Integrin inhibitors and their use in combination with other agents

Abstract

The present invention relates to (i) a method of treating a subject for a disease, (ii) a method of improving a decrease in forced vital capacity in a subject in need thereof, (iii) a method of modulating avf36 integrin, avf31 integrin, or both avf36 integrin and avf31 integrin in a subject in need thereof, (iv) a method of increasing the expression of one or more genes in a subject in need thereof, (v) a method of decreasing the expression of one or more genes in a subject in need thereof, and (vi) a method of modulating the activity of at least one gene that affects fibrotic activity in a subject in need thereof, comprising administering a compound of formula (A), formula (I), formula (II), or (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof as described herein, and administering to the subject at least a second drug selected from pirfenidone and nintedanib, or a salt thereof.

Description

Technical Field

[0001] Cross - reference to Related Applications This patent application claims priority to 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 incorporated herein by reference.

Background Art

[0002] Fibrosis, a pathological feature of many diseases, results from a dysfunction of the body's natural ability to repair damaged tissue. If left untreated, fibrosis can lead to irreversible damage and scarring of vital organs, causing ultimate organ failure.

[0003] Patients with non - alcoholic fatty liver disease (NAFLD) can progress from simple fatty liver to non - alcoholic steatohepatitis (NASH) and then to fibrosis. Hepatic fibrosis is reversible in its early stages, but progressive hepatic fibrosis can lead to cirrhosis.

[0004] Renal fibrosis, characterized by glomerulosclerosis and tubulointerstitial fibrosis, is the final common manifestation of a variety of chronic kidney diseases (CKD). Regardless of the initial cause, progressive CKD often results in extensive tissue scarring leading to destruction of the renal parenchyma, end - stage renal disease, and a devastating state requiring dialysis or renal replacement.

[0005] Scleroderma encompasses a complex and diverse set of conditions characterized by fibrosis, vascular changes, and autoimmunity. The spectrum of scleroderma disorders shares common features of fibrosis, resulting in hardening or thickening of the skin. This hardening occurs in only limited areas in some patients, but may spread to other major organs in other patients.

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

[0007] Crohn's disease is a chronic disease of unknown cause and tends to progress in the context of medical or surgical treatment. Enterofibrosis is one of the most common complications of Crohn's disease, with strictures forming in the small intestine and colon.

[0008] Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic disease of unknown cause that occurs in adults and is limited to the lungs. In IPF, lung tissue hypertrophies, hardens, and scars. As pulmonary fibrosis progresses, the lungs have difficulty delivering oxygen to the bloodstream, and organs are unable to receive the oxygen necessary to function properly. Currently, approximately 200,000 people in the United States are affected by IPF, and 40,000 people die from it each year. Patients diagnosed with IPF experience progressive shortness of breath and ultimately develop complete respiratory failure.

[0009] Primary biliary cholangitis (PBC), also known as primary biliary cirrhosis, is a chronic liver disease that causes damage and fibrosis in the liver. PBC occurs as the small bile ducts in the liver are slowly and progressively destroyed, causing bile and other toxins to accumulate in the liver, a condition called cholestasis. Over time, scarring and fibrosis occur in both the liver and the biliary tract.

[0010] Nonspecific interstitial pneumonia (NSIP) is a rare disease that affects the tissue surrounding and separating the small air sacs of the lungs. These air sacs, called alveoli, are the sites where the exchange of oxygen and carbon dioxide takes place between the lungs and the bloodstream. Interstitial pneumonia is a disease in which the reticular walls of the alveoli become inflamed. The pleura (a thin membrane that protects and cushions the lungs and the individual lobes of the lungs) can also become inflamed. NSIP has two main forms: cellular and fibrotic. The cellular form is mainly defined by inflammation of the interstitial cells. The fibrotic form is defined by thickening and scarring of the lung tissue. This scarring, known as fibrosis, is irreversible. When the lung tissue thickens or scars, the lungs can no longer function effectively. The efficiency of breathing deteriorates, and the oxygen concentration in the blood decreases. (Kim et al., Proc. Am. Thorac. Soc. (2006) 3:285-292; Lynch, D., Radiology (2001) 221:583-584; Kinder et al., Am. J. Respir. Crit. Care Med. (2007) 176:691-697)

[0011] Currently, the available treatment courses are limited because there are no options on the market that have been proven effective for the long-term survival or overall symptoms of patients. For example, agents such as pirfenidone and nintedanib have been studied for the treatment of fibrosis. In the treatment of IPF, pirfenidone and nintedanib are used, but the treatment effects are not as high as expected, and a number of side effects have also been observed. There is still a need for the treatment of fibrotic diseases.

[0012] α V αβ6 integrin is expressed in epithelial cells, binds to the latent peptide of transforming growth factor β1 (TGFβ1), and mediates the activation of TGFβ1. Its expression level increases significantly after damage to the lungs and bile duct cells and plays an important role in vivo in tissue fibrosis. The increase in levels is also associated with an increase in mortality in patients with IPF and NSIP.

[0013] Primary sclerosing cholangitis (PSC) is associated with bile duct inflammation and fibrosis that occludes the bile ducts. As a result, the flow of bile into the intestine is inhibited, causing cirrhosis, which can subsequently lead to complications such as liver failure and liver cancer. Alpha V The expression of αβ6 is elevated in the livers and bile ducts of PSC patients.

[0014] The present disclosure provides an α V β6 integrin inhibitor that may be useful for the treatment of fibrosis.

Summary of the Invention

[0015] Alpha V Amino acid compounds that are αβ6 integrin inhibitors, compositions containing these compounds, and methods for treating diseases such as fibrotic diseases mediated by α V β6 integrin are disclosed.

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

[0017] Furthermore, a pharmaceutical composition is provided that includes a compound of formula (A), or any variant thereof as detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient.

[0018] In another aspect, provided is a method of treating a fibrotic disease in an individual (such as a human) in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (A), or any variant thereof detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, cutaneous 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, cutaneous 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 cutaneous fibrosis. In some embodiments, the fibrotic disease is psoriasis. In some embodiments, the fibrotic disease is scleroderma. In some embodiments, the fibrotic disease is cardiac fibrosis. In some embodiments, the fibrotic disease is renal fibrosis. In some embodiments, the fibrotic disease is gastrointestinal fibrosis. In some embodiments, the fibrotic disease is primary sclerosing cholangitis. In some embodiments, the fibrotic disease is biliary fibrosis (PBC).

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

[0020] Also provided is a compound of formula (A), or any variant thereof detailed herein, or a pharmaceutical composition thereof, for the treatment of a fibrotic disease.

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

[0022] Further provided is a kit comprising a compound of formula (A), or any variant thereof detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the kit includes instructions for use according to methods described herein, such as a method for treating a fibrotic disease in an individual.

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

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

[0025] Furthermore, there is provided a pharmaceutical composition comprising a compound of formula (I), or any variant thereof as detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient.

[0026] In another aspect, there is provided a method of treating a fibrotic disease in an individual (such as a human) in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or any variant thereof as detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skin fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis (such as PBC). In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skin fibrosis, psoriasis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis (such as PBC). In some embodiments, the fibrotic disease is psoriasis.

[0027] In another aspect, 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 the fibrotic disease, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or any variant thereof detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skin fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or 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 the fibrotic disease has or is suspected of having NAFLD, NASH, CKD, scleroderma, Crohn's disease, NSIP, PSC, PBC, or has had or is suspected of having a myocardial infarction. In some embodiments, the individual at risk of developing the fibrotic disease has or is suspected of having psoriasis.

[0028] Also provided is a compound of formula (I), or any variant thereof detailed herein, or a pharmaceutical composition thereof, for the treatment of a fibrotic disease.

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

[0030] Further provided is a kit comprising a compound of formula (I), or any variant thereof detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises instructions for use according to a method described herein, such as a method for treating a fibrotic disease in an individual.

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

[0032] In another aspect, there is provided a method for treating a subject for a disease, comprising administering to the subject a first drug comprising a compound of formula (A) or a salt thereof, and administering to the subject at least a second drug selected from the group consisting of pirfenidone and nintedanib, or a salt thereof, whereby the subject is treated for the disease.

[0033] In another aspect, there is provided a method for improving 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)butanoic acid or a pharmaceutically acceptable salt thereof, whereby the decline in forced vital capacity (FVC) in the subject is improved.

[0034] In another aspect, α V β6 integrin, α V β1 integrin, or α V β6 integrin and α V both β1 integrins are regulated 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)butanoic acid or a pharmaceutically acceptable salt thereof, wherein the administration is without serious adverse events.

[0035] In another aspect, 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)butanoic 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, is provided.

[0036] In another aspect, 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)butanoic 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, is provided.

[0037] In another aspect, 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)butanoic 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, is provided.

[0038] In another aspect, 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)butanoic acid or a pharmaceutically acceptable salt thereof, and pirfenidone, wherein the one or more genes are selected from CDH2, COL1A1, COL5A3, ITGA5, or THBS2, is provided.

[0039] In another aspect, 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)butanoic 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, is provided.

[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 (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic 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.

[0041] In another aspect, a method of modulating the activity of at least one gene that affects fibrotic activity in a subject in need thereof, the method comprising (i) administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic 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)butanoic acid or a pharmaceutically acceptable salt thereof, and pirfenidone, wherein the at least one gene is substantially modulated by administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof, and nintedanib or a pharmaceutically acceptable salt thereof, or by administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof, and pirfenidone, but is not substantially modulated by administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof alone, nintedanib or a pharmaceutically acceptable salt thereof alone, or pirfenidone alone.

[0042] In any of the embodiments disclosed herein, a compound for use in any of the methods, including a method of treating a disease or a method of treating a subject in need thereof, may be a compound, salt, or polymorph disclosed in International Patent Application No. WO2022 / 109598, International Patent Application Publication No. US2022 / 0177468, U.S. Patent No. 10,793,564, U.S. Patent No. 11,419,869, or International Patent Application Publication No. US2023 / 0028658. The entire contents of each of the foregoing patent documents are incorporated herein by reference.

Brief Description of the Drawings

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[0044] The present disclosure provides, inter alia, 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 in the treatment of fibrotic diseases.

[0045] The present disclosure provides, inter alia, 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 in the treatment of fibrotic diseases.

[0046] **DEFINITIONS** For use herein, unless otherwise specified, the use of terms such as "a", "an", etc. refers to one or more.

[0047] References herein to "about" a value or parameter include (and describe) embodiments that target that value or parameter itself. For example, a reference to "about X" includes a description of "X".

[0048] As used herein, "small molecule" is an organic molecule characterized by a mass of less than 900 daltons. Non-limiting examples of small molecules include the compounds shown in FIG. 1 or salts thereof.

[0049] As used herein, "alkyl", unless otherwise specified, has the specified number of carbon atoms (i.e., C1-C 10(which means from 1 to 10 carbon atoms), refers to a straight-chain (i.e., unbranched) or branched monovalent saturated hydrocarbon chain or a combination thereof, and includes these. Specific alkyl groups are groups having from 1 to 20 carbon atoms (「C1-C 20 alkyl」), groups having from 1 to 10 carbon atoms (「C1-C 10 alkyl」), groups having from 6 to 10 carbon atoms (「C6-C 10 alkyl」), groups having from 1 to 6 carbon atoms (「C1-C6 alkyl」), groups having from 2 to 6 carbon atoms (「C2-C6 alkyl」), or groups having from 1 to 4 carbon atoms (「C1-C4 alkyl」). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc.

[0050] As used herein, 「alkylene」 refers to the same residue as alkyl but is divalent. Specific alkylene groups are groups having from 1 to 20 carbon atoms (「C1-C 20 alkylene」), groups having from 1 to 10 carbon atoms (「C1-C 10 alkylene」), groups having from 6 to 10 carbon atoms (「C6-C 10 alkylene」), groups having from 1 to 6 carbon atoms (「C1-C6 alkylene」), groups having from 1 to 5 carbon atoms (「C1-C5 alkylene」), groups having from 1 to 4 carbon atoms (「C1-C4 alkylene」) or groups having from 1 to 3 carbon atoms (「C1-C3 alkylene」). Examples of alkylene include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), butylene (-CH2(CH2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), pentylene (-CH2(CH2)3CH2-), hexylene (-CH2(CH2)4CH2-), heptylene (-CH2(CH2)5CH2-), octylene (-CH2(CH2)6CH2-), etc.

[0051] As used herein, "alkenyl", unless otherwise specified, has at least one olefinically unsaturated site (i.e., has at least one moiety of the formula C═C) and has a specified number of carbon atoms (i.e., C2-C 10 means 2 to 10 carbon atoms), and refers to a linear (i.e., unbranched) or branched monovalent unsaturated hydrocarbon chain or a combination thereof, including these. An alkenyl group may have a "cis" configuration or a "trans" configuration, or may have an "E" configuration or a "Z" configuration. Specific alkenyl groups are groups having 2 to 20 carbon atoms ("C2-C 20 alkenyl"), groups having 6 to 10 carbon atoms ("C6-C 10 alkenyl"), groups having 2 to 8 carbon atoms ("C2-C8 alkenyl"), groups having 2 to 6 carbon atoms ("C2-C6 alkenyl"), or groups having 2 to 4 carbon atoms ("C2-C4 alkenyl"). Examples of alkenyl groups include, but are not limited to, ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-dienyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, and the like.

[0052] As used herein, "alkenylene" refers to the same residue as alkenyl but is divalent. Specific alkenylene groups are groups having 2 to 20 carbon atoms ("C2-C 20 alkenylene"), groups having 2 to 10 carbon atoms ("C2-C 10 alkenylene"), groups having 6 to 10 carbon atoms ("C6-C 10"(an "alkenylene"), a group having 2 to 6 carbon atoms ("C2-C6 alkenylene"), a group having 2 to 4 carbon atoms ("C2-C4 alkenylene"), or a group having 2 to 3 carbon atoms ("C2-C3 alkenylene"). Examples of alkenylene include, but are not limited to, groups such as ethenylene (or vinylene) (-CH=CH-), propenylene (-CH=CHCH2-), 1,4-but-1-enylene (-CH=CH-CH2CH2-), 1,4-but-2-enylene (-CH2CH=CHCH2-), 1,6-hex-1-enylene (-CH=CH-(CH2)3CH2-), etc.

[0053] As used herein, "alkynyl", unless otherwise specified, has at least one acetylenic unsaturated site (i.e., has at least one moiety of the formula C≡C) and has the specified number of carbon atoms (i.e., C2-C 10 means 2 to 10 carbon atoms), and refers to a linear (i.e., unbranched) or branched monounsaturated hydrocarbon chain or a combination thereof, including these. Specific alkynyl groups are groups having 2 to 20 carbon atoms ("C2-C 20 alkynyl"), groups having 6 to 10 carbon atoms ("C6-C 10 alkynyl"), groups having 2 to 8 carbon atoms ("C2-C8 alkynyl"), groups having 2 to 6 carbon atoms ("C2-C6 alkynyl"), or groups having 2 to 4 carbon atoms ("C2-C4 alkynyl"). Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, etc.

[0054] As used herein, "alkynylene" refers to the same residue as alkynyl but is divalent. Specific alkynylene groups are groups having 2 to 20 carbon atoms ("C2-C 20 alkynylene"), groups having 2 to 10 carbon atoms ("C2-C 10("alkynylene"), a group having 6 to 10 carbon atoms ("C6-C 10 alkynylene"), a group having 2 to 6 carbon atoms ("C2-C6 alkynylene"), a group having 2 to 4 carbon atoms ("C2-C4 alkynylene") or a group having 2 to 3 carbon atoms ("C2-C3 alkynylene"). Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetylenylene) (-C≡C-), propynylene (-C≡CCH2-).

[0055] As used herein, "cycloalkyl", unless otherwise specified, refers to a cyclic monovalent saturated hydrocarbon structure having the specified number of carbon atoms (i.e., C3-C 10 means 3 to 10 carbon atoms), and includes these. Cycloalkyl can be composed of one ring such as cyclohexyl, or multiple rings such as adamantyl. Cycloalkyl containing two or more rings can be a fused ring, a spiro ring or a bridged ring, or a combination thereof. Specific cycloalkyl groups are groups having 3 to 12 ring carbon atoms. Preferred cycloalkyl is a cyclic hydrocarbon having 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"), a cyclic hydrocarbon having 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"), or a cyclic hydrocarbon having 3 to 4 ring carbon atoms ("C3-C4 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, etc.

[0056] As used herein, "cycloalkylene" refers to the same residue as cycloalkyl, but having divalency. Cycloalkylene may be composed of one ring, or may be composed of a plurality of rings which may be fused rings, spiro rings or bridged rings, or combinations thereof. Specific cycloalkylene groups are groups having 3 to 12 ring carbon atoms. Preferred cycloalkylene is a cyclic hydrocarbon having 3 to 8 ring carbon atoms ("C3-C8 cycloalkylene"), a cyclic hydrocarbon having 3 to 6 carbon atoms ("C3-C6 cycloalkylene"), or a cyclic hydrocarbon having 3 to 4 ring carbon atoms ("C3-C4 cycloalkylene"). Examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, etc. Cycloalkylene may be bonded to the remaining structure via the same ring carbon atom or different ring carbon atoms. When cycloalkylene is bonded to the remaining structure via two different ring carbon atoms, the connecting bonds may be cis or trans to each other. For example, cyclopropylene may include 1,1-cyclopropylene and 1,2-cyclopropylene (e.g., cis-1,2-cyclopropylene or trans-1,2-cyclopropylene), or mixtures thereof.

[0057] "Cycloalkenyl", unless otherwise specified, has at least one olefinic unsaturated site (i.e., has at least one moiety of the formula C=C) and has a specified number of carbon atoms (i.e., C3-C 10 means 3 to 10 carbon atoms), and refers to a cyclic non-aromatic monounsaturated hydrocarbon structure, including these. Cycloalkenyl may be composed of one ring such as cyclohexenyl, or may be composed of a plurality of rings such as norbornenyl. Preferred cycloalkenyl is a cyclic unsaturated hydrocarbon having 3 to 8 ring carbon atoms ("C3-C8 cycloalkenyl"). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, etc.

[0058] As used herein, "cycloalkenylene" refers to the same residue as cycloalkenyl, but is divalent.

[0059] As used herein, "aryl" or "Ar" refers to an aromatic unsaturated carbocyclic group having a monocyclic ring (e.g., phenyl) or a plurality of fused rings (e.g., naphthyl or anthryl), and the fused rings may or may not be aromatic. Specific aryl groups are groups having 6 to 14 ring carbon atoms ("C6-C 14 aryl"). An aryl group having two or more rings and at least one non-aromatic ring can be connected to the parent structure at either the position of the aromatic ring or the position of the non-aromatic ring. In one variant form, an aryl group having two or more rings and at least one non-aromatic ring is connected to the parent structure at the position of the aromatic ring.

[0060] As used herein, "arylene" refers to the same residue as aryl, but is divalent. Specific arylene groups are groups having 6 to 14 ring carbon atoms ("C6-C 14 arylene").

[0061] As used herein, "heteroaryl" refers to an unsaturated aromatic cyclic group having from 1 to 14 ring carbon atoms and at least one individual ring heteroatom including, but not limited to, heteroatoms such as nitrogen, oxygen and sulfur. The heteroaryl group may have a monocyclic ring (e.g., pyridyl, furyl) or a plurality of fused rings (e.g., indolizinyl, benzothienyl), and the fused rings may or may not be aromatic. Specific heteroaryl groups include a 5- to 14-membered ring having from 1 to 12 ring carbon atoms and from 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 10-membered ring having from 1 to 8 ring carbon atoms and from 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5-, 6- or 7-membered ring having from 1 to 5 ring carbon atoms and from 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variant, specific heteroaryl groups are monocyclic aromatic 5-, 6- or 7-membered rings having from 1 to 6 ring carbon atoms and from 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variant, specific heteroaryl groups are polycyclic aromatic rings having from 1 to 12 ring carbon atoms and from 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. A heteroaryl group having two or more rings and at least one ring being non-aromatic may be connected to the parent structure at either the position of the aromatic ring or the position of the non-aromatic ring. In one variant, a heteroaryl group having two or more rings and at least one ring being non-aromatic is connected to the parent structure at the position of the aromatic ring. The heteroaryl group may be connected to the parent structure by a ring carbon atom or a ring heteroatom.

[0062] As used herein, "heteroarylene" refers to the same residue as heteroaryl but having a divalent nature.

[0063] As used herein, "heterocyclic", "heterocyclic ring", or "heterocyclyl" refers to a saturated or unsaturated non-aromatic cyclic group having a monocyclic or polycondensed ring, with 1 to 14 ring carbon atoms and 1 to 6 ring heteroatoms such as nitrogen, sulfur or oxygen. A heterocyclic ring containing two or more rings can be a fused ring, a bridged ring or a spiro ring, or a combination thereof, but heteroaryl groups are excluded. The heterocyclyl group can be independently optionally substituted with one or more substituents described herein. Specific heterocyclyl 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 variant, the heterocyclyl includes a 3-, 4-, 5-, 6- or 7-membered monocyclic ring having 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 ring carbon atoms and 1 to 2, 1 to 3, or 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variant, the heterocyclyl includes a polycyclic non-aromatic ring having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0064] As used herein, "heterocyclylene" refers to the same residue as heterocyclyl, but having a divalent nature.

[0065] "Halo" or "halogen" refers to Group 17 elements having atomic numbers from 9 to 85. Preferred halo groups include radicals of fluorine, chlorine, bromine, and iodine. When the residue is substituted with two or more halogens, it can be designated by using a prefix according to the number of the attached halogen moieties. For example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may or may not be the same halogen. Thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced by a halo group is referred to as "perhaloalkyl". A preferred perhaloalkyl group is trifluoromethyl (-CF3). Similarly, "perhaloalkoxy" refers to an alkoxy group in which each H in the hydrocarbon constituting the alkyl part of the alkoxy group is replaced by a halogen. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

[0066] "Carbonyl" refers to the group C=O.

[0067] "Thiocarbonyl" refers to the group C=S.

[0068] "Oxo" refers to the moiety =O.

[0069] "D" refers to deuterium ( 2 H).

[0070] "T" refers to tritium ( 3 H).

[0071] An alkyl group in which each hydrogen is replaced by deuterium is referred to as "perdeuterated". An alkyl group in which each hydrogen is replaced by tritium is referred to as "pertriated".

[0072] "Optionally substituted" means that, unless otherwise specified, the group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group, and 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 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, or 2-5 substituents. In one embodiment, the optionally substituted group is unsubstituted.

[0073] It is understood that the optionally substituted moiety may be substituted with 6 or more substituents, provided that the number of valences available for substitution at that moiety permits. For example, a propyl group may be substituted with 7 halogen atoms to provide a perhalopropyl group. The substituents may be the same or different.

[0074] Unless otherwise indicated, as used herein, "subject" is intended to include mammals, including, but not limited to, primates, humans, cows, horses, cats, dogs, or rodents. In one variation, the subject is a human.

[0075] As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical outcomes. Beneficial or desired results include, but are not limited to, one or more of the following: reducing one or more symptoms caused by a disease, decreasing 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, bringing about remission of the disease (whether partial or complete), reducing the dosage of one or more other medicaments required for the treatment of the disease, enhancing the effect of another medicament, delaying the progression of the disease, improving the quality of life, and / or extending the survival period. Also included in "treatment" is the reduction of the pathological consequences of fibrosis. The methods of the present invention contemplate any one or more of these treatment modalities.

[0076] As used herein, the term "effective amount" is intended to refer to the amount of a compound of the present invention that should be effective in a given treatment modality. As understood in the art, an effective amount may be one or more doses, i.e., single or multiple administrations may be required to achieve the desired treatment endpoint. An effective amount may be considered in relation to the administration of one or more therapeutic agents (e.g., a compound, or a pharmaceutically acceptable salt thereof), and a single agent may be considered to be administered in an effective amount if, when administered with one or more other agents, a desired or beneficial result can be achieved, or is achieved. The appropriate dosage of any of the compounds administered concomitantly may optionally be reduced due to the combined action (e.g., additive or synergistic) of the compounds.

[0077] A "therapeutically effective amount" refers to an amount of a compound or a salt thereof sufficient to produce a desired therapeutic effect.

[0078] As used herein, "unit dosage form" refers to physically discrete units suitable as unit doses, each unit containing a predetermined quantity of an active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0079] As used herein, the term "controlled release" refers to a drug-containing formulation or a portion thereof in which the release of the drug is not immediate, i.e., upon administration of a "controlled release" formulation, the drug is not immediately released into the absorption pool. This term encompasses depot formulations designed to gradually release a drug compound over an extended period of time. Controlled release formulations can include a wide variety of drug delivery systems and generally involve mixing the drug compound with a carrier, polymer, or other compound having desired release characteristics (e.g., pH-dependent or pH-independent solubility, varying degrees of water solubility, etc.) and formulating the mixture according to a desired delivery route (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, etc.).

[0080] As used herein, "pharmaceutically acceptable" or "pharmacologically acceptable" means not being a biologically or otherwise undesirable material, e.g., the material does not cause an undesirable significant biological effect and does not interact detrimentally with any of the other components of the composition in which it is contained and can be incorporated into a pharmaceutical composition administered to a patient. A pharmaceutically acceptable carrier or excipient preferably meets the required criteria of toxicity tests and manufacturing tests and / or is listed in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0081] "Pharmaceutically acceptable salts" are salts that retain at least some of the biological activities of the free (non-salt) compound and can be administered to an individual as a drug or pharmaceutical. Such salts include, for example, (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid; (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth metal ions, or aluminum ions, or when coordinated with organic bases. 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 separately reacting the purified compound of the present invention in the form of its organic acid or organic base with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.

[0082] As used herein, the term "excipient" means an inert or inactive substance that can be used in the manufacture of drugs or pharmaceuticals, such as tablets, containing the compounds of the present invention as an active ingredient. The term "excipient" can include a variety of substances, including, but not limited to, binders, disintegrants, coating agents, compression / encapsulation aids, creams or lotions, lubricants, solutions for parenteral administration, materials for chewable agents, sweeteners or flavoring agents, suspending / gelling agents, or any substance used as a wet granulating agent. Examples of binders include, for example, carbomers, povidone, xanthan gum, etc.; examples of coating agents include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coating, etc.; examples of 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.; examples of disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; examples of creams or lotions include, for example, maltodextrin, carrageenan, etc.; examples of lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; examples of materials for chewable agents include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; examples of suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; examples of sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; examples of wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0083] Unless otherwise specified, "substantially pure" is intended to mean a composition containing 10% or less impurities. For example, the composition may contain 9%, 7%, 5%, 3%, 1%, less than 0.5% impurities.

[0084] It should be understood that the aspects and embodiments described herein as "comprising" include "consisting of" and "consisting essentially of" from the embodiments.

[0085] The blood level concentrations of drug substances and other substances in a subject can be measured in plasma or serum as appropriate. If the level of a substance is shown as a measured value in plasma, that level can be similarly measured in serum if such a measured value is appropriately accurate. If the level of a substance is shown as a measured value in serum, that level can be similarly measured in plasma if such a measured value is appropriately accurate.

[0086] Compound In one aspect, provided is a compound of formula (A):

Chemical formula

[0087] In one variant form, there is provided the exclusion of the free base of (2S)-4-[2-methoxyethyl-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]amino]-2-(quinazolin-4-ylamino)butanoic acid:

Chemical formula

[0088] In various embodiments, the compound excludes the free base of the compound represented by formula A, wherein R 1 is unsubstituted quinazolin-4-yl, R 2 is -CH2CH2OCH3, R 10 and R 11 and R 12 and R 13 and R 15 and R 16 are each H, p is 3, q is 0, R 1The carbon atom to which NH- is attached has the S configuration. For example, in some embodiments, the compound of Formula A excludes the free base of (2S)-4-[2-methoxyethyl-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]amino]-2-(quinazolin-4-ylamino)butanoic acid:

Chemical Structure

[0089] In some embodiments, the compound excludes the free base of the compound represented by Formula A, wherein R 2 is -CH2CH2OCH3, and R 10 , R 11 , R 12 , R 13 , R 15 , and R 16 are each H, p is 3, q is 0, and the carbon atom to which R 1 NH- is attached has the S configuration, and R 1 is one or more of embodiments (a) to (k) represented by the following distinct characters. (a) R 1 is unsubstituted quinazolin-4-yl. (b) R 1 is quinazolin-4-yl substituted by R 1a , where R 1a is methyl. (c) R 1 is quinazolin-4-yl substituted by R 1a , where R 1a is methyl or ethyl. (d) R 1 is quinazolin-4-yl substituted by R 1a , where R 1a is C1-C6 alkyl. (e) R 1 is quinazolin-4-yl substituted by R 1a . (f) R 1 is a 10-membered bicyclic fused heterocycle containing two ring nitrogen atoms, and R 1 is unsubstituted or substituted by R 1a . (g) R 1is an unsubstituted quinazolinyl. (h) R 1 is R 1a substituted quinazolinyl, where R 1a is methyl. (i) R 1 is R 1a substituted quinazolinyl, where R 1a is methyl or ethyl. (j) R 1 is R 1a substituted quinazolinyl, where R 1a is C1-C6 alkyl. (k) R 1 is R 1a substituted quinazolinyl.

[0090] In some embodiments, the compound excludes 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 attached is in the S configuration, and R 2 is one or more of embodiments (l)-(p) represented by the following distinct characters. (l) R 2 is R 2a 2-substituted ethylene by, and R 2a is methoxy. (m) R 2 is R 2a substituted methylene, ethylene, or propylene by, and R 2a is methoxy. (n) R 2 is R 2a substituted ethylene by, and R 2a is methoxy or ethoxy. (o) R 2 is R 2a substituted ethylene by, and R 2a is hydroxy. (p) R 2 is R 2ais methylene, ethylene, or propylene substituted by, and R 2a is hydroxy, methoxy, or ethoxy.

[0091] In some embodiments, the compound excludes the free base of the compound represented by formula A, wherein R 1 is unsubstituted quinazolin-4-yl, R 2 is -CH2CH2OCH3, R 15 and R 16 are each H, p is 3, q is 0, R 1 the carbon to which NH- is attached has the S configuration, R 10 , R 11 , R 12 , and R 13 together represent one or more of embodiments (q) to (u) represented by the following distinct letters. (q) R 10 , R 11 , R 12 , and R 13 are each hydrogen. (r) One of R 10 , R 11 , R 12 , and R 13 is deuterium and the rest are hydrogen. (s) Two of R 10 , R 11 , R 12 , and R 13 are deuterium and the rest are hydrogen. (t) Three of R 10 , R 11 , R 12 , and R 13 are deuterium and the rest are hydrogen. (u) Each of R 10 , R 11 , R 12 , and R 13 is deuterium.

[0092] In some embodiments, the compound excludes the free base of the compound represented by formula A, wherein R 1 is unsubstituted quinazolin-4-yl, R 2 is -CH2CH2OCH3, R 10 , R11 , R 12 , and R 13 are each H, p is 3, q is 0, and the carbon to which NH- is attached has the S configuration, R 1 15 and R 16 together represent one or more of the embodiments (v) to (aa) represented by the following distinct characters. (v) R 15 and R 16 are each hydrogen. (w) R 15 is hydrogen, R 16 is deuterium, or R 15 is deuterium, R 16 is hydrogen. (x) R 15 and R 16 are deuterium. (y) R 15 is hydrogen, R 16 is halogen, for example, fluorine, or R 15 is halogen, for example, fluorine, R 16 is hydrogen. (z) R 15 is deuterium, R 16 is halogen, for example, fluorine, or R 15 is halogen, for example, fluorine, R 16 is deuterium. (aa) R 15 and R 16 are each halogen, for example, fluorine.

[0093] In some embodiments, the compound excludes the free base of the compound represented by formula A, wherein R 1 is unsubstituted quinazolin-4-yl, R 2 is -CH2CH2OCH3, R 10 , R 11 , R 12 , R 13 , R 15 , and R 16 are each H, q is 0, and R 1 ​The carbon to which NH- is attached has an S configuration, and p is one of the embodiments (ab) to (ad) represented by the following distinct letters. (ab) p is 3. (ac) p is 4. (ad) p is 5.

[0094] In some embodiments, the compound excludes the free base of the compound represented by formula A, wherein R 1 is an unsubstituted quinazolin-4-yl, R 2 is -CH2CH2OCH3, R 10 , R 11 , R 12 , R 13 , R 15 , and R 16 are each H, p is 3, and the carbon to which R 1 NH- is attached has an S configuration, and q is one of the embodiments (ae) to (ah) represented by the following distinct letters. (ae) q is 0. (af) q is 1. (ag) q is 2. (ah) q is 3.

[0095] In some embodiments, R 1 ; R 2 ; R 10 , R 11 , R 12 , and R 13 ; R 15 and R 16 ; the variable element p; and the free base of the compound of any combination of the embodiments represented by letters, each selected for each of the variable elements q, is excluded. For example, R 1 which is one of (a) to (k); R 2 which is one of (l) to (p); R 10 which is one of (q) to (u), R 11 , R 12 , and R 13 ; R 15 and R 16; It can be selected from combinations of a variable element p which is one of (ab) to (ad); and a variable element q which is one of (ae) to (ah). Exemplary combinations of the embodiments represented by letters are, for example, (a), (l), (q), (v), (ab), and (ae); (b), (l), (q), (v), (ab), and (ae); (c), (l), (q), (v), (ab), and (ae); (d), (l), (q), (v), (ab), and (ae); (e), (l), (q), (v), (ab), and (ae); (f), (l), (q), (v), (ab), and (ae); (g), (l), (q), (v), (ab), and (ae); (h), (l), (q), (v), (ab), and (ae); (i), (l), (q), (v), (ab), and (ae); (j), (l), (q), (v), (ab), and (ae); (k), (l), (q), (v), (ab), and (ae); (a), (m), (q), (v), (ab), and (ae); (b), (m), (q), (v), (ab), and (ae); (c), (m), (q), (v), (ab), and (ae); (d), (m), (q), (v), (ab), and (ae); (e), (m), (q), (v), (ab), and (ae); (f), (m), (q), (v), (ab), and (ae); (g), (m), (q), (v), (ab), and (ae); (h), (m), (q), (v), (ab), and (ae); (i), (m), (q), (v), (ab), and (ae); (j), (m), (q), (v), (ab), and (ae); (k), (m), (q), (v), (ab), and (ae); (a), (n), (q), (v), (ab), and (ae); (b), (n), (q), (v), (ab), and (ae); (c), (n), (q), (v), (ab), and (ae); (d), (n), (q), (v), (ab), and (ae); (e), (n), (q), (v), (ab), and (ae); (f), (n), (q), (v), (ab), and (ae); (g), (n), (q), (v), (ab), and (ae); (h), (n), (q), (v), (ab), and (ae); (i), (n), (q), (v), (ab), and (ae); (j), (n), (q), (v), (ab), and (ae);(k), (n), (q), (v), (ab), and (ae); (a), (o), (q), (v), (ab), and (ae); (b), (o), (q), (v), (ab), and (ae); (c), (o), (q), (v), (ab), and (ae); (d), (o), (q), (v), (ab), and (ae); (e), (o), (q), (v), (ab), and (ae); (f), (o), (q), (v), (ab), and (ae); (g), (o), (q), (v), (ab), and (ae); (h), (o), (q), (v), (ab), and (ae); (i), (o), (q), (v), (ab), and (ae); (j), (o), (q), (v), (ab), and (ae); (k), (o), (q), (v), (ab), and (ae); (a), (p), (q), (v), (ab), and (ae); (b), (p), (q), (v), (ab), and (ae); (c), (p), (q), (v), (ab), and (ae); (d), (p), (q), (v), (ab), and (ae); (e), (p), (q), (v), (ab), and (ae); (f), (p), (q), (v), (ab), and (ae); (g), (p), (q), (v), (ab), and (ae); (h), (p), (q), (v), (ab), and (ae); (i), (p), (q), (v), (ab), and (ae); (j), (p), (q), (v), (ab), and (ae); (k), (p), (q), (v), (ab), and (ae); any one of the aforementioned combinations in which (v) is replaced by (y); any one of the aforementioned combinations in which (v) is replaced by (aa); any one of the aforementioned combinations in which (ab) is replaced by (ad); or any one of the aforementioned combinations in which (ab) is replaced by (ae).;

[0096] In some embodiments, salts of the compounds of any one or any combination of the above-described embodiments (a) to (ah) represented by letters are excluded. In some embodiments, pharmaceutical compositions comprising the compounds of any one or any combination of the above-described embodiments (a) to (ah) represented by letters or salts thereof are excluded. In some embodiments, kits comprising the compounds of any one or any combination of the above-described embodiments (a) to (ah) represented by letters or salts thereof are excluded. In some embodiments, dosage forms comprising the compounds of any one or any combination of the above-described embodiments (a) to (ah) represented by letters are excluded. In some embodiments, methods comprising the compounds of any one or any combination of the above-described embodiments (a) to (ah) represented by letters or salts thereof are excluded.

[0097] In one variant, CO2H and NHR 1 There is provided a compound of formula (A) or a salt thereof, wherein the carbon having the moiety is in the "S" configuration. In another variant, CO2H and NHR 1 There is provided a compound of formula (A) or a salt thereof, wherein the carbon having the moiety is in the "R" configuration. Mixtures of the compounds of formula (A) are also included, including racemic or non-racemic mixtures of a given compound and mixtures of two or more compounds of different chemical formulas.

[0098] In one variant of formula (A), R 2 has the condition that any carbon atom directly bonded to the nitrogen atom is either unsubstituted or substituted with deuterium.

[0099] It should be understood that in the description herein, all descriptions, variants, embodiments or aspects of a part can be combined with all descriptions, variants, embodiments or aspects of other parts in the same way as if all combinations of the descriptions were specifically and individually listed. For example, R of formula (A) 1All descriptions, variations, embodiments or aspects provided herein with respect to R are combinable with all descriptions, variations, embodiments or aspects of R 2 in the same manner as if every combination were specifically and individually recited.

[0100] In one aspect, provided is a compound of formula (I):

Chemical Formula

[0101] In one variant form, CO2H and NHR 1Compounds of formula (I) or salts thereof are provided, wherein the carbon atom having the moiety is in the "S" configuration. In another variant, CO2H and NHR 1 Compounds of formula (I) or salts thereof are provided, wherein the carbon atom having the moiety is in the "R" configuration. Mixtures of compounds of formula (I) are also included, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0102] In one variant of formula (I), R 2 is such that any carbon atom directly bonded to the nitrogen atom is optionally substituted with an R moiety other than halogen. In one variant of formula (I), R 2a is such that any carbon atom directly bonded to the nitrogen atom is either unsubstituted or substituted with deuterium. 2

[0103] It should be understood that in the description herein, all descriptions, variants, embodiments or aspects of a part can be combined with all descriptions, variants, embodiments or aspects of other parts, in the same way as if all combinations of the descriptions were specifically and individually listed. For example, all descriptions, variants, embodiments or aspects provided herein regarding R in formula (I) can be combined with all descriptions, variants, embodiments or aspects of R 1 in the same way as if all combinations were specifically and individually listed. 2

[0104] In some embodiments of the compounds of formula (I) or salts thereof, R 1a R 2a R 2b R 2c R 2e R 2f R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R11 , R 12 , R 13 , R 14 , R 15 , or R 16 At least one of them is deuterium.

[0105] In some embodiments of the compound of formula (I) or a salt thereof, R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a . In some embodiments, R 1 is pyrimidin-4-yl optionally substituted by R 1a . In some embodiments, R 1 is pyrimidin-4-yl optionally substituted by R 1a , where R 1a is C1-C6 alkyl (such as methyl, difluoromethyl, and trifluoromethyl) optionally substituted by a 5- to 10-membered heteroaryl (such as pyrazolyl) or halogen. In some embodiments, R 1 is pyrimidin-4-yl optionally substituted by R 1a , where R 1a is C1-C6 alkyl (such as methyl, difluoromethyl, and trifluoromethyl) optionally substituted by a 5- to 10-membered heteroaryl (such as pyrazolyl or pyridinyl) or halogen. In some embodiments, R 1 is pyrimidin-4-yl substituted by both methyl and trifluoromethyl. In some embodiments, R 1 is pyrimidin-4-yl substituted by both methyl and pyridinyl. In some embodiments, R 1 is pyrimidin-4-yl optionally substituted by R 1a , where R 1a is C6-C 14 aryl (such as phenyl). In some embodiments, R 1 is R 1ais a pyrimidin-4-yl optionally substituted by, wherein R 1a is -CN. In some embodiments, R 1 is a pyrimidin-2-yl optionally substituted by R 1a . In some embodiments, R 1 is a pyrimidin-2-yl optionally substituted by R 1a , wherein R 1a is halogen, C1-C6 alkyl optionally substituted by halogen (e.g., methyl or trifluoromethyl), -CN, or C3-C8 cycloalkyl (e.g., cyclopropyl). In some embodiments of the compound of formula (I) or a salt thereof, R 1 is a quinazolin-4-yl optionally substituted by R 1a . In some embodiments, R 1 is a quinazolin-4-yl optionally substituted by R 1a , wherein R 1a is halogen (e.g., fluoro and chloro), C1-C6 alkyl optionally substituted by halogen (e.g., methyl or trifluoromethyl), or C1-C6 alkoxy (e.g., methoxy). In some embodiments, R 1 is a quinazolin-4-yl optionally substituted by R 1a , wherein R 1a is a 5- to 10-membered heteroaryl (e.g., pyridinyl). In some embodiments, R 1 is a pyrazolopyrimidinyl optionally substituted by R 1a . In some embodiments, R 1 is a pyrazolopyrimidinyl optionally substituted by R 1a , wherein R 1a is C1-C6 alkyl (e.g., methyl). In some embodiments where R 1 is shown to be optionally substituted by R 1a , the R 1 moiety is unsubstituted. R1 is R 1a In some embodiments shown to be optionally substituted by R, R 1 moiety is substituted by one R 1a . R 1 is R 1a In some embodiments shown to be optionally substituted by R, R 1 moiety may be substituted by 2 to 6 or 2 to 5 or 2 to 4 or 2 to 3 R moieties, which may be the same or different. 1a

[0106] R 1 In some embodiments of formula (I) including embodiments describing the variable elements of R, R 10 , R 11 , R 12 and R 13 are hydrogen. R 1 's variable element, and / or R 10 , R 11 , R 12 and R 13 's variable element, in some embodiments of formula (I) including embodiments describing the variable elements of R, R 1 's variable element, and / or R 10 , R 11 , R 12 and R 13 's variable element and / or q's variable element, in some embodiments, p is 3, 4 or 5.

[0107] 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 is of formula (II):

Chemical formula

[0108] ​ R 1 is R 1a In some embodiments of the compound of formula (I), which is a 5- to 10-membered heteroaryl optionally substituted by R, the compound is of formula (I-A):

Chemical formula

[0109] In one embodiment, there is provided a compound of formula (I-A) or a salt thereof, wherein the carbon having the CO2H 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 having the CO2H and NH moieties is in the "R" configuration. Mixtures of compounds of formula (I-A) are also included, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0110] In some embodiments of the compound of formula (I-A), m is 0, 1, 2, or 3, and each R 1a , when applicable, 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 by deuterium. In further embodiments of the compound of formula (I-A), m is 0, 1, 2, or 3, and each R 1ais, when applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variant form can be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, where R 1a the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of are independently optionally substituted by deuterium. In some embodiments of formula (I-A), m is 1, 2, or 3.

[0111] In some embodiments of the compound of formula (I-A), m is 0. In some embodiments of the compound of formula (I-A), m is 1 and R 1a is at the 2-position. In some embodiments of the compound of formula (I-A), m is 1 and R 1a is at the 5-position. In some embodiments of the compound of formula (I-A), m is 1 and R 1a is at the 6-position. In some embodiments of the compound of formula (I-A), m is 2 and R 1a groups are at the 2- and 5-positions. In some embodiments of the compound of formula (I-A), m is 2 and R 1a groups are at the 2- and 6-positions. In some embodiments of the compound of formula (I-A), m is 2 and R 1a groups are at the 5- and 6-positions. In some embodiments of the compound of formula (I-A), m is 3 and R 1a groups are at the 2-, 5-, and 6-positions. When two or more R 1a groups are present, the R 1a groups can always be selected independently. In any of these embodiments of the compound of formula (I-A) or its salt, the carbon having the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0112] R 1a In some embodiments of formula (I-A), including the embodiments describing the variable elements of R and m, R 10 R 11 R12 and R 13 each of which is hydrogen. R 1a and variable elements of m, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (I-A) including embodiments describing variable elements of and m, and / or R 1a and variable elements of m, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (I-A) including embodiments describing variable elements of and / or variable elements of q, p is 3, 4, or 5.

[0113] 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 is of formula (II-A):

Chemical formula

[0114] R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a In some embodiments of the compound of formula (I), the compound is of formula (I-B):

Chemical formula

[0115] In one embodiment, there is provided a compound of formula (I-B) or a salt thereof in which the carbon having the CO2H and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-B) or a salt thereof in which the carbon having the CO2H and NH moieties is in the "R" configuration. Mixtures of compounds of formula (I-B) are also included, including racemic or non-racemic mixtures of a given compound and mixtures of two or more compounds of different chemical formulas.

[0116] In some embodiments of the compounds of formula (I-B), m is 0, 1, 2, 3, 4, or 5, and each R 1a , when applicable, 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 by deuterium. In further embodiments of the compounds of formula (I-B), m is 0, 1, 2, 3, 4, or 5, and each R 1a , when applicable, is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which can be C1-C6 perhaloalkyl in one variant), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, where the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R 1a are independently optionally substituted by deuterium. In some embodiments of the compounds of formula (I-B), m is 1, 2, 3, 4, or 5.

[0117] In some embodiments of the compound of formula (I-B), m is 0. In some embodiments of the compound of formula (I-B), m is 1 and R 1a is at the 2-position. In some embodiments of the compound of formula (I-B), m is 1 and R 1a is at the 5-position. In some embodiments of the compound of formula (I-B), m is 1 and R 1a is at the 6-position. In some embodiments of the compound of formula (I-B), m is 1 and R 1a is at the 7-position. In some embodiments of the compound of formula (I-B), m is 1 and R 1a is at the 8-position. In some embodiments of the compound of formula (I-B), m is 2 and R 1a groups are at the 2- and 5-positions. In some embodiments of the compound of formula (I-B), m is 2 and R 1a groups are at the 2- and 6-positions. In some embodiments of the compound of formula (I-B), m is 2 and R 1a groups are at the 2- and 7-positions. In some embodiments of the compound of formula (I-B), m is 2 and R 1a groups are at the 2- and 8-positions. In some embodiments of the compound of formula (I-B), m is 2 and R 1a groups are at the 5- and 6-positions. In some embodiments of the compound of formula (I-B), m is 2 and R 1a groups are at the 5- and 7-positions. In some embodiments of the compound of formula (I-B), m is 2 and R 1a groups are at the 5- and 8-positions. In some embodiments of the compound of formula (I-B), m is 2 and R 1a groups are at the 6- and 7-positions. In some embodiments of the compound of formula (I-B), m is 2 and R 1a groups are at the 6- and 8-positions. In some embodiments of the compound of formula (I-B), m is 2 and R 1a groups are at the 7- and 8-positions. In some embodiments of the compound of formula (I-B), m is 3 and R 1aThe group is at the 2-position, 5-position, and 6-position. In some embodiments of the compound of formula (I-B), m is 3, R 1a The group is at the 2-position, 5-position, and 7-position. In some embodiments of the compound of formula (I-B), m is 3, R 1a The group is at the 2-position, 5-position, and 8-position. In some embodiments of the compound of formula (I-B), m is 3, R 1a The group is at the 2-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-B), m is 3, R 1a The group is at the 2-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-B), m is 3, R 1a The group is at the 2-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-B), m is 3, R 1a The group is at the 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-B), m is 3, R 1a The group is at the 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-B), m is 3, R 1a The group is at the 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-B), m is 3, R 1a The group is at the 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-B), m is 4, R 1a The group is at the 2-position, 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-B), m is 4, R 1a The group is at the 2-position, 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-B), m is 4, R 1a The group is at the 2-position, 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-B), m is 4, 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-B), m is 4, 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-B), m is 5, R 1aThe groups are at the 2-, 5-, 6-, 7-, and 8-positions. When two or more R 1a groups are present, the R 1a groups can be independently selected. In any of these embodiments of the compound of formula (I-B) or a salt thereof, the carbon having the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0118] R 1a In some embodiments of formula (I-B) including embodiments describing the variable elements of R 10 and m, and / or R 11 and R 12 and R 13 each is hydrogen. In some embodiments of formula (I-B) including embodiments describing the variable elements of R 1a and m, and / or R 10 and R 11 and R 12 and R 13 q is 0. In some embodiments of formula (I-B) including embodiments describing the variable elements of R 1a and m, and / or R 10 and R 11 and R 12 and R 13 and / or the variable elements of q, p is 3, 4, or 5.

[0119] In some embodiments of formula (I-B), R 10 and R 11 and R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound is of formula (II-B):

Chemical formula

[0120] R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a In some embodiments of the compound of formula (I), the compound is of formula (I-C):

Chemical formula

[0121] In some embodiments of the compound of formula (I-C), m is 0, 1, 2, 3, or 4, and each R 1a is, when applicable, 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 by deuterium. In further embodiments of the compound of formula (I-C), m is 0, 1, 2, 3, or 4, and each R 1ais, when applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which may be C1-C6 perhaloalkyl in one variant form), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, where R 1a the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of are independently optionally substituted by deuterium. In some embodiments of the compounds of formula (I-C), m is 1, 2, 3, or 4.

[0122] 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 at the 2-position. In some embodiments of the compounds of formula (I-C), m is 1 and R 1a is at the 6-position. In some embodiments of the compounds of formula (I-C), m is 1 and R 1a is at the 7-position. In some embodiments of the compounds of formula (I-C), m is 1 and R 1a is 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 1agroups are at positions 2, 6, and 7. In some embodiments of compounds of Formula (IC), m is 3 and R 1a groups are at positions 2, 6, and 8. In some embodiments of compounds of Formula (IC), m is 3 and R 1a In some embodiments of compounds of Formula (IC), m is 3 and R 1a groups are at positions 6, 7, and 8. In some embodiments of compounds of Formula (IC), m is 4 and R 1a Groups are located at positions 2, 6, 7, and 8. Two or more R 1a Whenever a group is present, R 1a The groups can be independently selected. In any of these embodiments of the compound of formula (IC) or salt thereof, the carbon bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0123] R 1a In some embodiments of formula (IC), including embodiments reciting variables of and m, R 10 , R 11 , R 12 and R 13 Each of R is hydrogen. 1a and m variables, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (IC), including embodiments recited in the variable 1a and m variables, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (IC), including embodiments reciting variables of and / or q, p is 3, 4, or 5.

[0124] In some embodiments of Formula (IC), R 10 , R 11 , R 12 and R 13is hydrogen, p is 3, q is 0, and the compound is of formula (II-C): [Chemical formula] 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 formulas (I-C) and (II-C).

[0125] R 1 is optionally substituted by R 1a with a 5- to 10-membered heteroaryl group. In some embodiments of the compound of formula (I), the compound is of formula (I-D): [Chemical formula] 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.

[0126] In one embodiment, a compound of formula (I-D) or a salt thereof is provided, wherein the carbon having the CO2H and NH moieties is in the "S" configuration. In another embodiment, a compound of formula (I-D) or a salt thereof is provided, wherein the carbon having the CO2H and NH moieties is in the "R" configuration. Mixtures of compounds of formula (I-D) are also included, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0127] In some embodiments of the compound of formula (I-D), m is 0, 1, 2, 3, or 4, and each R 1a is, independently when 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 by deuterium. In further embodiments of the compound of formula (I-D), m is 0, 1, 2, 3, or 4, and each R 1a is, independently when applicable, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which can be C1-C6 perhaloalkyl in one variant), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, where the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R 1a are independently optionally substituted by deuterium. In some embodiments of the compound of formula (I-D), m is 1, 2, 3, or 4.

[0128] In some embodiments of the compound of formula (I-D), m is 0. In some embodiments of the compound of formula (I-D), m is 1 and R 1a is at the 2-position. In some embodiments of the compound of formula (I-D), m is 1 and R 1a is at the 5-position. In some embodiments of the compound of formula (I-D), m is 1 and R 1a is at the 6-position. In some embodiments of the compound of formula (I-D), m is 1 and R 1a is at the 8-position. In some embodiments of the compound of formula (I-D), m is 2 and the R 1a groups are at the 2- and 5-positions. In some embodiments of the compound of formula (I-D), m is 2 and the R 1a groups are at the 2- and 6-positions. In some embodiments of the compound of formula (I-D), m is 2 and R 1aThe groups are at the 2- and 8-positions. In some embodiments of the compounds of formula (I-D), m is 2, R 1a The groups are at the 5- and 6-positions. In some embodiments of the compounds of formula (I-D), m is 2, R 1a The groups are at the 5- and 8-positions. In some embodiments of the compounds of formula (I-D), m is 2, R 1a The groups are at the 6- and 8-positions. In some embodiments of the compounds of formula (I-D), m is 3, R 1a The groups are at the 2-, 5-, and 6-positions. In some embodiments of the compounds of formula (I-D), m is 3, R 1a The groups are at the 2-, 5-, and 8-positions. In some embodiments of the compounds of formula (I-D), m is 3, R 1a The groups are at the 2-, 6-, and 8-positions. In some embodiments of the compounds of formula (I-D), m is 3, R 1a The groups are at the 5-, 6-, and 8-positions. In some embodiments of the compounds of formula (I-D), m is 4, R 1a The groups are at the 2-, 5-, 6-, and 8-positions. When two or more R 1a groups are present, the R 1a groups can always be independently selected. In any of these embodiments of the compounds of formula (I-D) or salts thereof, the carbon having the CO2H and NH moieties can be in the “S” configuration or the “R” configuration.

[0129] R 1a In some embodiments of formula (I-D), including embodiments that describe the variable elements of R 10 and m, each of R 11 and R 12 and R 13 is hydrogen. In some embodiments of formula (I-D), including embodiments that describe the variable elements of R 1a and m, and / or the variable elements of R 10 and R 11 and R 12 and R 13 q is 0. In some embodiments of formula (I-D), including embodiments that describe the variable elements of R 1a and m, and / or the variable elements of R 10 and R11 , R 12 and R 13 In some embodiments of formula (I-D) that describe variable elements of p, and / or variable elements of q, p is 3, 4, or 5.

[0130] 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 is of formula (II-D):

Chemical formula

[0131] R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a In some embodiments of the compound of formula (I), the compound is of formula (I-E):

Chemical formula

[0132] In one embodiment, there is provided a compound of formula (I-E) or a salt thereof, wherein the carbon having the CO2H 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 having the CO2H and NH moieties is in the "R" configuration. Mixtures of compounds of formula (I-E) are also included, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0133] In some embodiments of the compounds of formula (I-E), m is 0, 1, 2, 3, or 4, and each R 1a , where applicable, 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 further embodiments of the compounds of formula (I-E), m is 0, 1, 2, 3, or 4, and each R 1a , where applicable, is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which may be C1-C6 perhaloalkyl in one variant), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, where the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R 1a are independently optionally substituted with deuterium. In some embodiments of the compounds of formula (I-E), m is 1, 2, 3, or 4.

[0134] In some embodiments of the compounds of formula (I-E), m is 0. In some embodiments of the compounds of formula (I-E), m is 1 and R 1a is at the 2-position. In some embodiments of the compounds of formula (I-E), m is 1 and R 1a is at the 5-position. In some embodiments of the compounds of formula (I-E), m is 1 and R 1ais in the 6th position. In some embodiments of the compound of formula (I-E), m is 1, and R 1a is in the 7th position. In some embodiments of the compound of formula (I-E), m is 2, and R 1a groups are in the 2nd and 5th positions. In some embodiments of the compound of formula (I-E), m is 2, and R 1a groups are in the 2nd and 6th positions. In some embodiments of the compound of formula (I-E), m is 2, and R 1a groups are in the 2nd and 7th positions. In some embodiments of the compound of formula (I-E), m is 2, and R 1a groups are in the 5th and 6th positions. In some embodiments of the compound of formula (I-E), m is 2, and R 1a groups are in the 5th and 7th positions. In some embodiments of the compound of formula (I-E), m is 2, and R 1a groups are in the 6th and 7th positions. In some embodiments of the compound of formula (I-E), m is 3, and R 1a groups are in the 2nd, 5th, and 6th positions. In some embodiments of the compound of formula (I-E), m is 3, and R 1a groups are in the 2nd, 5th, and 7th positions. In some embodiments of the compound of formula (I-E), m is 3, and R 1a groups are in the 2nd, 6th, and 7th positions. In some embodiments of the compound of formula (I-E), m is 3, and R 1a groups are in the 5th, 6th, and 7th positions. In some embodiments of the compound of formula (I-E), m is 4, and R 1a groups are in the 2nd, 5th, 6th, and 7th positions. When two or more R 1a groups are present, the R 1a groups can always be independently selected. In any of these embodiments of the compound of formula (I-E) or its salt, the carbon having the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0135] R 1a In some embodiments of formula (I-E), including embodiments that describe the variable elements of R 10 , R11 , R 12 and R 13 each of which is hydrogen. R 1a and the variable elements of m, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (I-E) including embodiments describing the variable elements of and m, and / or R 1a and the variable elements of m, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (I-E) including embodiments describing the variable elements of and / or the variable elements of q, p is 3, 4, or 5.

[0136] 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 is of formula (II-E):

Chemical formula

[0137] R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a In some embodiments of the compound of formula (I), the compound is of formula (I-F):

Chemical formula

[0138] In one embodiment, there is provided a compound of formula (I-F) or a salt thereof, wherein the carbon having the CO2H and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-F) or a salt thereof, wherein the carbon having the CO2H and NH moieties is in the "R" configuration. Mixtures of compounds of formula (I-F) are also included, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0139] 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, when applicable, 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 by 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, when applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which may be C1-C6 perhaloalkyl in one variant), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, where the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R 1a are independently optionally substituted by deuterium. In some embodiments of the compounds of formula (I-F), m is 1, 2, 3, 4, 5, or 6.

[0140] 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- and 3-positions. In some embodiments of the compounds of formula (I-F), m is 2 and R 1a groups are at the 2- and 5-positions. In some embodiments of the compounds of formula (I-F), m is 2 and R 1a groups are at the 2- and 6-positions. In some embodiments of the compounds of formula (I-F), m is 2 and R 1a groups are at the 2- and 7-positions. In some embodiments of the compounds of formula (I-F), m is 2 and R 1a groups are at the 2- and 8-positions. In some embodiments of the compounds of formula (I-F), m is 2 and R 1a groups are at the 3- and 5-positions. In some embodiments of the compounds of formula (I-F), m is 2 and R 1a groups are at the 3- and 6-positions. In some embodiments of the compounds of formula (I-F), m is 2 and R 1a groups are at the 3- and 7-positions. In some embodiments of the compounds of formula (I-F), m is 2 and R 1a groups are at the 3- and 8-positions. In some embodiments of the compounds of formula (I-F), m is 2 and R 1a groups are at the 5- and 6-positions. In some embodiments of the compounds of formula (I-F), m is 2 and R1a The group is at the 5- and 7-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a The group is at the 5- and 8-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a The group is at the 6- and 7-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a The group is at the 6- and 8-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a The group is at the 7- and 8-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is at the 2-, 3-, and 5-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is at the 2-, 3-, and 6-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is at the 2-, 3-, and 7-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is at the 2-, 3-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is at the 2-, 5-, and 6-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is at the 2-, 5-, and 7-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is at the 2-, 5-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is at the 2-, 6-, and 7-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is at the 2-, 6-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is at the 2-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1aThe groups are at the 3-, 5-, and 6-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The groups are at the 3-, 5-, and 7-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The groups are at the 3-, 5-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The groups are at the 3-, 6-, and 7-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The groups are at the 3-, 6-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The groups are at the 3-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The groups are at the 5-, 6-, and 7-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The groups are at the 5-, 6-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The groups are at the 5-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The groups are at the 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The groups are at the 2-, 3-, 5-, and 6-positions. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The groups are at the 2-, 3-, 5-, and 7-positions. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The groups are at the 2-, 3-, 5-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The groups are at the 2-, 3-, 6-, and 7-positions. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The groups are at the 2-, 3-, 6-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, and R 1aThe groups are at the 2-, 3-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 2-, 5-, 6-, and 7-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 2-, 5-, 6-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 2-, 5-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 2-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 3-, 5-, 6-, and 7-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 3-, 5-, 6-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 3-, 5-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 3-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 4, R 1a The groups are at the 5-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 5, R 1a The groups are at the 2-, 3-, 5-, 6-, and 7-positions. In some embodiments of the compound of formula (I-F), m is 5, R 1a The groups are at the 2-, 3-, 5-, 6-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 5, R 1a The groups are at the 2-, 3-, 5-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 5, R 1a The groups are at the 2-, 3-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 5, R 1aThe groups are at the 2-, 5-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 5, R 1a The groups are at the 3-, 5-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-F), m is 6, R 1a The groups are at the 2-, 3-, 5-, 6-, 7-, and 8-positions. When two or more R 1a groups are present, the R 1a groups can always be independently selected. In any of these embodiments of the compound of formula (I-F) or a salt thereof, the carbon having the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0141] R 1a In some embodiments of formula (I-F), including embodiments that describe the variable elements of R 10 and m, each of R 11 , R 12 and R 13 is hydrogen. In some embodiments of formula (I-F), including embodiments that describe the variable elements of R 1a and m, and / or the variable elements of R 10 and R 11 and R 12 and R 13 is 0. In some embodiments of formula (I-F), including embodiments that describe the variable elements of R 1a and m, and / or the variable elements of R 10 and R 11 and R 12 and R 13 and / or the variable elements of q, p is 3, 4, or 5.

[0142] In some embodiments of formula (I-F), R 10 and R 11 and R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound is of formula (II-F):

Chemical formula

[0143] R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a In some embodiments of the compound of formula (I), the compound is of formula (I-G):

Chemical formula

[0144] In one embodiment, there is provided a compound of formula (I-G) or a salt thereof in which the carbon having the CO2H and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-G) or a salt thereof in which the carbon having the CO2H and NH moieties is in the "R" configuration. Mixtures of compounds of formula (I-G) are also included, including racemic or non-racemic mixtures of a given compound and mixtures of two or more compounds of different chemical formulas.

[0145] In some embodiments of the compound of formula (I-G), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1a is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, where R 1aThe alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl are each independently optionally substituted with deuterium. In a further embodiment of the compound of formula (I-G), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1a is, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variant form can be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, where the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R 1a are each independently optionally substituted with deuterium. In some embodiments of the compound of formula (I-G), m is 1, 2, 3, 4, 5, or 6.

[0146] In some embodiments of the compound of formula (I-G), m is 0. In some embodiments of the compound of formula (I-G), m is 1 and R 1a is in the 3-position. In some embodiments of the compound of formula (I-G), m is 1 and R 1a is in the 4-position. In some embodiments of the compound of formula (I-G), m is 1 and R 1a is in the 5-position. In some embodiments of the compound of formula (I-G), m is 1 and R 1a is in the 6-position. In some embodiments of the compound of formula (I-G), m is 1 and R 1a is in the 7-position. In some embodiments of the compound of formula (I-G), m is 1 and R 1a is in the 8-position. In some embodiments of the compound of formula (I-G), m is 2 and the R 1a groups are in the 3- and 4-positions. In some embodiments of the compound of formula (I-G), m is 2 and the R 1a groups are in the 4- and 5-positions. In some embodiments of the compound of formula (I-G), m is 2 and the R 1a groups are in the 4- and 6-positions. In some embodiments of the compound of formula (I-G), m is 2 and R1a The groups are at the 4- and 7-positions. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The groups are at the 4- and 8-positions. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The groups are at the 3- and 5-positions. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The groups are at the 3- and 6-positions. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The groups are at the 3- and 7-positions. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The groups are at the 3- and 8-positions. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The groups are at the 5- and 6-positions. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The groups are at the 5- and 7-positions. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The groups are at the 5- and 8-positions. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The groups are at the 6- and 7-positions. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The groups are at the 6- and 8-positions. In some embodiments of the compounds of formula (I-G), m is 2, and R 1a The groups are at the 7- and 8-positions. In some embodiments of the compounds of formula (I-G), m is 3, and R 1a The groups are at the 3-, 4-, and 5-positions. In some embodiments of the compounds of formula (I-G), m is 3, and R 1a The groups are at the 3-, 4-, and 6-positions. In some embodiments of the compounds of formula (I-G), m is 3, and R 1a The groups are at the 3-, 4-, and 7-positions. In some embodiments of the compounds of formula (I-G), m is 3, and R 1a The groups are at the 3-, 4-, and 8-positions. In some embodiments of the compounds of formula (I-G), m is 3, and R 1aThe 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 1a The group is at the 5-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 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1aThe group is at the 6th, 7th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is at the 3rd, 4th, 5th, and 6th positions. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is at the 3rd, 4th, 5th, and 7th positions. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is at the 3rd, 4th, 5th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is at the 3rd, 4th, 6th, and 7th positions. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is at the 4th, 3rd, 6th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is at the 3rd, 4th, 7th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is at the 4th, 5th, 6th, and 7th positions. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is at the 4th, 5th, 6th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is at the 4th, 5th, 7th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is at the 4th, 6th, 7th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is at the 3rd, 5th, 6th, and 7th positions. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is at the 3rd, 5th, 6th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is at the 3rd, 5th, 7th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is at the 3rd, 6th, 7th, and 8th positions. In some embodiments of the compound of formula (I-G), m is 4, and R 1aThe group is at the 5-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-G), m is 5, R 1a The group is at the 3-, 4-, 5-, 6-, and 7-positions. In some embodiments of the compound of formula (I-G), m is 5, R 1a The group is at the 3-, 4-, 5-, 6-, and 8-positions. In some embodiments of the compound of formula (I-G), m is 5, R 1a The group is at the 3-, 4-, 5-, 7-, and 8-positions. In some embodiments of the compound of formula (I-G), m is 5, R 1a The group is at the 3-, 4-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-G), m is 5, R 1a The group is at the 4-, 5-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-G), m is 5, R 1a The group is at the 3-, 5-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-G), m is 6, R 1a The group is at the 3-, 4-, 5-, 6-, 7-, and 8-positions. When two or more R 1a groups are present, the R 1a groups can always be independently selected. In any of these embodiments of the compound of formula (I-G) or its salt, the carbon having the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0147] R 1a In some embodiments of formula (I-G) including the embodiments describing the variable elements of R 10 and m, and / or R 11 and R 12 and R 13 each of which is hydrogen. In some embodiments of formula (I-G) including the embodiments describing the variable elements of R 1a and m, and / or the variable elements of R 10 and R 11 and R 12 and R 13 q is 0. In some embodiments of formula (I-G) including the embodiments describing the variable elements of R 1a and m, and / or R 10 and R11 , R 12 and R 13 In some embodiments of formula (I-G) that describe variable elements of p, and / or variable elements of q, p is 3, 4, or 5.

[0148] 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 is of formula (II-G):

Chemical formula

[0149] R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a In some embodiments of the compound of formula (I), the compound is of formula (I-H):

Chemical formula

[0150] In one embodiment, there is provided a compound of formula (I-H) or a salt thereof, wherein the carbon having the CO2H 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 having the CO2H and NH moieties is in the "R" configuration. Mixtures of compounds of formula (I-H) are also included, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0151] In some embodiments of the compounds of formula (I-H), m is 0, 1, or 2, and each R 1a is, where applicable, 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-H), m is 0, 1, or 2, and each R 1a is, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which may be C1-C6 perhaloalkyl in one variant), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R 1a are independently optionally substituted with deuterium. In some embodiments of the compounds of formula (I-H), m is 1 or 2.

[0152] In some embodiments of the compounds of formula (I-H), m is 0. In some embodiments of the compounds of formula (I-H), m is 1 and R 1a is at the 3-position. In some embodiments of the compounds of formula (I-H), m is 1 and R 1a is at the 6-position. In some embodiments of the compounds of formula (I-H), m is 2 and the R 1a groups are at the 3- and 6-positions. Two or more R 1aWhen a base is present, R is always present. 1a The groups can be independently selected. In any of these embodiments of the compound of formula (I-H) or a salt thereof, the carbon atom having the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0153] R 1a In some embodiments of formula (I-H), including embodiments that describe the variable elements of R and m, R 10 , R 11 , R 12 and R 13 are each hydrogen. R 1a and the variable elements of m, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (I-H), including embodiments that describe the variable elements of R and m, and / or the variable elements of R and q, q is 0. R 1a and the variable elements of m, and / or R 10 , R 11 , R 12 and R 13 In some embodiments of formula (I-H), including embodiments that describe the variable elements of R and m, and / or the variable elements of R and q, p is 3, 4, or 5.

[0154] 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 is of formula (II-H):

Chemical formula

[0155] Also, R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a , and there are also provided compounds of formula (I) or (II), or salts thereof. In some embodiments, R 1 is unsubstituted 5- to 10-membered heteroaryl (e.g., pyridinyl, pyrimidinyl, quinoxalinyl, quinazolinyl, pyrazolopyrimidinyl, quinolinyl, pyridopyrimidinyl, thienopyrimidinyl, pyridinyl, pyrrolopyrimidinyl, benzothiazolyl, isoquinolinyl, purinyl, or benzoxazolyl). In some embodiments, R 1 is 5- to 10-membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 R 1a groups, where each R 1a is independently selected from halogen (e.g., fluoro, chloro, or bromo), C1-C6 alkyl optionally substituted by halogen (e.g., -CH3, -CHF2, -CF3, or C(CH3)3), C3-C6 cycloalkyl (e.g., cyclopropyl), 5- to 10-membered heteroaryl (e.g., pyridinyl or pyrazolyl), C6-C 14 aryl (e.g., phenyl), -CN, -OR 3 (e.g., -OCH3), and -NR 4 R 5 (e.g., -N(CH3)2). In some embodiments, R 1 is 5-membered heteroaryl (e.g., pyrazolyl) optionally substituted by 1, 2, 3, or 4 R 1a groups selected from -CH3, -CH2F, -CHF2, and -CF3. In some embodiments, R 1 is halogen (e.g., fluoro, chloro, or bromo), C3-C6 cycloalkyl (e.g., cyclopropyl), 5- to 6-membered heteroaryl (e.g., pyridinyl or pyrazolyl), C6-C 10Aryl (e.g., phenyl), C1-C4 alkyl optionally substituted by halogen (e.g., -CH3, -CF3 or C(CH3)3), -CN, -OR 3 (e.g., -OCH3), and -NR 4 R 5 1, 2, 3, 4, or 5 R's, which may be the same or different, selected from the group consisting of 1a 6-membered heteroaryl (e.g., pyridinyl, pyrimidinyl, or pyrazinyl) substituted by a group. In some embodiments, R 1 is 1, 2, 3, 4, or 5 R's, which may be the same or different, selected from the group consisting of -CH3, -CH2F, -CHF2, and -CF3 1a 9-membered heteroaryl (e.g., pyrazolopyrimidinyl, pyrrolopyrimidinyl, thienopyrimidinyl, indazolyl, indolyl, or benzimidazolyl) substituted by a group. In some embodiments, R 1 is 1, 2, 3, 4, or 5 R's, which may be the same or different, selected from the group consisting of halogen (e.g., fluoro or chloro), 5-6 membered heteroaryl (e.g., pyridinyl), C1 alkyl optionally substituted by halogen (e.g., -CH3 or -CF3), and -OR 3 (e.g., -OCH3). 1a 10-membered heteroaryl (e.g., quinazolinyl) substituted by a group.

[0156] Also provided are compounds of formula (I) or (II), or salts thereof, selected from the group consisting of any of the aforementioned groups in which any one or more hydrogen atoms (plural available) are replaced by deuterium atoms (plural available). Also, R 1 is

Chemical formula

[0157] Also, R 1 is

Chemical formula

[0158] Also, R 1 is

Chemical formula

[0159] Also, R 1 is

Chemical formula

[0160] Also, R 1 is

Chemical formula

[0161] The R 1 group described herein as part (symbol

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0162] 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 C1-C6 alkyl optionally substituted by R 2a . In some embodiments, R 2 is C1-C6 alkyl optionally substituted by R 2a , where R 2a is halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluoro); 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., pyrazolyl optionally substituted by methyl); -S(O)2R 3 ; -NR 4 R 5 ; -NR 3 C(O)R 4 ; oxo; or -OR 3 . In some embodiments, R 2 is C1-C6 alkyl optionally substituted by R 2a , where R 2ais halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluoro); 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., pyrazolyl optionally substituted by methyl); 3- to 12-membered heterocyclyl optionally substituted by halogen (e.g., oxetanyl optionally substituted by fluoro), -S(O)2R 3 ;-NR 4 R 5 ;-NR 3 C(O)R 4 ; oxo; or -OR 3 is. In some embodiments, R 2 is C1-C6 alkyl optionally substituted by -OR 3 , where R 3 is hydrogen; C1-C6 alkyl optionally substituted by halogen (e.g., methyl, ethyl, difluoromethyl, -CH2CHF2, and -CH2CF3); C3-C6 cycloalkyl optionally substituted by halogen (e.g., cyclopropyl substituted by fluoro); C6-C 14 aryl optionally substituted by halogen (e.g., phenyl optionally substituted by fluoro); or 5- to 6-membered heteroaryl optionally substituted by halogen or C1-C6 alkyl (e.g., pyridinyl optionally substituted by fluoro or methyl). In some embodiments, R 2 is -CH2CH2OCH3. In some embodiments, R 2 is C1-C6 alkyl substituted by both halogen and OR 3 . In some embodiments, R 2 is n-propyl substituted by both halogen and alkoxy (e.g., -CH2CH(F)CH2OCH3). In some embodiments where R 2 is shown to be optionally substituted by R 2a , R 2The moiety is unsubstituted. R 2 is R 2a In some embodiments shown to be optionally substituted by R 2 the moiety is substituted by one R 2a is R 2 is R 2a In some embodiments shown to be optionally substituted by R 2 the moiety may be the same or different and is substituted by 2 to 6 or 2 to 5 or 2 to 4 or 2 to 3 R 2a moieties.

[0163] 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 C1-C6 alkyl optionally substituted by R 2a In some embodiments, R 2 is C1-C6 alkyl optionally substituted by R 2a wherein R 2a is halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluoro); 5-10 membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., pyrazolyl optionally substituted by methyl); -S(O)2R 3 ; -NR 4 R 5 ; -NR 3 C(O)R 4 ; oxo; or -OR 3 is. In some embodiments, R 2 is C1-C6 alkyl optionally substituted by R 2a wherein R 2ais halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluoro); 5-10 membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., pyrazolyl optionally substituted by methyl); 3-12 membered heterocyclyl optionally substituted by halogen (e.g., oxetanyl optionally substituted by fluoro); -S(O)2R 3 ; -NR 4 R 5 ; -NR 3 C(O)R 4 ; oxo; or -OR 3 In some embodiments, R 2 is C1-C6 alkyl optionally substituted by R 2a , where R 2a is halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluoro); C6-C 14 aryl (e.g., phenyl); 5-10 membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., thiazolyl or pyrazolyl optionally substituted by methyl); 3-12 membered heterocyclyl optionally substituted by halogen or oxo (e.g., R 2a is oxetanyl optionally substituted by fluoro; tetrahydrofuranyl; pyrrolidinyl optionally substituted by oxo; morpholinyl optionally substituted by oxo; or dioxanyl); -S(O)2R 3 ; -NR 4 R 5 ; -NR 3 C(O)R 4 ; oxo; -OR 3 ; or -CN. In some embodiments, R 2 is C1-C6 alkyl optionally substituted by -OR 3 , where R 3is hydrogen; C1-C6 alkyl optionally substituted by halogen (e.g., methyl, ethyl, difluoromethyl, -CH2CHF2, and -CH2CF3); C3-C6 cycloalkyl optionally substituted by halogen (e.g., cyclopropyl substituted by fluoro); C6-C 14 aryl (e.g., phenyl optionally substituted by fluoro); or 5- to 6-membered heteroaryl optionally substituted by halogen or C1-C6 alkyl (e.g., pyridinyl optionally substituted by fluoro or methyl). In some embodiments, R 2 is -CH2CH2OCH3. In some embodiments, R 2 is C1-C6 alkyl substituted by both halogen and OR 3 . In some embodiments, R 2 is n-propyl substituted by both halogen and alkoxy (e.g., -CH2CH(F)CH2OCH3). In some embodiments where R 2 is shown to be optionally substituted by R 2a , the R 2 moiety is unsubstituted. In some embodiments where R 2 is shown to be optionally substituted by R 2a , the R 2 moiety is substituted by one R 2a . In some embodiments where R 2 is shown to be 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 C1-C6 alkyl substituted by 2 halogen groups which may be the same or different (e.g., 2 fluoro groups). In some embodiments, R 2 is C1-C6 alkyl substituted by 2 -OR 3It is C1-C6 alkyl substituted by a group (for example, two -OH groups, one -OH group and one -OCH3 group, or two -OCH3 groups). In some embodiments, R 2 is C1-C6 alkyl substituted by one halogen group (for example, fluoro) and one -OR 3 group (for example, -OH or -OCH3). In some embodiments, R 2 is C1-C6 alkyl substituted by two halogen groups (for example, two fluoro groups) which may be the same or different, and one -OR 3 group (for example, -OH or -OCH3). In some embodiments, R 2 is C1-C6 alkyl substituted by one halogen group (for example, fluoro) and two -OR 3 groups (for example, two -OH groups, one -OH group and one -OCH3 group, or two -OCH3 groups) which may be the same or different.

[0164] 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 C3-C6 cycloalkyl optionally substituted by R 2b . In some embodiments, R 2 is C3-C6 cycloalkyl substituted by one or two R 2b moieties which may be the same or different. In some embodiments, R 2 is C3-C4 cycloalkyl optionally substituted by halogen (for example, unsubstituted cyclopropyl or cyclobutyl optionally substituted by fluoro). In some embodiments, R 2is C3-C4 cycloalkyl optionally substituted by deuterium or tritium atom(s). For example, in some embodiments, each hydrogen bonded to a ring carbon in the aforementioned group can be replaced by the corresponding isotope, e.g., deuterium or tritium. Each hydrogen bonded to an acyclic carbon in the aforementioned group, e.g., the carbon of methyl or methoxy, can be replaced by the corresponding isotope, e.g., deuterium or tritium. Further, for example, the aforementioned group may be a perdeuterated group in which all hydrogens are replaced by deuterium, or a pertritiated group in which all hydrogens are replaced by tritium. In some embodiments, one or more ring carbons in the aforementioned group may be 13 replaced by C. For example, in the polycyclic ring of the aforementioned group, one or more ring carbons in the ring directly bonded to the rest of the compound may be 13 replaced by C. In the polycyclic ring of the aforementioned group, one or more ring carbons that replace the ring bonded to the rest of the compound or are condensed to the ring may be 13 replaced by C. Further, for example, all ring carbons in the aforementioned group may be 13 replaced by C.

[0165] 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.

[0166] 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 R 2ais -O-C1-C6 alkyl optionally substituted. In some embodiments, R 2 is -OCH3.

[0167] Also, R 2 is

Chemical formula

[0168] Also, R 2 is

Chemical formula

[0169] Also, R 2 is

Chemical formula

[0170] Also, R 2 is

Chemical formula

[0171] Also, R 2 is

Chemical formula

[0172] In one embodiment of formula (I), the tetrahydronaphthyridinyl group is disubstituted with deuterium at the 2-position.

[0173] In one aspect, compounds of formula (I), or salts thereof (including pharmaceutically acceptable salts thereof), are provided, wherein the compound or its salt has any one or more of the following structural features ("SF"): (SFI) p is 3; (SFII) Each R 10 , R 11 , R 12 , R 13 is hydrogen; (SFIII) R 1 is (A) unsubstituted 5- to 10-membered heteroaryl; (B) 5- to 10-membered heteroaryl substituted by 1, 2, 3, 4 or 5 R 1a groups which may be the same or different (wherein the 5- to 10-membered heteroaryl of (III)(A) and (III)(B) is (i) pyridinyl; (ii) pyrimidinyl; (iii) quinoxalinyl; (iv) quinazolinyl; (v) pyrazolopyrimidinyl; (vi) quinolinyl; (vii) pyridopyrimidinyl; (viii) thienopyrimidinyl; (ix) purinyl; (x) pyrrolopyrimidinyl; (xi) benzoxazolyl; (xii) benzothiazolyl; (xiii) isoquinolinyl; (xiv) indolyl; (xv) benzimidazolyl; (xvi) pyrazinyl; (xvii) indazolyl; or (xviii) pyrazolyl); (C) unsubstituted naphthalenyl; or (D) naphthalenyl substituted by 1, 2, 3, 4 or 5 R 1a groups which may be the same or different (SFIV) Each R 1a is (A) halogen, for example, fluoro, chloro, or bromo; (B) C1-C6 alkyl optionally substituted by halogen, for example, -CH3, -CHF2, -CF3, or C(CH3)3; (C) C3-C6 cycloalkyl, for example, cyclopropyl; (D) 5- to 10-membered heteroaryl, for example, pyridinyl or pyrazolyl; (E) C6-C 14 aryl, for example, phenyl; (F) -CN; (G) -OR 3 , for example, -OCH3; or (H) -NR 4 R 5 , for example, -N(CH3)2; (SFV) R 2 is (A) unsubstituted C1-C6 alkyl, for example, C1-C2 alkyl; (B) C1-C6 alkyl, for example, C1-C2 alkyl (each of which may be the same or different and is substituted by 1, 2, 3, 4, or 5 R 2a groups); (C) unsubstituted -O-C1-C6 alkyl, for example, -O-C1-C2 alkyl; (D) -O-C1-C6 alkyl, for example, -O-C1-C2 alkyl (each of which may be the same or different and is substituted by 1, 2, 3, 4, or 5 R 2a groups); (E) unsubstituted C3-C6 cycloalkyl, for example, cyclopropyl or cyclobutyl; or (F) C3-C6 cycloalkyl, for example, cyclopropyl or cyclobutyl (each of which may be the same or different and is substituted by 1, 2, 3, 4, or 5 R 2b groups); (SFVI) R 2a is (A) halogen, for example, fluoro; (B) C3-C8 cycloalkyl, for example, cyclopropyl or cyclobutyl (each of which is optionally substituted by halogen); (C) A 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl, for example, pyrazolyl substituted by methyl; (D) A 3- to 12-membered heterocyclyl optionally substituted by halogen or oxo, for example, oxetanyl optionally substituted by fluoro, unsubstituted tetrahydrofuranyl, pyrrolidinyl substituted by oxo, unsubstituted morpholinyl, morpholinyl substituted by oxo, or dioxanyl; (E) -S(O)2R 3 For example, -S(O)2CH3; (F) -C(O)NR 4 R 5 For example, -C(O)N(CH3)2; (G) -NR 3 C(O)R 4 For example, -NHC(O)CH3; or (H) -OR 3 (wherein R 3 is (i) hydrogen; (ii) -CH3; (iii) -CH2CH3; (iv) -CH2CHF2; (v) -CH2CF3; (vi) phenyl substituted by 0 to 2 fluoro groups; or (vii) pyridinyl substituted by 0 to 1 methyl groups).

[0174] The compound of formula (I) or any variant thereof described herein, or a salt thereof, is understood in one embodiment to have any one or more of the above structural features. For example, the compound of formula (I) or any variant thereof described herein, or a salt thereof, can in one embodiment have one or two or three or all of the following structural features: (SFI), (SFII), (SFIII) and (SFV). In one such example, the compound of formula (I) or any variant thereof described herein, or a salt thereof, can in one embodiment have the following structural features: (SFI) and any one or two or all of (SFII), (SFIII) and (SFV) or any sub - embodiments thereof. In one such example, the compound of formula (I) or any variant thereof described herein, or a salt thereof, can in one embodiment have the following structural features: (SFII) and any one or two or all of (SFI), (SFIII) and (SFV) or any sub - embodiments thereof. In one such example, the compound of formula (I) or any variant thereof described herein, or a salt thereof, can in one embodiment have the following structural features: (SFIII) and any one or two or all of (SFI), (SFII) and (SFV) or any sub - embodiments thereof. In one such example, the compound of formula (I) or any variant thereof described herein, or a salt thereof, can in one embodiment have the following structural features: (SFV) and any one or two or all of (SFI), (SFII) and (SFIII) or any sub - embodiments thereof. It is understood that sub - embodiments of the structural features can also be combined in any manner. Although specific combinations of structural features are shown below, it is understood that all combinations of features are included. In one aspect of this variant, (SFI) and (SFII) are applicable. In another variant, (SFI) and (SFIII) are applicable. In another variant, (SFI) and (SFV) are applicable.In another variant, (SFII) and (SFIII) are applied. In another variant, (SFII) and (SFV) are applied. In another variant, (SFIII) and (SFV) are applied. In another variant, (SFI), (SFII), and (SFIII) are applied. In another variant, (SFI), (SFII), and (SFV) are applied. In another variant, (SFI), (SFIII), and (SFV) are applied. In another variant, (SFII), (SFIII), and (SFV) are applied. It is understood that each sub-embodiment of the structural features is applied. 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 variant, (SFV) is (SFV)(A), (SFV)(B), (SFV)(C), (SFV)(D), (SFV)(E), or (SFV)(F).

[0175] In another variant, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(A) are applicable.In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(A) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(A) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(A) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(A) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(A) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(A) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(A) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(A) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(A) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(A) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(A) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(A) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(A) are applicable.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 (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(A) apply.In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(A) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(A) are applicable.

[0176] In another variant, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(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), (SFV)(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) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) are applicable.In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii) are applicable.In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) are applicable.In another variant, (SFI), (SFII), (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)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply.

[0177] In another variant, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) are applicable.In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) are applicable.In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) are applicable.In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) are applicable.In another variant, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply.

[0178] In another variant, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(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), (SFII), (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) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) are applicable.In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) are applicable.In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) are applicable.In another variant, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply.

[0179] In another variant, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (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 form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) are applicable.In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) are applicable.In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant form, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) are applicable.In another variant, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) are applicable. In another variant, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) are applicable.

[0180] Any variant or combination cited herein for the compounds of formula (I) also applies to formula (A), with any possible combination of R 15 and R 16 added.

[0181] Representative compounds are listed in Figure 1.

[0182] In some embodiments, a compound selected from compound numbers 1 - 66 of Figure 1, or a stereoisomer thereof (including a mixture of two or more of its stereoisomers), or a salt thereof is provided. In some embodiments, the compound is a salt of a compound selected from compound numbers 1 - 66 of Figure 1 or a stereoisomer thereof.

[0183] In some embodiments, a compound selected from compound numbers 1 - 147, or a stereoisomer thereof (including a mixture of two or more of its stereoisomers), or a salt thereof is provided. In some embodiments, the compound is a salt of a compound selected from compound numbers 1 - 147 or a stereoisomer thereof.

[0184] In some embodiments, a compound selected from Compound Nos. 1 to 665, or a stereoisomer thereof (including a mixture of two or more of its stereoisomers), or a salt thereof is provided. In some embodiments, the compound is a salt of a compound selected from Compound Nos. 1 to 665 or a stereoisomer thereof.

[0185] In some embodiments, a compound selected from Compound Nos. 1 to 780, or a stereoisomer thereof (including a mixture of two or more of its stereoisomers), or a salt thereof is provided. In some embodiments, the compound is a salt of a compound selected from Compound Nos. 1 to 780 or a stereoisomer thereof.

[0186] In one variant, the compounds detailed herein are selected from the group consisting of: 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-(difluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-Hydroxy-2-methylpropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((3,3-Difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)butanoic acid; 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-(trifluoromethyl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((8-(trifluoromethyl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,4-d]pyrimidin-4-ylamino)butanoic acid; 2-((5-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((8-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6,7-Difluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((6-(Difluoromethyl)pyrimidin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methyl-2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-(Methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-(((3,3-Difluorocyclobutyl)methyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-fluoro-2-methylquinazolin-4-yl)amino)butanoic acid; 2-(Isoquinolin-1-ylamino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(Difluoromethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinolin-4-ylamino)butanoic acid; 2-((7-Chloroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((8-Chloroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-(Quinazolin-4-ylamino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid; 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-methoxyquinazolin-4-yl)amino)butanoic acid; 4-((2-(2,2-Difluorocyclopropoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-fluoro-2-methylquinazolin-4-yl)amino)butanoic acid; 4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((8-methoxyquinazolin-4-yl)amino)butanoic acid; 2-((6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-(((S)-2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid; 4-((2-(3,5-Difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((8-Chloroquinazolin-4-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-(2,2-Difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-(Pyrido[3,2-d]pyrimidin-4-ylamino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid; 4-((2-((2-Methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-((2-Methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butanoic acid; 4-((2-Ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-((6-Methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butanoic acid; 4-((2-((5-Fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-((6-Methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-((5-Fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butanoic acid; 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-(((R)-2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-(Dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; and 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid.

[0187] In another variant form, the compounds detailed herein are selected from the group consisting of: 2-((3-Cyanopyrazin-2-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-Cyanopyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-Hydroxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((3-Cyanopyrazin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-Fluoropyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((1H-Pyrazolo[4,3-d]pyrimidin-7-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid; 2-((1-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-Cyanopyrimidin-2-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-Bromopyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 2-((1-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(Methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(Methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-((2-(Methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 2-((6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid; 2-((5-Cyanopyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-Cyanopyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-fluoropyrimidin-2-yl)amino)butanoic acid; 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-(4-Fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((Oxetan-2-ylmethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((3-Hydroxy-2-(hydroxymethyl)propyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((5-Bromopyrimidin-2-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-Cyanopyrimidin-2-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(4-Fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 4-((2-(Dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-(Dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid; 2-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(Dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; and 4-(((3-Fluorooxetan-3-yl)methyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid.

[0188] In some embodiments, a composition such as a pharmaceutical composition is provided, the composition comprising a compound selected from the group consisting of Compound Numbers 1 to 66 in Figure 1, or a stereoisomer thereof (including a mixture of two or more of its stereoisomers), or one or more of its salts. In some embodiments, the composition comprises a compound selected from the group consisting of one or more salts of Compound Numbers 1 to 66. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0189] In some embodiments, a composition such as a pharmaceutical composition is provided, the composition comprising a compound selected from the group consisting of Compound Numbers 1 to 147, or a stereoisomer thereof (including a mixture of two or more of its stereoisomers), or one or more of its salts. In some embodiments, the composition comprises a compound selected from the group consisting of one or more salts of Compound Numbers 1 to 147. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0190] In some embodiments, a composition such as a pharmaceutical composition is provided, the composition comprising a compound selected from the group consisting of Compound Numbers 1 to 665, or a stereoisomer thereof (including a mixture of two or more of its stereoisomers), or one or more of its salts. In some embodiments, the composition comprises a compound selected from the group consisting of one or more salts of Compound Numbers 1 to 665. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0191] In some embodiments, a composition such as a pharmaceutical composition is provided, the composition comprising a compound selected from the group consisting of Compound Numbers 1 to 780, or a stereoisomer thereof (including a mixture of two or more of its stereoisomers), or one or more of its salts. In some embodiments, the composition comprises a compound selected from the group consisting of one or more salts of Compound Numbers 1 to 780. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0192] The present invention also includes all salts of the compounds referred to herein, such as pharmaceutically acceptable salts. The present invention also includes any enantiomeric or diastereomeric form of the described compounds, and any tautomeric or other forms, including any or all of the stereochemical forms. Unless stereochemistry is explicitly indicated in the chemical structure or name, the structure or name is intended to encompass all possible stereoisomers of the indicated compound. In addition, when a particular stereochemical form is indicated, it should be understood that other stereochemical forms are also described and encompassed by the present invention. All forms of the compounds, such as crystalline or amorphous forms of the compounds, are also encompassed by the present invention. It is also understood that prodrugs, solvates and metabolites of the compounds are included in the present disclosure. Compositions comprising the compounds of the present invention, for example, compositions of substantially pure compounds comprising their particular stereochemical forms are also contemplated. Compositions comprising mixtures of any ratios of the compounds of the present invention are also encompassed by the present invention, for example, mixtures of two or more stereochemical forms of the compounds of the present invention in any ratio, including racemic mixtures, non-racemic mixtures, enantiomerically enriched mixtures and scalemic mixtures of the compounds. When one or more tertiary amine moieties are present in the compound, N-oxides are also provided and described.

[0193] The compounds described herein are α V β6 integrin inhibitors. In some cases, it is desirable for the compound to inhibit other integrins in addition to α V β6 integrin. In some embodiments, the compound inhibits α V β6 integrin and one or more of α V β1, α V β3, α V β5, α2β1, α3β1, α6β1, α7β1 and α 11 β1 integrin. In some embodiments, the compound inhibits α V β6 integrin and α V β1 integrin. In some embodiments, the compound inhibits α V β6 integrin, α V β3 integrin and α VInhibits β5 integrin. In some embodiments, the compound is α V Inhibits β6 integrin and α2β1 integrin. In some embodiments, the compound is α V Inhibits β6 integrin, α2β1 integrin and α3β1 integrin. In some embodiments, the compound is α V Inhibits β6 integrin and α6β1 integrin. In some embodiments, the compound is α V Inhibits β6 integrin and α7β1 integrin. In some embodiments, the compound is α V β6 integrin and α 11 β1 integrin.

[0194] In some cases, it is desirable to avoid inhibiting other integrins. In some embodiments, the compound is a selective α V β6 integrin inhibitor. In some embodiments, the compound does not substantially inhibit α4β1, α V β8 and / or α2β3 integrin. In some embodiments, the compound inhibits α V β6 integrin but does not substantially inhibit α4β1 integrin. In some embodiments, the compound inhibits α V β6 integrin but does not substantially inhibit α V β8 integrin. In some embodiments, the compound inhibits α V β6 integrin but does not substantially inhibit α2β3 integrin. In some embodiments, the compound inhibits α V β6 integrin but does not substantially inhibit α V β8 integrin and α4β1 integrin.

[0195] The present invention also contemplates isotopically labeled and / or isotopically enriched forms of the compounds described herein. The compounds herein may also contain a different proportion of atomic isotopes than normal in one or more of the atoms that make up such compounds. In some embodiments, the compound is isotopically labeled, for example, an isotopically labeled compound of formula (I) or a variant thereof described herein, wherein one or more atoms are replaced by isotopes of the same element. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 17 O, 32 P, 35 S, 18 F, 36 Cl. The incorporation of heavier isotopes such as deuterium ( 2 H or D) may be preferred in some situations because it can provide certain therapeutic advantages due to improved metabolic stability, such as an extended in vivo half-life or a reduced required dose. Each instance of replacement of hydrogen by deuterium as used herein is also a disclosure of replacement of that hydrogen by tritium. As used herein, each instance of enrichment, substitution, or replacement of an atom with the corresponding isotope of that atom encompasses an isotopic enrichment level of one of about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or 100%, or a range between any two of the aforementioned percentages.

[0196] The isotopically labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those of ordinary skill in the art, or by procedures similar to those described in the accompanying examples, using appropriate isotopically labeled reagents in place of the unlabeled reagents.

[0197] In various embodiments, for each of the compounds named or shown herein, corresponding isotopically substituted compounds are specifically disclosed in accordance with the following description. For example, for structural variable element R 1 and R 1a the corresponding groups can be independently deuterated, and the corresponding isotopically substituted compounds, for example, structural variable elements R 1 and R 1a can be perdeuterated, whereby all hydrogens can be independently replaced by deuterium, and the corresponding isotopically substituted compounds are disclosed. One or more hydrogens in the group corresponding to structural variable element R 1 can be independently replaced by deuterium, and the corresponding isotopically substituted compounds with no replacement of optional substituent R 1a are further disclosed. For example, all hydrogens bonded to the ring of the group corresponding to R 1 can be replaced by deuterium, and the corresponding isotopically substituted compounds with no replacement of optional substituent R 1a are disclosed. Also, the corresponding isotopically substituted compounds, for example, in which one or more hydrogens in R 1a can be independently replaced by deuterium, and the corresponding isotopically substituted compounds, for example, in which all hydrogens in the group corresponding to R 1a can be replaced by deuterium are also disclosed.

[0198] For example, the corresponding groups corresponding to structural variable elements R 2 and R 2a can be independently deuterated, and the corresponding isotopically substituted compounds, for example, structural variable elements R 2 and R 2a can be perdeuterated, whereby all hydrogens can be independently replaced by deuterium, and the corresponding isotopically substituted compounds are further disclosed. Also, one or more hydrogens in the group corresponding to R 2 can be independently replaced by deuterium, and the corresponding isotopically substituted compounds with no replacement of optional substituent R 2a are also disclosed. Further, the carbon that binds the remaining part of the compound and R 2 is R 2The corresponding isotopically substituted compounds in which each hydrogen in the 1-position can be independently replaced by deuterium are also disclosed. For example, for a compound named as having -CH2CH2CH2F corresponding to R 2 the corresponding isotopically substituted compound in which R 2 is -CD2CH2CH2F is also disclosed, and for a compound named as having -CH2-cyclopropyl corresponding to R 2 the corresponding isotopically substituted compound in which R 2 is -CD2-cyclopropyl is also disclosed. The corresponding isotopically substituted compounds in which all hydrogens in the group corresponding to R 2a can be independently replaced by deuterium are disclosed. For example, for each compound in which R 2a is -OCH3, the corresponding isotopically substituted compound in which R 2a can be -OCD3 is also disclosed, and for each compound in which R 2a is -N(CH3)2, the corresponding isotopically substituted compound in which R 2a can be -N(CD3)2 is also disclosed. Compounds are further disclosed in which the 1-position of R 2 can be deuterated and the hydrogens in the group corresponding to R 2a can be replaced by deuterium.

[0199] Also, the corresponding isotopically substituted compounds in which R 10 , R 11 , R 12 , R 13 , and each R 14 are independently deuterated are disclosed. For example, the corresponding isotopically substituted compounds in which 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 are disclosed. Compounds are further disclosed in which R 14 is deuterium and R 14 substitutes the 3-position, 4-position, or both the 3-position and 4-position of the tetrahydronaphthyridin-2-yl group. Also, compounds are further disclosed in which R 14 is deuterium and each R14 Compounds that independently replace each hydrogen 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 in the tetrahydronaphthyridin-2-yl group are also disclosed. For example, compounds in which the 7-position can be substituted with two deuterium atoms are also disclosed.

[0200] In some embodiments, all of the ring hydrogens in R 1 can be replaced with deuterium, the 1-position of R 2 can be deuterated, and the corresponding isotopically substituted compounds in which R 2a can be perdeuterated are disclosed. All of the ring hydrogens in R 1 can be replaced with deuterium, and the corresponding isotopically substituted compounds are disclosed. All of the ring hydrogens in R 1 can be replaced with deuterium, the 1-position of R 2 can be deuterated, and the corresponding isotopically substituted compounds in which R 2a can be perdeuterated, and R 12 and R 13 can be deuterium, and the corresponding isotopically substituted compounds in which the 7-position of the tetrahydronaphthyridin-2-yl group can be deuterated are disclosed. All of the ring hydrogens in R 1 can be replaced with deuterium, and the corresponding isotopically substituted compounds in which each hydrogen in R 2a can be independently replaced with deuterium are disclosed. All of the ring hydrogens in R 1 can be replaced with deuterium, the 1-position of R 2 can be deuterated, and the corresponding isotopically substituted compounds in which R 2a can be perdeuterated, and R 12 and R 13 can be deuterium are disclosed. R 1 and R 1a can be perdeuterated, the 1-position of R 2 can be deuterated, and the corresponding isotopically substituted compounds in which R 2a can be perdeuterated, and R 12 and R 13 can be deuterium, and the corresponding isotopically substituted compounds in which the 7-position of the tetrahydronaphthyridin-2-yl group can be deuterated are disclosed. All of the ring hydrogens in R 1 can be replaced with deuterium, the 1-position of R 2 can be deuterated,2a can be perdeuterated, R 12 and R 13 can be deuterium, and the corresponding isotope-substituted compounds are disclosed.

[0201] In some embodiments of the named compounds, each hydrogen represented in R 1 , R 1a , R 2 , R 2a , R 10 , R 11 , R 12 [[ID=…]] , R 13 , and R 14 can independently be tritium. For example, R 1 , R 1a , or one or more hydrogens in R 1 and R 1a can independently be substituted by tritium, and the corresponding isotope-substituted compounds are disclosed. One or more ring hydrogens in R 1 , R 1a , or R 1 and R 1a can independently be substituted by tritium, and the corresponding isotope-substituted compounds are disclosed. One or more hydrogens in R 2 , R 2a , or R 2 and R 2a can independently be substituted by tritium, and the corresponding isotope-substituted compounds are disclosed. One or more hydrogens in R 2 , R 2a , or R 2 and R 2a can independently be substituted by tritium, and the corresponding isotope-substituted compounds are disclosed. One of the 3-position or 4-position of the tetrahydronaphthyridin-2-yl group, for example, the 3-position can be tritiated, and the corresponding isotope-substituted compounds are disclosed. One of the 5-position, 6-position, or 7-position of the tetrahydronaphthyridin-2-yl group can be mono- or di-tritiated, for example, the 7-position can be di-tritiated, and the corresponding isotope-substituted compounds are disclosed.

[0202] In some embodiments of the named compounds, one or more carbons are 13Corresponding isotope-substituted compounds that can be replaced with C are disclosed. For example, R represented by the structural formulas herein 1 、R 1a 、R 2 、R 2a 、one or more carbons such as the carbon in the tetrahydronaphthyridin-2-yl ring can be 13 replaced with C. Corresponding isotope-substituted compounds are disclosed. For example, R 1 、R 1a 、R 2 、R 2a 、and / or in the ring represented by the tetrahydronaphthyridin-2-yl group, one or more ring carbons can be 13 substituted with C. For example, R 1 、R 1a 、R 2 、R 2a 、and / or in the polycyclic ring represented by the tetrahydronaphthyridin-2-yl group, one or more ring carbons in the ring directly bonded to the rest of the compound can be 13 replaced with C. For example, in the tetrahydronaphthyridin-2-yl group, the ring directly bonded to the rest of the compound is an aromatic heterocyclic ring bonded at the 2-position. R 1 、R 1a 、R 2 、R 2a 、and / or in the polycyclic ring corresponding to the tetrahydronaphthyridin-2-yl group, one or more ring carbons in the ring substituting or fused to the ring bonded to the rest of the compound can be 13 replaced with C. For example, in the tetrahydronaphthyridin-2-yl ring, the non-aromatic heterocyclyl ring is fused to the ring bonded to the rest of the compound. Further, for example, R 1 、R 1a 、R 2 、R 2a 、and / or all ring carbons or all carbons in the group corresponding to the tetrahydronaphthyridin-2-yl ring can be 13 replaced with C.

[0203] The present invention also includes any or all of the metabolites of the described compounds. Metabolites can include any chemical species produced by the in vivo conversion of any of the described compounds, such as intermediates and products resulting from the metabolism of the compounds.

[0204] There is provided a manufactured article in a suitable container comprising a compound of the present invention, or a salt or solvate thereof. The container can be a vial, jar, ampoule, pre-filled syringe, or intravenous bag.

[0205] Preferably, the compounds detailed herein are orally bioavailable. However, the compounds can also be formulated for parenteral (e.g., intravenous) administration.

[0206] One or more of the compounds described herein can be used in the preparation of a medicament by combining one or more of the compounds as an active ingredient with a pharmacologically acceptable carrier known in the art. Depending on the therapeutic form of the medicament, the carrier can be in various forms.

[0207] General synthetic methods The compounds of the present invention can be prepared by a number of processes (such as the schemes provided in the following examples) outlined below and detailed in the following examples. In the description of the following processes, it should be understood that the symbols used in the indicated formulas represent the groups described above in relation to the formulas of this specification.

[0208] If it is desired to obtain a specific enantiomer of a compound, this can be achieved by using any conventional procedure suitable for separating or resolving the enantiomers from the corresponding enantiomeric mixture. Thus, for example, diastereomeric derivatives can be produced by reacting an enantiomeric mixture, such as a racemate, with a suitable chiral compound. The diastereomers can then be separated by any convenient means, such as crystallization, and the desired enantiomer recovered. In another resolution process, 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 processes described.

[0209] Chromatography, recrystallization and other conventional separation procedures can also be used with the intermediates or the final products if it is desired to obtain a specific isomer of a compound or otherwise purify the reaction product.

[0210] Solvates and / or polymorphs of the compounds or their pharmaceutically acceptable salts provided herein are also contemplated. Solvates contain either a stoichiometric or non-stoichiometric amount of solvent and are often formed during the process of crystallization. When the solvent is water, hydrates are formed and when the solvent is alcohol, alcoholates are formed. Polymorphs contain different crystal packing arrangements of the same elemental composition. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability, and / or solubility. Depending on various factors such as the recrystallization solvent, crystallization rate, and storage temperature, the formation of single crystals can be favored.

[0211] 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.

[0212] 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.

[0213] Compounds 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 variant detailed herein. General Scheme A

Chemical Formula

[0214] Coupling of 1A with a compound of Formula 2A in the presence of a suitable coupling agent affords a compound of Formula 3A, which upon reduction gives a compound of Formula 4A. Reductive amination of the compound of Formula 4A with compound 5A gives a compound of Formula 6A. Exposure of the compound of Formula 6A to a suitable acid to remove the N-Boc protecting group gives a compound of Formula 7A, which upon coupling with a compound of Formula 8A gives 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.

[0215] The reaction conditions for the transformations of General Scheme A are provided in the following General Procedures, specifically, General Procedures A, D, E, F, G, H, and P.

[0216] Modifying General Scheme A, R 2Starting from variants of 1A that contain 5- and 6-carbon linkers between the nitrogen having a base and the tetrahydronaphthyridinyl group, variants of the compounds of formula 11A can be prepared. These variants of the compounds of formula 11A can be synthesized by replacing 1A with either 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid or 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid and using the route described in General Scheme A. Condensing 6-oxoheptanoic acid and 7-oxooctanoic acid with 2-aminonicotinaldehyde in the presence of a suitable catalyst converts them 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. Subsequently, hydrogenating the resulting naphthyridine ring using procedures known in the chemical literature gives the 5,6,7,8-tetrahydronaphthyridine ring.

[0217] Alternatively, the compounds 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 applicable variant detailed herein. General Scheme B

Chemical formula

[0218] In the presence of a suitable base and di-tert-butyl dicarbonate, the N-Boc group of 1B is introduced to obtain a compound of formula 2B, which is reduced to obtain a compound of formula 3B. Oxidation of the compound of formula 3B with a suitable oxidizing agent gives a compound of formula 4B. Reductive amination of the compound of formula 4B with compound 2A gives a compound of formula 5B. Reductive amination of the compound of formula 5B with compound 5A gives a compound of formula 7B. Exposure of the compound of formula 7B to a suitable acid to remove the N-Boc protecting group gives a compound of formula 7A, which is coupled with a compound of formula 8A to give a compound of formula 10A. Hydrolysis of the compound of formula 10A in the presence of a suitable source of hydroxide gives a compound of formula 11A.

[0219] The reaction conditions for the conversions of General Scheme B are provided in the following general procedures, specifically, General Procedures B, D, F, G, H, and P.

[0220] Modify General Scheme B to start from variants of 1B containing 5- and 6-carbon linkers between the nitrogen bearing the R 2 group and the tetrahydronaphthyridine group to prepare variants of the compound of formula 11A. These variants of the compound of formula 11A can be synthesized by replacing 1B with either ethyl 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentanoate or ethyl 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexanoate and using the pathways described in General Scheme B. Condensation of ethyl 6-oxoheptanoate and ethyl 7-oxooctanoate with 2-aminonicotinaldehyde in the presence of a suitable catalyst converts them 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, and subsequent hydrogenation of the resulting naphthyridine ring using procedures known in the chemical literature gives a 5,6,7,8-tetrahydronaphthyridine ring.

[0221] The compound of formula 10C can be prepared according to General Scheme C, where R is C1-C5 alkyl optionally substituted by R 2a and R 1 and R 2a are as defined for formula (I) or any applicable variant detailed herein. General Scheme C

Chemical formula

[0222] Coupling of a compound of 1C with a compound of 4C in the presence of a suitable coupling agent gives a compound of 2C, which upon reduction gives a compound of 3C. Reductive amination of the compound of 3C with compound 5A gives a compound of 5C. Exposure of the compound of 5C to a suitable acid to remove the N-Boc protecting group in its entirety gives a compound of 6C, which upon coupling with a compound of 8A gives a compound of 9C. Hydrolysis of the compound of 9C in the presence of a suitable source of hydroxide gives a compound of 10C.

[0223] The reaction conditions for the conversions of General Scheme C are provided in the following general procedures, in particular, General Procedures B, D, F, G, H, and P.

[0224] By modifying general scheme C and starting from a 1C variant containing 5- and 6-carbon linkers between nitrogen having a -CH2R group and the tetrahydronaphthyridine group, variants of the compound of formula 10C can be prepared. These variants of the compound of formula 10C can be synthesized by replacing 1C with either 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentan-1-amine or 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexan-1-amine and using the route described in general scheme C. Condensing 6-oxoheptanoic acid and 7-oxooctanoic acid with 2-aminonicotinaldehyde in the presence of a suitable catalyst converts them 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. Subsequently, hydrogenating the resulting naphthyridine ring using procedures known in the chemical literature gives a 5,6,7,8-tetrahydronaphthyridine ring. The resulting carboxylic acids can be converted to primary amines by a two-step procedure involving coupling of the carboxylic acid with a suitable ammonia source in the presence of a suitable coupling reagent, followed by reduction.

[0225] Alternatively, the compound of formula 10C can be prepared according to general scheme D, wherein R is C1-C5 alkyl optionally substituted by 2a and R 1 and R 2a are as defined for formula (I) or any applicable variant detailed herein. General scheme D

Chemical formula

[0226] Alkylation of 1C with a compound of formula 2D in the presence of a suitable alkyl halide gives a compound of formula 3C. Reductive amination of the compound of formula 3C with compound 5A gives a compound of formula 5C. Exposure of the compound of formula 5C to a suitable acid to remove the N-Boc protecting group gives a compound of formula 6C, which upon coupling with a compound of formula 9A gives a compound of formula 9C. Hydrolysis of the compound of formula 8A in the presence of a suitable source of hydroxide gives a compound of formula 10C.

[0227] The reaction conditions for the conversions of General Scheme D are provided in the following general procedures, in particular, General Procedures C, F, G, H, and P.

[0228] General Scheme D can be modified to prepare variants of the compound of formula 10C starting from variants of 1C containing 5- and 6-carbon linkers between the nitrogen having a -CH2R group and the tetrahydronaphthyridine group. These variants of the compound of formula 10C can be synthesized by replacing 1C with either 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentan-1-amine or 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexan-1-amine and using the route described in General Scheme D. Condensation of 6-oxoheptanoic acid and 7-oxooctanoic acid with 2-aminonicotinaldehyde in the presence of a suitable catalyst converts them 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, and subsequent hydrogenation of the resulting naphthyridine ring using procedures known in the chemical literature gives a 5,6,7,8-tetrahydronaphthyridine ring. The resulting carboxylic acids can be converted to primary amines by a two-step procedure involving coupling of the carboxylic acid with a suitable source of ammonia in the presence of a suitable coupling reagent followed by reduction.

[0229] The compound of formula 1f can be prepared according to General Scheme E. It is understood that the ring having the Het description can be any aromatic heterocycle. General Scheme E

Chemical formula

[0230] Hydrolysis of the compound of formula 1a gives the compound of formula 1b, alkylation of which with a suitable electrophile gives the compound of formula 1c. Deprotection of the compound of formula 1c under reducing conditions gives the compound of formula 1d. The compound of formula 1e is obtained by metal-catalyzed cross-coupling of an aryl halide with the compound of formula 1d, and hydrolysis of this under acidic conditions gives the compound of formula 1f.

[0231] The reaction conditions for the conversions of General Scheme E are provided in the following general procedures, in particular, General Procedures Q, R, S, T, and U.

[0232] It is understood that by varying the above scheme and selecting appropriate reagents and starting materials, various compounds of the present invention can be reached. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene’s Protective Groups in Organic Synthesis 4 th edition, Wiley-Interscience, New York, 2006, which is hereby incorporated by reference in its entirety.

[0233] Additional methods for preparing the compounds according to formula (I) and their salts are provided in the Examples. As will be recognized by those skilled in the art, the preparation methods taught herein can be varied, for example, by selecting starting materials that will provide the desired compound, to provide additional compounds within the scope of formula (I).

[0234] Pharmaceutical Compositions and Formulations A pharmaceutical composition comprising a compound 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 a salt thereof, any of the compounds detailed herein, or any of the compounds of Figure 1, or a salt thereof, or a mixture thereof, is encompassed by the present invention. A pharmaceutical composition comprising a compound 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 a salt thereof, any of the compounds detailed herein, or any of the compounds of Figure 1, or a salt thereof, or a mixture thereof, is encompassed by the present invention. A pharmaceutical composition comprising a compound of formula (A), or a salt thereof, or a mixture thereof, is encompassed by the present invention. Accordingly, the present invention includes a pharmaceutical composition 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 composition according to the present invention can take a form suitable for oral administration, buccal administration, parenteral administration, nasal administration, topical administration, or rectal administration, or a form suitable for administration by inhalation. In one embodiment, the pharmaceutical composition is a controlled release composition of any of the compounds detailed herein.

[0235] The compounds detailed herein can, in one aspect, be in a purified form, and compositions containing the compounds in a purified form are described herein. In one embodiment, the composition can have 35% or less impurities, where impurities refer to compounds other than the compound that constitutes the majority of the composition or its salt. For example, a composition of a compound selected from the compounds of Figure 1 can contain 35% or less impurities, where impurities refer to compounds other than the compound of Figure 1 or its salt. In one embodiment, the composition can have 35% or less impurities, where impurities refer to compounds other than the compound that constitutes the majority of the composition or its salt. For example, a composition of a compound selected from the compounds of Figure 1 can contain 35% or less impurities, where impurities refer to compounds other than the compound of Figure 1 or its salt. In one embodiment, the composition can contain 25% or less impurities. In one embodiment, the composition can contain 20% or less impurities. In yet further embodiments, a composition containing the compound detailed herein or its salt is provided as a composition of a substantially pure compound. A "substantially pure" composition contains 10% or less impurities, for example, a composition containing 9%, 7%, 5%, 3%, 1%, or less than 0.5% impurities. In some embodiments, a composition containing the compound detailed herein or its salt is in a substantially pure form. In yet another variant, a composition of a substantially pure compound or its salt is provided, where the composition contains 10% or less impurities. In a further variant, a composition of a substantially pure compound or its salt is provided, where the composition contains 9% or less impurities. In a further variant, a composition of a substantially pure compound or its salt is provided, where the composition contains 7% or less impurities. In a further variant, a composition of a substantially pure compound or its salt is provided, where the composition contains 5% or less impurities. In another variant, a composition of a substantially pure compound or its salt is provided, where the composition contains 3% or less impurities. In yet another variant, a composition of a substantially pure compound or its salt is provided, where the composition contains 1% or less impurities.In a further variant form, a composition of a substantially pure compound or a salt thereof is provided, where the composition contains impurities of 0.5% or less. In still other variant forms, a composition of a substantially pure compound means that the composition contains impurities of 10% or less, or preferably 5% or less, or more preferably 3% or less, or even more preferably 1% or less, or most preferably 0.5% or less, and the impurities can be compounds in different stereochemical forms. For example, a composition of a substantially pure (S) compound means that the composition contains a compound in the (R) form of 10% or less or 5% or less or 3% or less or 1% or less or 0.5% or less.

[0236] In one variant form, the compounds herein are synthetic compounds prepared for administration to an individual such as a human. In another variant form, a composition containing the compound in a substantially pure form is provided. In another variant form, the present invention encompasses a pharmaceutical composition comprising a compound detailed herein and a pharmaceutically acceptable carrier or excipient. In another variant form, a method of administering the compound is provided. The purified form, the pharmaceutical composition and the method of administering the compound are suitable for any of the compounds or their forms detailed herein.

[0237] The compounds or salts thereof detailed herein can be formulated for any available route of delivery, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery forms. The compound or its salt can be formulated with a carrier suitable for providing a delivery form including, but not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, poultices (wet compresses), 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.

[0238] One or more of the compounds or salts thereof described in one or more of the present specifications can be used for the preparation of pharmaceutical preparations such as pharmaceutical formulations by combining one or more compounds or salts thereof as an active ingredient with a pharmaceutically acceptable carrier such as those described above. Depending on the treatment modality of the system (e.g., transdermal patch or oral tablet), the carrier can be in various forms. In addition, the pharmaceutical formulation can contain preservatives, solubilizing agents, stabilizers, rewetting agents, emulsifying agents, sweeteners, coloring agents, regulators, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants. The formulation containing the compound can also contain other substances having beneficial 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, 21 st ed. (2005), which is hereby incorporated by reference in its entirety.

[0239] The compounds described in the present specification can be administered to an individual (e.g., a human) in the form of generally acceptable oral compositions such as tablets, coated tablets, and hard or soft shell gel capsules, emulsions or suspensions. Examples of carriers that can be used in the preparation of such compositions are lactose, corn starch or its derivatives, talc, stearates or their salts, etc. Carriers acceptable for soft shell gel capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. In addition, the pharmaceutical formulation can contain preservatives, solubilizing agents, stabilizers, rewetting agents, emulsifying agents, sweeteners, coloring agents, regulators, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants.

[0240] In one embodiment, the compound can be administered in the liquid vehicle ORA-SWEET® (PERRIGO, Allegan, Michigan), which has the components of purified water, glycerin, sorbitol, sodium saccharin, xanthan gum, and flavoring and odor-masking agents, buffered with citric acid and sodium citrate, and preserved with methylparaben (0.03%), potassium sorbate (0.1%), and propylparaben (0.008%), or can be administered in a mixture of ORA-SWEET® and water in any ratio, for example, a 50:50 mixture of ORA-SWEET® and water. The water used is of pharmaceutically acceptable grade, for example, sterile water.

[0241] Any of the compounds described herein can be formulated into tablets of any dosage form described, for example, the compounds or pharmaceutically acceptable salts thereof described herein can be formulated as 10 mg tablets.

[0242] Compositions comprising the compounds provided herein are also described. In one variant, the composition comprises a compound and a pharmaceutically acceptable carrier or excipient. In another variant, a composition of substantially pure compound is provided. In some embodiments, the composition is for use as a human or veterinary medicine. In some embodiments, the composition is for use in the methods described herein. In some embodiments, the composition is for use in the treatment of the diseases or disorders described herein.

[0243] Method of Use The compounds and compositions of the present invention, for example, pharmaceutical compositions containing a compound of any of the formulas provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, can be used in the methods of administration and treatment provided herein. The compounds and compositions can also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells, for screening purposes and / or for performing quality control assays.

[0244] In one aspect, there is provided a method of treating a fibrotic disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or any variant thereof, for example, 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 to 66 of Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, there is provided a method of treating a fibrotic disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or any variant thereof, for example, 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 to 147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, there is provided a method of treating a fibrotic disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or any variant thereof, for example, 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 to 665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.In one aspect, a method of treating a fibrotic disease in an individual in need thereof, the method 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 compound numbers 1 to 780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is provided. In one aspect, a method of treating a fibrotic disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (A), or any variant thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is provided. In one aspect, the individual is a human. An individual such as a human may be in need of treatment, for example, a human having or suspected of having a fibrotic disease, etc.

[0245] In another aspect, a method is provided for delaying the onset and / or development of a fibrotic disease in an individual (such as a human) at risk of developing the fibrotic disease. It is recognized that delaying development may include prevention if the individual has not yet developed the fibrotic disease. An individual at risk of developing a fibrotic disease, in one aspect, has or is suspected of having one or more risk factors for developing the fibrotic disease. Risk factors for fibrotic diseases can include the age of the individual (e.g., middle-aged or elderly), the presence of inflammation, having one or more genetic elements associated with the development of the fibrotic disease, treatment with drugs or procedures thought to be associated with increased susceptibility to fibrosis (e.g., radiation medicine), or medical history such as medical conditions thought to be associated with fibrosis, smoking history, and the presence of occupational and / or environmental factors such as exposure to contaminants associated with the development of the fibrotic disease. In some embodiments, the individual at risk of developing a fibrotic disease is an individual who has or is 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, the individual at risk of developing a fibrotic disease has or is suspected of having psoriasis.

[0246] 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).

[0247] 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.

[0248] 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 interstitial lung disease associated with systemic sclerosis.

[0249] 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.

[0250] In some embodiments, the fibrotic disease is fibrotic nonspecific interstitial pneumonia (NSIP).

[0251] In some embodiments, the fibrotic disease is liver fibrosis, such as liver fibrosis due to infection (by pathogens such as HCV, HBV or parasites such as Schistosoma mansoni), NASH, alcohol-induced 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.

[0252] In some embodiments, the fibrotic disease is biliary fibrosis.

[0253] In some embodiments, the fibrotic disease is kidney fibrosis, such as diabetic nephrosclerosis, hypertensive nephrosclerosis, focal segmental glomerulosclerosis ("FSGS"), and acute kidney injury due to contrast-induced nephropathy. In some embodiments, the fibrotic disease is diabetic nephropathy, diabetic kidney disease, or chronic kidney disease.

[0254] In some embodiments, the fibrotic disease is characterized by one or more of glomerulonephritis, end-stage renal disease, hearing loss, changes in the eye's lens, hematuria, or proteinuria. In some embodiments, the fibrotic disease is Alport syndrome.

[0255] In some embodiments, the fibrotic disease is systemic and local sclerosis or scleroderma, keloid and hypertrophic scar, or postoperative adhesion. In some embodiments, the fibrotic disease is scleroderma or systemic scleroderma.

[0256] In some embodiments, the fibrotic disease is atherosclerosis or restenosis.

[0257] In some embodiments, the fibrotic disease is gastrointestinal fibrosis, such as Crohn's disease.

[0258] In some embodiments, the fibrotic disease is cardiac fibrosis, such as fibrosis induced after myocardial infarction and genetic cardiomyopathy.

[0259] In some embodiments, the fibrotic disease is psoriasis.

[0260] In some embodiments, the method can include modulating the activity of at least one integrin in a subject in need thereof. For example, the method can include modulating the activity of α V β6. The method can include modulating the activity of α V β1. The method can include modulating the activity of α V β1 and α V β6. Modulating the activity of at least one integrin can include, for example, inhibiting at least one integrin. The method can include, in a subject, at least one integrin, such as α V β1 and α VIt may include administering to a subject an effective amount of a compound or a pharmaceutically acceptable salt thereof effective to modulate the activity of at least one of β6. 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, the fibrotic disease or condition may include idiopathic pulmonary fibrosis, interstitial lung disease, radiation-induced pulmonary fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcohol-induced liver disease-induced fibrosis, Alport syndrome, primary sclerosing cholangitis, primary biliary cholangitis (also known as primary biliary cirrhosis), biliary atresia, interstitial lung disease associated with systemic sclerosis, scleroderma (also known as systemic sclerosis), diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, or Crohn's disease. The fibrotic disease or condition may include psoriasis. The method is, in a subject, at least one integrin, for example, α V β1 and α V It may include administering to a subject an effective amount of a compound or a pharmaceutically acceptable salt thereof effective to modulate the activity of at least one of β6, and the subject is a subject in need of treatment of NASH. The method is, in a subject, at least one integrin, for example, α V β1 and α V It may include administering to a subject an effective amount of a compound or a pharmaceutically acceptable salt thereof effective to modulate the activity of at least one of β6, and the subject is a subject in need of treatment of IPF.

[0261] Fibrotic diseases may be mediated mainly by α V β6, for example, the fibrotic disease may include idiopathic pulmonary fibrosis or renal fibrosis. Thus, the method may include modulating the activity of α V β6 for treating a condition mediated mainly by α V β6, for example, IPF. Fibrotic diseases may be mediated mainly by α V β1, for example, the fibrotic disease may include NASH. Thus, the method may include, for treating a condition mediated mainly by α V β1, for example, NASH, Vmay involve modulating the activity of β1. Fibrotic diseases may be mediated by α V β1 and α V β6, for example, fibrotic diseases may include PSC or biliary atresia. Thus, the method may involve modulating the activity of α V β1 and α V β6 to treat conditions mediated by both. V β1 and α V β6.

[0262] The compound may be a modulator of α V β1, for example, an inhibitor. The compound may be a modulator of α V β6, for example, an inhibitor. The compound may be a dual modulator, for example, a dual inhibitor, for example, a dual selective inhibitor of α V β1 and α V β6. For example, Table B-3 shows that some exemplary compounds predominantly inhibit α V β6 rather than α V β1, some exemplary compounds predominantly inhibit α V β1 rather than α V β6, and some exemplary compounds inhibit α V β1 and α V β6 equally, and can thus be considered, for example, "dual α V β1 / α V β6 inhibitors".

[0263] α V β1 integrin and α V β6 integrin, or both, to treat a subject with a fibrotic disease, indicates that α V β1 integrin, α V β6 integrin, or α V β1 integrin and α V β6 integrin are modulated or inhibited to a sufficient extent to treat the subject's fibrotic disease.

[0264] In one aspect, provided are compounds of formula (A), formula (I), or any variant thereof, such as compounds 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), compounds selected from compound numbers 1 to 66 of Figure 1, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, for use in the treatment of fibrotic diseases.

[0265] In one aspect, provided are compounds of formula (A), formula (I), or any variant thereof, such as compounds 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), compounds selected from compound numbers 1 to 147, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, for use in the treatment of fibrotic diseases.

[0266] In one aspect, provided are compounds of formula (A), formula (I), or any variant thereof, such as compounds 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), compounds selected from compound numbers 1 to 665, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, for use in the treatment of fibrotic diseases.

[0267] In one aspect, provided is 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 to 780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of fibrotic diseases.

[0268] Also provided is the use of 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 to 66 of Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of fibrotic diseases.

[0269]

[0270] Also provided is the use of 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 to 147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of fibrotic diseases.Also provided is the use of a compound of formula (A), formula (I), or any variant thereof, for example, 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 to 665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of fibrotic diseases.

[0271] Also provided is the use of a compound of formula (A), formula (I), or any variant thereof, for example, 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 to 780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of fibrotic diseases.

[0272] In another aspect, provided herein is a method of treating in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or any variant thereof, for example, 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 to 66 of Figure 1, or a stereoisomer thereof, 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 α V β1 integrin activity and / or expression; α VA method having an increase in at least one level of β6 integrin activity and / or expression; pSMAD / SMAD value; formation or accumulation of new collagen; total collagen; and expression of type I collagen gene Col1a1, wherein the level is increased compared to a tissue in a healthy state. In some embodiments, at least one tissue of the subject comprises one or more of lung tissue, liver tissue, skin tissue, heart tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue. In some embodiments, the tissue has a high pSMAD2 / SMAD2 value or a high pSMAD3 / SMAD3 value compared to a tissue in a healthy state.

[0273] α V β1 integrin activity and / or expression; α V Methods for determining β6 integrin activity and / or expression; pSMAD / SMAD value; formation or accumulation of new collagen; total collagen; and expression of type I collagen gene Col1a1 are known in the art, and exemplary methods, such as antibody assays of tissue samples such as biopsy samples, are disclosed in the examples.

[0274] In some embodiments, the method selectively reduces α V β1 integrin activity and / or expression in the subject compared to α V β6 integrin activity and / or expression. In some embodiments, the method selectively reduces α V β6 integrin activity and / or expression in the subject compared to α V β1 integrin activity and / or expression. In some embodiments, the method reduces α V β1 integrin and α V the activities and / or expressions of both β6 integrins compared to at least one other α V containing integrin. In some embodiments, the α V activity of β1 integrin in one or more fibroblasts in the subject is reduced. In some embodiments, αV The activity of β6 integrin decreases.

[0275] In another aspect, provided herein is a method of treating in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or any variant thereof, e.g., 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 1-66 of FIG. 1, or a stereoisomer thereof, 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 an elevated level of at least one of α V β1 integrin activity and / or expression; α V β6 integrin activity and / or expression; pSMAD / SMAD value; formation or accumulation of new collagen; total collagen; and increased expression of type I collagen gene Col1a1, wherein the level is elevated compared to a healthy tissue. In some embodiments, at least one tissue of the subject comprises one or more of lung tissue, liver tissue, skin tissue, heart tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue. In some embodiments, the tissue has a high pSMAD2 / SMAD2 value or a high pSMAD3 / SMAD3 value compared to a healthy tissue.

[0276] α V β1 integrin activity and / or expression; α V β6 integrin activity and / or expression; pSMAD / SMAD value; formation or accumulation of new collagen; total collagen; and methods for determining the value of type I collagen gene Col1a1 expression are known in the art, and exemplary methods, e.g., antibody assays of tissue samples such as biopsy samples, are disclosed in the Examples.

[0277] In some embodiments, the method selectively reduces α V β1 integrin activity and / or expression in a subject, compared to α V β6 integrin activity and / or expression. In some embodiments, the method selectively reduces α V β6 integrin activity and / or expression in a subject, compared to α V β1 integrin activity and / or expression. In some embodiments, the method reduces the activity and / or expression of both α V β1 integrin and α V β6 integrin in a subject, compared to at least one other α V containing integrin. In some embodiments, the activity of α V β1 integrin in one or more fibroblasts in the subject is reduced. In some embodiments, the activity of α V β6 integrin in one or more epithelial cells in the subject is reduced.

[0278] Also provided is a method of characterizing the anti-fibrotic activity of a small molecule in a subject, the method comprising providing a first viable cell sample from the subject, the first viable cell sample being characterized by the presence of at least one integrin capable of activating transforming growth factor β (TGF-β) from latent peptide TGF-β; determining a first pSMAD / SMAD value of the first viable cell sample; administering the small molecule to the subject; providing a second viable cell sample from the subject, the second viable cell sample being taken from the same tissue as the subject's first viable cell sample; determining a second pSMAD / SMAD value of the second viable cell sample; and characterizing the anti-fibrotic activity of the small molecule in the subject by comparing the second pSMAD / SMAD value to the first pSMAD / SMAD value. In some embodiments, the small molecule is a compound disclosed herein and, optionally, is in a dosage form disclosed herein.

[0279] In some embodiments, each live cell sample is a plurality of cells derived from a tissue of a subject or a plurality of macrophages associated with a tissue of the subject. In some embodiments, the tissue includes one of lung tissue, liver tissue, skin tissue, heart tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue. In some embodiments, each live cell sample includes a plurality of alveolar macrophages derived from a bronchoalveolar lavage fluid of a subject.

[0280] In some embodiments, the method further includes performing bronchoalveolar lavage on the subject's lung effective to yield a bronchoalveolar lavage fluid that includes a plurality of macrophages as a plurality of alveolar macrophages.

[0281] 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), alcoholic liver disease-induced fibrosis, Alport syndrome, primary sclerosing cholangitis (PSC), primary biliary cholangitis, biliary atresia, interstitial lung disease associated with systemic sclerosis, 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.

[0282] 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), alcoholic liver disease-induced fibrosis, Alport syndrome, primary sclerosing cholangitis (PSC), primary biliary cholangitis, biliary atresia, interstitial lung disease associated with systemic sclerosis, 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.

[0283] In some embodiments, the subject is in a Gender-Age-Physiological function (GAP) stage based on a Gender-Age-Physiological function (GAP) index system and has a GAP stage I. In some embodiments, the subject has a GAP stage of GAP stage II. In some embodiments, the subject has a GAP stage of GAP stage III.

[0284] In some embodiments, at least one integrin comprises α V In some embodiments, at least one integrin comprises α V β1. In some embodiments, at least one integrin comprises α V β6.

[0285] In some embodiments, determining a first pSMAD / SMAD value of at least one live cell comprises determining a pSMAD2 / SMAD2 value or a pSMAD3 / SMAD3 value, and determining a second pSMAD / SMAD value of at least one live cell after contacting the at least one live cell with a small molecule comprises determining a pSMAD2 / SMAD2 value or a pSMAD3 / SMAD3 value.

[0286] Also provided is a method of treating a fibrotic disease in a subject in need thereof, the method comprising: providing a first sample of live cells from the subject, the first sample of live cells having at least one integrin capable of activating transforming growth factor β (TGF-β) from its latent peptide form; determining a first pSMAD / SMAD value of the first sample of live cells; administering a small molecule to the subject; providing a second sample of live cells from the subject, the second sample of live cells being taken from the same tissue as the subject's first sample of live cells; determining a second pSMAD / SMAD value of the second sample of live cells; comparing the second pSMAD / SMAD value with the first pSMAD / SMAD value; and, when 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 sample of live cells is obtained from the subject prior to treatment with the small molecule.

[0287] In some embodiments, each sample of live cells 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 lung tissue, liver tissue, skin tissue, heart tissue, kidney tissue, gastrointestinal tissue, gallbladder tissue, and bile duct tissue. In some embodiments, each sample of live cells comprises a plurality of alveolar macrophages derived from the subject's bronchoalveolar lavage fluid. In some embodiments, the method further comprises performing bronchoalveolar lavage on the subject's lungs effective to yield a bronchoalveolar lavage fluid comprising a plurality of macrophages as a plurality of alveolar macrophages.

[0288] In some embodiments, the subject is characterized by having a fibrotic disease selected from the group consisting of idiopathic pulmonary fibrosis (IPF), interstitial lung disease, radiation-induced pulmonary fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease-induced fibrosis, Alport syndrome, primary sclerosing cholangitis (PSC), primary biliary cholangitis, biliary atresia, interstitial lung disease associated with systemic sclerosis, scleroderma, diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn's disease. In some embodiments, the subject is characterized by having psoriasis.

[0289] In some embodiments, at least one integrin comprises α V In some embodiments, at least one integrin comprises α V β1. In some embodiments, at least one integrin comprises α V β6.

[0290] In some embodiments, determining the first pSMAD / SMAD value of the first live cell sample comprises determining the pSMAD2 / SMAD2 value or the pSMAD3 / SMAD3 value, and determining the second pSMAD / SMAD value of 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.

[0291] In another aspect, provided is a method of inhibiting α V β6 integrin in an individual, the method comprising administering 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 stereoisomer thereof, or a compound selected from Compound Numbers 1 to 66 of FIG. 1, or a pharmaceutically acceptable salt thereof.

[0292] In another aspect, in an individual, α V A method of inhibiting αβ6 integrin, comprising administering a compound of formula (A), formula (I), or any variant thereof, for example, 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 compound numbers 1 to 147, or a pharmaceutically acceptable salt thereof, is provided.

[0293] In another aspect, in an individual, α V A method of inhibiting αβ6 integrin, comprising administering a compound of formula (A), formula (I), or any variant thereof, for example, 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 compound numbers 1 to 665, or a pharmaceutically acceptable salt thereof, is provided.

[0294] In another aspect, in an individual, α V A method of inhibiting αβ6 integrin, comprising administering a compound of formula (A), formula (I), or any variant thereof, for example, 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 compound numbers 1 to 780, or a pharmaceutically acceptable salt thereof, is provided.

[0295] Also provided is a method for inhibiting TGFβ activation in a cell, which comprises administering to the cell 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 numbers 1 to 66 in Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0296] Also provided is a method for inhibiting TGFβ activation in a cell, which comprises administering to the cell 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 numbers 1 to 147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0297] Also provided is a method for inhibiting TGFβ activation in a cell, which comprises administering to the cell 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 numbers 1 to 665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0298] Also provided is a method of inhibiting TGFβ activation in a cell, which comprises administering to the cell 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 to 780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0299] Also, α V β6 integrin is inhibited in an individual in need thereof, which 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 to 66 of Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Also, α V β6 integrin is inhibited in an individual in need thereof, which 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 to 147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Also, α VA method of inhibiting β6 integrin in an individual in need thereof, the method comprising administering to the individual 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 numbers 1 to 665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Also, α V A method of inhibiting β6 integrin in an individual in need thereof, the method comprising administering to the individual 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 numbers 1 to 780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one such method, the compound is a selective α V β6 integrin inhibitor.

[0300] In another such method, the compound does not substantially inhibit α4β1, α V β8 and / or α2β3 integrin. In yet another such method, the compound inhibits α V β6 integrin but does not substantially inhibit α4β1 integrin. In yet another such method, the compound inhibits α V β6 integrin but does not substantially inhibit α V β8 integrin. In a further such method, the compound inhibits α V β6 integrin but does not substantially inhibit α2β3 integrin. In one embodiment, α V β6 integrin and α V β1, α V β3, α Vβ5, α2β1, α3β1, α6β1, α7β1, and α 11 in an individual in need thereof, a method of inhibiting one or more of β1 integrins is provided. In another embodiment, α V β6 integrin and α V a method of inhibiting β1 integrin is provided. In another embodiment, α V β6 integrin, α V β3 integrin, and α V a method of inhibiting β5 integrin is provided. In another embodiment, α V a method of inhibiting β6 integrin and α2β1 integrin is provided. In another embodiment, α V a method of inhibiting β6 integrin, α2β1 integrin, and α3β1 integrin is provided. In another embodiment, α V a method of inhibiting β6 integrin and α6β1 integrin is provided. In another embodiment, α V a method of inhibiting β6 integrin and α7β1 integrin is provided. In another embodiment, α V β6 integrin and α 11Methods for inhibiting β1 integrin are provided. In all such embodiments, in one aspect, the inhibiting method is for an individual in need thereof, such as an individual having or suspected of having a fibrotic disease, and the method comprises administering to the individual a compound of formula (A), a compound of formula (I), or any variant thereof, for example, 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 to 66 in Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In all such embodiments, in one aspect, the inhibiting method is for an individual in need thereof, such as an individual having or suspected of having a fibrotic disease, and the method comprises administering to the individual a compound of formula (A), a compound of formula (I), or any variant thereof, for example, 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 to 147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In all such embodiments, in one aspect, the inhibiting method is for an individual in need thereof, such as an individual having or suspected of having a fibrotic disease, and the method comprises administering to the individual a compound of formula (A), a compound of formula (I), or any variant thereof, for example, 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 to 665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.In all such embodiments, in one aspect, the method of inhibition is for an individual in need thereof, such as an individual having or suspected of having a fibrotic disease, and the method comprises administering to the individual a compound of formula (A), a compound of formula (I), or any variant thereof, for example, 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 to 780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0301] Also, without substantially increasing lung inflammation, α V β6 integrin is regulated or inhibited in an individual in need thereof, the method comprising administering to the individual a compound of formula (A), a compound of formula (I), or any variant thereof, for example, 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 to 66 of Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Also, without substantially increasing lung inflammation, α V β6 integrin is regulated or inhibited in an individual in need thereof, the method comprising administering to the individual a compound of formula (A), a compound of formula (I), or any variant thereof, for example, 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 to 147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Also, without substantially increasing lung inflammation, α VA method of modulating or inhibiting β6 integrin in an individual in need thereof, the method comprising administering to the individual 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 to 665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Also, without substantially increasing lung inflammation, α V A method of modulating or inhibiting β6 integrin in an individual in need thereof, the method comprising administering to the individual 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 to 780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one such method, the compound is a selective α V β6 integrin inhibitor. In one such method, the compound is a selective α V β1 integrin inhibitor. In one such method, the compound is a selective α V β6 integrin inhibitor and a selective α V β1 integrin inhibitor.

[0302] In another embodiment, without substantially increasing lung inflammation, α V β6 integrin and α VMethods for modulating or inhibiting β1-integrin are provided. In all such embodiments, in one aspect, the inhibitory method is for an individual in need thereof, such as an individual having or suspected of having a fibrotic disease, and the method comprises administering to the individual, without substantially increasing pulmonary inflammation, a compound of formula (A), a compound of formula (I), or any variant thereof, for example, 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. 1-66 in Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In all such embodiments, in one aspect, the inhibitory method is for an individual in need thereof, such as an individual having or suspected of having a fibrotic disease, and the method comprises administering to the individual, without substantially increasing pulmonary inflammation, a compound of formula (A), a compound of formula (I), or any variant thereof, for example, 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. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In all such embodiments, in one aspect, the inhibitory method is for an individual in need thereof, such as an individual having or suspected of having a fibrotic disease, and the method comprises administering to the individual, without substantially increasing pulmonary inflammation, a compound of formula (A), a compound of formula (I), or any variant thereof, for example, 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. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.In all such embodiments, in one aspect, the method of inhibition is for an individual in need thereof, such as an individual having or suspected of having a fibrotic disease, and the method comprises administering to the individual a compound of formula (A), a compound of formula (I), or any variant thereof, for example, 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 to 780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, without substantially increasing lung inflammation.

[0303] The compound of formula (A) can be used in any of the compositions, methods, and uses cited herein for formula (I) and variants of formula (I).

[0304] In any of the methods described, in one aspect, the individual is a human, such as a human in need of the method. The individual can be a human diagnosed with or suspected of having a fibrotic disease. The individual can be a human who does not have a detectable disease but has one or more risk factors for developing a fibrotic disease.

[0305] Also provided herein is a pharmaceutical dosage form configured for daily administration, comprising a pharmaceutically acceptable carrier or excipient and a unit dose of a compound of formula (A), a compound of formula (I), or any variant thereof, for example, 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 to 780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0306] The unit dosage, for example, the unit dosage for daily administration, is 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 in the range between any two of the aforementioned values, for example, about 1-125, 1-5, 2.5-7.5, 5-15, 10-15, 10-20, 10-25, 10-30, 10-35, 10-40, 10-50, 10-75, 15-20, 15-25, 15-30, 15-35, 15-40, 15-50, 15-75, 20-25, 20-30, 20-35, 20-40, 20-50, 20-75, 25-30, 25-35, 25-40, 25-50, 25-75, 30-35, 30-40, 30-50, 30-75, 35-40, 35-50, 35-75, 40-50, 40-75, 50-75, 50-100, 60-85, 70-90, 70-100, 80-125, 90-125, or 100-125 mg of the compound may be included.

[0307] Unit dosages, for example, unit dosages for daily administration, may include 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 ranges between any two of the foregoing values, for example, 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 dosage may be 10 mg. The unit dosage may be 15 mg. The unit dosage may be 20 mg. The unit dosage may be 30 mg. The unit dosage may be 40 mg. The unit dosage may be 50 mg. The unit dosage may be 60 mg. The unit dosage may be 70 mg. The unit dosage may be 75 mg. The unit dosage may be 80 mg. The unit dosage may be 90 mg. The unit dosage may be 100 mg. The unit dosage may be 110 mg. The unit dosage may be 120 mg. The unit dosage may be 125 mg. The unit dosage may be 150 mg. The unit dosage may be 175 mg. The unit dosage may be 200 mg. The unit dosage may be 225 mg. The unit dosage may be 250 mg.

[0308] The unit dosage, for example, the unit dosage for daily administration, when administered to an individual, is at least one of about 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 or more; or in the range between any two of the aforementioned concentrations, for example, 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. of C in the plasma of the individual in ng / mL units max may contain the compound in an amount effective to result in, for example, C max may be about 700 ng / mL or more. C max may be about 750 ng / mL or more. C max may be about 800 ng / mL or more. C max may be about 850 ng / mL or more. C max may be about 900 ng / mL or more. C max may be about 950 ng / mL or more. C max may be about 1000 ng / mL or more. C max may be about 1050 ng / mL or more. C max may be about 1100 ng / mL or more. C max may be about 1200 ng / mL or more. C max may be about 1300 ng / mL or more. C max may be about 1400 ng / mL or more. C max may be about 1500 ng / mL or more.

[0309] The unit dosage, for example, the unit dosage for daily administration, when administered to an individual, may contain the compound in an amount effective to result in C in the plasma of the individual in ng / mL units max and C maxis, in an individual, at least about one of 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 percent, or a range between any two of the foregoing percentages (e.g., 50-100, 60-90, 70-90, 75-95 percent, etc.) of α V β6 or α V corresponds to a plasma-adjusted concentration effective to inhibit β1. In some embodiments, the compound is α V β6 and α V can be a dual inhibitor of β1, and C max is, in an individual, α V β6 and α V can correspond to a plasma-adjusted concentration effective to inhibit a respective percentage of β1, each percentage being independently selected from the foregoing percentages or a range between any two of the foregoing percentages. For example, the plasma-adjusted concentration can be effective to inhibit α V β6 by at least about 50%. The plasma-adjusted concentration can be effective to inhibi...

Claims

**Claim 1** A method for improving the decline of forced vital capacity (FVC) in a subject in need thereof, the method 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)butanoic acid or a pharmaceutically acceptable salt thereof, whereby the decline of the forced vital capacity (FVC) in the subject is improved. **Claim 2** The method according to claim 1, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount sufficient to suppress the decline of the FVC in the subject as compared to a subject not administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof. **Claim 3** The method according to claim 1, wherein the administration is for at least about 12 weeks. **Claim 4** The method according to any one of claims 1 to 3, wherein the administration is for a period of about 12 weeks. **Claim 5** The method according to any one of claims 1 to 3, wherein the administration is for a period of about 24 weeks. **Claim 6** The method according to any one of claims 1 to 5, wherein the administration is daily. **Claim 7** The method according to any one of claims 1 to 6, wherein the administration is once a day. **Claim 8** The method according to any one of claims 1 to 7, wherein the improvement of the decline of the FVC is a decline of less than about 10% after administration of the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof. **Claim 9** The method according to any one of claims 1 to 8, wherein the improvement of the decline of the FVC is suppression of the decline of the FVC. **Claim 10** The method according to claim 8, wherein the suppression of the decline of the FVC is about 50 mL or less. **Claim 11** The method according to claim 8, wherein the suppression of the decline of the FVC is about 30 mL or less. **Claim 12** The method according to claim 8, wherein suppression of the decrease in FVC is about 15 mL or less.

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

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

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

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

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

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

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

20. The method according to any one of claims 8 to 15, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic 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)butanoic acid.

21. The method according to any one of claims 8 to 15, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic 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)butanoic acid of about 1,000 ng / mL plus or minus 200 ng / mL.

22. The method according to any one of claims 8 to 15, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic 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)butanoic acid of about 1,600 ng / mL plus or minus 300 ng / mL.

23. The method according to any one of claims 8 to 15, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic 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)butanoic acid of about 2,700 ng / mL plus or minus 400 ng / mL.

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

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

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

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

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

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

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

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

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

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

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

37. The method according to any one of claims 24 to 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 to 33, wherein the administration is for a period of about 12 weeks, and 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 from the start to the end of the period.

39. The method according to any one of claims 24 to 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 from the start to the end of the period.

40. The method according to any one of claims 24 to 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 from the start to the end of the period.

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

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

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

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

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

46. The method according to any one of claims 24 to 41, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic 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)butanoic acid of at least about 700 ng / mL.

47. The method according to any one of claims 24 to 41, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic 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)butanoic acid of about 1,000 ng / mL plus or minus 200 ng / mL.

48. The method according to any one of claims 24 to 41, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic 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)butanoic acid of about 1,600 ng / mL plus or minus 300 ng / mL.

49. The method according to any one of claims 24 to 41, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic 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)butanoic acid of about 2,700 ng / mL plus or minus 400 ng / mL.

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

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

52. The method according to any one of claims 1 to 51, wherein the subject has a 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 to 53, wherein the subject is human.

55. The method according to any one of claims 1 to 54, wherein the subject is being treated concurrently with a standard drug therapy or standard treatment.

56. The method according to claim 55, wherein the standard drug therapy or standard treatment comprises administration of pirfenidone, administration of nintedanib, or administration of pirfenidone and nintedanib.

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

58. The method according to claim 57, wherein the standard drug therapy or standard treatment includes administration of pirfenidone, administration of nintedanib, or administration of pirfenidone and nintedanib.

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

60. The method according to claim 59, wherein the standard drug therapy or standard treatment includes administration of pirfenidone, administration of nintedanib, or administration of pirfenidone and nintedanib.

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

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

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

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

65. The method according to any one of claims 1 to 61, wherein the incidence rate of adverse events is lower than the incidence rate of a standard drug therapy or standard treatment for lung disorders.

66. The method according to claim 65, wherein the standard drug therapy or standard treatment includes administration of pirfenidone, administration of nintedanib, or administration of 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 to 67, wherein the cough severity is reduced after administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof.

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

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

71. The method according to any one of claims 1 to 70, wherein a ground glass-like appearance is not observed or is reduced after administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof.

72. The method according to any one of claims 1 to 71, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic 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 to 73, wherein (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof is a phosphate in crystalline form I.

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

76. α Ｖ β ６ Integrin, α Ｖ β １ Integrin, or α Ｖ β ６ Integrin and α Ｖ β １ A method of modulating both Integrin and α and β in a subject in need thereof The method comprising administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof, wherein the administration is not accompanied by severe adverse events.

77. The α Ｖ β ６ Integrin, α Ｖ β １ Integrin, or α Ｖ β ６ Integrins and α Ｖ β １ Regulating both integrins Ｖ β ６ Integrin, α Ｖ β １ Integrin, or α Ｖ β ６ Integrins and α Ｖ β １ 77. The method of claim 76, comprising inhibiting both of the integrins.

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

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

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

81. The method according to any one of claims 76 to 80, wherein a ground glass-like appearance is not observed or is decreased after administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic 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 deuterated pirfenidone according to claim 82, which is represented by the formula: 【Chemical 1】 or a pharmaceutically acceptable salt thereof.

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

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

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

87. A method of increasing the expression of one or more genes in a subject in need thereof, the method 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)butanoic 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, PPARG C1A, 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)butanoic 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)butanoic acid is administered as a phosphate salt in crystalline form I.

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)butanoic acid is administered as the phosphate salt in crystalline form IV, the fumarate salt in crystalline form II, the naphthalenedisulfonate salt in crystalline form III, the zwitterionic form, or the amorphous form.

91. The method according to any one of claims 87 to 90, wherein nintedanib is administered as the ethanesulfonate salt.

92. A method of increasing the expression of one or more genes in a subject in need thereof, the method 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)butanoic 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)butanoic acid is administered as the 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)butanoic acid is administered as the phosphate salt in crystalline form I.

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)butanoic acid is administered as the phosphate salt in crystalline form IV, the fumarate salt in crystalline form II, the naphthalenedisulfonate salt in crystalline form III, the zwitterionic form, or the amorphous form.

96. A method of 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)butanoic 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, said method.

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)butanoic 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)butanoic acid is administered as a phosphate in crystalline form I.

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)butanoic acid is administered as a phosphate in crystalline form IV, a fumarate in crystalline form II, a naphthalenedisulfonate in crystalline form III, an zwitterionic form, or an amorphous form.

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

101. A method of reducing the expression of one or more genes in a subject in need thereof, the method 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)butanoic 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)butanoic 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)butanoic acid is administered as a phosphate in crystalline form I.

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)butanoic acid is administered as a phosphate in crystalline form IV, a fumarate in crystalline form II, a naphthalenedisulfonate in crystalline form III, an amphoteric ion form, or an amorphous form.

105. The method according to any one of claims 87 to 104, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof, or the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof and pirfenidone are administered in an amount effective to provide the action shown against 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)butanoic 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)butanoic acid is administered as a phosphate in crystalline form I.

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)butanoic acid is administered as a phosphate in crystalline form IV, a fumarate in crystalline form II, a naphthalenedisulfonate in crystalline form III, an zwitterionic form, or an amorphous form.

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

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

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

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

113. A method of increasing the expression of one or more genes in a subject in need thereof, the method comprising administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic 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)butanoic 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)butanoic acid is administered as a phosphate in crystalline form I.

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)butanoic acid is administered as a phosphate in crystalline form IV, a fumarate in crystalline form II, a naphthalenedisulfonate in crystalline form III, an zwitterionic form, or an amorphous form.

117. A method of 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)butanoic 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)butanoic 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)butanoic acid is administered as a phosphate in crystalline form I.

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)butanoic acid is administered as the phosphate salt in crystalline form IV, the fumarate salt in crystalline form II, the naphthalenedisulfonate salt in crystalline form III, the zwitterionic form, or the 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)butanoic 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)butanoic acid or a pharmaceutically acceptable salt thereof, and pirfenidone, wherein the at least one gene is substantially modulated by administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof, and nintedanib or a pharmaceutically acceptable salt thereof, or by administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof, and pirfenidone, but not substantially modulated by administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof alone, nintedanib or a pharmaceutically acceptable salt thereof alone, or pirfenidone alone.

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)butanoic 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)butanoic acid or a pharmaceutically acceptable salt thereof is a phosphate in crystalline form I.

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)butanoic acid or a pharmaceutically acceptable salt thereof is selected from a phosphate in crystalline form IV, a fumarate in crystalline form II, a naphthalenedisulfonate in crystalline form III, an amphoteric ion form, and an amorphous form.

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

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