further, for example, the foregoing group may be fully deuterated, in which each hydrogen is replaced by deuterium, or fully tritiated, in which each hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the foregoing group may be 13 Replaced by C. For example, in a polycyclic ring among the foregoing groups, one or more ring carbons directly bonded to the remainder of the compound in the ring may be 13C substitution. In the polycyclic rings among the foregoing groups, in the ring that is substituted or fused to the ring bonded to the rest of the compound, one or more ring carbons can be 13 C substitution. Further, for example, each ring carbon in the foregoing groups can be 13 C substitution.

[0307] The R 1 group (represented by the symbol) is shown as being connected at a specific position (e.g., pyrimidin-4-yl, quinazolin-4-yl, isoquinolin-1-yl), but they can also be connected via any other available valence (e.g., pyrimidin-2-yl). In some embodiments of the compound of formula (I) or (II) or its salt, R 1 is where m is 0, 1, 2, or 3, and each R 1a is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, where the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R 1a are independently optionally substituted with deuterium. In a further embodiment of the compound of formula (I) or (II) or its salt, R 1 is where m is 1, 2, or 3, and each R 1a is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, where the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R 1a are independently optionally substituted with deuterium. In another embodiment, R 1 is

[0308] where m is 0, 1, 2, 3, 4, or 5, and each R 1a is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, where the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R 1a are independently optionally substituted with deuterium. In a further embodiment of the compound of formula (I) or (II) or its salt, R 1 is where m is 1, 2, 3, 4, or 5, and each R 1a is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, where the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R 1a are independently optionally substituted with deuterium. In a further variation of such embodiments, each R 1aIndependently, when applicable, deuterium, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl (which in one variation can be C 1 -C 6 -perhaloalkyl), C 1 -C 6 -alkoxy, hydroxy, -CN or 5- to 10-membered heteroaryl, where the C 1a of R 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, hydroxy and 5- to 10-membered heteroaryl are independently optionally substituted with deuterium.

[0309] In some embodiments of the compounds of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or salts thereof, R 2 is C 2a -C 1 -alkyl optionally substituted with R 6 . In some embodiments, R 2 is C 2a -C 1 -alkyl optionally substituted with R 6 where R 2a is: halogen (e.g., fluoro); C 3 -C 8 -cycloalkyl optionally substituted with halogen (e.g., cyclobutyl optionally substituted with fluoro); 5- to 10-membered heteroaryl optionally substituted with C 1 -C 6 -alkyl (e.g., pyrazolyl optionally substituted with methyl); -S(O) 2 R 3 ; -NR 4 R 5 ; -NR 3 C(O)R 4 ; oxo; or -OR 3 . In some embodiments, R 2 is C 2a -C 1 -alkyl optionally substituted with R 6 where R 2a is: halogen (e.g., fluoro); C3 -C 8 Cycloalkyl (e.g., cyclobutyl optionally substituted with fluoro); 5- to 10-membered heteroaryl optionally substituted with C 1 -C 6 alkyl (e.g., pyrazolyl optionally substituted with methyl); 3- to 12-membered heterocyclic group optionally substituted with halogen (e.g., oxetanyl optionally substituted with fluoro), -S(O) 2 R 3 ; -NR 4 R 5 ; -NR 3 C(O)R 4 ; oxo; or -OR 3 . In some embodiments, R 2 is C 3 -C 1 alkyl optionally substituted with -OR 6 , wherein R 3 is: hydrogen; C 1 -C 6 alkyl optionally substituted with halogen (e.g., methyl, ethyl, difluoromethyl, -CH 2 CHF 2 and -CH 2 CF 3 ); C 3 -C 6 cycloalkyl optionally substituted with halogen (e.g., cyclopropyl substituted with fluoro); C 6 -C 14 aryl optionally substituted with halogen (e.g., phenyl optionally substituted with fluoro); or 5- to 6-membered heteroaryl optionally substituted with halogen or C 1 -C 6 alkyl (e.g., pyridyl optionally substituted with fluoro or methyl). In some embodiments, R 2 is –CH 2 CH 2 OCH 3 . In some embodiments, R 2 is C 3 -C 1 alkyl substituted with both halogen and OR 6 . In some embodiments, R 2 is n-propyl substituted with both halogen and alkoxy (e.g., -CH 2 CH(F)CH 2 OCH 3 ). In some embodiments where it is indicated that R 2 is optionally substituted with R 2a , the R 2 moiety is unsubstituted. In some embodiments where it is indicated that R 2 is optionally substituted with R2a In some embodiments where it is substituted, R 2 is partially substituted by one R 2a substituent. In some embodiments where it is indicated that R 2 is optionally substituted by R 2a substituent, R 2 is partially substituted by 2 to 6 or 2 to 5 or 2 to 4 or 2 to 3 R 2a substituents which may be the same or different.

[0310] In some embodiments of the compounds of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or salts thereof, R 2 is C 2a -C 1 alkyl optionally substituted by R 6 substituent. In some embodiments, R 2 is C 2a -C 1 alkyl optionally substituted by R 6 substituent, where R 2a is: halogen (e.g., fluoro); C 3 -C 8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluoro); 5- to 10-membered heteroaryl optionally substituted by C 1 -C 6 alkyl (e.g., pyrazolyl optionally substituted by methyl); -S(O) 2 R 3 ; -NR 4 R 5 ; -NR 3 C(O)R 4 ; oxo; or -OR 3 substituent. In some embodiments, R 2 is C 2a -C 1 alkyl optionally substituted by R 6 substituent, where R 2a is: halogen (e.g., fluoro); C 3 -C 8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluoro); 5- to 10-membered heteroaryl optionally substituted by C 1 -C 6 alkyl (e.g., pyrazolyl optionally substituted by methyl); 3- to 12-membered heterocyclic group optionally substituted by halogen (e.g., oxetanyl optionally substituted by fluoro), -S(O)2 R 3 ; -NR 4 R 5 ; -NR 3 C(O)R 4 ; oxo; or -OR 3 . In some embodiments, R 2 is optionally substituted with R 2a substituted C 1 -C 6 alkyl, where R 2a is: halogen (e.g., fluoro); optionally halogen-substituted C 3 -C 8 cycloalkyl (e.g., cyclobutyl optionally substituted with fluoro); C 6 -C 14 aryl (e.g., phenyl); optionally C 1 -C 6 alkyl-substituted 5- to 10-membered heteroaryl (e.g., thiazolyl or pyrazolyl optionally substituted with methyl); optionally halogen- or oxo-substituted 3- to 12-membered heterocyclic group (e.g., R 2a is: oxetanyl optionally substituted with fluoro; tetrahydrofuranyl; pyrrolidinyl optionally substituted with oxo; morpholinyl optionally substituted with oxo; or dioxolanyl); -S(O) 2 R 3 ; -NR 4 R 5 ; -NR 3 C(O)R 4 ; oxo; -OR 3 ; or -CN. In some embodiments, R 2 is optionally substituted with -OR 3 substituted C 1 -C 6 alkyl, where R 3 is: hydrogen; optionally halogen-substituted C 1 -C 6 alkyl (e.g., methyl, ethyl, difluoromethyl, -CH 2 CHF 2 and -CH 2 CF 3 ); optionally halogen-substituted C 3 -C 6 cycloalkyl (e.g., cyclopropyl substituted with fluoro); optionally halogen-substituted C 6 -C 14 aryl (e.g., phenyl optionally substituted with fluoro); or optionally halogen- or C 1 -C 6 alkyl-substituted 5- to 6-membered heteroaryl (e.g., pyridyl optionally substituted with fluoro or methyl). In some embodiments, R2 is –CH 2 CH 2 OCH 3 . In some embodiments, R 2 is C 3 -C 1 alkyl substituted by both a halogen and OR 6 . In some embodiments, R 2 is n-propyl substituted by both a halogen and an alkoxy group (e.g., -CH 2 CH(F)CH 2 OCH 3 ). In some embodiments where it is indicated that R 2 is optionally substituted by R 2a , the R 2 moiety is unsubstituted. In some embodiments where it is indicated that R 2 is optionally substituted by R 2a , the R 2 moiety is substituted by one R 2a . In some embodiments where it is indicated that R 2 is optionally substituted by R 2a , the R 2 moiety is substituted by 2 to 6 or 2 to 5 or 2 to 4 or 2 to 3 R 2a moieties which may be the same or different. In some embodiments, R 2 is C 1 -C 6 alkyl substituted by two halogen groups which may be the same or different (e.g., two fluoro groups). In some embodiments, R 2 is C 3 -C 3 alkyl substituted by two -OR 3 groups which may be the same or different (e.g., two –OH groups, one –OH group and one –OCH 1 group, or two –OCH 6 groups). In some embodiments, R 2 is C 3 -C 3 alkyl substituted by one halogen group (e.g., fluoro) and one -OR 1 group (e.g., -OH or -OCH 6 ). In some embodiments, R 2 is C 3 -C 3 alkyl substituted by two halogen groups which may be the same or different (e.g., two fluoro groups) and one -OR 1 group (e.g., -OH or -OCH 6alkyl group. In some embodiments, R 2 is a C 3 -C 3 alkyl group substituted by one halogen group (e.g., fluoro) and two -OR 3 groups which may be the same or different (e.g., two -OH groups, one -OH group and one -OCH 1 group, or two -OCH 6 groups).

[0311] In some embodiments of the compounds of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or salts thereof, R 2 is an optionally R 2b -substituted C 3 -C 6 cycloalkyl group. In some embodiments, R 2 is a C 2b -C 3 cycloalkyl group substituted by 1 or 2 R 6 moieties which may be the same or different. In some embodiments, R 2 is an optionally halogen-substituted C 3 -C 4 cycloalkyl group (e.g., unsubstituted cyclopropyl or cyclobutyl optionally substituted by fluoro). In some embodiments, R 2 is an optionally deuterium- or tritium-atom-substituted C 3 -C 4 cycloalkyl group. For example, in some embodiments, each hydrogen bonded to a ring carbon in the foregoing groups may be replaced by the corresponding isotope (e.g., deuterium or tritium). Each hydrogen bonded to a non-ring carbon (e.g., methyl or methoxy carbon) in the foregoing groups may be replaced by the corresponding isotope (e.g., deuterium or tritium). Further, for example, the foregoing groups may be fully deuterated, where each hydrogen is replaced by deuterium, or fully tritiated, where each hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the foregoing groups may be replaced by 13 C. For example, in a polycyclic ring among the foregoing groups, one or more ring carbons directly bonded to the remainder of the compound in the ring may be replaced by 13 C. In a polycyclic ring among the foregoing groups, in a ring that is substituted or fused to a ring that is bonded to the remainder of the compound, one or more ring carbons may be replaced by 13 C. Further, for example, each ring carbon in the foregoing groups may be replaced by 13C substitution.

[0312] In some embodiments of the compounds of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or salts thereof, R 2 is hydrogen.

[0313] In some embodiments of the compounds of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or salts thereof, R 2 is optionally R 2a substituted –O-C 1 -C 6 alkyl. In some embodiments, R 2 is –OCH 3 .

[0314] Also provided are compounds of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or salts thereof, wherein R 2 is selected from the group consisting of:

[0315] and any of the foregoing groups wherein any one or more hydrogen atoms are replaced by deuterium atoms.

[0316] Also provided are compounds of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or salts thereof, wherein R 2 is selected from the group consisting of:

[0317] and any of the foregoing groups wherein any one or more hydrogen atoms are replaced by deuterium atoms.

[0318] Also provided are compounds of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (IIC), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or salts thereof, wherein R 2 is wherein R 3 and each R 2a is as defined for formula (I).

[0319] Also provided are compounds of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (IIC), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or salts thereof, wherein R 2 is wherein each R 2a is as defined for formula (I).

[0320] Also provided are compounds of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (IIC), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or salts thereof, wherein R 2 is wherein R 3 is as defined for formula (I).

[0321] In one embodiment of formula (I), the tetrahydronaphthyridine group is doubly substituted with deuterium at the 2-position.

[0322] In one aspect, provided are compounds of formula (I) or salts thereof (including pharmaceutically acceptable salts thereof), wherein the compound or salt thereof has any one or more of the following structural features (“SF”):

[0323] (SFI) p is 3;

[0324] (SFII) each R 10 , R 11 , R 12 , R 13 is hydrogen;

[0325] (SFIII) R 1 is:

[0326] (A) an unsubstituted 5- to 10-membered heteroaryl;

[0327] (B) 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4 or 5 R groups which may be the same or different; 1a ;

[0328] wherein the 5- to 10-membered heteroaryl of (III)(A) and (III)(B) is:

[0329] (i) pyridyl;

[0330] (ii) pyrimidinyl;

[0331] (iii) quinoxalinyl;

[0332] (iv) quinazolinyl;

[0333] (v) pyrazolopyrimidinyl;

[0334] (vi) quinolinyl;

[0335] (vii) pyridopyrimidinyl;

[0336] (viii) thienopyrimidinyl;

[0337] (ix) purinyl;

[0338] (x) pyrrolopyrimidinyl;

[0339] (xi) benzoxazolyl;

[0340] (xii) benzothiazolyl;

[0341] (xiii) isoquinolinyl;

[0342] (xiv) indolyl;

[0343] (xv) benzimidazolyl;

[0344] (xvi) pyrazinyl;

[0345] (xvii) indazolyl; or

[0346] (xviii) pyrazolyl;

[0347] (C) unsubstituted naphthyl; or

[0348] (D) naphthyl substituted with 1, 2, 3, 4 or 5 R groups which may be the same or different; 1a ;

[0349] (SFIV) Each R 1a is:

[0350] (A) a halogen such as fluoro, chloro or bromo;

[0351] (B) Optionally halogen-substituted C 1 -C 6 alkyl, such as -CH 3 -, -CHF 2 -, -CF 3 - or C(CH 3 ) 3 ;

[0352] (C) C 3 -C 6 cycloalkyl, such as cyclopropyl;

[0353] (D) 5- to 10-membered heteroaryl, such as pyridyl or pyrazolyl;

[0354] (E) C 6 -C 14 aryl, such as phenyl;

[0355] (F) –CN;

[0356] (G) –OR 3 , such as –OCH 3 ; or

[0357] (H) -NR 4 R 5 , such as -N(CH 3 ) 2 ;

[0358] (SFV) R 2 is:

[0359] (A) Unsubstituted C 1 -C 6 alkyl, such as C 1 -C 2 alkyl;

[0360] (B) C 1 -C 6 alkyl, such as C 1 -C 2 alkyl, each of which is substituted by 1, 2, 3, 4 or 5 R 2a groups that may be the same or different;

[0361] (C) Unsubstituted -O-C 1 -C 6 alkyl, such as -O-C 1 -C 2 alkyl;

[0362] (D) -O-C 1 -C 6 alkyl, such as -O-C 1 -C 2an alkyl group, each of which is substituted by 1, 2, 3, 4 or 5 R groups which may be the same or different; 2a ;

[0363] (E) unsubstituted C 3 -C 6 cycloalkyl, such as cyclopropyl or cyclobutyl; or

[0364] (F) C 3 -C 6 cycloalkyl, such as cyclopropyl or cyclobutyl, each of which is substituted by 1, 2, 3, 4 or 5 R groups which may be the same or different; and 2b ;

[0365] (SFVI) R 2a is:

[0366] (A) halogen, such as fluoro;

[0367] (B) C 3 -C 8 cycloalkyl, such as cyclopropyl or cyclobutyl, each of which is optionally substituted by halogen;

[0368] (C) a 5- to 10-membered heteroaryl optionally substituted by C 1 -C 6 alkyl, such as pyrazolyl substituted by methyl;

[0369] (D) a 3- to 12-membered heterocyclic group 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 dioxolanyl;

[0370] (E) -S(O) 2 R 3 , such as -S(O) 2 CH 3 ;

[0371] (F) –C(O)NR 4 R 5 , such as –C(O)N(CH 3 ) 2 ;

[0372] (G) -NR 3 C(O)R 4 , such as –NHC(O)CH 3 ; or

[0373] (H) -OR 3 , where R 3 is:

[0374] (i) hydrogen;

[0375] (ii) -CH 3 ;

[0376] (iii) -CH 2 CH 3 ;

[0377] (iv) -CH 2 CHF 2 ;

[0378] (v) -CH 2 CF 3 ;

[0379] (vi) phenyl substituted with 0 - 2 fluoro groups; or

[0380] (vii) pyridyl substituted with 0 - 1 methyl group.

[0381] It is to be understood that the compounds of formula (I) described herein, or any variant thereof, or its salts, may in one embodiment have any one or more of the structural features described above. For example, the compounds of formula (I) described herein, or any variant thereof, or its salts, may in one embodiment have the following structural features: one or both or three or all of (SFI), (SFII), (SFIII), and (SFV). In one such instance, the compounds of formula (I) described herein, or any variant thereof, or its salts, may in one embodiment have the following structural features: (SFI) and any one or both or all of (SFII), (SFIII), and (SFV), or any of its sub - embodiments. In one such instance, the compounds of formula (I) described herein, or any variant thereof, or its salts, may in one embodiment have the following structural features: (SFII) and any one or both or all of (SFI), (SFIII), and (SFV), or any of its sub - embodiments. In one such instance, the compounds of formula (I) described herein, or any variant thereof, or its salts, may in one embodiment have the following structural features: (SFIII) and any one or both or all of (SFI), (SFII), and (SFV), or any of its sub - embodiments. In one such instance, the compounds of formula (I) described herein, or any variant thereof, or its salts, may in one embodiment have the following structural features: (SFV) and any one or both or all of (SFI), (SFII), and (SFIII), or any of its sub - embodiments. It is to be understood that the sub - embodiments of the structural features may also be combined in any manner. Although specific combinations of the structural features are specifically given below, it is to be understood that every combination of the features is covered herein. In one aspect of this variant, (SFI) and (SFII) apply. In another variant, (SFI) and (SFIII) apply. In another variant, (SFI) and (SFV) apply. In another variant, (SFII) and (SFIII) apply. In another variant, (SFII) and (SFV) apply. In another variant, (SFIII) and (SFV) apply. In another variant, (SFI), (SFII), and (SFIII) apply. In another variant, (SFI), (SFII), and (SFV) apply. In another variant, (SFI), (SFIII), and (SFV) apply. In another variant, (SFII), (SFIII), and (SFV) apply. It is to be understood that each sub - embodiment of the structural features 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).

[0382] In another variant, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SF VI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFV I)(A) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SF II), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(A) apply.In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B) and (SFVI)(A) apply. In another variant, (SF I), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B) and (SF VI)(A) apply.In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SF IV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFI I), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SF VI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SF IV)(E), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFI I), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SF VI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SF IV)(H), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFI I), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SF VI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SF IV)(C), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFI I), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SF VI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SF IV)(F), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFI I), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(A) apply.In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B) and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B) and (SFVI)(A) apply.

[0383] In another variant, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SF VI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFI II)(A)(iii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xiii), (SF V)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) apply.In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B) and (SFVI)(H)(ii) apply.In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFI I), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply.

[0384] In another variant, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply.In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) apply.In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply.

[0385] In another variant, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SF VI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SF III)(A)(iii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFI I), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply.In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFI I), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B) and (SFVI)(H)(vi) apply.In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply.

[0386] In another variant, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SF VI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SF III)(A)(iii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SF I), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (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), (SF II), (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, (SF I), (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 variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (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, (SF I), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFI V)(B), (SFV)(B), and (SFVI)(H)(vii) apply.

[0387] Any variation or combination cited herein for the compound of formula (I) also applies to formula (A) if it increases any possible combination of R 15 and R 16 .

[0388] Figure 1 Representative compounds are listed.

[0389] In some embodiments, provided are compounds selected from Figure 1 compounds numbered 1 - 66 therein or their stereoisomers (including mixtures of two or more of their stereoisomers) or their salts. In some embodiments, the compound is a salt of a compound numbered 1 - 66 selected from Figure 1 therein or its stereoisomer.

[0390] In some embodiments, provided are compounds selected from compounds numbered 1 - 147 or their stereoisomers (including mixtures of two or more of their stereoisomers) or their salts. In some embodiments, the compound is a salt of a compound numbered 1 - 147 or its stereoisomer.

[0391] In some embodiments, provided are compounds selected from compounds numbered 1 - 665 or their stereoisomers (including mixtures of two or more of their stereoisomers) or their salts. In some embodiments, the compound is a salt of a compound numbered 1 - 665 or its stereoisomer.

[0392] In some embodiments, provided are compounds selected from compounds numbered 1 - 780 or their stereoisomers (including mixtures of two or more of their stereoisomers) or their salts. In some embodiments, the compound is a salt of a compound numbered 1 - 780 or its stereoisomer.

[0393] In one variation, the compounds detailed herein are selected from the group consisting of:

[0394] 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-(difluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0395] 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butyric acid;

[0396] 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)butyric acid;

[0397] 4-((2-Hydroxy-2-methylpropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butyric acid;

[0398] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0399] 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0400] 2-((7-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0401] 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0402] 4-((3,3-Difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0403] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butyric acid;

[0404] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)butyric acid;

[0405] 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0406] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-(trifluoromethyl)quinazolin-4-yl)amino)butyric acid;

[0407] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)quinazolin-4-yl)amino)butyric acid;

[0408] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((8-(trifluoromethyl)quinazolin-4-yl)amino)butyric acid;

[0409] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butyric acid;

[0410] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,4-d]pyrimidin-4-ylamino)butyric acid;

[0411] 2-((5-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0412] 2-((6-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0413] 2-((8-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0414] 2-((6,7-Difluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0415] 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)butyric acid;

[0416] 2-((6-(Difluoromethyl)pyrimidin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0417] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0418] 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0419] 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)butyric acid;

[0420] 4-((2-(Methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0421] 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0422] 4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0423] 4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0424] 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0425] 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)butyric acid;

[0426] 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)butyric acid;

[0427] 2-(Isoquinolin-1-ylamino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0428] 4-((2-(Difluoromethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0429] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinolin-4-ylamino)butyric acid;

[0430] 2 - ((7 - chloroquinazolin - 4 - yl)amino)-4 - ((2 - methoxyethyl)(4 - (5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)butyric acid;

[0431] 2 - ((8 - chloroquinazolin - 4 - yl)amino)-4 - ((2 - methoxyethyl)(4 - (5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)butyric acid;

[0432] 2 - (quinazolin - 4 - ylamino)-4 - ((4 - (5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)(2 - (2,2,2 - trifluoroethoxy)ethyl)amino)butyric acid;

[0433] 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)butyric acid;

[0434] 4 - ((3 - fluoropropyl)(4 - (5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2 - ((7 - methoxyquinazolin - 4 - yl)amino)butyric acid;

[0435] 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)butyric acid;

[0436] 4 - ((3 - fluoropropyl)(4 - (5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2 - ((8 - methoxyquinazolin - 4 - yl)amino)butyric acid;

[0437] 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)butyric acid;

[0438] 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)butyric acid;

[0439] 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)butyric acid;

[0440] 4-((2-(3,5-Difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0441] 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)butyric acid;

[0442] 4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0443] 4-((2-(2,2-Difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0444] 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)butyric acid;

[0445] 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)butyric acid;

[0446] 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)butyric acid;

[0447] 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)butyric acid;

[0448] 4-((2-Ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0449] 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)butyric acid;

[0450] 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)butyric acid;

[0451] 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)butyric acid;

[0452] 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)butyric acid;

[0453] 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)butyric acid;

[0454] 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)butyric acid;

[0455] 4-(((R)-2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0456] 4-((2-Acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0457] 4-((2-(Dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0458] 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid; and

[0459] 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butyric acid.

[0460] In another variation, the compounds detailed herein are selected from the group consisting of:

[0461] 2-((3-Cyanopyrazin-2-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0462] 2-((5-Cyanopyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0463] 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butyric acid;

[0464] 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0465] 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)butyric acid;

[0466] 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0467] 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-phenylpyrimidin-4-yl)amino)butyric acid;

[0468] 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)butyric acid;

[0469] 4-((2-Hydroxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0470] 2-((3-Cyanopyrazin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0471] 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)butyric acid;

[0472] 2-((5-Fluoropyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0473] 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)butyric acid;

[0474] 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butyric acid;

[0475] 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butyric acid;

[0476] 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)butyric acid;

[0477] 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0478] 2-((5-Cyanopyrimidin-2-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0479] 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)butyric acid;

[0480] 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0481] 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)butyric acid;

[0482] 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)butyric acid;

[0483] 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butyric acid;

[0484] 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)butyric acid;

[0485] 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)butyric acid;

[0486] 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0487] 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butyric acid;

[0488] 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)butyric acid;

[0489] 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butyric acid;

[0490] 2-((5-Bromopyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0491] 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0492] 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)butyric acid;

[0493] 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)butyric acid;

[0494] 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)butyric acid;

[0495] 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)butyric acid;

[0496] 4-((2-(Methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butyric acid;

[0497] 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0498] 4-((2-(Methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0499] 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)butyric acid;

[0500] 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butyric acid;

[0501] 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)butyric acid;

[0502] 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)butyric acid;

[0503] 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)butyric acid;

[0504] 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butyric acid;

[0505] 2-((5-cyanopyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0506] 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)butyric acid;

[0507] 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butyric acid;

[0508] 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0509] 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)butyric acid;

[0510] 2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0511] 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;

[0512] 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;

[0513] 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid;

[0514] 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;

[0515] 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;

[0516] 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;

[0517] 2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid;

[0518] 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;

[0519] 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;

[0520] 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid;

[0521] 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butyric acid;

[0522] 4-((Oxetan-2-ylmethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0523] 4-((3-Hydroxy-2-(hydroxymethyl)propyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0524] 2-((5-Bromopyrimidin-2-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0525] 4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butyric acid;

[0526] 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)butyric acid;

[0527] 4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0528] 2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0529] 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)butyric acid;

[0530] 4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butyric acid;

[0531] 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;

[0532] 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;

[0533] 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;

[0534] 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;

[0535] 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;

[0536] 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;

[0537] 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;

[0538] 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;

[0539] 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

[0540] 4-(((3-fluoroxetan-3-yl)methyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid.

[0541] In some embodiments, a composition, such as a pharmaceutical composition, is provided, wherein the composition comprises a compound selected from the group consisting of one or more of Compound Nos. 1-66 or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof) or a salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of salts of one or more of Compound Nos. 1-66. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. Figure 1

[0542] In some embodiments, a composition, such as a pharmaceutical composition, is provided, wherein the composition comprises a compound selected from the group consisting of one or more of Compound Nos. 1-147 or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof) or a salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of salts of one or more of Compound Nos. 1-147. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0543] In some embodiments, a composition, such as a pharmaceutical composition, is provided, wherein the composition comprises a compound selected from the group consisting of one or more of Compound Nos. 1-665 or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof) or a salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of salts of one or more of Compound Nos. 1-665. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0544] In some embodiments, a composition, such as a pharmaceutical composition, is provided, wherein the composition comprises a compound selected from the group consisting of one or more of Compound Nos. 1-780 or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof) or a salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of salts of one or more of Compound Nos. 1-780. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0545] The present invention also includes all salts of the compounds mentioned herein, such as pharmaceutically acceptable salts. The present invention also includes any or all stereochemical forms of the compounds, including any enantiomeric or diastereomeric forms, as well as any tautomers or other forms. Unless stereochemistry is explicitly indicated in the chemical structure or name, the structure or name is intended to cover all possible stereoisomers of the described compounds. Additionally, where a specific stereochemical form is described, it is understood that the present invention also describes and encompasses other stereochemical forms. The present invention also encompasses all forms of the compounds, such as crystalline or non-crystalline forms of the compounds. It is also understood that the present disclosure encompasses prodrugs, solvates, and metabolites of the compounds. Compositions comprising the compounds of the present invention are also contemplated, such as compositions of substantially pure compounds, including their specific stereochemical forms. The present invention also encompasses compositions comprising mixtures of the compounds of the present invention in any ratio, including mixtures of two or more stereochemical forms of the compounds of the present invention in any ratio, thereby encompassing racemic, non-racemic, enantiomerically enriched, and mixtures with different enantiomeric ratios of the compounds. In the case where one or more tertiary amine moieties are present in the compound, N-oxides are also provided and described.

[0546] The compounds described herein are α V β 6 integrin inhibitors. In some cases, it is desirable for the compounds to inhibit other integrins in addition to inhibiting α V β 6 integrin. In some embodiments, the compounds inhibit α V β 6 integrin and α V β 1 、α V β 3 、α V β 5 、α 2 β 1 、α 3 β 1 、α 6 β 1 、α 7 β 1 and α 11 β 1 integrin, one or more of which. In some embodiments, the compounds inhibit α V β 6 integrin and α V β 1 integrin. In some embodiments, the compounds inhibit α V β 6 integrin, α V β 3 integrin and αV β 5 Integrin. In some embodiments, the compound inhibits α V β 6 integrin and α 2 β 1 integrin. In some embodiments, the compound inhibits α V β 6 integrin, α 2 β 1 integrin and α 3 β 1 integrin. In some embodiments, the compound inhibits α V β 6 integrin and α 6 β 1 integrin. In some embodiments, the compound inhibits α V β 6 integrin and α 7 β 1 integrin. In some embodiments, the compound inhibits α V β 6 integrin and α 11 β 1 integrin.

[0547] In some cases, it is desirable to avoid inhibiting other integrins. In some embodiments, the compound is a selective α V β 6 integrin inhibitor. In some embodiments, the compound substantially does not inhibit α 4 β 1 、α V β 8 and / or α 2 β 3 integrin. In some embodiments, the compound inhibits α V β 6 integrin, but substantially does not inhibit α 4 β 1 integrin. In some embodiments, the compound inhibits α V β 6 integrin, but substantially does not inhibit α V β 8 integrin. In some embodiments, the compound inhibits α V β 6 integrin, but substantially does not inhibit α 2 β 3 integrin. In some embodiments, the compound inhibits α V β 6 integrin, but substantially does not inhibit α Vβ 8 Integrin and α 4 β 1 integrin.

[0548] The present invention also contemplates isotopically labeled and / or isotopically enriched forms of the compounds described herein. The compounds herein can contain unnatural proportions of atomic isotopes at one or more atoms that make up such compounds. In some embodiments, the compounds are isotopically labeled, such as the isotopically labeled compounds of formula (I) described herein or variations thereof, wherein one or more atoms are replaced with isotopes of the same element. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 17 O, 32 P, 35 S, 18 F, 36 Cl. Incorporation of a heavier isotope such as deuterium ( 2 H or D) can confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some cases. As used herein, each instance of replacing hydrogen with deuterium also discloses replacing hydrogen with tritium. As used herein, each instance of enriching, substituting, or replacing an atom with the corresponding isotope of that atom encompasses an isotopic enrichment level of about one of the following: 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%, or a range between any two of the foregoing percentages.

[0549] The 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 appended examples for substituting appropriate isotopically labeled reagents for the corresponding unlabeled reagents.

[0550] In various embodiments, for each of the compounds named or described herein, the corresponding isotopically substituted compounds are specifically disclosed as described below. For example, the corresponding isotopically substituted compounds are disclosed, wherein the groups corresponding to the structural variables R 1 and R 1a can be independently deuterated, such as the structural variables R 1 and R 1aIt can be fully deuterated such that each hydrogen therein can be independently replaced by deuterium. Also disclosed are corresponding isotopically substituted compounds wherein in the group corresponding to the structural variable R 1 but not in an optional substituent R 1a one or more hydrogens can be independently replaced by deuterium. For example, disclosed are corresponding isotopically substituted compounds wherein each hydrogen that is ring-bonded in the group corresponding to R 1 but not in an optional substituent R 1a can be replaced by deuterium. Also disclosed are corresponding isotopically substituted compounds wherein one or more hydrogens in R 1a can be independently replaced by deuterium, for example each hydrogen in the group corresponding to R 1a can be replaced by deuterium

[0551] Also disclosed are, for example, corresponding isotopically substituted compounds wherein the groups corresponding to the structural variables R 2 and R 2a can be independently deuterated, for example the structural variables R 2 and R 2a can be fully deuterated such that each hydrogen therein can be independently replaced by deuterium. Also disclosed are corresponding isotopically substituted compounds wherein in the group corresponding to R 2 but not in an optional substituent R 2a one or more hydrogens can be independently replaced by deuterium. Additionally disclosed are corresponding isotopically substituted compounds wherein each hydrogen at the 1-position of R 2 (i.e., on the carbon bonding R 2 to the remainder of the compound) can be independently replaced by deuterium. For example, for a named compound having -CH 2 CH 2 CH 2 CH 2 F corresponding to R 2 also disclosed is the corresponding isotopically substituted compound wherein R 2 is -CD 2 CH 2 CH 2 F; for a named compound having -CH 2 -cyclopropyl corresponding to R 2 also disclosed is the corresponding isotopically substituted compound wherein R 2 is -CD 2a -cyclopropyl; and so on. Disclosed are corresponding isotopically substituted compounds wherein each hydrogen in the group corresponding to R 2a is -OCH 3For each compound, the corresponding isotopically substituted compound is also disclosed, wherein R 2a can be -OCD 3 ; for each compound wherein R 2a is -N(CH 3 ) 2 the corresponding isotopically substituted compound is also disclosed, wherein R 2a can be -N(CD 3 ) 2 ; and so on. Compounds are further disclosed wherein the 1-position of R 2 can be di-deuterated and each hydrogen in the group corresponding to R 2a can be replaced by deuterium.

[0552] The corresponding isotopically substituted compounds are also disclosed, wherein R 10 , R 11 , R 12 , R 13 and each R 14 are independently deuterated. For example, the corresponding isotopically substituted compounds are disclosed wherein R 10 , R 11 are deuterium, or R 12 , R 13 are deuterium, or R 10 , R 11 , R 12 and R 13 are all deuterium. Compounds are further disclosed wherein R 14 is deuterium and R 14 substitutes tetrahydronaphthyridin-2-yl at the 3-position, 4-position or 3- and 4-positions. Compounds are also disclosed wherein R 14 is deuterium and each R 14 independently substitutes each hydrogen in tetrahydronaphthyridin-2-yl at the 5-position, 6-position, 7-position, 5- and 6-positions, 5- and 7-positions, 6- and 7-positions or 5-, 6- and 7-positions, for example, the 7-position can be substituted by two deuterium atoms.

[0553] In some embodiments, the corresponding isotopically substituted compounds are disclosed, wherein: each ring hydrogen in R 1 can be replaced by deuterium; the 1-position of R 2 can be di-deuterated; and R 2a can be fully deuterated. The corresponding isotopically substituted compounds are disclosed wherein each ring hydrogen in R 1 can be replaced by deuterium. The corresponding isotopically substituted compounds are disclosed wherein: each ring hydrogen in R 1 can be replaced by deuterium; the 1-position of R 2 can be di-deuterated; R2a can be fully deuterated; R 12 and R 13 can be deuterium; and the 7-position of the tetrahydronaphthyridin-2-yl can be deuterated with two deuterium atoms. The corresponding isotopically substituted compounds are disclosed, wherein: each ring hydrogen in R 1 can be replaced by deuterium; and each hydrogen in R 2a can be independently replaced by deuterium. The corresponding isotopically substituted compounds are disclosed, wherein: each ring hydrogen in R 1 can be replaced by deuterium; the 1-position of R 2 can be deuterated with two deuterium atoms; R 2a can be fully deuterated; and R 12 and R 13 can be deuterium. The corresponding isotopically substituted compounds are disclosed, wherein: R 1 and R 1a can be fully deuterated; the 1-position of R 2 can be deuterated with two deuterium atoms; R 2a can be fully deuterated; R 12 and R 13 can be deuterium; and the 7-position of the tetrahydronaphthyridin-2-yl can be deuterated with two deuterium atoms. The corresponding isotopically substituted compounds are disclosed, wherein: each ring hydrogen in R 1 can be replaced by deuterium; the 1-position of R 2 can be deuterated with two deuterium atoms; R 2a can be fully deuterated; and R 12 and R 13 can be deuterium.

[0554] In some embodiments of naming the compounds, each hydrogen represented by R 1 , R 1a , R 2 , R 2a , R 10 , R 11 , R 12 , R 13 and R 14 can independently be tritium. For example, the corresponding isotopically substituted compounds are disclosed, wherein one or more hydrogens in R 1 , R 1a or R 1 and R 1a can independently be replaced by tritium. The corresponding isotopically substituted compounds are disclosed, wherein one or more ring hydrogens in R 1 , R 1a or R 1 and R 1a can independently be replaced by tritium. The corresponding isotopically substituted compounds are disclosed, wherein R 2 , R 2a or R2 and R 2a one or more hydrogens in may be independently replaced by tritium. The corresponding isotopically substituted compounds are disclosed, wherein R 2 , R 2a or R 2 and R 2a one or more hydrogens in may be independently replaced by tritium. The corresponding isotopically substituted compounds are disclosed, wherein one of the 3- or 4-positions of the tetrahydronaphthyridin-2-yl may be tritiated, for example, the 3-position. The corresponding isotopically substituted compounds are disclosed, wherein one of the 5-, 6- or 7-positions of the tetrahydronaphthyridin-2-yl may be mono- or di-tritiated, for example, the 7-position may be di-tritiated.

[0555] In some embodiments of naming compounds, the corresponding isotopically substituted compounds are disclosed, wherein one or more carbons may be replaced by 13 C. For example, the corresponding isotopically substituted compounds are disclosed, wherein one or more carbons may be replaced by 13 C, such as R described in the structural formulas herein 1 , R 1a , R 2 , R 2a , R 1 , R 1a , R 2 , R 2a and / or the carbons in the tetrahydronaphthyridin-2-yl ring, etc. For example, in the ring represented by R 13 , R 1 , R 1a , R 2 , R 2a and / or the polycyclic ring represented by the tetrahydronaphthyridin-2-yl, one or more ring carbons directly bonded to the rest of the compound may be replaced by 13 C; for example, in the tetrahydronaphthyridin-2-yl, the ring directly bonded to the rest of the compound is a heteroaromatic ring bonded at the 2-position. In the polycyclic ring corresponding to R 1 , R 1a , R 2 , R 2a and / or the group represented by the tetrahydronaphthyridin-2-yl, in the ring substituted with or fused to the ring directly bonded to the rest of the compound, one or more ring carbons may be replaced by 13 C. For example, in the tetrahydronaphthyridin-2-yl ring, a non-aromatic heterocyclic ring is fused to the ring directly bonded to the rest of the compound. Further, for example, corresponding to R 1 , R 1a , R 2 , R 2aEach ring carbon or each carbon in the group of the tetrahydronaphthyridin-2-yl ring and / or can be 13 substituted by C.

[0556] The present invention also includes any and all metabolites of any of the said compounds. Metabolites can include any chemical substances produced by the biotransformation of any of the said compounds, such as intermediates and metabolites of the compounds.

[0557] An article containing a compound of the present invention or a salt or solvate thereof in a suitable container is provided. The container can be a vial, a wide-mouth bottle, an ampoule, a pre-loaded syringe, an i.v. bag, etc.

[0558] Preferably, the compounds detailed herein are orally bioavailable. However, the compounds can also be formulated for parenteral (e.g., intravenous) administration.

[0559] One or several of the compounds described herein can be used to prepare a medicament by combining one or more compounds as active ingredients with a pharmacologically acceptable carrier known in the art. Depending on the form of treatment of the drug, the carrier can have various forms.

[0560] General synthetic methods

[0561] The compounds of the present invention can be prepared by various methods as generally described below and more specifically described in the examples below (such as the schemes provided in the following examples). In the following method descriptions, the symbols are to be understood as representing those groups as described above in relation to the chemical formulas herein when used in the described chemical formulas.

[0562] In the case where a specific enantiomer of a compound is desired, this can be achieved from the corresponding mixture of enantiomers by any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, a mixture of enantiomers (e.g., a racemate) can be reacted with a suitable chiral compound to produce diastereomeric derivatives. The diastereomers can then be separated by any convenient method, such as by crystallization, and the desired enantiomer recovered. In another method of resolution, chiral high performance liquid chromatography can be used to separate the racemate. Alternatively, if desired, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the said methods.

[0563] In the case where a specific isomer of a compound is needed or otherwise to purify the reaction product, chromatography, recrystallization and other conventional separation procedures can also be used for intermediates or final products.

[0564] Solvates and / or polymorphs of the compounds provided herein, or pharmaceutically acceptable salts thereof, are also contemplated. Solvates contain a stoichiometric or non-stoichiometric amount of a solvent and are generally formed during the crystallization process. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is an alcohol. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and / or solubility. A variety of factors such as the recrystallization solvent, crystallization rate, and storage temperature can result in the predominance of a single crystal form.

[0565] 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.

[0566] 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.

[0567] The compound of formula 11A can be prepared according to General Scheme A, where R 1 and R 2 are as defined for formula (I), or any applicable variations detailed herein.

[0568] General Scheme A

[0569]

[0570] Couple 1A with a compound of formula 2A in the presence of a suitable coupling agent to obtain a compound of formula 3A, which is reduced to obtain a compound of formula 4A. Reductive amination of the compound of formula 4A with compound 5A gives a compound of formula 6A. Removal of the N-Boc protecting group from the 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 obtain a compound of formula 10A. Hydrolysis of the compound of formula 10A in the presence of a suitable source of hydroxide gives a compound of formula 11A.

[0571] The reaction conditions for the transformations of General Scheme A are provided in the subsequent General Procedures, particularly General Procedures A, D, E, F, G, H, and P.

[0572] General Scheme A can be modified to remove the N-Boc protecting group by reacting with an acid in the presence of an R 2Variants of 1A having 5- and 6-carbon linkers between the group and the tetrahydronaphthyridine group were initiated to prepare variants of the compound of formula 11A. These variants of the compound of formula 11A can be synthesized by substituting 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 using the routes 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 a 5,6,7,8-tetrahydronaphthyridine ring using procedures known in the chemical literature.

[0573] Alternatively, the compound of formula 11A can be prepared according to General Scheme B, wherein R 1 and R 2 are as defined for formula (I), or any suitable variant thereof detailed herein.

[0574] General Scheme B

[0575]

[0576] The N-Boc group of 1B was installed in the presence of a suitable base and di-tert-butyl dicarbonate to give the compound of formula 2B, which was reduced to give the compound of formula 3B. The compound of formula 3B was oxidized with a suitable oxidant to give the compound of formula 4B. The compound of formula 4B was reductive aminated with compound 2A to give the compound of formula 5B. The compound of formula 5B was reductive aminated with compound 5A to give the compound of formula 7B. The N-Boc protecting group was removed from the compound of formula 7B by exposure to a suitable acid to give the compound of formula 7A, which can be coupled with the compound of formula 8A to give the compound of formula 10A. The compound of formula 10A was hydrolyzed in the presence of a suitable source of hydroxide to give the compound of formula 11A.

[0577] The reaction conditions for the transformations of General Scheme B are provided in the subsequent general procedures, particularly General Procedures B, D, F, G, H, and P.

[0578] General Scheme B can be modified to introduce a nitrogen-bearing R 2Variants of 1B having 5- and 6-carbon linkers between the group and the tetrahydronaphthyridine group were started to prepare variants of the compound of formula 11A. These variants of the compound of formula 11A can be synthesized by substituting 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 using the routes 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 a 5,6,7,8-tetrahydronaphthyridine ring using procedures known in the chemical literature.

[0579] The compound of formula 10C can be prepared according to General Scheme C, where R is optionally substituted C 2a -C 1 -alkyl, and R 5 and R 1 are as defined for formula (I), or any suitable variant forms detailed herein. 2a General Scheme C

[0580] Couple 1C with the compound of formula 4C in the presence of a suitable coupling agent to obtain the compound of formula 2C, which is reduced to obtain the compound of formula 3C. Reductive amination of the compound of formula 3C with compound 5A gives the compound of formula 5C. Removal of the N-Boc protecting group from the compound of formula 5C in toto by exposure to a suitable acid gives the compound of formula 6C, which can be coupled with the compound of formula 8A to give the compound of formula 9C. Hydrolysis of the compound of formula 9C in the presence of a suitable source of hydroxide gives the compound of formula 10C.

[0581]

[0582] The reaction conditions for the transformations of General Scheme C are provided in the subsequent general procedures, particularly General Procedures B, D, F, G, H, and P.

[0583] General Scheme C can be modified to, by -CH with nitrogen

[0584] 2 ​Variants of 1C with 5- and 6-carbon linkers between the R group and the tetrahydronaphthyridine group were initiated to prepare variants of the compound of formula 10C. These variants of the compound of formula 10C can be synthesized by substituting 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 using the routes 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 a 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 procedure that includes coupling the carboxylic acid with a suitable ammonia source in the presence of a suitable coupling agent, followed by reduction.

[0585] Alternatively, the compound of formula 10C can be prepared according to General Scheme D, where R is an optionally R 2a substituted C 1 -C 5 alkyl, and R 1 and R 2a are as defined for formula (I), or any suitable variations detailed herein.

[0586] General Scheme D

[0587]

[0588] Alkylate 1C with a compound of formula 2D in the presence of a suitable alkyl halide to give a compound of formula 3C. Reductive amination of the compound of formula 3C with compound 5A gives a compound of formula 5C. Removal of the N-Boc protecting group from the compound of formula 5C by exposure to a suitable acid gives a compound of formula 6C, which can be coupled with a compound of formula 9A to give a compound of formula 9C. Hydrolysis of the compound of formula 8A in the presence of a suitable source of hydroxide gives the compound of formula 10C.

[0589] The reaction conditions for the transformations of General Scheme D are provided in the subsequent general procedures, particularly General Procedures C, F, G, H, and P.

[0590] General Scheme D can be modified to alkylate 1C at the nitrogen-bearing -CH 2Variants of 1C having 5- and 6-carbon linkers between the R group and the tetrahydronaphthyridine group were started to prepare variants of the compound of formula 10C. These variants of the compound of formula 10C can be synthesized by substituting 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 using the routes 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 a 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 procedure comprising coupling the carboxylic acid with a suitable ammonia source in the presence of a suitable coupling agent, followed by reduction.

[0591] Compounds of formula 1f can be prepared according to General Scheme E. It is to be understood that the ring described with Het can be any heteroaromatic ring.

[0592] General Scheme E

[0593]

[0594] Hydrolysis of the compound of formula 1a gives the compound of formula 1b, which can be alkylated with a suitable electrophile to give the compound of formula 1c. Deprotection of the compound of formula 1c under reducing conditions gives the compound of formula 1d. Metal-catalyzed cross-coupling of a haloarene with the compound of formula 1d gives the compound of formula 1e, which can be hydrolyzed under acidic conditions to give the compound of formula 1f.

[0595] The reaction conditions for the transformations of General Scheme E are provided in the general procedures that follow, specifically General Procedures Q, R, S, T, and U.

[0596] It is to be understood that the above schemes can be modified by choosing appropriate reagents and starting materials to obtain the various compounds of the invention. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene’s Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience, New York, 2006, which is incorporated herein by reference in its entirety.

[0597] Additional methods for preparing the compounds of formula (I) and their salts are provided in the Examples. As will be appreciated by those skilled in the art, 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 will provide the desired compounds.

[0598] Pharmaceutical Compositions and Formulations

[0599] The present invention encompasses pharmaceutical compositions of any of the compounds detailed herein, said compounds including compounds of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H) or salts thereof, or Figure 1 any of the compounds or salts thereof, or mixtures thereof. The present invention encompasses pharmaceutical compositions of any of the compounds detailed herein, said compounds including compounds of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H) or salts thereof, or Figure 1 any of the compounds or salts thereof, or mixtures thereof. The present invention encompasses pharmaceutical compositions of the compounds of formula (A) or salts or mixtures thereof. Accordingly, the present invention includes pharmaceutical compositions comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic acid or an organic acid. The pharmaceutical compositions according to the present invention can take forms suitable for oral, buccal, parenteral, nasal, topical or rectal administration or forms suitable for administration by inhalation. In one embodiment, the pharmaceutical composition is a composition for controlled release of any of the compounds detailed herein.

[0600] In one aspect, the compounds as detailed herein can be in purified form, and compositions comprising the compounds in purified form are detailed herein. In one embodiment, the composition can have no more than 35% impurities, where impurities represent compounds other than the compound or its salt that constitutes the majority of the composition, for example, selected from Figure 1 a composition of a compound can contain no more than 35% impurities, where impurities represent compounds other than Figure 1 the compound or its salt. In one embodiment, the composition can have no more than 35% impurities, where impurities represent compounds other than the compound or its salt that constitutes the majority of the composition, for example, selected from Figure 1The composition of the compound may contain no more than 35% impurities, where the impurities represent compounds other than the Figure 1 compound or its salt. In one embodiment, the composition may contain no more than 25% impurities. In one embodiment, the composition may contain no more than 20% impurities. In a further embodiment, the composition comprising the compound or its salt detailed herein is provided in the form of a substantially pure compound composition. A "substantially pure" composition contains no more than 10% impurities, such as a composition containing less than 9%, 7%, 5%, 3%, 1% or 0.5% impurities. In some embodiments, the composition containing the compound or its salt detailed herein is in substantially pure form. In yet another variation, a composition of a substantially pure compound or its salt is provided, wherein the composition contains no more than 10% impurities. In a further variation, a composition of a substantially pure compound or its salt is provided, wherein the composition contains no more than 9% impurities. In a further variation, a composition of a substantially pure compound or its salt is provided, wherein the composition contains no more than 7% impurities. In a further variation, a composition of a substantially pure compound or its salt is provided, wherein the composition contains no more than 5% impurities. In another variation, a composition of a substantially pure compound or its salt is provided, wherein the composition contains no more than 3% impurities. In yet another variation, a composition of a substantially pure compound or its salt is provided, wherein the composition contains no more than 1% impurities. In a further variation, a composition of a substantially pure compound or its salt is provided, wherein the composition contains no more than 0.5% impurities. In still other variations, 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% impurities, and the impurities may be compounds in 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.

[0601] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual (such as a human). In another variation, a composition containing the compound in substantially pure form is provided. In another variation, the present invention encompasses a pharmaceutical composition comprising the compound detailed herein and a pharmaceutically acceptable carrier or excipient. In another variation, a method of administering the compound is provided. The purified form, pharmaceutical composition and method of administering the compound are applicable to any compound or its form detailed herein.

[0602] The compounds or salts thereof described herein can be formulated for any available route of delivery, including oral, transmucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery forms. The compounds or salts thereof can be formulated with suitable carriers to provide delivery forms including but not limited to the following: tablets, cachets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), sachets, troches, lozenges, chewing gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, 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 and elixirs.

[0603] One or several of the compounds or salts thereof described herein can be used to prepare formulations, such as pharmaceutical formulations, by combining one or more compounds or salts thereof as active ingredients with pharmaceutically acceptable carriers (such as those mentioned above). Depending on the form of treatment of the system (e.g., transdermal patch vs. oral tablet), the carrier can be in various forms. In addition, the pharmaceutical formulation can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators and salts for adjusting osmotic pressure, buffers, coating agents or antioxidants. The formulation containing the compound can also contain other substances with valuable therapeutic properties. The pharmaceutical formulation 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, 21st Edition (2005), which is incorporated herein by reference in its entirety.

[0604] The compounds as described herein can be administered to an individual (e.g., a human) in the form of generally accepted oral compositions, such as tablets, coated tablets and gel capsules in hard or soft shells, 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. Carriers acceptable for gel capsules with soft shells include, for example, vegetable oils, waxes, fats, semi-solids and liquid polyols, and so on. In addition, the pharmaceutical formulation can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators and salts for adjusting osmotic pressure, buffers, coating agents or antioxidants.

[0605] In one embodiment, the compound can be administered in the form of a liquid vehicle which is from Allegan, Michigan, is a syrup vehicle having the ingredients of purified water, glycerin, sorbitol, sodium saccharin, xanthan gum, and flavoring agent, buffered with citric acid and sodium citrate, and preserved with methylparaben (0.03%), potassium sorbate (0.1%), and propylparaben (0.008%); or a mixture in any ratio with water, such as a 50:50 mixture with water. The water used should be of pharmaceutically acceptable grade, such as sterile water.

[0606] Any compound described herein can be formulated into tablets of any of the dosage forms described above. For example, a compound or a pharmaceutically acceptable salt thereof as described herein can be formulated into 10 mg tablets.

[0607] Compositions comprising the compounds provided herein are also described. In one variation, the composition comprises a compound and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of a substantially pure compound is provided. In some embodiments, the composition is used as a human or veterinary medicine. In some embodiments, the composition is used in the methods described herein. In some embodiments, the composition is used to treat the diseases or disorders described herein.

[0608] Method of Use

[0609] The compounds and compositions of the present invention (such as pharmaceutical compositions containing a compound or a salt thereof of any chemical formula provided herein and a pharmaceutically acceptable carrier or excipient) can be used in the administration and treatment methods provided herein. The compounds and compositions can also be used in in vitro methods, such as in vitro methods of administering a compound or a composition to cells for screening purposes and / or for performing quality control assays.

[0610] In one aspect, there is provided a method of treating a fibrotic disease in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), selected from Figure 1Compounds numbered 1 - 66, or their stereoisomers or pharmaceutically acceptable salts thereof. In one aspect, there is provided a method for treating a fibrotic disease in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compounds numbered 1 - 147, or their stereoisomers or pharmaceutically acceptable salts thereof. In one aspect, there is provided a method for treating a fibrotic disease in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compounds numbered 1 - 665, or their stereoisomers or pharmaceutically acceptable salts thereof. In one aspect, there is provided a method for treating a fibrotic disease in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compounds numbered 1 - 780, or their stereoisomers or pharmaceutically acceptable salts thereof. In one aspect, there is provided a method for treating a fibrotic disease in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (A) or any variant thereof or its stereoisomers or pharmaceutically acceptable salts thereof. In one aspect, the individual is a human. An individual (such as a human) may be in need of treatment, such as a human suffering from or suspected of suffering from a fibrotic disease.

[0611] In another aspect, methods are provided for delaying the onset and / or development of a fibrotic disease in an individual (such as a human) at risk of developing a fibrotic disease. It is to be understood that if the individual does not have a fibrotic disease, delaying development can encompass prevention. In one aspect, 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 a fibrotic disease can include the age of the individual (e.g., middle-aged or elderly), the presence of inflammation, having one or more genetic components associated with the development of the fibrotic disease, medical history (such as treatment with a drug or procedure believed to be associated with an increased susceptibility to fibrosis (e.g., radiation) or a medical condition believed to be associated with fibrosis), smoking history, the presence of occupational and / or environmental factors (such as exposure to pollutants associated with developing a fibrotic disease). In some embodiments, an individual at risk of developing a fibrotic disease is an individual having or suspected of having NAFLD, NASH, CKD, scleroderma, Crohn's disease, NSIP, PSC, PBC, or an individual who has had or is suspected of having a myocardial infarction. In some embodiments, an individual at risk of developing a fibrotic disease has or is suspected of having psoriasis.

[0612] In some embodiments, the fibrotic disease is fibrosis of tissues such as the lung (pulmonary fibrosis), liver, skin, heart (cardiac fibrosis), kidney (renal fibrosis), or gastrointestinal tract (gastrointestinal fibrosis).

[0613] In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skin fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis (such as PBC). In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skin fibrosis, psoriasis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis (such as PBC). In some embodiments, the fibrotic disease is psoriasis.

[0614] In some embodiments, the fibrotic disease is pulmonary fibrosis, such as 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.

[0615] 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.

[0616] In some embodiments, the fibrotic disease is fibrotic nonspecific interstitial pneumonia (NSIP).

[0617] In some embodiments, the fibrotic disease is liver fibrosis, such as infectious liver fibrosis (from pathogens such as HCV, HBV or parasites such as schistosomiasis), NASH, alcoholic steatohepatitis-induced liver fibrosis and cirrhosis. In some embodiments, the liver fibrosis is non-alcoholic fatty liver disease (NAFLD). In some embodiments, the liver fibrosis is NASH.

[0618] In some embodiments, the fibrotic disease is biliary fibrosis.

[0619] In some embodiments, the fibrotic disease is kidney fibrosis, such as diabetic nephrosclerosis, hypertensive nephrosclerosis, focal segmental glomerulosclerosis (“FSGS”) and acute kidney injury caused by contrast-induced nephropathy. In certain embodiments, the fibrotic disease is diabetic nephropathy, diabetic kidney disease or chronic kidney disease.

[0620] In some embodiments, the fibrotic disease is characterized by one or more of glomerulonephritis, end-stage kidney disease, hearing loss, eye lens changes, hematuria or proteinuria. In some embodiments, the fibrotic disease is Alport syndrome.

[0621] In some embodiments, the fibrotic disease is systemic and local sclerosis or scleroderma, keloids and hypertrophic scars or postoperative adhesions. In some embodiments, the fibrotic disease is scleroderma or systemic sclerosis.

[0622] In some embodiments, the fibrotic disease is atherosclerosis or restenosis.

[0623] In some embodiments, the fibrotic disease is gastrointestinal fibrosis, such as Crohn's disease.

[0624] In some embodiments, the fibrotic disease is cardiac fibrosis, such as fibrosis induced after myocardial infarction and hereditary cardiomyopathy.

[0625] In some embodiments, the fibrotic disease is psoriasis.

[0626] In some embodiments, the method may include modulating the activity of at least one integrin in a subject in need thereof. For example, the method may include modulating the activity of α V β 6 . The method may include modulating the activity of α V β 1 . The method may include modulating the activity of α V β 1 and α V β 6activity. Modulating the activity of at least one integrin can include, for example, inhibiting at least one integrin. The method can include administering to a subject an amount of a compound or a pharmaceutically acceptable salt thereof that is effective to modulate the activity of at least one integrin (e.g., α V β 1 and α V β 6 in the subject). A 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, fibrotic diseases or conditions can include idiopathic pulmonary fibrosis, interstitial lung disease, radiation-induced pulmonary fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis induced by alcoholic liver disease, Alagille 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. Fibrotic diseases or conditions can include psoriasis. The method can include administering to a subject an amount of a compound or a pharmaceutically acceptable salt thereof that is effective to modulate the activity of at least one integrin (e.g., α V β 1 and α V β 6 in the subject), the subject being in need of treatment for NASH. The method can include administering to a subject an amount of a compound or a pharmaceutically acceptable salt thereof that is effective to modulate the activity of at least one integrin (e.g., α V β 1 and α V β 6 in the subject), the subject being in need of treatment for IPF.

[0627] Fibrotic diseases can be mediated primarily by α V β 6 , e.g., fibrotic diseases can include idiopathic pulmonary fibrosis or renal fibrosis. Thus, the method can include modulating the activity of α V β 6 to treat conditions mediated primarily by α V β 6 , such as IPF. Fibrotic diseases can be mediated primarily by α V β 1 , e.g., fibrotic diseases can include NASH. Thus, the method can include modulating the activity of α V β 1 to treat conditions mediated primarily by α V β 1Mediated conditions, such as NASH. Fibrotic diseases can be caused by α V β 1 and α V β 6 mediated. For example, fibrotic diseases can include PSC or biliary atresia. Thus, the method can include modulating α V β 1 and α V β 6 activities to treat conditions mediated by α V β 1 and α V β 6 .

[0628] The compound can be a modulator of α V β 1 , such as an inhibitor. The compound can be a modulator of α V β 6 , such as an inhibitor. The compound can be a dual modulator of α V β 1 and α V β 6 , such as a dual inhibitor, for example, a dual selective inhibitor. For example, Table B-3 shows that some exemplary compounds predominantly inhibit α V β 6 compared to α V β 1 ; some exemplary compounds predominantly inhibit α V β 1 compared to α V β 6 ; and some exemplary compounds equally inhibit α V β 1 and α V β 6 , and can be considered, for example, "dual α V β 1 / α V β 6 inhibitors".

[0629] Modulating or inhibiting the activity of one or both of α V β 1 integrin and α V β 6 integrin to treat a subject having a fibrotic disease means α V β 1 integrin, α V β 6 integrin, or α V β 1 integrin and α V β 6Integrins are modulated or inhibited to an extent sufficient to treat a fibrotic disease in a subject.

[0630] In one aspect, there is provided a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Figure 1 compound numbers 1-66 of the compounds therein, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for treating a fibrotic disease.

[0631] In one aspect, there is provided a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Figure 1 compound numbers 1-147 of the compounds therein, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for treating a fibrotic disease.

[0632] In one aspect, there is provided a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Figure 1 compound numbers 1-665 of the compounds therein, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for treating a fibrotic disease.

[0633] In one aspect, there is provided a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Figure 1 compound numbers 1-780 of the compounds therein, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for treating a fibrotic disease.

[0634] Also provided is the use of the following compounds in the preparation of a medicament for treating fibrotic diseases: a compound of formula (A), formula (I), or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Figure 1 compounds numbered 1-66 among the compounds, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0635] Also provided is the use of the following compounds in the preparation of a medicament for treating fibrotic diseases: a compound of formula (A), formula (I), or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compounds numbered 1-147, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0636] Also provided is the use of the following compounds in the preparation of a medicament for treating fibrotic diseases: a compound of formula (A), formula (I), or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compounds numbered 1-665, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0637] Also provided is the use of the following compounds in the preparation of a medicament for treating fibrotic diseases: a compound of formula (A), formula (I), or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compounds numbered 1-780, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0638] In another aspect, the present disclosure provides methods of treating a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound numbered 1-66 selected from Figure 1 the compounds therein, or a stereoisomer or a pharmaceutically acceptable salt thereof, or a dosage form disclosed herein, wherein the subject has at least one tissue in need of treatment and the tissue has at least one elevated level of the following: α V β 1 integrin activity and / or expression; α V β 6 integrin activity and / or expression; pSMAD / SMAD value; neo-collagen formation or accumulation; total collagen; and type I collagen gene Col1a1 expression; and wherein said level is elevated compared to the healthy state of the tissue. In some embodiments, at least one tissue in the subject comprises one or more of the following: lung tissue, liver tissue, skin tissue, heart tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue. In some embodiments, the tissue has an elevated pSMAD2 / SMAD2 value or an elevated pSMAD3 / SMAD3 value compared to the healthy state of the tissue.

[0639] Methods of determining the values of the following are known in the art: α V β 1 integrin activity and / or expression; α V β 6 integrin activity and / or expression; pSMAD / SMAD value; neo-collagen formation or accumulation; total collagen; and type I collagen gene Col1a1 expression, and exemplary methods are disclosed in the Examples, such as antibody assays of tissue samples (e.g., biopsy samples).

[0640] In some embodiments, the method selectively reduces α V β 6 integrin activity and / or expression compared to α V β 1 integrin activity and / or expression in the subject. In some embodiments, the method selectively reduces α V β 1 integrin activity and / or expression compared to α V β 6Integrin activity and / or expression. In some embodiments, compared to at least one other α-containing integrin in a subject, the method reduces the α V of the integrin, the method reduces the α V β 1 integrin and the α V β 6 integrin activity and / or expression. In some embodiments, the activity of α V β 1 integrin in one or more fibroblasts in a subject is reduced. In some embodiments, the activity of α V β 6 integrin in one or more epithelial cells in a subject is reduced.

[0641] In another aspect, provided herein is a method of treating a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Figure 1 compounds numbered 1-66 of the compounds, or a stereoisomer or a pharmaceutically acceptable salt thereof, or a dosage form disclosed herein, wherein the subject has at least one tissue in need of treatment and the tissue has at least one of the following elevated levels: α V β 1 integrin activity and / or expression; α V β 6 integrin activity and / or expression; pSMAD / SMAD value; de novo collagen formation or accumulation; total collagen; and type I collagen gene Col1a1 expression; and wherein the level is elevated compared to the healthy state of the tissue. In some embodiments, at least one tissue in the subject comprises one or more of the following: lung tissue, liver tissue, skin tissue, heart tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue. In some embodiments, the tissue has an elevated pSMAD2 / SMAD2 value or an elevated pSMAD3 / SMAD3 value compared to the healthy state of the tissue.

[0642] Methods for determining the values of the following are known in the art: α V β 1 integrin activity and / or expression; α V β 6Integrin activity and / or expression; pSMAD / SMAD value; de novo collagen formation or accumulation; total collagen; and expression of the type I collagen gene Col1a1, and exemplary methods are disclosed in the Examples, such as antibody assays of tissue samples (e.g., biopsy samples).

[0643] In some embodiments, compared to α V β 6 integrin activity and / or expression in a subject, the method selectively reduces α V β 1 integrin activity and / or expression. In some embodiments, compared to α V β 1 integrin activity and / or expression in a subject, the method selectively reduces α V β 6 integrin activity and / or expression. In some embodiments, compared to at least one other α V -containing integrin in a subject, the method reduces α V β 1 integrin and α V β 6 integrin activity and / or expression. In some embodiments, the activity of α V β 1 integrin in one or more fibroblasts in a subject is reduced. In some embodiments, the activity of α V β 6 integrin in one or more epithelial cells in a subject is reduced.

[0644] Also provided herein are methods for characterizing the anti-fibrotic activity of small molecules in a subject, comprising: providing a first live cell sample from the subject, the first live cell sample being characterized by the presence of at least one integrin capable of activating transforming growth factor β (TGF-β) from latency-associated peptide-TGF-β; determining a first pSMAD / SMAD value in the first live cell sample; administering the small molecule to the subject; providing a second live cell sample from the subject, the second live cell sample being drawn 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 anti-fibrotic 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.

[0645] In some embodiments, each live cell sample is a plurality of cells derived from a subject's tissue or a plurality of macrophages associated with the subject's tissue. In some embodiments, the tissue includes one of the following: lung tissue, liver tissue, skin tissue, heart tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue. In some embodiments, each live cell sample comprises a plurality of alveolar macrophages derived from a subject's bronchoalveolar lavage fluid.

[0646] In some embodiments, the method further comprises performing bronchoalveolar lavage on the subject's lungs effectively to produce a bronchoalveolar lavage fluid comprising a plurality of macrophages as a plurality of alveolar macrophages.

[0647] 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, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis induced by alcoholic liver disease, Alagille syndrome, primary sclerosing cholangitis (PSC), primary biliary cholangitis, biliary atresia, systemic sclerosis-related 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.

[0648] In some embodiments, the subject is diagnosed with a fibrotic disease selected from the group consisting of: idiopathic pulmonary fibrosis (IPF), interstitial lung disease, radiation-induced pulmonary fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis induced by alcoholic liver disease, Alagille syndrome, primary sclerosing cholangitis (PSC), primary biliary cholangitis, biliary atresia, systemic sclerosis-related interstitial lung disease, scleroderma, diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, Crohn's disease, and psoriasis. In some embodiments, the subject is diagnosed with a fibrotic disease, such as idiopathic pulmonary fibrosis (IPF) or psoriasis, at an age of about 55 years or older, about 60 years or older, about 65 years or older, about 70 years or older, or about 75 years or older.

[0649] In some embodiments, based on the Gender-Age-Physiology (GAP) index system, the subject's Gender-Age-Physiology (GAP) stage is GAP stage I. In some embodiments, the subject's GAP stage is GAP stage II. In some embodiments, the subject's GAP stage is GAP stage III.

[0650] In some embodiments, at least one integrin comprises α V。In some embodiments, at least one integrin comprises α V β 1 。In some embodiments, at least one integrin comprises α V β 6 。

[0651] In some embodiments, determining a first pSMAD / SMAD value in at least one live cell 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 at least one live cell with a small molecule comprises determining a pSMAD2 / SMAD2 value or a pSMAD3 / SMAD3 value.

[0652] Also provided herein are methods of treating a subject in need of treatment for a fibrotic disease, comprising: providing a first live cell sample from the subject, the first live cell sample having at least one integrin capable of activating transforming growth factor β (TGF-β) from 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 drawn 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 if the second pSMAD / SMAD value is lower than the first pSMAD / SMAD value, administering the small molecule to the subject. In some embodiments, the small molecule is a compound or a salt thereof disclosed herein, optionally in a dosage form disclosed herein. In some embodiments, the first live cell sample is obtained from the subject prior to treatment with the small molecule.

[0653] In some embodiments, each live cell sample is a plurality of cells derived from the subject's tissue, or a plurality of macrophages associated with the subject's tissue. In some embodiments, the tissue comprises one of the following: lung tissue, liver tissue, skin tissue, heart tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue. In some embodiments, each live cell sample comprises a plurality of alveolar macrophages derived from the bronchoalveolar lavage fluid of the subject. In some embodiments, the method further comprises performing bronchoalveolar lavage on the subject's lungs effectively to produce a bronchoalveolar lavage fluid comprising a plurality of macrophages as a plurality of alveolar macrophages.

[0654] In some embodiments, the subject is characterized as having a fibrotic disease selected from the group consisting of idiopathic pulmonary fibrosis (IPF), interstitial lung disease, radiation-induced pulmonary fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis induced by alcoholic liver disease, Alagille syndrome, primary sclerosing cholangitis (PSC), primary biliary cholangitis, biliary atresia, systemic sclerosis-related 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 as having psoriasis.

[0655] In some embodiments, at least one integrin comprises α V 。In some embodiments, at least one integrin comprises α V β 1 。In some embodiments, at least one integrin comprises α V β 6 。

[0656] In some embodiments, determining the first pSMAD / SMAD value in a first live cell sample comprises determining the pSMAD2 / SMAD2 value or the pSMAD3 / SMAD3 value; and determining the second pSMAD / SMAD value in at least one live cell after contacting the first live cell sample with a small molecule comprises determining the pSMAD2 / SMAD2 value or the pSMAD3 / SMAD3 value.

[0657] In another aspect, there is provided a method of inhibiting α V β 6 integrin in an individual, comprising administering a compound of formula (A), formula (I), or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (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 Figure 1 compounds numbered 1-66 therein or a pharmaceutically acceptable salt thereof.

[0658] In another aspect, there is provided a method of inhibiting α V β 6Methods for integrins, including administering a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), its stereoisomers, or a compound selected from Compound Nos. 1-147 or a pharmaceutically acceptable salt thereof.

[0659] In another aspect, provided is a method for inhibiting α V β 6 integrins in an individual, including administering a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), its stereoisomers, or a compound selected from Compound Nos. 1-665 or a pharmaceutically acceptable salt thereof.

[0660] In another aspect, provided is a method for inhibiting α V β 6 integrins in an individual, including administering a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), its stereoisomers, or a compound selected from Compound Nos. 1-780 or a pharmaceutically acceptable salt thereof.

[0661] Also provided is a method for inhibiting TGFβ activation in cells, including administering to the cells a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Figure 1 Compound Nos. 1-66 in the compounds, or its stereoisomers or a pharmaceutically acceptable salt thereof.

[0662] Also provided is a method for inhibiting TGFβ activation in cells, which includes administering to the cells a compound of formula (A), formula (I), or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compound numbers 1-147, or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0663] Also provided is a method for inhibiting TGFβ activation in cells, which includes administering to the cells a compound of formula (A), formula (I), or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compound numbers 1-665, or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0664] Also provided is a method for inhibiting TGFβ activation in cells, which includes administering to the cells a compound of formula (A), formula (I), or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compound numbers 1-780, or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0665] Also provided is a method for inhibiting α V β 6 integrin in an individual in need thereof, which includes administering to the individual a compound of formula (A), formula (I), or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Figure 1 compound numbers 1-66 among the compounds, or a stereoisomer or a pharmaceutically acceptable salt thereof. Also provided is a method for inhibiting α V β 6A method for inhibiting integrin, comprising administering to the individual a compound of formula (A), formula (I) or any variation 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. Also provided is a method for inhibiting α V β 6 A method for inhibiting integrin, comprising administering to the individual a compound of formula (A), formula (I) or any variation 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 1-665, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. Also provided is a method for inhibiting α V β 6 A method for treating an integrin, comprising administering to the subject a compound of formula (A), formula (I) or any variation 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 1-780, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In one such method, the compound is a selective α V β 6 Integrin inhibitors.

[0666] In another such method, the compound does not substantially inhibit α 4 β 1 , α V β 8 and / or α 2 β 3 In yet another such method, the compound inhibits α V β 6 Integrins, but do not substantially inhibit α 4 β 1 In yet another such method, the compound inhibits α V β 6 Integrins, but do not substantially inhibit αV β 8 In further such methods, the compound inhibits α V β 6 Integrins, but do not substantially inhibit α 2 β 3 In one embodiment, a method for inhibiting α V β 6 Integrin and α V β 1 , α V β 3 , α V β 5 , α 2 β 1 , α 3 β 1 , α 6 β 1 , α 7 β 1 and α 11 β 1 In another embodiment, a method for inhibiting one or more of the integrins is provided. V β 6 Integrin and α V β 1 In another embodiment, there is provided a method for inhibiting α V β 6 Integrin, α V β 3 Integrin and α V β 5 In another embodiment, there is provided a method for inhibiting α V β 6 Integrin and α 2 β 1 In another embodiment, there is provided a method for inhibiting α V β 6 Integrin, α 2 β 1 Integrin and α 3 β 1 In another embodiment, there is provided a method for inhibiting α V β 6 Integrin and α 6 β 1 In another embodiment, there is provided a method for inhibiting α V β 6 Integrin and α 7 β 1 In another embodiment, there is provided a method for inhibiting α V β6 Integrin and alpha 11 beta 1 Methods of integrin. In all such embodiments, on the one hand, the method of inhibition is used in an individual in need, such as an individual suffering from or suspected of suffering from a fibrotic disease, and wherein the method comprises administering to the individual a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), selected from Figure 1Compounds of compound numbers 1-66, or their stereoisomers or their pharmaceutically acceptable salts. In all such embodiments, in one aspect, the method of inhibition is for an individual in need, such as an individual suffering from or suspected of suffering from a fibrotic disease, and wherein the method comprises administering to the individual a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compound numbers 1-147, or their stereoisomers or their pharmaceutically acceptable salts. In all such embodiments, in one aspect, the method of inhibition is for an individual in need, such as an individual suffering from or suspected of suffering from a fibrotic disease, and wherein the method comprises administering to the individual a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compound numbers 1-665, or their stereoisomers or their pharmaceutically acceptable salts. In all such embodiments, in one aspect, the method of inhibition is for an individual in need, such as an individual suffering from or suspected of suffering from a fibrotic disease, and wherein the method comprises administering to the individual a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compound numbers 1-780, or their stereoisomers or their pharmaceutically acceptable salts.

[0667] There is also provided a method of modulating or inhibiting α V β 6 integrin in an individual in need with substantially no increase in pulmonary inflammation, comprising administering to the individual a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Figure 1Compounds numbered 1-66, or their stereoisomers or pharmaceutically acceptable salts thereof. Also provided is a method of modulating or inhibiting α V β 6 integrin in an individual in need thereof, substantially without increasing pulmonary inflammation, comprising administering to the individual a compound of formula (A), formula (I), or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compounds numbered 1-147, or their stereoisomers or pharmaceutically acceptable salts thereof. Also provided is a method of modulating or inhibiting α V β 6 integrin in an individual in need thereof, substantially without increasing pulmonary inflammation, comprising administering to the individual a compound of formula (A), formula (I), or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compounds numbered 1-665, or their stereoisomers or pharmaceutically acceptable salts thereof. Also provided is a method of modulating or inhibiting α V β 6 integrin in an individual in need thereof, substantially without increasing pulmonary inflammation, comprising administering to the individual a compound of formula (A), formula (I), or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from compounds numbered 1-780, or their stereoisomers or pharmaceutically acceptable salts thereof. In one such method, the compound is a selective α V β 6 integrin inhibitor. In one such method, the compound is a selective α V β 1 integrin inhibitor. In one such method, the compound is a selective α V β 6 integrin inhibitor and a selective α V β 1 integrin inhibitor.

[0668] In another embodiment, provided is a method of modulating or inhibiting α V β 6 integrin and α V β 1 integrin without substantially increasing pulmonary inflammation. In all such embodiments, in one aspect, the method of inhibition is used in an individual in need thereof, such as an individual suffering from or suspected of suffering from a fibrotic disease, and wherein the method comprises administering to the individual a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Figure 1Compounds numbered 1-66, or their stereoisomers or pharmaceutically acceptable salts, with substantially no increase in pulmonary inflammation. In all such embodiments, in one aspect, the method of inhibition is used for an individual in need, such as an individual suffering from or suspected of suffering from a fibrotic disease, and wherein the method comprises administering to the individual a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compounds numbered 1-147, or their stereoisomers or pharmaceutically acceptable salts, with substantially no increase in pulmonary inflammation. In all such embodiments, in one aspect, the method of inhibition is used for an individual in need, such as an individual suffering from or suspected of suffering from a fibrotic disease, and wherein the method comprises administering to the individual a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compounds numbered 1-665, or their stereoisomers or pharmaceutically acceptable salts, with substantially no increase in pulmonary inflammation. In all such embodiments, in one aspect, the method of inhibition is used for an individual in need, such as an individual suffering from or suspected of suffering from a fibrotic disease, and wherein the method comprises administering to the individual a compound of formula (A), formula (I) or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compounds numbered 1-780, or their stereoisomers or pharmaceutically acceptable salts, with substantially no increase in pulmonary inflammation.

[0669] The compound of formula (A) can be used in any composition, method and use enumerated herein for formula (I) and variants of formula (I).

[0670] In any of the said methods, in one aspect, the individual is a human, such as a human in need of the method. The individual can be a human who has been diagnosed with or suspected of having a fibrotic disease. The individual can be a human who has no detectable disease but has one or more risk factors for developing a fibrotic disease.

[0671] The present invention also provides a dosage form configured for daily administration, which comprises a pharmaceutically acceptable carrier or excipient; and a unit dose of the following compounds: a compound of formula (A), a compound of formula (I), or any variant thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (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 or a pharmaceutically acceptable salt thereof.

[0672] The unit dose (such as the unit dose for daily administration) may comprise 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, such as 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 said compound.

[0673] A unit dose (such as a unit dose for daily administration) may contain 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, such as about 1-125, 1-250, 1-5, 2.5-7.5, 5-15, 10-15, 10-20, 10-25, 10-30, 10-35, 10-40, 10-50, 10-75, 15-20, 15-25, 15-30, 15-35, 15-40, 15-50, 15-75, 20-25, 20-30, 20-35, 20-40, 20-50, 20-75, 25-30, 25-35, 25-40, 25-50, 25-75, 30-35, 30-40, 30-50, 30-75, 35-40, 35-50, 35-75, 40-50, 40-75, 50-75, 50-100, 50-150, 50-250, 60-85, 70-90, 70-100, 80-125, 90-125, 100-125, 100-150, 100-200, 125-175, 100-225, 100-250, and 150-250 mg) of the compound. For example, the unit dose can be 10 mg. The unit dose can be 15 mg. The unit dose can be 20 mg. The unit dose can be 30 mg. The unit dose can be 40 mg. The unit dose can be 50 mg. The unit dose can be 60 mg. The unit dose can be 70 mg. The unit dose can be 75 mg. The unit dose can be 80 mg. The unit dose can be 90 mg. The unit dose can be 100 mg. The unit dose can be 110 mg. The unit dose can be 120 mg. The unit dose can be 125 mg. The unit dose can be 150 mg. The unit dose can be 175 mg. The unit dose can be 200 mg. The unit dose can be 225 mg. The unit dose can be 250 mg.

[0674] A unit dose (such as a unit dose for daily administration) may contain, when administered to an individual, a C that is effective in the plasma of the individual to produce at least about or greater than about one of the following maxThe amount of said compound (in ng / mL): 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450 or 1500; or a range between any two of the foregoing concentrations, such as 700 - 1500, 700 - 900, 800 - 1300, 750 - 950, 800 - 1000, 850 - 950, 850 - 1050, 900 - 1400, 900 - 1300, 900 - 1200, 900 - 1100, 950 - 1050, 950 - 1400, 950 - 1150, 1000 - 1400, 1000 - 1300, 1000 - 1200, etc. For example, C max can be about 700 ng / mL or greater. C max can be about 750 ng / mL or greater. C max can be about 800 ng / mL or greater. C max can be about 850 ng / mL or greater. C max can be 900 ng / mL or greater. C max can be about 950 ng / mL or greater. C max can be about 1000 ng / mL or greater. C max can be about 1050 ng / mL or greater. C max can be about 1100 ng / mL or greater. C max can be about 1200 ng / mL or greater. C max can be about 1300 ng / mL or greater. C max can be about 1400 ng / mL or greater. C max can be about 1500 ng / mL or greater.

[0675] A unit dose (such as a unit dose for daily administration) can contain an amount of said compound that, when administered to an individual, effectively produces C max (in ng / mL) in the plasma of the individual, C max corresponding to a plasma regulatory concentration that effectively inhibits α V β 6 or α V β 1 by at least about one of 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 or a range between any two of the foregoing percentages (e.g., 50 - 100, 60 - 90, 70 - 90, 75 - 95, etc.). In some embodiments, the compound can be a dual α V β 6 and αV β 1 inhibitor, and C max may correspond to a plasma regulatory concentration effective to inhibit α in an individual V β 6 and α V β 1 each by a percentage, each percentage independently selected from the foregoing percentages, or a range between any two of the foregoing percentages. For example, the plasma regulatory concentration may inhibit α V β 6 by at least about 50%. The plasma regulatory concentration may inhibit α V β 6 by at least about 60%. The plasma regulatory concentration may inhibit α V β 6 by at least about 70%. The plasma regulatory concentration may inhibit α V β 6 by at least about 80%. The plasma regulatory concentration may inhibit α V β 6 by at least about 90%. Further, for example, the plasma regulatory concentration may inhibit α V β 1 by at least about 50%. The plasma regulat...

Claims

1. A method for improving the decline of forced vital capacity (FVC) in a subject in need thereof, comprising administering to the subject (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof, thereby improving the decline of forced vital capacity (FVC) in the subject.

2. The method according to claim 1, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount, and the therapeutically effective amount is sufficient to reduce the decline of FVC in the subject as compared to a subject who has not been administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1, wherein the administration continues for at least about 12 weeks.

4. The method according to any one of claims 1-3, wherein the administration continues for a period of about 12 weeks.

5. The method according to any one of claims 1-3, wherein the administration continues for a period of about 24 weeks.

6. The method according to any one of claims 1-5, wherein the administration is carried out daily.

7. The method according to any one of claims 1-6, wherein the administration is carried out once a day.

8. The method according to any one of claims 1-7, wherein after administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof, the improvement in the decline of FVC is a reduction of less than about 10%.

9. The method according to any one of claims 1-8, wherein the improvement in the decline of FVC is a reduction in the decline of FVC.

10. The method according to claim 8, wherein the reduction in the decline of FVC is about 50 mL or less.

11. The method according to claim 8, wherein the reduction in the decline of FVC is about 30 mL or less.

12. The method according to claim 8, wherein the reduction in the decline of FVC is about 15 mL or less.

13. The method according to any one of claims 8-12, wherein the administration continues for a period of about 12 weeks, and the decline of FVC from the start to the end of the period is about 50 mL or less.

14. The method according to any one of claims 8-12, wherein the decline of FVC from the start to the end of the period is about 30 mL or less.

15. The method according to any one of claims 8-12, wherein the decline of FVC from the start to the end of the period is about 15 mL or less.

16. The method according to any one of claims 8 - 15, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered in an amount of about 40 mg per day, or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 40 mg per day of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

17. The method according to any one of claims 8 - 15, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered in an amount of about 80 mg per day, or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 80 mg per day of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

18. The method according to any one of claims 8 - 15, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered in an amount of about 160 mg per day, or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 160 mg per day of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

19. The method according to any one of claims 8 - 15, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered in an amount of about 320 mg per day, or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 320 mg per day of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

20. The method according to any one of claims 8 - 15, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to provide an average plasma level of at least about 700 ng / mL of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

21. The method according to any one of claims 8 - 15, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to provide an average plasma level of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid of about 1,000 ng / mL plus or minus 200 ng / mL.

22. The method according to any one of claims 8 - 15, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to provide an average plasma level of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid of about 1,600 ng / mL plus or minus 300 ng / mL.

23. The method according to any one of claims 8 - 15, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to provide an average plasma level of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid of about 2,700 ng / mL plus or minus 400 ng / mL.

24. The method according to any one of claims 1 - 7, wherein the improvement in the decline of FVC is an increase in FVC.

25. The method according to claim 24, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount, which is sufficient to increase FVC in the subject as compared to a subject who has not received (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof.

26. The method according to claim 24 or claim 25, wherein the administration continues for at least about 4 weeks.

27. The method according to claim 24 or claim 25, wherein the administration continues for at least about 8 weeks.

28. The method according to claim 24 or claim 25, wherein the administration continues for at least about 12 weeks.

29. The method according to claim 24 or claim 25, wherein the administration lasts for a period of about 4 weeks.

30. The method according to claim 24 or claim 25, wherein the administration lasts for a period of about 8 weeks.

31. The method according to claim 24 or claim 25, wherein the administration lasts for a period of about 12 weeks.

32. The method according to any one of claims 24 - 31, wherein the administration is carried out daily.

33. The method according to any one of claims 24 - 31, wherein the administration is carried out once a day.

34. The method according to any one of claims 24 - 33, wherein the increase in FVC is about 10 mL or more, about 20 mL or more, about 30 mL or more, about 40 mL or more, about 50 mL or more, or about 60 mL or more.

35. The method according to any one of claims 24 - 33, wherein the increase in FVC is about 70 mL or more, about 80 mL or more, about 90 mL or more, about 100 mL or more, about 110 mL or more, or about 120 mL or more.

36. The method according to any one of claims 24 - 33, wherein the increase in FVC is up to about 10 mL, up to about 20 mL, up to about 30 mL, up to about 40 mL, up to about 50 mL, up to about 60 mL, up to about 70 mL, up to about 80 mL, up to about 90 mL, up to about 100 mL, up to about 110 mL, up to about 120 mL, up to about 130 mL, up to about 140 mL, up to about 150 mL, up to about 160 mL, up to about 170 mL, up to about 180 mL, or up to about 185 mL.

37. The method according to any one of claims 24 - 33, wherein the increase in FVC is about 130 mL or more, about 140 mL or more, about 150 mL or more, about 160 mL or more, about 170 mL or more, about 180 mL or more, or about 185 mL or more.

38. The method according to any one of claims 24 - 33, wherein the administration lasts for a period of about 12 weeks, and the increase in FVC from the start to the end of the period is about 10 mL or more, about 20 mL or more, about 30 mL or more, about 40 mL or more, about 50 mL or more, or about 60 mL or more.

39. The method according to any one of claims 24 - 33, wherein the increase in FVC from the start to the end of the period is about 70 mL or more, about 80 mL or more, about 90 mL or more, about 100 mL or more, about 110 mL or more, or about 120 mL or more.

40. The method according to any one of claims 24 - 33, wherein the increase in FVC from the start to the end of the period is about 130 mL or more, about 140 mL or more, about 150 mL or more, about 160 mL or more, about 170 mL or more, about 180 mL or more, or about 185 mL or more.

41. The method according to any one of claims 24 - 33, wherein the FVC increases by up to about 10 mL, up to about 20 mL, up to about 30 mL, up to about 40 mL, up to about 50 mL, up to about 60 mL, up to about 70 mL, up to about 80 mL, up to about 90 mL, up to about 100 mL, up to about 110 mL, up to about 120 mL, up to about 130 mL, up to about 140 mL, up to about 150 mL, up to about 160 mL, up to about 170 mL, up to about 180 mL, or up to about 185 mL from the start to the end of the period.

42. The method according to any one of claims 24 - 41, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered in an amount of about 40 mg per day, or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 40 mg per day of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

43. The method according to any one of claims 24 - 41, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered in an amount of about 80 mg per day, or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 80 mg per day of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

44. The method according to any one of claims 24 - 41, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered in an amount of about 160 mg per day, or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 160 mg per day of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

45. The method according to any one of claims 24 - 41, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered in an amount of about 320 mg per day, or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 320 mg per day of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

46. The method according to any one of claims 24-41, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to provide an average plasma level of at least about 700 ng / mL of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

47. The method according to any one of claims 24-41, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to provide an average plasma level of about 1,000 ng / mL plus or minus 200 ng / mL of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

48. The method according to any one of claims 24-41, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to provide an average plasma level of about 1,600 ng / mL plus or minus 300 ng / mL of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

49. The method according to any one of claims 24-41, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to provide an average plasma level of about 2,700 ng / mL plus or minus 400 ng / mL of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

50. The method according to any one of claims 1-49, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

51. The method according to any one of claims 1-50, wherein the subject has a fibrotic disease.

52. The method according to any one of claims 1-51, wherein the subject has fibrotic lung disease.

53. The method according to claim 52, wherein the fibrotic lung disease is idiopathic pulmonary fibrosis (IPF).

54. The method according to any one of claims 1-53, wherein the subject is a human.

55. The method according to any one of claims 1-54, wherein the subject is being treated with standard medical therapy or standard of care simultaneously.

56. The method according to claim 55, wherein the standard medical therapy or standard of care includes administering pirfenidone, administering nintedanib, or administering pirfenidone and nintedanib.

57. The method according to any one of claims 1-54, wherein the subject has not been previously treated with standard medical therapy or standard of care for a lung disorder.

58. The method according to claim 57, wherein the standard medical therapy or standard of care includes administering pirfenidone, administering nintedanib, or administering pirfenidone and nintedanib.

59. The method according to any one of claims 1-54 or 57-58, wherein the subject is not being treated with standard medical therapy or standard of care simultaneously.

60. The method according to claim 59, wherein the standard medical therapy or standard of care includes administering pirfenidone, administering nintedanib, or administering pirfenidone and nintedanib.

61. The method according to any one of claims 1-54 or 57-60, wherein the subject has not received treatment for any lung disorder other than (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof.

62. The method according to any one of claims 1-61, wherein the method is not accompanied by serious adverse events.

63. The method according to any one of claims 1-61, wherein the probability of serious adverse events is less than about 20%.

64. The method according to claim 62 or claim 63, wherein the serious adverse event is a gastrointestinal adverse event.

65. The method according to any one of claims 1-61, wherein the incidence of adverse events is lower than the incidence of adverse events of standard medical therapy or standard of care for a lung disorder.

66. The method according to claim 65, wherein the standard medical therapy or standard of care includes administering pirfenidone, administering nintedanib, or administering pirfenidone and nintedanib.

67. The method according to claim 65 or claim 66, wherein the adverse event is a gastrointestinal adverse event.

68. The method according to any one of claims 1-67, wherein after administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof, the cough severity is reduced.

69. The method according to claim 68, wherein the cough severity is determined by a visual analogue scale.

70. The method according to any one of claims 1-69, wherein after administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof, the pulmonary inflammation is alleviated.

71. The method according to any one of claims 1-70, wherein after administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof, no ground-glass appearance is observed or the ground-glass appearance is reduced.

72. The method according to any one of claims 1-71, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is a phosphate.

73. The method according to claim 72, wherein the phosphate is crystalline.

74. The method according to any one of claims 1-73, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is crystalline form I phosphate.

75. The method according to any one of claims 1-71, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is selected from crystalline form IV phosphate, crystalline form II fumarate, crystalline form III naphthalenedisulfonate, zwitterionic form, and amorphous form.

76. A method for modulating α V β 6 integrin, α V β 1 integrin or α V β 6 integrin and α V β 1 integrin in a subject in need, Comprising: Administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof, wherein the administration is not accompanied by serious adverse events.

77. The method according to claim 76, wherein α is adjusted V β 6 integrin, α V β 1 integrin or α V β 6 integrin and α V β 1 both integrin and α V β 6 integrin, α V β 1 integrin or α V β 6 integrin and α V β 1 both integrin.

78. The method according to claim 76 or 77, wherein after administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof, the severity of cough is alleviated.

79. The method according to claim 78, wherein the severity of cough is determined by a visual analogue scale.

80. The method according to any one of claims 76-79, wherein after administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof, the pulmonary inflammation is alleviated.

81. The method according to any one of claims 76 - 80, wherein no ground - glass appearance or reduction in ground - glass appearance is observed after administration of (S)-4-((2 - methoxyethyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2-(quinazolin - 4 - ylamino)butyric acid or a pharmaceutically acceptable salt thereof.

82. The method according to any one of claims 56, 58, 60 or 66, wherein the pirfenidone or a pharmaceutically acceptable salt thereof is deuterated pirfenidone or a pharmaceutically acceptable salt thereof.

83. The method according to claim 82, wherein the deuterated pirfenidone has the following formula: or a pharmaceutically acceptable salt thereof.

84. The method according to any one of claims 76 - 83, wherein (S)-4-((2 - methoxyethyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2-(quinazolin - 4 - ylamino)butyric acid is administered as a phosphate.

85. The method according to any one of claims 76 - 83, wherein (S)-4-((2 - methoxyethyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2-(quinazolin - 4 - ylamino)butyric acid is administered as crystalline form I phosphate.

86. The method according to any one of claims 76 - 83, wherein (S)-4-((2 - methoxyethyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2-(quinazolin - 4 - ylamino)butyric acid is administered as crystalline form IV phosphate, crystalline form II fumarate, crystalline form III naphthalenedisulfonate, zwitterionic form or amorphous form.

87. A method for increasing the expression of one or more genes in a subject in need thereof, comprising administering to the subject (S)-4-((2 - methoxyethyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2-(quinazolin - 4 - ylamino)butyric acid or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof, wherein the one or more genes are selected from ACACA, AKR1B10, APOB, BCL2L1, C3, C6, CCL2, CXCL8, CYP4A11 / 22, DAPK1, DLL1, EGFR, ELOVL6, EPHX2, F11R, FASN, FLNB, FZD5, GCNT1, GPC4, HADH, IL1RAP, IL20RB, JAG2, KIR2DL3, KLRB1, LYN, MS4A1, MUC5B, PLIN4, PPARGC1A, PTGER4, SAA1, SCD, SCIN, SLC25A10, SLC2A2, SPIB, SREBF1 or VAMP8.

88. The method according to claim 87, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as a phosphate salt.

89. The method according to claim 87, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as crystalline form I phosphate salt.

90. The method according to claim 87, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as crystalline form IV phosphate salt, crystalline form II fumarate, crystalline form III naphthalenedisulfonate, zwitterionic form or amorphous form.

91. The method according to any one of claims 87-90, wherein nintedanib is administered as an esylate salt.

92. A method of increasing the expression of one or more genes in a subject in need thereof, comprising administering to the subject (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and pirfenidone, wherein the one or more genes are selected from BCL2L1, C3, CCL4, CD209, CYP2J2, EGFR, FLNB, GPC4, GZMA, HCAR2, HDC, IL1B, JAG2, LYN, MAPK10, MMP12, MUC5B, SLC25A10, SPIB, SREBF1, TJP2, TNF or VAMP8.

93. The method according to claim 92, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as a phosphate salt.

94. The method according to claim 92, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as crystalline form I phosphate salt.

95. The method according to claim 92, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as crystalline form IV phosphate salt, crystalline form II fumarate, crystalline form III naphthalenedisulfonate, zwitterionic form or amorphous form.

96. A method for reducing the expression of one or more genes in a subject in need thereof, comprising administering to the subject (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof, wherein the one or more genes are selected from APOC2, CDH2, COL1A1, COL4A2, FCGR3A / B, ITGB3, LOXL2, NID1, SERPINH1, SPP1, TGFB1, THBS2, FAP, LOX, PDGFRB, POSTN or SERPINE1.

97. The method according to claim 96, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as a phosphate.

98. The method according to claim 96, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as crystalline form I phosphate.

99. The method according to claim 96, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as crystalline form IV phosphate, crystalline form II fumarate, crystalline form III naphthalenedisulfonate, zwitterionic form or amorphous form.

100. The method according to any one of claims 96-99, wherein nintedanib is administered as an ethanesulfonate.

101. A method for reducing the expression of one or more genes in a subject in need thereof, comprising administering to the subject (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and pirfenidone, wherein the one or more genes are selected from CDH2, COL1A1, COL5A3, ITGA5 or THBS2.

102. The method according to claim 101, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as a phosphate.

103. The method according to claim 101, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as crystalline form I phosphate.

104. The method according to claim 101, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as a crystalline form IV phosphate, a crystalline form II fumarate, a crystalline form III naphthalenedisulfonate, an zwitterionic form, or an amorphous form.

105. The method according to any one of claims 87 - 104, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof or (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and pirfenidone are administered in an amount effective to indicate an effect on gene expression.

106. The method according to claim 105, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as a phosphate.

107. The method according to claim 105, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as a crystalline form I phosphate.

108. The method according to claim 105, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as a crystalline form IV phosphate, a crystalline form II fumarate, a crystalline form III naphthalenedisulfonate, an zwitterionic form, or an amorphous form.

109. The method according to any one of claims 105 - 108, wherein nintedanib is administered as an esylate.

110. The method according to any one of claims 87 - 104, wherein the subject has a fibrotic disorder.

111. The method according to any one of claims 87 - 104, wherein the subject has a fibrotic lung disorder.

112. The method according to claim 111, wherein the fibrotic lung disorder is idiopathic pulmonary fibrosis.

113. A method for increasing the expression of one or more genes in a subject in need thereof, comprising administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof, wherein the one or more genes are selected from CCL13, IFI6, CXCL2, MET, NOS1, APOA2, OAS1, CIITA, WWC1, TTN, ALDH7A1, CD19, LTA, GPC4, TNF, XAF1, SMAD3, FZD5, IFI35, and PTGER4.

114. The method according to claim 113, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as a phosphate.

115. The method according to claim 113, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as crystalline Form I phosphate.

116. The method according to claim 113, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as crystalline Form IV phosphate, crystalline Form II fumarate, crystalline Form III naphthalenedisulfonate, zwitterionic form, or amorphous form.

117. A method for decreasing the expression of one or more genes in a subject in need thereof, comprising administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof, wherein the one or more genes are selected from COL10A1, POSTN, COL5A1, MARCO, MMP8, COL6A3, GREM1, PECAM1, COL1A2, CXCR4, COL3A1, LOX, MMP11, FAP, PDGFRB, FN1, SERPINE1, PLPP4, LOXL1, and TIMP1.

118. The method according to claim 117, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as a phosphate.

119. The method according to claim 117, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as crystalline Form I phosphate.

120. The method according to claim 117, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid is administered as a crystalline form IV phosphate, a crystalline form II fumarate, a crystalline form III naphthalenedisulfonate, an zwitterionic form, or an amorphous form.

121. A method of modulating the activity of at least one gene that affects fibrotic activity in a subject in need thereof, comprising (i) administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof, or (ii) administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and pirfenidone, wherein the at least one gene is modulated substantially by administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof or by administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof and pirfenidone, but substantially not by administering only (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof, only nintedanib or a pharmaceutically acceptable salt thereof, or only pirfenidone.

122. The method according to claim 121, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is a phosphate.

123. The method according to claim 121, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is a crystalline form I phosphate.

124. The method according to claim 121, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof is selected from the group consisting of crystalline form IV phosphate, crystalline form II fumarate, crystalline form III naphthalenedisulfonate, zwitterionic form, and amorphous form.

125. The method according to any one of claims 121-124, wherein modulating the activity is reducing the activity.

Images