Amino acid compounds and methods of use

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 639,988, filed March 7, 2018, and U.S. Provisional Patent Application No. 62 / 690,933, filed June 27, 2018, the disclosures of which are incorporated herein by reference in their entireties. [Background technology]

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

[0003] Patients with nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis to nonalcoholic steatohepatitis (NASH) and then to fibrosis. While early-stage liver fibrosis is reversible, progressive liver fibrosis can lead to cirrhosis.

[0004] Renal fibrosis, characterized by glomerular sclerosis and tubulointerstitial fibrosis, is a common and final manifestation of a wide variety of chronic kidney diseases (CKD). Regardless of the initial cause, progressive CKD often leads to extensive tissue scarring that leads to destruction of the renal parenchyma and end-stage renal failure, a devastating condition requiring dialysis or kidney replacement surgery.

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

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

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

[0008] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic disease of unknown cause that occurs in adults and is limited to the lungs. In IPF, lung tissue thickens, stiffens, and scars. As pulmonary fibrosis progresses, the lungs have difficulty transporting oxygen into the bloodstream, preventing organs from receiving the oxygen they need to function properly. IPF currently affects approximately 200,000 people in the United States and causes 40,000 deaths annually. Patients diagnosed with IPF experience progressive shortness of breath and, eventually, complete respiratory failure.

[0009] Primary biliary cholangitis (PBC), also known as primary biliary cirrhosis, is a chronic disease of the liver that causes liver damage and fibrosis. It results from the slow, progressive destruction of the liver's small bile ducts, causing bile and other toxins to accumulate in the liver, a condition called cholestasis. Over time, this leads to scarring and fibrosis in both the liver and biliary tract.

[0010] Nonspecific interstitial pneumonia (NSIP) is a rare disease affecting the tissues surrounding and separating the tiny air sacs of the lungs. These air sacs, called alveoli, are where oxygen and carbon dioxide exchange occurs between the lungs and the bloodstream. Interstitial pneumonia is a disease in which the mesh-like walls of the alveoli become inflamed. The pleura (the thin covering that protects and cushions the lungs and their individual lobes) can also become inflamed. NSIP has two main forms: cellular and fibrotic. The cellular form is primarily defined by inflammation of the interstitial cells. The fibrotic form is defined by thickening and scarring of lung tissue. This scarring, known as fibrosis, is irreversible. When lung tissue thickens or scars, it no longer functions effectively. Breathing becomes less efficient, resulting in decreased blood oxygen levels. (Non-Patent Document 1; Non-Patent Document 2; Non-Patent Document 3)

[0011] Currently, available treatment courses are inadequate, with no options on the market proven to impact long-term patient survival or symptomatology. There remains a need for treatments for fibrotic diseases.

[0012] The αvβ6 integrin is expressed in epithelial cells, binds to the latent-related peptide of transforming growth factor β1 (TGFβ1), and mediates TGFβ1 activation. Its expression level is significantly increased after injury to lung and bile duct cells, and it plays an important role in tissue fibrosis in vivo. Increased levels are also associated with increased mortality in patients with IPF and NSIP.

[0013] Primary sclerosing cholangitis (PSC) involves bile duct inflammation and fibrosis that obstructs the bile duct. The resulting obstruction of bile flow to the intestine can lead to liver cirrhosis and subsequent complications, such as liver failure and liver cancer. αvβ6 expression is elevated in the liver and bile ducts of PSC patients.

[0014] The present disclosure provides αvβ6 integrin inhibitors that may be useful in the treatment of fibrosis. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] Kim et al., Proc. Am. Thorac. Soc. (2006) 3:285-292 [Non-patent document 2] Lynch, D., Radiology (2001) 221:583-584 [Non-patent document 3] Kinder et al., Am. J. Respir. Crit. Care Med. (2007) 176:691-697 Summary of the Invention

[0016] Amino acid compounds that are αvβ6 integrin inhibitors, compositions containing these compounds, and methods for treating diseases mediated by αvβ6 integrin, such as fibrotic diseases, are disclosed.

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

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

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

[0020] In another aspect, methods are provided for delaying the onset and / or development of a fibrotic disease in an individual (e.g., a human) at risk of developing a fibrotic disease, comprising administering to the individual a therapeutically effective amount of a compound of Formula (A), or a variant thereof as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the fibrotic disease is pulmonary fibrosis (e.g., IPF), liver fibrosis, skin fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or PBC. In some embodiments, the individual at risk of developing a fibrotic disease has or is suspected of having NAFLD, NASH, CKD, scleroderma, Crohn's disease, NSIP, PSC, PBC, or has had or is suspected of having myocardial infarction.

[0021] Also provided is a compound of formula (A), or a variant thereof as detailed herein, or a pharmaceutical composition thereof, for the treatment of a fibrotic disorder.

[0022] There is also provided the use of a compound of Formula (A), or a variant thereof as detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing, in the manufacture of a medicament for treating a fibrotic disease.

[0023] Additionally provided are kits comprising a compound of Formula (A), or a variant thereof as detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the kits include instructions for use in accordance with the methods described herein, such as the method of treating a fibrotic disorder in an individual.

[0024] In another aspect, there is provided a method for preparing a compound of Formula (A), or a variant thereof, or a pharmaceutically acceptable salt thereof. Also provided are intermediate compounds useful in the synthesis of a compound of Formula (A), or a variant thereof.

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

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

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

[0028] In another aspect, methods are provided for delaying the onset and / or development of a fibrotic disease in an individual (e.g., a human) at risk of developing a fibrotic disease, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a variant thereof as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the fibrotic disease is pulmonary fibrosis (e.g., IPF), liver fibrosis, skin fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or PBC. In some embodiments, the individual at risk of developing a fibrotic disease has or is suspected of having NAFLD, NASH, CKD, scleroderma, Crohn's disease, NSIP, PSC, PBC, or has had or is suspected of having myocardial infarction.

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

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

[0031] Additionally provided are kits comprising a compound of Formula (I), or a variant thereof as detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the kits include instructions for use in accordance with the methods described herein, such as the method of treating a fibrotic disorder in an individual.

[0032] In another aspect, there is provided a method for preparing a compound of formula (I), or a variant thereof, or a pharmaceutically acceptable salt thereof. Also provided are intermediate compounds useful in the synthesis of a compound of formula (I), or a variant thereof. [Brief explanation of the drawings]

[0033] [Figure 1] FIG. 1 shows compounds 1-780 disclosed herein.

[0034] [Figure 2] FIG. 2 shows Table B-3, which lists biological data for various compounds disclosed herein. DETAILED DESCRIPTION OF THE INVENTION

[0035] The present disclosure provides, inter alia, compounds of formula (A), and variants thereof, or salts thereof, pharmaceutical compositions comprising compounds of formula (A) or salts thereof, and methods of using the compounds and compositions in the treatment of fibrotic diseases.

[0036] The present disclosure provides, inter alia, compounds of formula (I) and variants thereof, or salts thereof, pharmaceutical compositions comprising compounds of formula (I) or salts thereof, and methods of using the compounds and compositions in the treatment of fibrotic diseases.

[0037] definition As used herein, unless clearly indicated otherwise, the use of the terms "a," "an," etc. means one or more.

[0038] Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to that value or parameter itself. For example, a reference to "about X" includes a description of "X."

[0039] As used herein, unless otherwise specified, "alkyl" refers to and includes monovalent saturated, linear (i.e., unbranched) or branched hydrocarbon chains or combinations thereof, having the specified number of carbon atoms (i.e., C1 to C6). 10 means 1 to 10 carbon atoms). Particular alkyl groups are those having 1 to 20 carbon atoms ("C1-C 20 alkyl"), those having 1 to 10 carbon atoms ("C1-C 10 alkyl"), those with 6 to 10 carbon atoms ("C6-C 10 alkyl"), those having 1 to 6 carbon atoms ("C1-C6 alkyl"), those having 2 to 6 carbon atoms ("C2-C6 alkyl"), or those having 1 to 4 carbon atoms ("C1-C4 alkyl"). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0040] As used herein, "alkylene" refers to the same residues as alkyl, but with divalency. Particular alkylene groups are those having 1 to 20 carbon atoms ("C1-C 20 alkylene), those having 1 to 10 carbon atoms ("C1-C 10 alkylene), those with 6 to 10 carbon atoms ("C6-C 10alkylene"), those having 1 to 6 carbon atoms ("C1-C6 alkylene"), those having 1 to 5 carbon atoms ("C1-C5 alkylene"), those having 1 to 4 carbon atoms ("C1-C4 alkylene"), or those having 1 to 3 carbon atoms ("C1-C3 alkylene"). Examples of alkylene include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), butylene (-CH2(CH2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), pentylene (-CH2(CH2)3CH2-), hexylene (-CH2(CH2)4CH2-), heptylene (-CH2(CH2)5CH2-), octylene (-CH2(CH2)6CH2-), and the like.

[0041] As used herein, unless otherwise specified, "alkenyl" refers to an alkyl group having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and a specified number of carbon atoms (i.e., C2-C6). 10 "C" means 2 to 10 carbon atoms), monovalent unsaturated, straight (i.e., unbranched) or branched hydrocarbon chains, or combinations thereof. Alkenyl groups may have the "cis" or "trans" configuration, or alternatively, the "E" or "Z" configuration. Particular alkenyl groups are those having 2 to 20 carbon atoms ("C2-C 20 alkenyl), those with 6 to 10 carbon atoms ("C6-C 10alkenyl"), those having 2 to 8 carbon atoms ("C-C alkenyl"), those having 2 to 6 carbon atoms ("C-C alkenyl"), or those having 2 to 4 carbon atoms ("C-C alkenyl"). Examples of alkenyl groups include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbut-1,3-dienyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, and the like.

[0042] As used herein, "alkenylene" refers to the same residues as alkenyl, but with divalency. Particular alkenylene groups are those having 2 to 20 carbon atoms ("C-C"). 20 alkenylene"), those having 2 to 10 carbon atoms ("C2-C 10 alkenylene"), those having 6 to 10 carbon atoms ("C6-C 10 alkenylene"), those having 2 to 6 carbon atoms ("C-C alkenylene"), those having 2 to 4 carbon atoms ("C-C alkenylene"), or those having 2 to 3 carbon atoms ("C-C alkenylene"). Examples of alkenylene include, but are not limited to, groups such as ethenylene (or vinylene) (-CH=CH-), propenylene (-CH=CHCH-), 1,4-but-1-enylene (-CH=CH-CHCH-), 1,4-but-2-enylene (-CHCH=CHCH-), 1,6-hex-1-enylene (-CH=CH-(CH)CH-).

[0043] As used herein, unless otherwise specified, "alkynyl" refers to an alkyl group having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and a specified number of carbon atoms (i.e., C-C). 10"C" means 2 to 10 carbon atoms), monovalent unsaturated straight (i.e., unbranched) or branched hydrocarbon chains, or combinations thereof. Particular alkynyl groups are those having 2 to 20 carbon atoms ("C2 to C6" means 2 to 10 carbon atoms), 20 alkynyl), those with 6 to 10 carbon atoms ("C6-C 10 alkynyl"), those having 2 to 8 carbon atoms ("C2-C8 alkynyl"), those having 2 to 6 carbon atoms ("C2-C6 alkynyl"), or those having 2 to 4 carbon atoms ("C2-C4 alkynyl"). Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.

[0044] As used herein, "alkynylene" refers to the same residues as alkynyl, but with divalency. Particular alkynylene groups are those having 2 to 20 carbon atoms ("C2-C 20 alkynylene"), those having 2 to 10 carbon atoms ("C2-C 10 alkynylene"), those having 6 to 10 carbon atoms ("C6-C 10 alkynylene"), those having 2 to 6 carbon atoms ("C-C alkynylene"), those having 2 to 4 carbon atoms ("C-C alkynylene"), or those having 2 to 3 carbon atoms ("C-C alkynylene"). Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetylenylene) (-C≡C-), propynylene (-C≡CCH-).

[0045] As used herein, unless otherwise specified, "cycloalkyl" refers to a group having a specified number of carbon atoms (i.e., C3-C6). 10means 3 to 10 carbon atoms). Cycloalkyl can consist of a single ring, such as cyclohexyl, or multiple rings, such as adamantyl. Cycloalkyls containing more than one ring may be fused, spiro, or bridged, or combinations thereof. Particular cycloalkyl groups are those having 3 to 12 ring carbon atoms. Preferred cycloalkyls are cyclic hydrocarbons having 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"), cyclic hydrocarbons having 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"), or cyclic hydrocarbons having 3 to 4 ring carbon atoms ("C3-C4 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0046] As used herein, "cycloalkylene" refers to the same residues as cycloalkyl, but with divalency. Cycloalkylene can consist of a single ring or multiple rings that may be fused, spiro, or bridged, or combinations thereof. Particular cycloalkylene groups are those having 3 to 12 ring carbon atoms. Preferred cycloalkylenes are cyclic hydrocarbons having 3 to 8 ring carbon atoms ("C3-C8 cycloalkylene"), 3 to 6 carbon atoms ("C3-C6 cycloalkylene"), or 3 to 4 ring carbon atoms ("C3-C4 cycloalkylene"). Examples of cycloalkylenes include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, and the like. Cycloalkylenes can be attached to the rest of the structure through the same ring carbon atom or different ring carbon atoms. When a cycloalkylene is attached to the rest of the structure through two different ring carbon atoms, the bonds can be cis or trans to each other, for example, cyclopropylene can include 1,1-cyclopropylene and 1,2-cyclopropylene (e.g., cis-1,2-cyclopropylene or trans-1,2-cyclopropylene), or mixtures thereof.

[0047] "Cycloalkenyl" means, unless otherwise specified, cycloalkenyl having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having a specified number of carbon atoms (i.e., C3-C6). 10 "C" refers to and includes monovalent unsaturated, cyclic, non-aromatic hydrocarbon structures ("C" means 3 to 10 carbon atoms). Cycloalkenyl can consist of one ring, such as cyclohexenyl, or multiple rings, such as norbornenyl. Preferred cycloalkenyls are unsaturated cyclic hydrocarbons having 3 to 8 ring carbon atoms ("C3-C8 cycloalkenyl"). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like.

[0048] As used herein, "cycloalkenylene" refers to the same residues as cycloalkenyl, but with divalency.

[0049] As used herein, "aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or an unsaturated aromatic carbocyclic group having multiple fused rings (which may or may not be aromatic) (e.g., naphthyl or anthryl). Particular aryl groups are those having 6 to 14 ring carbon atoms ("C6-C6"). 14 Aryl groups having two or more rings, where at least one ring is non-aromatic, can be attached to the parent structure at either an aromatic or non-aromatic ring position. In one variation, an aryl group having two or more rings, where at least one ring is non-aromatic, is attached to the parent structure at an aromatic ring position.

[0050] As used herein, "arylene" refers to the same residues as aryl, but with divalency. Particular arylene groups are those having 6 to 14 ring carbon atoms ("C6-C 14 arylene).

[0051] As used herein, "heteroaryl" refers to an unsaturated aromatic ring group having 1 to 14 ring carbon atoms and at least one ring heteroatom, including, but not limited to, heteroatoms such as nitrogen, oxygen, and sulfur. Heteroaryl groups can have a single ring (e.g., pyridyl, furyl) or multiple fused rings (which may or may not be aromatic) (e.g., indolizinyl, benzothienyl). Particular heteroaryl groups are 5- to 14-membered rings having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 10-membered rings having 1 to 8 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 5-, 6-, or 7-membered rings having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, certain heteroaryl groups are 5-, 6-, or 7-membered monocyclic aromatic rings having 1 to 6 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, certain heteroaryl groups are polycyclic aromatic rings having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heteroaryl groups having two or more rings, in which at least one ring is non-aromatic, can be attached to the parent structure at either an aromatic ring position or a non-aromatic ring position. In one variation, heteroaryl groups having two or more rings, in which at least one ring is non-aromatic, can be attached to the parent structure at an aromatic ring position. Heteroaryl groups can be attached to the parent structure at a ring carbon atom or a ring heteroatom.

[0052] As used herein, "heteroarylene" refers to the same residues as heteroaryl, but which have divalency.

[0053] As used herein, "heterocycle," "heterocyclic," or "heterocyclyl" refers to a saturated or unsaturated non-aromatic ring group having a single ring or multiple fused rings, 1 to 14 ring carbon atoms, and 1 to 6 ring heteroatoms such as nitrogen, sulfur, or oxygen. Heterocycles having more than one ring may be fused, bridged, or spiro, or combinations thereof, excluding heteroaryl groups. Heterocyclyl groups may be independently substituted with one or more substituents described herein. Particular heterocyclyl groups are 3- to 14-membered rings having 1 to 13 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 12-membered rings having 1 to 11 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 10-membered rings having 1 to 9 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 8-membered rings having 1 to 7 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 3- to 6-membered rings having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, heterocyclyl includes monocyclic 3-, 4-, 5-, 6-, or 7-membered rings having 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 ring carbon atoms and 1 to 2, 1 to 3, or 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, heterocyclyl includes polycyclic non-aromatic rings having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0054] As used herein, "heterocyclylene" refers to the same residues as heterocyclyl, but which have divalency.

[0055] "Halo" or "halogen" refers to Group 17 elements having atomic numbers 9-85. Preferred halo groups include radicals of fluorine, chlorine, bromine, and iodine. When a residue is substituted with more than one halogen, it may be designated with a prefix corresponding to the number of halogen moieties attached. For example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may, but need not, be the same halogen; thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced by a halo group is referred to as a "perhaloalkyl." A preferred perhaloalkyl group is trifluoromethyl (-CF3). Similarly, "perhaloalkoxy" refers to an alkoxy group in which a halogen replaces each H in the hydrocarbon comprising the alkyl portion of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

[0056] "Carbonyl" refers to the group C=O.

[0057] "Thiocarbonyl" refers to the group C=S.

[0058] "Oxo" refers to the moiety =O.

[0059] "D" stands for deuterium ( 2 H).

[0060] "T" stands for tritium ( 3 H).

[0061] An alkyl group in which each hydrogen is replaced by a deuterium is said to be "perdeuterated." An alkyl group in which each hydrogen is replaced by a tritium is said to be "pertritiated."

[0062] "Optionally substituted" means, unless otherwise specified, that the group is unsubstituted or optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group, where the substituents can be the same or different. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In another embodiment, the optionally substituted group has four substituents. In some embodiments, the optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, the optionally substituted group is unsubstituted.

[0063] It is understood that an optionally substituted moiety can be substituted with more than six substituents, if permitted by the number of valences available for substitution on the moiety. For example, a propyl group can be substituted with seven halogen atoms to provide a perhalopropyl group. The substituents can be the same or different.

[0064] As used herein, unless expressly indicated otherwise, the term "individual" refers to a mammal, including but not limited to a primate, human, bovine, equine, feline, canine, or rodent. In one variation, the individual is a human.

[0065] As used herein, "treatment" or "treating" refers to an approach to obtaining beneficial or desired results, including clinical results. Beneficial or desired results include, but are not limited to, one or more of the following: reducing one or more symptoms caused by a disease, reducing the severity of the disease, stabilizing the disease (e.g., preventing or slowing the progression of the disease), preventing or slowing the spread of the disease, delaying the onset or recurrence of the disease, slowing or slowing the progression of the disease, ameliorating the condition, providing remission (partial or total) of the disease, reducing the dose of one or more other drugs required to treat the disease, enhancing the effectiveness of another drug, slowing the progression of the disease, improving quality of life, and / or extending survival. "Treatment" also includes reducing the pathological consequences of fibrosis. The methods of the present invention contemplate any one or more of these therapeutic aspects.

[0066] As used herein, the term "effective amount" refers to the amount of the compound of the present invention that should be effective in a given treatment regimen.As understood in the art, an effective amount may be in one or more administrations, i.e., a single administration or multiple administrations may be required to achieve a desired therapeutic endpoint.An effective amount may be considered in relation to the administration of one or more therapeutic agents (e.g., a compound or its pharmaceutically acceptable salt), and a single agent may be considered to be administered in an effective amount when a desired or beneficial result can be achieved or is achieved in conjunction with one or more other agents.The appropriate dose of any of the co-administered compounds may be reduced in some cases due to the combined effects (e.g., additive or synergistic effects) of the compounds.

[0067] "Therapeutically effective amount" refers to that amount of a compound or salt thereof sufficient to effect the desired therapeutic result.

[0068] As used herein, "unit dosage form" refers to physically discrete units suitable as unitary dosages, each containing a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may include monotherapy or combination therapy.

[0069] As used herein, the term "controlled release" refers to a drug-containing formulation or fraction thereof in which the release of the drug is not immediate; i.e., administration of a "controlled release" formulation does not result in immediate release of the drug into the absorption pool. The term also encompasses depot formulations designed to gradually release the drug compound over an extended period of time. Controlled release formulations can encompass a variety of drug delivery systems, generally involving mixing the drug compound with a carrier, polymer, or other compound with the desired release characteristics (e.g., pH-dependent or non-pH-dependent solubility, different degrees of water solubility, etc.) and formulating the mixture according to the desired delivery route (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, etc.).

[0070] As used herein, "pharmaceutically acceptable" or "pharmacologically acceptable" means a material that is not biologically or otherwise undesirable, e.g., the material can be incorporated into a pharmaceutical composition administered to a patient without producing significant undesirable biological effects or interacting adversely with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients preferably have met the required standards of toxicology and manufacturing testing and / or are included in the Inactive Ingredient Guide established by the U.S. Food and Drug Administration.

[0071] "Pharmaceutically acceptable salts" are those salts that retain at least some of the biological activity of the free (non-salt) compound and can be administered to an individual as a drug or pharmaceutical. Such salts include, for example, (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, and the like; and (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth metal ion, or aluminum ion, or when coordinated with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Pharmaceutically acceptable salts may be prepared in situ during the manufacturing process or by reacting purified compounds of the present invention in their free acid or free base form with a suitable organic or inorganic base or acid, respectively, and then isolating the salt formed during purification.

[0072] As used herein, the term "excipient" refers to an inactive or non-active substance that can be used in the manufacture of a drug or pharmaceutical product, such as a tablet, containing a compound of the present invention as an active ingredient. The term excipient can encompass a variety of substances, including, but not limited to, substances used as binders, disintegrants, coatings, compression / encapsulation aids, creams or lotions, lubricants, parenteral solutions, chewable tablet materials, sweeteners or flavoring agents, suspending / gelling agents, or wet granulation agents. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coatings include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, Examples of lubricants include magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; examples of chewable tablet materials include dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; examples of suspending / gelling agents include carrageenan, sodium starch glycolate, xanthan gum, etc.; examples of sweeteners include aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; examples of wet granulating agents include calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0073] Unless otherwise specified, "substantially pure" intends a composition containing 10% or less impurities, for example, a composition containing less than 9%, 7%, 5%, 3%, 1%, 0.5% impurities.

[0074] Aspects and embodiments described herein as "comprising" are understood to encompass "consisting of" and "consisting essentially of" embodiments.

[0075] compound In one embodiment, the compound of formula (A): [ka] [In the formula, R 1 is C6~C 14 aryl or 5- to 10-membered heteroaryl, wherein the C6 to C 14 Aryl and 5- to 10-membered heteroaryl are R 1a may be replaced by; R 2 is hydrogen; deuterium; R 2a C1-C6 alkyl optionally substituted by -OH; R 2a -O-C1-C6 alkyl optionally substituted by R 2b C3-C6 cycloalkyl optionally substituted by R 2b -O-C3-C6 cycloalkyl optionally substituted by R 2c 3- to 12-membered heterocyclyl optionally substituted by -S(O)R 2d provided that the carbon atom directly bonded to the nitrogen atom is R other than halogen. 2a may be substituted with a moiety; Each R 1a are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-C 14 Aryl, deuterium, halogen, -CN, -OR 3 , -SR 3 , -NR 4 R 5 , -NO2, -C=NH(OR 3 ), -C(O)R 3 , -OC(O)R 3, -C(O)OR 3 , -C(O)NR 4 R 5 , -NR 3 C(O)R 4 , -NR 3 C(O)OR 4 , -NR 3 C(O)NR 4 R 5 , -S(O)R 3 , -S(O)2R 3 , -NR 3 S(O)R 4 , -NR 3 S(O)2R 4 , -S(O)NR 4 R 5 , -S(O)NR 4 R 5 , or -P(O)(OR 4 )(OR 5 ) where each R 1a are independently deuterium, halogen, oxo, -OR, if possible. 6 , -NR 6 R 7 , -C(O)R 6 , -CN, -S(O)R 6 , -S(O)2R 6 , -P(O)(OR 6 )(OR 7 ), C3-C8 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C6-C 14 optionally substituted by aryl, or C1-C6 alkyl optionally substituted by deuterium, oxo, —OH or halogen; Each R 2a , R 2b , R 2c , R 2e and R 2f are independently oxo or R 1a and; R 2d is R 2e C1-C6 alkyl optionally substituted by, or R 2f C3-C5 cycloalkyl optionally substituted by R 3are independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R 3 The C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C6 cycloalkyl, C6 to C 14 Aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from halogen, deuterium, oxo, -CN, -OR 8 , -NR 8 R 9 , -P(O)(OR 8 )(OR 9 ), or C1-C6 alkyl optionally substituted by deuterium, halogen, —OH or oxo; R 4 and R 5 are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R 4 and R 5 The C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C6 cycloalkyl, C6 to C 14 Aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from deuterium, halogen, oxo, -CN, -OR 8 , -NR 8 R 9 or C1-C6 alkyl optionally substituted by deuterium, halogen, —OH or oxo; or R 4 and R 5 together with the atom to which they are attached, deuterium, halogen, oxo, -OR 8 , -NR 8 R 9or a 3- to 6-membered heterocyclyl optionally substituted by C1-C6 alkyl optionally substituted by deuterium, halogen, oxo or -OH; R 6 and R 7 are each independently hydrogen, deuterium, or C1-C6 alkyl optionally substituted with deuterium, halogen, or oxo, or C2-C6 alkenyl optionally substituted with deuterium, halogen, or oxo, or C2-C6 alkynyl optionally substituted with deuterium, halogen, or oxo; or R 6 and R 7 together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted by deuterium, halogen, or oxo; R 8 and R 9 are each independently hydrogen, deuterium, or C1-C6 alkyl optionally substituted with deuterium, halogen, or oxo, or C2-C6 alkenyl optionally substituted with deuterium, halogen, or oxo, or C2-C6 alkynyl optionally substituted with deuterium, halogen, or oxo; or R 8 and R 9 together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted by deuterium, oxo, or halogen; Each R 10 , R 11 , R 12 and R 13 are independently hydrogen or deuterium; R 14 is deuterium; q is 0, 1, 2, 3, 4, 5, 6, 7 or 8; Each R 15 are independently selected from hydrogen, deuterium, or a halogen; Each R 16 are independently selected from hydrogen, deuterium, or a halogen; p is 3, 4, 5, 6, 7, 8, or 9] or a salt thereof.

[0076] In one variation, CO2H and NHR 1 In another variation, a compound of formula (A) or a salt thereof is provided, wherein the carbon bearing the moiety is in the "S" configuration. 1 Compounds of formula (A) or salts thereof are provided in which the carbon bearing the moiety is in the "R" configuration. Also included are mixtures of compounds of formula (A), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0077] In one variation of formula (A), R 2 has the proviso that the carbon atom directly bonded to the nitrogen atom is unsubstituted or substituted with deuterium.

[0078] In the description herein, it is understood that every statement, variation, embodiment, or aspect of one moiety can be combined with every statement, variation, embodiment, or aspect of any other moiety as if each and every combination of statements were specifically and individually set forth. For example, R 1 All descriptions, variations, embodiments, or aspects provided herein with respect to R are intended to be illustrative and not restrictive, and are not intended to be limiting unless each and every combination is specifically and individually set forth. 2 All descriptions, variations, embodiments or aspects of the present invention may be combined.

[0079] In one embodiment, the compound of formula (I): [ka] [In the formula, R 1 C6~C 14 aryl or 5- to 10-membered heteroaryl, wherein the C6 to C14 Aryl and 5- to 10-membered heteroaryl are R 1a may be replaced by; R 2 is R 2a C1-C6 alkyl optionally substituted by R 2b C3-C6 cycloalkyl optionally substituted by R 2c 3- to 12-membered heterocyclyl optionally substituted by -S(O)R 2d and; Each R 1a are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-C 14 Aryl, deuterium, halogen, -CN, -OR 3 , -SR 3 , -NR 4 R 5 , -NO2, -C=NH(OR 3 ), -C(O)R 3 , -OC(O)R 3 , -C(O)OR 3 , -C(O)NR 4 R 5 , -NR 3 C(O)R 4 , -NR 3 C(O)OR 4 , -NR 3 C(O)NR 4 R 5 , -S(O)R 3 , -S(O)2R 3 , -NR 3 S(O)R 4 , -NR 3 S(O)2R 4 , -S(O)NR 4 R 5 , -S(O)NR 4 R 5 , or -P(O)(OR 4 )(OR 5 ) where each R 1a are independently deuterium, halogen, oxo, -OR, if possible. 6 , -NR6 R 7 , -C(O)R 6 , -CN, -S(O)R 6 , -S(O)2R 6 , -P(O)(OR 6 )(OR 7 ), C3-C8 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C6-C 14 optionally substituted by aryl or C1-C6 alkyl optionally substituted by deuterium, oxo, —OH or halogen; Each R 2a , R 2b , R 2c , R 2e and R 2f are independently oxo or R 1a and; R 2d is R 2e C1-C6 alkyl optionally substituted by, or R 2f C3-C5 cycloalkyl optionally substituted by R 3 are independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R 3 The C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C6 cycloalkyl, C6 to C 14 Aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from halogen, deuterium, oxo, -CN, -OR 8 , -NR 8 R 9 , -P(O)(OR 8 )(OR 9 ), or C1-C6 alkyl optionally substituted by deuterium, halogen, —OH or oxo; R 4 and R 5are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R 4 and R 5 The C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C6 cycloalkyl, C6 to C 14 Aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from deuterium, halogen, oxo, -CN, -OR 8 , -NR 8 R 9 or C1-C6 alkyl optionally substituted by deuterium, halogen, —OH or oxo; or R 4 and R 5 together with the atom to which they are attached, deuterium, halogen, oxo, -OR 8 , -NR 8 R 9 or a 3- to 6-membered heterocyclyl optionally substituted by C1-C6 alkyl optionally substituted by deuterium, halogen, oxo or -OH; R 6 and R 7 are each independently hydrogen, deuterium, or C1-C6 alkyl optionally substituted with deuterium, halogen, or oxo, or C2-C6 alkenyl optionally substituted with deuterium, halogen, or oxo, or C2-C6 alkynyl optionally substituted with deuterium, halogen, or oxo; or R 6 and R 7 together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted by deuterium, halogen, or oxo; R 8 and R 9are each independently hydrogen, deuterium, or C1-C6 alkyl optionally substituted with deuterium, halogen, or oxo, or C2-C6 alkenyl optionally substituted with deuterium, halogen, or oxo, or C2-C6 alkynyl optionally substituted with deuterium, halogen, or oxo; or R 8 and R 9 together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted by deuterium, oxo, or halogen; Each R 10 , R 11 , R 12 and R 13 are independently hydrogen or deuterium; R 14 is deuterium; q is 0, 1, 2, 3, 4, 5, 6, 7 or 8; p is 3, 4, 5, 6, 7, 8, or 9] or a salt thereof.

[0080] In one variation, CO2H and NHR 1 In another variation, a compound of formula (I) or a salt thereof is provided, wherein the carbon bearing the moiety is in the "S" configuration. 1 Compounds of formula (I) or salts thereof are provided in which the carbon bearing the moiety is in the "R" configuration. Also included are mixtures of compounds of formula (I), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0081] In one variation of formula (I), R 2 The carbon atom directly bonded to the nitrogen atom is R other than halogen. 2a In one variation of formula (I), R 2includes the proviso that the carbon atom directly bonded to the nitrogen atom is unsubstituted or substituted with deuterium.

[0082] In the description herein, it is understood that every statement, variation, embodiment, or aspect of one moiety can be combined with every statement, variation, embodiment, or aspect of any other moiety as if each and every combination of statements were specifically and individually set forth. For example, R 1 All descriptions, variations, embodiments, or aspects provided herein with respect to R are intended to be illustrative and not restrictive, and are not intended to be limiting unless each and every combination is specifically and individually set forth. 2 All descriptions, variations, embodiments or aspects of the present invention may be combined.

[0083] In some embodiments of the compounds of Formula (I) or salts thereof, R 1a , R 2a , R 2b , R 2c , R 2e , R 2f , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 or R 16 At least one of these is deuterium.

[0084] In some embodiments of the compounds of Formula (I) or salts thereof, R 1 is R 1a In some embodiments, R is a 5- to 10-membered heteroaryl optionally substituted by 1 is R 1a In some embodiments, R 1 is R 1apyrimidin-4-yl optionally substituted by 1a is a 5-10 membered heteroaryl (e.g., pyrazolyl) or a C1-C6 alkyl optionally substituted with halogen (e.g., methyl, difluoromethyl, and trifluoromethyl). In some embodiments, R 1 is R 1a pyrimidin-4-yl optionally substituted by 1a is a 5-10 membered heteroaryl (e.g., pyrazolyl or pyridinyl) or a C1-C6 alkyl optionally substituted with halogen (e.g., methyl, difluoromethyl, and trifluoromethyl). In some embodiments, R 1 is pyrimidin-4-yl substituted with both methyl and trifluoromethyl. In some embodiments, R 1 is pyrimidin-4-yl substituted with both methyl and pyridinyl. In some embodiments, R 1 is R 1a pyrimidin-4-yl optionally substituted by 1a C6~C 14 aryl (e.g., phenyl). In some embodiments, R 1 is R 1a pyrimidin-4-yl optionally substituted by 1a is -CN. In some embodiments, R 1 is R 1a In some embodiments, R 1 is R 1a pyrimidin-2-yl optionally substituted by 1a is halogen, or C1-C6 alkyl optionally substituted with halogen (e.g., methyl or trifluoromethyl), or —CN, or C3-C8 cycloalkyl (e.g., cyclopropyl). In some embodiments of a compound of Formula (I) or a salt thereof, R 1 is R 1aIn some embodiments, R 1 is R 1a quinazolin-4-yl optionally substituted by 1a is halogen (e.g., fluoro and chloro), C1-C6 alkyl optionally substituted with halogen (e.g., methyl or trifluoromethyl), or C1-C6 alkoxy (e.g., methoxy). In some embodiments, R 1 is R 1a quinazolin-4-yl optionally substituted by 1a is a 5-10 membered heteroaryl (e.g., pyridinyl). In some embodiments, R 1 is R 1a In some embodiments, R is a pyrazolopyrimidinyl optionally substituted by 1 is R 1a pyrazolopyrimidinyl optionally substituted by, wherein R 1a is C1-C6 alkyl (e.g., methyl). 1 R 1a In some embodiments where R is indicated as being optionally substituted by 1 The R moiety is unsubstituted. 1 R 1a In some embodiments where R is indicated as being optionally substituted by 1 The part is one R 1a is replaced by R 1 R 1a In some embodiments where R is indicated as being optionally substituted by 1 The moieties may be the same or different and may consist of 2 to 6, 2 to 5, 2 to 4, or 2 to 3 R 1a is replaced by a part.

[0085] Variable Element R 1 In some embodiments of Formula (I), including embodiments that describe 10 , R 11 , R 12 and R13 are hydrogen. 1 , and / or variable R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (I), including those described below, q is 0. 1 , and / or variable R 10 , R 11 , R 12 and R 13 and / or in some embodiments, including those recited in variable q, p is 3, 4, or 5.

[0086] In some embodiments of Formula (I), R 10 , R 11 , R 12 and R 13 is hydrogen, p is 3, and q is 0, and the compound has the formula (II): [ka] [In the formula, R 1 and R 2 is as defined for formula (I). or a salt thereof.

[0087] R 1 R 1a In some embodiments of compounds of Formula (I) that are 5-10 membered heteroaryl optionally substituted by, the compound has the formula (IA): [ka] [In the formula, R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), and m is 0, 1, 2 or 3, and the positions on the pyrimidine ring and tetrahydronaphthyridine ring are indicated. or a salt thereof.

[0088] In one embodiment, there is provided a compound of formula (IA), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (IA), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (IA), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0089] In some embodiments of compounds of Formula (IA), m is 0, 1, 2, or 3, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of the compound of formula (IA), m is 0, 1, 2, or 3, and each R 1a are, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a wherein said C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5-10 membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of Formula (IA), m is 1, 2, or 3.

[0090] In some embodiments of the compounds of Formula (IA), m is 0. In some embodiments of the compounds of Formula (IA), m is 1 and R 1a In some embodiments of compounds of Formula (IA), m is 1 and R 1ais at the 5-position. In some embodiments of compounds of Formula (IA), m is 1 and R 1a is at the 6-position. In some embodiments of compounds of Formula (IA), m is 2 and the group R 1a In some embodiments of compounds of Formula (IA), m is 2 and the group R 1a In some embodiments of compounds of Formula (IA), m is 2 and the group R 1a are at positions 5 and 6. In some embodiments of compounds of formula (IA), m is 3 and the group R 1a are at positions 2, 5 and 6. Two or more groups R 1a Whenever present, the group R 1a can be independently selected. In any of these embodiments of the compound of formula (IA) or a salt thereof, the carbons bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0091] Variable Element R 1a In some embodiments of Formula (IA), including embodiments recited in R 10 , R 11 , R 12 and R 13 are hydrogen. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (IA), including those embodiments that describe: q is 0. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 and / or p is 3, 4, or 5 in some embodiments of formula (IA), including embodiments recited in variable q.

[0092] In some embodiments of Formula (IA), R 10 , R 11 , R 12 and R13 is hydrogen, p is 3, and q is 0, and the compound has formula (II-A): [ka] [In the formula, R 1a and R 2 is as defined for formula (I), m is 0, 1, 2 or 3, and the position on the pyrimidine ring is indicated. or a salt thereof. 1a , R 2 and m all apply to formulas (IA) and (II-A) as well.

[0093] R 1 R 1a In some embodiments of compounds of Formula (I) that are 5-10 membered heteroaryl optionally substituted by, the compound has the formula (IB): [ka] [In the formula, R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), and m is 0, 1, 2, 3, 4 or 5, and the position on the quinazoline ring is indicated. or a salt thereof.

[0094] In one embodiment, there is provided a compound of formula (IB), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (IB), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (IB), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0095] In some embodiments of compounds of Formula (IB), m is 0, 1, 2, 3, 4, or 5, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of the compound of formula (IB), m is 0, 1, 2, 3, 4, or 5, and each R 1a are, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5-10 membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of compounds of formula (IB), m is 1, 2, 3, 4, or 5.

[0096] In some embodiments of the compound of Formula (IB), m is 0. In some embodiments of the compound of Formula (IB), m is 1 and R 1a In some embodiments of compounds of Formula (IB), m is 1 and R 1a In some embodiments of compounds of Formula (IB), m is 1 and R 1a is at the 6-position. In some embodiments of compounds of Formula (IB), m is 1 and R 1a is at the 7-position. In some embodiments of compounds of Formula (IB), m is 1 and R 1a is at position 8. In some embodiments of compounds of Formula (IB), m is 2 and the group R 1a In some embodiments of compounds of formula (IB), m is 2 and the group R 1aIn some embodiments of compounds of formula (IB), m is 2 and the group R 1a are at positions 2 and 7. In some embodiments of compounds of formula (IB), m is 2 and the group R 1a are at positions 2 and 8. In some embodiments of compounds of formula (IB), m is 2 and the group R 1a are at positions 5 and 6. In some embodiments of compounds of formula (IB), m is 2 and the group R 1a are at positions 5 and 7. In some embodiments of compounds of formula (IB), m is 2 and the group R 1a are at positions 5 and 8. In some embodiments of compounds of formula (IB), m is 2 and the group R 1a are at positions 6 and 7. In some embodiments of compounds of formula (IB), m is 2 and the group R 1a are at positions 6 and 8. In some embodiments of compounds of formula (IB), m is 2 and the group R 1a are at positions 7 and 8. In some embodiments of compounds of formula (IB), m is 3 and the group R 1a are at positions 2, 5, and 6. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1a are at positions 2, 5, and 7. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1a are at positions 2, 5, and 8. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1a are at positions 2, 6, and 7. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1a are at positions 2, 6, and 8. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1a are at positions 2, 7, and 8. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1a are at positions 5, 6 and 7. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1aare at positions 5, 6 and 8. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1a are at positions 5, 7 and 8. In some embodiments of compounds of formula (IB), m is 3 and the groups R 1a are at positions 6, 7, and 8. In some embodiments of compounds of formula (IB), m is 4 and the groups R 1a are at positions 2, 5, 6 and 7. In some embodiments of compounds of formula (IB), m is 4 and the groups R 1a are at positions 2, 5, 6 and 8. In some embodiments of compounds of formula (IB), m is 4 and the groups R 1a are at positions 2, 5, 7 and 8. In some embodiments of compounds of formula (IB), m is 4 and the groups R 1a are at positions 2, 6, 7 and 8. In some embodiments of compounds of formula (IB), m is 4 and the groups R 1a are at positions 5, 6, 7 and 8. In some embodiments of compounds of formula (IB), m is 5 and the groups R 1a are at positions 2, 5, 6, 7 and 8. Two or more groups R 1a Whenever present, the group R 1a can be independently selected. In any of these embodiments of a compound of formula (IB) or a salt thereof, the carbons bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0097] Variable Element R 1a In some embodiments of formula (IB), including embodiments recited in R 10 , R 11 , R 12 and R 13 are hydrogen. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (IB), including those embodiments that describe: q is 0. Variable R 1aand m, and / or variable R 10 , R 11 , R 12 and R 13 and / or p is 3, 4, or 5 in some embodiments of formula (IB), including embodiments recited in variable q.

[0098] In some embodiments of Formula (IB), R 10 , R 11 , R 12 and R 13 is hydrogen, p is 3, and q is 0, and the compound has formula (II-B): [ka] [In the formula, R 1a and R 2 is as defined for formula (I), m is 0, 1, 2, 3, 4 or 5, and the position on the quinazoline ring is indicated. or a salt thereof. 1a , R 2 and m all apply to formulas (IB) and (II-B) as well.

[0099] R 1 R 1a In some embodiments of the compound of Formula (I), the compound is a 5-10 membered heteroaryl optionally substituted by formula (IC): [ka] [In the formula, R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), and m is 0, 1, 2, 3, or 4, and the position on the pyrido[3,2-d]pyrimidine ring is indicated. or a salt thereof.

[0100] In one embodiment, there is provided a compound of formula (IC), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (IC), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (IC), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0101] In some embodiments of compounds of Formula (IC), m is 0, 1, 2, 3, or 4, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of a compound of formula (IC), m is 0, 1, 2, 3, or 4, and each R 1a are, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5-10 membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of a compound of formula (IC), m is 1, 2, 3, or 4.

[0102] In some embodiments of the compounds of Formula (IC), m is 0. In some embodiments of the compounds of Formula (IC), m is 1 and R 1a In some embodiments of compounds of Formula (IC), m is 1 and R 1a is at the 6-position. In some embodiments of compounds of Formula (IC), m is 1 and R1a is at the 7-position. In some embodiments of compounds of Formula (IC), m is 1 and R 1a is at position 8. In some embodiments of compounds of formula (IC), m is 2 and the group R 1a In some embodiments of compounds of formula (IC), m is 2 and the group R 1a are at positions 2 and 7. In some embodiments of compounds of formula (IC), m is 2 and the group R 1a In some embodiments of compounds of formula (IC), m is 2 and the group R 1a are at positions 6 and 7. In some embodiments of compounds of formula (IC), m is 2 and the group R 1a are at positions 6 and 8. In some embodiments of compounds of formula (IC), m is 2 and the group R 1a are at positions 7 and 8. In some embodiments of compounds of formula (IC), m is 3 and the group R 1a are at positions 2, 6, and 7. In some embodiments of compounds of formula (IC), m is 3 and the groups R 1a are at positions 2, 6, and 8. In some embodiments of compounds of formula (IC), m is 3 and the groups R 1a are at positions 2, 7, and 8. In some embodiments of compounds of formula (IC), m is 3 and the groups R 1a are at positions 6, 7 and 8. In some embodiments of compounds of formula (IC), m is 4 and the groups R 1a are at positions 2, 6, 7 and 8. Two or more groups R 1a Whenever present, the group R 1a can be independently selected. In any of these embodiments of a compound of formula (IC) or a salt thereof, the carbons bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0103] Variable Element R 1a In some embodiments of formula (IC), including embodiments recited in R 10 , R 11, R 12 and R 13 are hydrogen. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (IC), including those embodiments that describe: q is 0. Variable R 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 and / or in some embodiments of formula (IC), including embodiments reciting variable q, p is 3, 4, or 5.

[0104] In some embodiments of Formula (IC), R 10 , R 11 , R 12 and R 13 is hydrogen, p is 3, and q is 0, and the compound has formula (II-C): [ka] [In the formula, R 1a and R 2 is as defined for formula (I), and m is 0, 1, 2, 3, or 4, and the position on the pyrido[3,2-d]pyrimidine ring is indicated. or a salt thereof. 1a , R 2 and m all apply to formulas (IC) and (II-C) as well.

[0105] R 1 R 1a In some embodiments of the compound of Formula (I), the compound is a 5-10 membered heteroaryl optionally substituted by: [ka] [In the formula, R 1a , R 2 , R10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), and m is 0, 1, 2, 3, or 4, and the position on the pyrido[3,4-d]pyrimidine ring is indicated. or a salt thereof.

[0106] In one embodiment, there is provided a compound of formula (ID), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (ID), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (ID), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0107] In some embodiments of compounds of Formula (ID), m is 0, 1, 2, 3, or 4, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of the compound of formula (ID), m is 0, 1, 2, 3, or 4, and each R 1a are, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5-10 membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of the compound of formula (ID), m is 1, 2, 3, or 4.

[0108] In some embodiments of the compounds of Formula (ID), m is 0. In some embodiments of the compounds of Formula (ID), m is 1 and R 1a is at position 2. In some embodiments of compounds of Formula (ID), m is 1 and R 1a is at the 5-position. In some embodiments of compounds of Formula (ID), m is 1 and R 1a is at the 6-position. In some embodiments of compounds of Formula (ID), m is 1 and R 1a is at position 8. In some embodiments of compounds of formula (ID), m is 2 and the group R 1a are at positions 2 and 5. In some embodiments of compounds of formula (ID), m is 2 and the group R 1a are at positions 2 and 6. In some embodiments of compounds of formula (ID), m is 2 and the group R 1a In some embodiments of compounds of formula (ID), m is 2 and the group R 1a are at positions 5 and 6. In some embodiments of compounds of formula (ID), m is 2 and the group R 1a are at positions 5 and 8. In some embodiments of compounds of formula (ID), m is 2 and the group R 1a are at positions 6 and 8. In some embodiments of compounds of formula (ID), m is 3 and the group R 1a are at positions 2, 5, and 6. In some embodiments of compounds of formula (ID), m is 3 and the groups R 1a are at positions 2, 5, and 8. In some embodiments of compounds of formula (ID), m is 3 and the groups R 1a are at positions 2, 6, and 8. In some embodiments of compounds of formula (ID), m is 3 and the groups R 1a are at positions 5, 6 and 8. In some embodiments of compounds of formula (ID), m is 4 and the groups R 1a are at positions 2, 5, 6 and 8. Two or more groups R 1a Whenever present, the group R 1acan be independently selected. In any of these embodiments of a compound of formula (ID) or a salt thereof, the carbons bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0109] Variable Element R 1a In some embodiments of formula (ID), including those recited in R 10 , R 11 , R 12 and R 13 are hydrogen. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (ID), including those embodiments that describe: q is 0. Variable R 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 and / or in some embodiments of formula (ID), including embodiments reciting variable q, p is 3, 4, or 5.

[0110] In some embodiments of Formula (ID), R 10 , R 11 , R 12 and R 13 is water, p is 3, and q is 0, and the compound has formula (II-D): [ka] [In the formula, R 1a and R 2 is as defined for formula (I), m is 0, 1, 2, 3 or 4, and the position on the pyrido[3,4-d]pyrimidine ring is indicated. or a salt thereof. 1a , R 2 and m all apply to formulas (ID) and (II-D) as well.

[0111] R 1 R 1a In some embodiments of compounds of Formula (I) that are 5-10 membered heteroaryl optionally substituted by, the compound has the formula (IE): [ka] [In the formula, R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), and m is 0, 1, 2, 3, or 4, and the position on the pyrido[2,3-d]pyrimidine ring is indicated. or a salt thereof.

[0112] In one embodiment, there is provided a compound of formula (IE), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (IE), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (IE), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0113] In some embodiments of compounds of Formula (IE), m is 0, 1, 2, 3, or 4, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of the compound of formula (IE), m is 0, 1, 2, 3, or 4, and each R 1aare, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5-10 membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of compounds of formula (IE), m is 1, 2, 3, or 4.

[0114] In some embodiments of the compounds of Formula (IE), m is 0. In some embodiments of the compounds of Formula (IE), m is 1 and R 1a is at position 2. In some embodiments of compounds of Formula (IE), m is 1 and R 1a is at the 5-position. In some embodiments of compounds of Formula (IE), m is 1 and R 1a is at the 6-position. In some embodiments of compounds of Formula (IE), m is 1 and R 1a is at the 7-position. In some embodiments of compounds of Formula (IE), m is 2 and the group R 1a are at positions 2 and 5. In some embodiments of compounds of formula (IE), m is 2 and the group R 1a are at positions 2 and 6. In some embodiments of compounds of formula (IE), m is 2 and the group R 1a are at positions 2 and 7. In some embodiments of compounds of formula (IE), m is 2 and the group R 1a are at positions 5 and 6. In some embodiments of compounds of formula (IE), m is 2 and the group R 1a are at positions 5 and 7. In some embodiments of compounds of formula (IE), m is 2 and the group R 1a are at positions 6 and 7. In some embodiments of compounds of formula (IE), m is 3 and the group R 1a are at positions 2, 5 and 6. In some embodiments of compounds of formula (IE), m is 3 and the groups R1a are at positions 2, 5, and 7. In some embodiments of compounds of formula (IE), m is 3 and the groups R 1a are at positions 2, 6, and 7. In some embodiments of compounds of formula (IE), m is 3 and the groups R 1a are at positions 5, 6 and 7. In some embodiments of compounds of formula (IE), m is 4 and the groups R 1a are at positions 2, 5, 6 and 7. Two or more groups R 1a Whenever present, the group R 1a can be independently selected. In any of these embodiments of a compound of formula (IE) or a salt thereof, the carbons bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0115] Variable Element R 1a In some embodiments of formula (IE), including embodiments recited in R 10 , R 11 , R 12 and R 13 are hydrogen. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (IE), including those embodiments that describe: q is 0. Variable R 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 and / or in some embodiments of formula (IE), including embodiments recited variable q, p is 3, 4, or 5.

[0116] In some embodiments of Formula (IE), R 10 , R 11 , R 12 and R 13 is water, p is 3, and q is 0, and the compound has formula (II-E): [ka] [In the formula, R 1a and R 2 is as defined for formula (I), m is 0, 1, 2, 3 or 4, and the position on the pyrido[2,3-d]pyrimidine ring is indicated. or a salt thereof. 1a , R 2 and m all apply to formulas (IE) and (II-E) as well.

[0117] R 1 R 1a In some embodiments of a compound of Formula (I), the compound has the formula (IF): [ka] [In the formula, R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), and m is 0, 1, 2, 3, 4, 5 or 6, and the position on the quinoline ring is indicated. or a salt thereof.

[0118] In one embodiment, there is provided a compound of formula (IF), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (IF), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (IF), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0119] In some embodiments of compounds of Formula (IF), m is 0, 1, 2, 3, 4, 5, or 6; and each R 1aare independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of the compound of formula (IF), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1a are, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a wherein said C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5-10 membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of a compound of formula (IF), m is 1, 2, 3, 4, 5, or 6.

[0120] In some embodiments of the compounds of Formula (IF), m is 0. In some embodiments of the compounds of Formula (IF), m is 1 and R 1a In some embodiments of compounds of Formula (IF), m is 1 and R 1a In some embodiments of compounds of Formula (IF), m is 1 and R 1a In some embodiments of compounds of Formula (IF), m is 1 and R 1a In some embodiments of compounds of Formula (IF), m is 1 and R 1a is at the 7-position. In some embodiments of compounds of Formula (IF), m is 1 and R 1a is at position 8. In some embodiments of compounds of formula (IF), m is 2 and the group R 1a In some embodiments of compounds of formula (IF), m is 2 and the group R 1aIn some embodiments of compounds of formula (IF), m is 2 and the group R 1a In some embodiments of compounds of formula (IF), m is 2 and the group R 1a In some embodiments of compounds of formula (IF), m is 2 and the group R 1a In some embodiments of compounds of formula (IF), m is 2 and the group R 1a In some embodiments of compounds of formula (IF), m is 2 and the group R 1a are at positions 3 and 6. In some embodiments of compounds of formula (IF), m is 2 and the group R 1a are at positions 3 and 7. In some embodiments of compounds of formula (IF), m is 2 and the group R 1a are at positions 3 and 8. In some embodiments of compounds of formula (IF), m is 2 and the group R 1a are at positions 5 and 6. In some embodiments of compounds of formula (IF), m is 2 and the group R 1a are at positions 5 and 7. In some embodiments of compounds of formula (IF), m is 2 and the group R 1a are at positions 5 and 8. In some embodiments of compounds of formula (IF), m is 2 and the group R 1a are at positions 6 and 7. In some embodiments of compounds of formula (IF), m is 2 and the group R 1a are at positions 6 and 8. In some embodiments of compounds of formula (IF), m is 2 and the group R 1a are at positions 7 and 8. In some embodiments of compounds of formula (IF), m is 3 and the group R 1a are at positions 2, 3 and 5. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 3 and 6. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 3 and 7. In some embodiments of compounds of formula (IF), m is 3 and the groups R1a are at positions 2, 3 and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 5 and 6. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 5, and 7. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 5, and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 6, and 7. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 6, and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 2, 7, and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 3, 5 and 6. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 3, 5 and 7. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 3, 5 and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 3, 6 and 7. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 3, 6 and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 3, 7 and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 5, 6 and 7. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 5, 6 and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1a are at positions 5, 7 and 8. In some embodiments of compounds of formula (IF), m is 3 and the groups R 1aare at positions 6, 7 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 3, 5 and 6. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 3, 5 and 7. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 3, 5 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 3, 6 and 7. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 3, 6 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 3, 7 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 5, 6 and 7. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 5, 6 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 5, 7 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 2, 6, 7 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 3, 5, 6 and 7. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 3, 5, 6 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 3, 5, 7 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1a are at positions 3, 6, 7 and 8. In some embodiments of compounds of formula (IF), m is 4 and the groups R 1aare at positions 5, 6, 7 and 8. In some embodiments of compounds of formula (IF), m is 5 and the groups R 1a are at positions 2, 3, 5, 6 and 7. In some embodiments of compounds of formula (IF), m is 5 and the groups R 1a are at positions 2, 3, 5, 6 and 8. In some embodiments of compounds of formula (IF), m is 5 and the groups R 1a are at positions 2, 3, 5, 7 and 8. In some embodiments of compounds of formula (IF), m is 5 and the groups R 1a are at positions 2, 3, 6, 7 and 8. In some embodiments of compounds of formula (IF), m is 5 and the groups R 1a are at positions 2, 5, 6, 7 and 8. In some embodiments of compounds of formula (IF), m is 5 and the groups R 1a are at positions 3, 5, 6, 7 and 8. In some embodiments of compounds of formula (IF), m is 6 and the groups R 1a are at positions 2, 3, 5, 6, 7 and 8. Two or more groups R 1a Whenever present, the group R 1a can be independently selected. In any of these embodiments of a compound of formula (IF) or a salt thereof, the carbons bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0121] Variable Element R 1a In some embodiments of Formula (IF), including embodiments recited in R 10 , R 11 , R 12 and R 13 are hydrogen. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (IF), including those embodiments that state: 1a and m, and / or variable R 10 , R 11 , R12 and R 13 and / or in some embodiments of formula (IF), including embodiments reciting variable q, p is 3, 4, or 5.

[0122] In some embodiments of Formula (IF), R 10 , R 11 , R 12 and R 13 is hydrogen, p is 3, and q is 0, and the compound has formula (II-F): [ka] [In the formula, R 1a and R 2 is as defined for formula (I), m is 0, 1, 2, 3, 4, 5 or 6, and the position on the quinoline ring is indicated. or a salt thereof. 1a , R 2 and m all apply to formulas (IF) and (II-F) as well.

[0123] R 1 R 1a In some embodiments of compounds of Formula (I) that are 5-10 membered heteroaryl optionally substituted by, the compound has the formula (IG): [ka] [In the formula, R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), and m is 0, 1, 2, 3, 4, 5, or 6, and the position on the isoquinoline ring is indicated. or a salt thereof.

[0124] In one embodiment, there is provided a compound of formula (IG), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (IG), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (IG), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0125] In some embodiments of compounds of Formula (IG), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of the compound of formula (IG), m is 0, 1, 2, 3, 4, 5, or 6, and each R 1a are, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5-10 membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of compounds of formula (IG), m is 1, 2, 3, 4, 5, or 6.

[0126] In some embodiments of the compounds of Formula (IG), m is 0. In some embodiments of the compounds of Formula (IG), m is 1 and R 1a is at the 3-position. In some embodiments of compounds of Formula (IG), m is 1 and R 1a In some embodiments of compounds of Formula (IG), m is 1 and R1a is at the 5-position. In some embodiments of compounds of Formula (IG), m is 1 and R 1a is at the 6-position. In some embodiments of compounds of Formula (IG), m is 1 and R 1a is at the 7-position. In some embodiments of compounds of Formula (IG), m is 1 and R 1a is at position 8. In some embodiments of compounds of Formula (IG), m is 2 and the group R 1a are at positions 3 and 4. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 4 and 5. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 4 and 6. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 4 and 7. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 4 and 8. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 3 and 5. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 3 and 6. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 3 and 7. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 3 and 8. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 5 and 6. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 5 and 7. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 5 and 8. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 6 and 7. In some embodiments of compounds of formula (IG), m is 2 and the group R 1aare at positions 6 and 8. In some embodiments of compounds of formula (IG), m is 2 and the group R 1a are at positions 7 and 8. In some embodiments of compounds of formula (IG), m is 3 and the group R 1a are at positions 3, 4 and 5. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 4 and 6. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 4 and 7. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 4, and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 4, 5 and 6. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 4, 5 and 7. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 4, 5 and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 4, 6, and 7. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 4, 6, and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 4, 7, and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 5 and 6. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 5, and 7. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 5, and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 6, and 7. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1aare at positions 3, 6, and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 3, 7, and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 5, 6 and 7. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 5, 6 and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 5, 7, and 8. In some embodiments of compounds of formula (IG), m is 3 and the groups R 1a are at positions 6, 7 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 4, 5 and 6. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 4, 5 and 7. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 4, 5 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 4, 6 and 7. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 4, 3, 6 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 4, 7 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 4, 5, 6 and 7. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 4, 5, 6 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 4, 5, 7 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1aare at positions 4, 6, 7 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 5, 6 and 7. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 5, 6 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a are at positions 3, 5, 7 and 8. In some embodiments of compounds of formula (IG), m is 4 and the groups R 1a In some embodiments of compounds of formula (IG), m is 4 and the group R 1a are at positions 5, 6, 7 and 8. In some embodiments of compounds of formula (IG), m is 5 and the groups R 1a are at positions 3, 4, 5, 6 and 7. In some embodiments of compounds of formula (IG), m is 5 and the groups R 1a are at positions 3, 4, 5, 6 and 8. In some embodiments of compounds of formula (IG), m is 5 and the groups R 1a are at positions 3, 4, 5, 7 and 8. In some embodiments of compounds of formula (IG), m is 5 and the groups R 1a are at positions 3, 4, 6, 7 and 8. In some embodiments of compounds of formula (IG), m is 5 and the groups R 1a are at positions 4, 5, 6, 7 and 8. In some embodiments of compounds of formula (IG), m is 5 and the groups R 1a are at positions 3, 5, 6, 7 and 8. In some embodiments of compounds of formula (IG), m is 6 and the groups R 1a are at positions 3, 4, 5, 6, 7 and 8. Two or more groups R 1a Whenever present, the group R 1a can be independently selected. In any of these embodiments, in a compound of formula (IG) or a salt thereof, the carbon bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0127] Variable Element R1a In some embodiments of Formula (IG), including embodiments recited in R 10 , R 11 , R 12 and R 13 are hydrogen. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (IG), including those embodiments that describe: q is 0. Variable R 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 and / or in some embodiments of formula (IG), including embodiments recited variable q, p is 3, 4, or 5.

[0128] In some embodiments of Formula (IG), R 10 , R 11 , R 12 and R 13 is hydrogen, p is 3, and q is 0, and the compound has formula (II-G): [ka] [In the formula, R 1a and R 2 is as defined for formula (I), m is 0, 1, 2, 3, 4, 5 or 6, and the position on the isoquinoline ring is indicated. or a salt thereof. 1a , R 2 and m all apply to formulas (IG) and (II-G) as well.

[0129] R 1 R 1a In some embodiments of compounds of Formula (I), the compound is a 5-10 membered heteroaryl optionally substituted by: [ka] [In the formula, R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined for formula (I), m is 0, 1 or 2, and the position on the 1-methyl-1H-pyrazolo[3,4-d]pyrimidine ring is indicated. or a salt thereof.

[0130] In one embodiment, there is provided a compound of formula (IH), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (IH), or a salt thereof, wherein the carbon bearing the COH and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (IH), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0131] In some embodiments of compounds of Formula (IH), m is 0, 1, or 2, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of a compound of formula (IH), m is 0, 1, or 2, and each R 1a are, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1awherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5-10 membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of compounds of Formula (IH), m is 1 or 2.

[0132] In some embodiments of the compounds of Formula (IH), m is 0. In some embodiments of the compounds of Formula (IH), m is 1 and R 1a is at position 3. In some embodiments of compounds of Formula (IH), m is 1 and R 1a is at the 6-position. In some embodiments of compounds of Formula (IH), m is 2 and the group R 1a are at positions 3 and 6. Two or more groups R 1a Whenever present, the group R 1a can be independently selected. In any of these embodiments of a compound of formula (IH) or a salt thereof, the carbons bearing the COH and NH moieties can be in the "S" or "R" configuration.

[0133] Variable Element R 1a In some embodiments of Formula (IH), including embodiments recited in R 10 , R 11 , R 12 and R 13 are hydrogen. 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 In some embodiments of Formula (IH), including those embodiments that describe: q is 0. Variable R 1a and m, and / or variable R 10 , R 11 , R 12 and R 13 and / or p is 3, 4, or 5 in some embodiments of formula (IH), including embodiments recited in formula (IH) above.

[0134] In some embodiments of Formula (IH), R 10 , R 11 , R 12 and R 13 is hydrogen, p is 3, and q is 0, and the compound has formula (II-H): [ka] [In the formula, R 1a and R 2 is as defined for formula (I), m is 0, 1 or 2, and the position on the 1-methyl-1H-pyrazolo[3,4-d]pyrimidine ring is indicated. or a salt thereof. 1a , R 2 and m all apply to formulas (IH) and (II-H) as well.

[0135] R 1 R 1a Also provided are compounds of Formula (I) or (II), or salts thereof, wherein R is a 5- to 10-membered heteroaryl optionally substituted by 1 is an unsubstituted 5-10 membered heteroaryl (e.g., pyridinyl, pyrimidinyl, quinoxalinyl, quinazolinyl, pyrazolopyrimidinyl, quinolinyl, pyridopyrimidinyl, thienopyrimidinyl, pyridinyl, pyrrolopyrimidinyl, benzothiazolyl, isoquinolinyl, purinyl, or benzoxazolyl). 1 is 1, 2, 3, 4 or 5 groups R, which may be the same or different 1a wherein each R 1a are 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, -OR3 (e.g., -OCH3), and -NR 4 R 5 (e.g., —N(CH3)2). In some embodiments, R 1 is 1, 2, 3 or 4 groups R selected from -CH3, -CH2F, -CHF2, and -CF3, which may be the same or different; 1a In some embodiments, R is a 5-membered heteroaryl (e.g., pyrazolyl) substituted by 1 may be the same or different, halogen (e.g., fluoro, chloro, or bromo), C3-C6 cycloalkyl (e.g., cyclopropyl), 5-6 membered heteroaryl (e.g., pyridinyl or pyrazolyl), C6-C 10 Aryl (e.g., phenyl), C1-C4 alkyl optionally substituted with halogen (e.g., —CH3, —CF3 or C(CH3)3), —CN, —OR 3 (e.g., -OCH3), and -NR 4 R 5 (e.g., —N(CH3)2) 1a In some embodiments, R is a 6-position heteroaryl (e.g., pyridinyl, pyrimidinyl, or pyrazinyl) substituted by 1 is 1, 2, 3, 4 or 5 groups R selected from -CH3, -CH2F, -CHF2, and -CF3, which may be the same or different; 1a In some embodiments, R is a 9-membered heteroaryl substituted by (e.g., pyrazolopyrimidinyl, pyrrolopyrimidinyl, thienopyrimidinyl, indazolyl, indolyl, or benzimidazolyl). 1 are the same or different and include halogen (e.g., fluoro or chloro), 5- to 6-membered heteroaryl (e.g., pyridinyl), C alkyl optionally substituted by halogen (e.g., —CH or —CF), and —OR 3 (e.g., —OCH3) 1aand 10-membered heteroaryl substituted with (eg, quinazolinyl).

[0136] R 1 but, [ka] Also provided are compounds of formula (I) or (II) or salts thereof, wherein R is selected from the group consisting of any of the above groups in which one or more hydrogen atoms are replaced by deuterium atoms. 1 Also provided are compounds of formula (I) or (II) or salts thereof selected from any of the above groups, wherein one or more hydrogen atoms are replaced with tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon of the above groups can be replaced with a corresponding isotope, such as deuterium or tritium. Each hydrogen bonded to a non-ring carbon of the above groups, such as a methyl or methoxy carbon, can be replaced with a corresponding isotope, such as deuterium or tritium. Also, for example, the above groups can be perdeuterated, where all hydrogens therein are replaced with deuterium, or part-lithiated, where all hydrogens therein are replaced with tritium. In some embodiments, one or more ring carbons of the above groups can be 13 For example, in the polycyclic rings of the above groups, one or more ring carbons of the ring directly bonded to the remainder of the compound may be replaced by C. 13 In the polycyclic rings of the above groups, one or more ring carbons in the ring substituting or fused to the ring bonded to the remainder of the compound may be replaced by C. 13 C. Also, for example, all ring carbons of the above groups can be replaced by 13 It can be replaced by C.

[0137] R 1 but, [ka] Also provided are compounds of formula (I) or (II) or salts thereof, wherein R is selected from the group consisting of any of the above groups in which one or more hydrogen atoms are replaced by deuterium atoms. 1 Also provided are compounds of formula (I) or (II) or salts thereof, wherein the compound is selected from any of the above groups in which one or more hydrogen atoms have been replaced with tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon of the above groups can be replaced with a corresponding isotope, such as deuterium or tritium. Each hydrogen bonded to a non-ring carbon of the above groups, such as a methyl or methoxy carbon, can be replaced with a corresponding isotope, such as deuterium or tritium. Also, for example, the above groups can be per-deuterated, in which all hydrogens therein are replaced with deuterium, or part-lithiated, in which all hydrogens therein are replaced with tritium. In some embodiments, one or more ring carbons of the above groups can be 13 For example, in the polycyclic rings of the above groups, one or more ring carbons of the ring directly bonded to the remainder of the compound may be replaced by C. 13 In the polycyclic rings of the above groups, one or more ring carbons in the ring substituting or fused to the ring bonded to the remainder of the compound may be replaced by C. 13 C. Also, for example, all ring carbons of the above groups can be replaced by 13 It can be replaced by C.

[0138] R 1 but, [ka] Also provided are compounds of formula (I) or (II) or salts thereof, wherein R is selected from the group consisting of any of the above groups in which one or more hydrogen atoms are replaced by deuterium atoms. 1Also provided are compounds of formula (I) or (II) or salts thereof, wherein the compound is selected from any of the above groups, wherein one or more hydrogen atoms are replaced with tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon of the above groups can be replaced with a corresponding isotope, such as deuterium or tritium. Each hydrogen bonded to a non-ring carbon of the above groups, such as a methyl or methoxy carbon, can be replaced with a corresponding isotope, such as deuterium or tritium. Also, for example, the above groups can be per-deuterated, where all hydrogens are replaced with deuterium, or per-lithiated, where all hydrogens are replaced with tritium. In some embodiments, one or more ring carbons of the above groups can be 13 For example, in the polycyclic rings of the above groups, one or more ring carbons of the ring directly bonded to the remainder of the compound may be replaced by C. 13 In the polycyclic rings of the above groups, one or more ring carbons in the ring substituting or fused to the ring bonded to the remainder of the compound may be replaced by C. 13 C. Also, for example, all ring carbons of the above groups can be replaced by 13 It can be replaced by C.

[0139] R 1 but, [ka] Also provided are compounds of formula (I) or (II) or salts thereof selected from any of the above groups in which one or more hydrogen atoms are replaced by deuterium atoms. 1Also provided are compounds of formula (I) or (II) or salts thereof, wherein the compound is selected from any of the above groups in which one or more hydrogen atoms have been replaced with tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon of the above groups can be replaced with a corresponding isotope, such as deuterium or tritium. Each hydrogen bonded to a non-ring carbon of the above groups, such as a methyl or methoxy carbon, can be replaced with a corresponding isotope, such as deuterium or tritium. Also, for example, the above groups can be per-deuterated, in which all hydrogens therein are replaced with deuterium, or part-lithiated, in which all hydrogens therein are replaced with tritium. In some embodiments, one or more ring carbons of the above groups can be 13 For example, in the polycyclic rings of the above groups, one or more of the ring carbons of the ring that is directly bonded to the remainder of the compound may be replaced by C. 13 In the polycyclic rings of the above groups, one or more ring carbons in the ring substituting or fused to the ring bonded to the remainder of the compound may be replaced by C. 13 C. Also, for example, all ring carbons of the above groups can be replaced by 13 It can be replaced by C.

[0140] R 1 but, [ka] Also provided are compounds of formula (I) or (II) or salts thereof selected from any of the above groups in which one or more hydrogen atoms are replaced by deuterium atoms. 1Also provided are compounds of formula (I) or (II) or salts thereof, wherein the compound is selected from any of the above groups in which one or more hydrogen atoms have been replaced with tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon of the above groups can be replaced with a corresponding isotope, such as deuterium or tritium. Each hydrogen bonded to a non-ring carbon of the above groups, such as a methyl or methoxy carbon, can be replaced with a corresponding isotope, such as deuterium or tritium. Also, for example, the above groups can be per-deuterated, in which all hydrogens therein are replaced with deuterium, or part-lithiated, in which all hydrogens therein are replaced with tritium. In some embodiments, one or more ring carbons of the above groups can be 13 For example, in the polycyclic rings of the above groups, one or more of the ring carbons of the ring that is directly bonded to the remainder of the compound may be replaced by C. 13 In the polycyclic rings of the above groups, one or more ring carbons in the ring substituting or fused to the ring bonded to the remainder of the compound may be replaced by C. 13 C. Also, for example, all ring carbons of the above groups can be replaced by 13 It can be replaced by C.

[0141] (symbol [ka] The group R described herein as a moiety represented by 1 Although R is shown as being attached at a particular position (e.g., pyrimidin-4-yl, quinazolin-4-yl, isoquinolin-1-yl), they can also be attached through other available valencies (e.g., pyrimidin-2-yl). In some embodiments of a compound of Formula (I) or (II) or a salt thereof, R 1 teeth, [ka] where m is 0, 1, 2, or 3, and each R 1aare independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of the compound of formula (I) or (II) or a salt thereof, R 1 teeth, [ka] where m is 1, 2, or 3, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a The alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl in R may be independently substituted with deuterium. 1 teeth, [ka] where m is 0, 1, 2, 3, 4, or 5, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a In a further embodiment of the compound of formula (I) or (II) or a salt thereof, R 1 teeth, [ka] where m is 1, 2, 3, 4, or 5, and each R 1a are independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1aIn a further variation of this embodiment, the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl in each R may be independently substituted with deuterium. 1a are, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in one variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, —CN, or 5-10 membered heteroaryl, where R 1a The C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and 5- to 10-membered heteroaryl may be independently substituted with deuterium.

[0142] In some embodiments of a compound of Formula (I), (II), (IA), (II-A), (IB), (II-B), (IC), (II-C), (ID), (II-D), (IE), (II-E), (IF), (II-F), (IG), (II-G), (IH), or (II-H), or a salt thereof, R 2 is R 2a In some embodiments, R 2 is R 2a C1-C6 alkyl optionally substituted by, where R 2a is halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted with halogen (e.g., cyclobutyl optionally substituted with fluoro); 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl (e.g., pyrazolyl optionally substituted with methyl); -S(O)R 3 ;-NR 4 R 5 ;-NR 3 C(O)R 4 ;Oxo;or -OR 3 In some embodiments, R 2 is R 2a C1-C6 alkyl optionally substituted by, where R 2ais halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted with halogen (e.g., cyclobutyl optionally substituted with fluoro); 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl (e.g., pyrazolyl optionally substituted with methyl); 3-12 membered heterocyclyl optionally substituted with halogen (e.g., oxetanyl optionally substituted with fluoro), -S(O)R 3 ;-NR 4 R 5 ;-NR 3 C(O)R 4 ;Oxo;or -OR 3 In some embodiments, R 2 -OR 3 C1-C6 alkyl optionally substituted by, where R 3 is hydrogen; C1-C6 alkyl optionally substituted 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 with fluoro); or 5-6 membered heteroaryl (e.g., pyridinyl optionally substituted with fluoro or methyl) optionally substituted with halogen or C1-C6 alkyl. In some embodiments, R 2 is —CH2CH2OCH3. In some embodiments, R 2 is halogen and -OR 3 In some embodiments, R 2 is n-propyl substituted with both halogen and alkoxy (e.g., —CHCH(F)CHOCH). R 2 R 2a In some embodiments where R is indicated as being optionally substituted by 2 The R moiety is unsubstituted. 2R 2a In some embodiments where R is indicated as being optionally substituted by 2 The part is one R 2a is replaced by R 2 R 2a In some embodiments where R is indicated as being optionally substituted by 2 The moieties may be the same or different, and may consist of 2 to 6, or 2 to 5, or 2 to 4, or 2 to 3 R 2a is replaced by a part.

[0143] In some embodiments of a compound of Formula (I), (II), (IA), (II-A), (IB), (II-B), (IC), (II-C), (ID), (II-D), (IE), (II-E), (IF), (II-F), (IG), (II-G), (IH), or (II-H), or a salt thereof, R 2 is R 2a In some embodiments, R 2 is R 2a C1-C6 alkyl optionally substituted by, where R 2a is halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted with halogen (e.g., cyclobutyl optionally substituted with fluoro); 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl (e.g., pyrazolyl optionally substituted with methyl); -S(O)R 3 ;-NR 4 R 5 ;-NR 3 C(O)R 4 ;Oxo;Or -OR 3 In some embodiments, R 2 is R 2a C1-C6 alkyl optionally substituted by, where R 2ais halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted with halogen (e.g., cyclobutyl optionally substituted with fluoro); 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl (e.g., pyrazolyl optionally substituted with methyl); 3-12 membered heterocyclyl optionally substituted with halogen (e.g., oxetanyl optionally substituted with fluoro); -S(O)R 3 ;-NR 4 R 5 ;-NR 3 C(O)R 4 ;Oxo;Or -OR 3 In some embodiments, R 2 is R 2a C1-C6 alkyl optionally substituted by, where R 2a is halogen (e.g., fluoro); C3-C8 cycloalkyl optionally substituted 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)R 3 ;-NR 4 R 5 ;-NR 3 C(O)R 4 ;Oxo;-OR 3 or -CN. In some embodiments, R 2 -OR 3 C1-C6 alkyl optionally substituted by, where R 3is hydrogen; C1-C6 alkyl optionally substituted 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 with fluoro); or 5-6 membered heteroaryl (e.g., pyridinyl optionally substituted with fluoro or methyl) optionally substituted with halogen or C1-C6 alkyl. In some embodiments, R 2 is —CH2CH2OCH3. In some embodiments, R 2 is halogen and -OR 3 In some embodiments, R 2 is n-propyl substituted with both halogen and alkoxy (e.g., —CHCH(F)CHOCH). R 2 R 2a In some embodiments where R is indicated as being optionally substituted by 2 The R moiety is unsubstituted. 2 R 2a In some embodiments where R is indicated as being optionally substituted by 2 The part is one R 2a is replaced by R 2 R 2a In some embodiments where R is indicated as being optionally substituted by 2 The moieties may be the same or different, and may consist of 2 to 6, or 2 to 5, or 2 to 4, or 2 to 3 R 2a In some embodiments, R 2 is a C1-C6 alkyl substituted with two halogen groups (e.g., two fluoro groups), which may be the same or different. In some embodiments, R 2 is two -ORs which may be the same or different 3In some embodiments, R is a C1-C6 alkyl substituted with a group (e.g., two -OH groups, one -OH group and one -OCH3 group, or two -OCH3 groups). 2 contains one halogen group (e.g., fluoro) and one -OR 3 In some embodiments, R is a C1-C6 alkyl substituted with a group (e.g., —OH or —OCH3). 2 is two halogen groups (e.g., two fluoro groups) and one -OR, which may be the same or different. 3 In some embodiments, R is a C1-C6 alkyl substituted with a group (e.g., —OH or —OCH3). 2 is one halogen group (e.g., fluoro) and two -OR groups which may be the same or different. 3 and C1-C6 alkyl substituted with groups (for example, two -OH groups, one -OH group and one -OCH3 group, or two -OCH3 groups).

[0144] In some embodiments of a compound of Formula (I), (II), (IA), (II-A), (IB), (II-B), (IC), (II-C), (ID), (II-D), (IE), (II-E), (IF), (II-F), (IG), (II-G), (IH), or (II-H), or a salt thereof, R 2 is R 2b In some embodiments, R 2 is one or two R, which may be the same or different 2b In some embodiments, R is a C-C cycloalkyl substituted by a moiety. 2 is a C3-C4 cycloalkyl optionally substituted with halogen (e.g., unsubstituted cyclopropyl, or cyclobutyl optionally substituted with fluoro). In some embodiments, R 2is a C3-C4 cycloalkyl optionally substituted with a deuterium or tritium atom. For example, in some embodiments, each hydrogen bonded to a ring carbon of the above group can be replaced with a corresponding isotope, such as deuterium or tritium. Each hydrogen bonded to a non-ring carbon of the above group, such as a methyl or methoxy carbon, can be replaced with a corresponding isotope, such as deuterium or tritium. Also, for example, the above group can be per-deuterated, in which all hydrogens are replaced with deuterium, or per-lithiated, in which all hydrogens are replaced with tritium. In some embodiments, one or more ring carbons of the above group can be 13 For example, in the polycyclic rings of the above groups, one or more ring carbons of the ring directly bonded to the remainder of the compound may be replaced by C. 13 In the polycyclic rings of the above groups, one or more ring carbons in the ring substituting or fused to the ring bonded to the remainder of the compound may be replaced by C. 13 C. Also, for example, all ring carbons of the above groups can be replaced by 13 It can be replaced by C.

[0145] In some embodiments of a compound of Formula (I), (II), (IA), (II-A), (IB), (II-B), (IC), (II-C), (ID), (II-D), (IE), (II-E), (IF), (II-F), (IG), (II-G), (IH), or (II-H), or a salt thereof, R 2 is hydrogen.

[0146] In some embodiments of a compound of Formula (I), (II), (IA), (II-A), (IB), (II-B), (IC), (II-C), (ID), (II-D), (IE), (II-E), (IF), (II-F), (IG), (II-G), (IH), or (II-H), or a salt thereof, R 2 is R 2a In some embodiments, R 2 is -OCH3.

[0147] R 2 but, [ka] and a compound having formula (I), (II), (IA), (II-A), (IB), (II-B), (IC), (II-C), (ID), (II-D), (IE), (II-E), (IF), (II-F), (IG), (II-G), (IH) or (II-H), or a salt thereof, selected from any of the above groups in which one or more hydrogen atoms are replaced with deuterium atoms.

[0148] R 2 but, [ka] and a compound having formula (I), (II), (IA), (II-A), (IB), (II-B), (IC), (II-C), (ID), (II-D), (IE), (II-E), (IF), (II-F), (IG), (II-G), (IH) or (II-H), or a salt thereof, selected from any of the above groups in which one or more hydrogen atoms are replaced with deuterium atoms.

[0149] R 2 but, [ka] where R 3 and each R 2a is as defined for formula (I), or a salt thereof.

[0150] R 2 but, [ka] where each R 2a is as defined for formula (I), or a salt thereof.

[0151] R 2 but, [ka] where R 3 is as defined for formula (I), or a salt thereof.

[0152] In one embodiment of formula (I), the tetrahydronaphthyridine group is disubstituted at the 2-position with deuterium.

[0153] In one aspect, there is provided a compound of Formula (I) or a salt thereof (including a pharmaceutically acceptable salt thereof) having one or more of the following structural features (“SF”): (SFI)p is 3; (SFII)R 10 , R 11 , R 12 , R 13 are hydrogen; (SFIII)R 1 teeth, (A) unsubstituted 5- to 10-membered heteroaryl; (B) 1, 2, 3, 4 or 5 groups R, which may be the same or different. 1awherein the 5-10 membered heteroaryl of (III)(A) and (III)(B) is (i) pyridinyl; (ii) pyrimidinyl; (iii) quinoxalinyl; (iv) quinazolinyl; (v) pyrazolopyrimidinyl; (vi) quinolinyl; (vii) pyridopyrimidinyl; (viii) thienopyrimidinyl; (ix) Purinil; (x) pyrrolopyrimidinyl; (xi) benzoxazolyl; (xii) benzothiazolyl; (xiii) isoquinolinyl; (xiv) indolyl; (xv) benzimidazolyl; (xvi) pyrazinyl; (xvii) indazolyl; or (xviii) pyrazolyl is); (C) unsubstituted naphthalenyl; or (D) 1, 2, 3, 4 or 5 groups R, which may be the same or different. 1a Naphthalenyl substituted by is; (SFIV)Each R 1a teeth, (A) halogen, such as fluoro, chloro, or bromo; (B) C1-C6 alkyl optionally substituted by halogen, such as -CH3, -CHF2, -CF3, or C(CH3)3; (C) C3-C6 cycloalkyl, for example, cyclopropyl; (D) 5-10 membered heteroaryl, such as pyridinyl or pyrazolyl; (E)C6~C 14 aryl, for example phenyl; (F)-CN; (G)-OR 3, e.g., -OCH3; or (H)-NR 4 R 5 , e.g. -N(CH3)2 is; (SFV)R 2 teeth, (A) unsubstituted C1-C6 alkyl, for example C1-C2 alkyl; (B) 1, 2, 3, 4 or 5 groups R, which may be the same or different. 2a C1-C6 alkyl, for example C1-C2 alkyl, substituted by (C) unsubstituted —O—C1-C6 alkyl, for example —O—C1-C2 alkyl; (D) 1, 2, 3, 4 or 5 groups R, which may be the same or different. 2a -O-C1-C6 alkyl, for example -O-C1-C2 alkyl, substituted by (E) unsubstituted C3-C6 cycloalkyl, such as cyclopropyl or cyclobutyl; or (F) 1, 2, 3, 4 or 5 groups R, which may be the same or different 2b C3-C6 cycloalkyl, such as cyclopropyl or cyclobutyl, substituted by is; and (SFVI)R 2a teeth, (A) halogens, such as fluoro; (B) C3-C8 cycloalkyl, such as cyclopropyl or cyclobutyl, optionally substituted by halogen; (C) 5-10-membered heteroaryl optionally substituted by C1-C6 alkyl, for example, pyrazolyl substituted by methyl; (D) 3- to 12-membered heterocyclyl optionally substituted by halogen or oxo, such as oxetanyl optionally substituted by fluoro, unsubstituted tetrahydrofuranyl, pyrrolidinyl substituted by oxo, unsubstituted morpholinyl, morpholinyl substituted by oxo, or dioxanyl; (E)-S(O)2R 3, e.g., -S(O)2CH3; (F)-C(O)NR 4 R 5 , e.g., -C(O)N(CH3)2; (G)-NR 3 C(O)R 4 , e.g., -NHC(O)CH3; or (H)-OR 3 (where R 3 teeth, (i) Hydrogen; (ii) -CH3; (iii) -CH2CH3; (iv) -CH2CHF2; (v)-CH2CF3; (vi) phenyl substituted by 0 to 2 fluoro groups; or (vii) pyridinyl substituted with 0 to 1 methyl groups is) is.

[0154] It is understood that a compound of formula (I) or a variation thereof described herein, or a salt thereof, in one embodiment, can have one or more of the structural features described above. For example, a compound of formula (I) or a variation thereof described herein, or a salt thereof, in one embodiment, can have the following structural features: one, two, three, or all of (SFI), (SFII), (SFIII), and (SFV). In one example, a compound of formula (I) or a variation thereof described herein, or a salt thereof, in one embodiment, can have the following structural features: (SFI) and one, two, or all of (SFII), (SFIII), and (SFV) or subembodiments thereof. In one example, a compound of formula (I) or a variation thereof described herein, or a salt thereof, in one embodiment, can have the following structural features: (SFII) and one, two, or all of (SFI), (SFIII), and (SFV) or subembodiments thereof. In one example, a compound or salt thereof represented by formula (I) or a variation thereof described herein can have, in one embodiment, the following structural features: (SFIII) and one, two, or all of (SFI), (SFII), and (SFV), or subembodiments thereof. In one example, a compound or salt thereof represented by formula (I) or a variation thereof described herein can have, in one embodiment, the following structural features: (SFV) and one, two, or all of (SFI), (SFII), and (SFIII), or subembodiments thereof. It is understood that subembodiments of structural features can likewise be combined in any manner. Although particular combinations of structural features are specifically described below, it is understood that any combination of features is encompassed. In one aspect of this variation, (SFI) and (SFII) apply. In another variation, (SFI) and (SFIII) apply. In another variation, (SFI) and (SFV) apply. In another variation, (SFII) and (SFIII) apply. In another variation, (SFII) and (SFV) apply. In another variation, (SFIII) and (SFV) apply.In another variation, (SFI), (SFII) and (SFIII) apply. In another variation, (SFI), (SFII) and (SFV) apply. In another variation, (SFI), (SFIII) and (SFV) apply. In another variation, (SFII), (SFIII) and (SFV) apply. It is understood that each subembodiment of the structural feature applies. For example, (SFIII) is (SFIII)(A)(i), (SFIII)(A)(ii), (SFIII)(A)(iii), (SFIII)(A)(iv), (SFIII)(A)(v), (SFIII)(A)(vi), (SFIII)(A)(vii), (SFIII)(A)(viii), (SFIII)(A)(ix), (SFIII)(A)(x), (SFIII)(A)(xi), (SFIII)(A)(xii), (SFIII)(A)(xiii), (SFIII)(A)(xiv), (SFIII)(A)(xv), (SFIII)(A)(xvi), (SFIII)(A)(xvii), (SFIII)(A)(xviii), (SFIII) (B)(i), (SFIII)(B)(ii), (SFIII)(B)(iii), (SFIII)(B)(iv), (SFIII)(B)(v), (SFIII)(B)(vi), (SFIII)(B)(vii), (SFIII)(B)(viii), (SFIII)(B)(ix), (SFIII)(B)(x), (SFIII )(B)(xi), (SFIII)(B)(xii), (SFIII)(B)(xiii), (SFIII)(B)(xiv), (SFIII)(B)(xv), (SFIII)(B)(xvi), (SFIII)(B)(xvii), (SFIII)(B)(xviii), (SFIII)(C) or (SFIII)(D). In one aspect of this variation, (SFV) is (SFV)(A), (SFV)(B), (SFV)(C), (SFV)(D), (SFV)(E) or (SFV)(F).

[0155] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(A).In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(A). In other variations, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B) and (SFVI)(A) apply.In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(A). In other variations, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B) and (SFVI)(A) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(A). In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(A).

[0156] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B) and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B) and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B) and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B) and (SFVI)(H)(ii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B) and (SFVI)(H)(ii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B) and (SFVI)(H)(ii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii). In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B) and (SFVI)(H)(ii) apply.

[0157] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B) and (SFVI)(H)(v) apply.In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B) and (SFVI)(H)(v) apply.In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B) and (SFVI)(H)(v) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v). In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v).

[0158] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B) and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B) and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B) and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B) and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B) and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B) and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B) and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B) and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B) and (SFVI)(H)(vi) apply.In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B) and (SFVI)(H)(vi) apply.In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi). In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B) and (SFVI)(H)(vi) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B) and (SFVI)(H)(vi) apply.

[0159] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B) and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B) and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B) and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B) and (SFVI)(H)(vii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B) and (SFVI)(H)(vii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply.

[0160] The variations or combinations described herein for compounds of formula (I) may be any of R 15 and R 16 This also applies to formula (A), with the addition of the possible combinations of

[0161] Representative compounds are listed in Figure 1.

[0162] In some embodiments, a compound selected from compound numbers 1-66 in Figure 1, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof is provided. In some embodiments, the compound is a compound selected from compound numbers 1-66 in Figure 1, or a salt of a stereoisomer thereof.

[0163] In some embodiments, a compound selected from Compound Nos. 1-147, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof is provided. In some embodiments, the compound is a compound selected from Compound Nos. 1-147, or a salt of a stereoisomer thereof.

[0164] In some embodiments, provided is a compound selected from Compound Nos. 1-665, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the compound is a compound selected from Compound Nos. 1-665, or a salt of a stereoisomer thereof.

[0165] In some embodiments, provided is a compound selected from Compound Nos. 1-780, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the compound is a compound selected from Compound Nos. 1-780, or a salt of a stereoisomer thereof.

[0166] In one variation, the compounds detailed herein are selected from the group consisting of: 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-(difluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-hydroxy-2-methylpropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((3,3-Difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)butanoic acid; 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-(trifluoromethyl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((8-(trifluoromethyl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,4-d]pyrimidin-4-ylamino)butanoic acid; 2-((5-fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6-fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((8-fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6,7-difluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((6-(difluoromethyl)pyrimidin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methyl-2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-(((3,3-difluorocyclobutyl)methyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-fluoro-2-methylquinazolin-4-yl)amino)butanoic acid; 2-(Isoquinolin-1-ylamino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(Difluoromethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinolin-4-ylamino)butanoic acid; 2-((7-chloroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((8-chloroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-(quinazolin-4-ylamino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid; 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-methoxyquinazolin-4-yl)amino)butanoic acid; 4-((2-(2,2-difluorocyclopropoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-fluoro-2-methylquinazolin-4-yl)amino)butanoic acid; 4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((8-methoxyquinazolin-4-yl)amino)butanoic acid; 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-(((S)-2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid; 4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((8-chloroquinazolin-4-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-(pyrido[3,2-d]pyrimidin-4-ylamino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid; 4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butanoic acid; 4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butanoic acid; 4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butanoic acid; 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-(((R)-2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; and 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid.

[0167] In another variation, the compounds detailed herein are selected from the group consisting of: 2-((3-cyanopyrazin-2-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-cyanopyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-bromopyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-hydroxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((3-cyanopyrazin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-fluoropyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((1H-pyrazolo[4,3-d]pyrimidin-7-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid; 2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-bromopyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-cyanopyrimidin-2-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-bromopyrimidin-2-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-bromopyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-bromopyrimidin-2-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid; 2-((5-cyanopyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-cyanopyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-fluoropyrimidin-2-yl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino)butanoic acid; 4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid; 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid; 4-((Oxetan-2-ylmethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 4-((3-hydroxy-2-(hydroxymethyl)propyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; 2-((5-bromopyrimidin-2-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 2-((5-cyanopyrimidin-2-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid; 4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid; 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid; 2-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 2-((5-bromopyrimidin-2-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; 4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid; 2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; and 4-(((3-fluorooxetan-3-yl)methyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid.

[0168] In some embodiments, compositions, such as pharmaceutical compositions, are provided that include a compound selected from the group consisting of one or more of Compound Nos. 1-66 in Figure 1, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the composition includes a compound selected from the group consisting of one or more salts of Compound Nos. 1-66 in Figure 1. In one aspect, the composition is a pharmaceutical composition that further includes a pharmaceutically acceptable carrier.

[0169] In some embodiments, compositions, such as pharmaceutical compositions, are provided that include a compound selected from the group consisting of one or more of Compound Nos. 1-147, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the composition includes a compound selected from the group consisting of one or more salts of Compound Nos. 1-147. In one aspect, the composition is a pharmaceutical composition that further includes a pharmaceutically acceptable carrier.

[0170] In some embodiments, compositions, such as pharmaceutical compositions, are provided that include a compound selected from the group consisting of one or more of Compound Nos. 1-665, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the composition includes a compound selected from the group consisting of one or more salts of Compound Nos. 1-665. In one aspect, the composition is a pharmaceutical composition that further includes a pharmaceutically acceptable carrier.

[0171] In some embodiments, compositions, such as pharmaceutical compositions, are provided that include a compound selected from the group consisting of one or more of Compound Nos. 1-780, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the composition includes a compound selected from the group consisting of one or more salts of Compound Nos. 1-780. In one aspect, the composition is a pharmaceutical composition that further includes a pharmaceutically acceptable carrier.

[0172] The present invention also includes all salts of the compounds described herein, such as pharmaceutically acceptable salts. The present invention also includes any or all stereochemical forms, including enantiomeric or diastereomeric forms, and tautomeric or other forms, of the described compounds. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure and name are intended to encompass all possible stereoisomers of the described compound. Furthermore, when a specific stereochemical form is described, it is understood that other stereochemical forms are also described and encompassed by the present invention. All forms of the compounds, including crystalline or amorphous forms of the compounds, are also encompassed by the present invention. Prodrug solvates and metabolites of the compounds are understood to be encompassed by this disclosure. Compositions comprising the compounds of the present invention, such as compositions of substantially pure compounds containing a specific stereochemistry, are also contemplated. Compositions comprising mixtures of the compounds of the present invention in any proportion, including mixtures of two or more stereochemical forms of the compounds of the present invention in any proportion, are also encompassed by the present invention, thereby encompassing racemic, non-racemic, enantioenriched, and scalemic mixtures of the compounds. If one or more tertiary amine moieties are present in the compound, the N-oxides are also provided and described.

[0173] The compounds described herein are αvβ6 integrin inhibitors. In some cases, it is desirable for the compounds to inhibit other integrins in addition to αvβ6 integrin. In some embodiments, the compounds inhibit αvβ6 integrin and one or more of αvβ1 integrin, αvβ3 integrin, αvβ5 integrin, α2β1 integrin, α3β1 integrin, α6β1 integrin, α7β1 integrin, and α11β1 integrin. In some embodiments, the compounds inhibit αvβ6 integrin and αvβ1 integrin. In some embodiments, the compounds inhibit αvβ6 integrin, αvβ3 integrin, and αvβ5 integrin. In some embodiments, the compounds inhibit αvβ6 integrin and αvβ1 integrin. In some embodiments, the compounds inhibit αvβ6 integrin, αvβ3 integrin, and αvβ5 integrin. In some embodiments, the compounds inhibit αvβ6 integrin and α2β1 integrin. In some embodiments, the compounds inhibit αvβ6 integrin, α2β1 integrin, and α3β1 integrin. In some embodiments, the compounds inhibit αvβ6 integrin and α6β1 integrin. In some embodiments, the compound inhibits αvβ6 integrin and α7β1 integrin. In some embodiments, the compound inhibits αvβ6 integrin and α11β1 integrin.

[0174] In some cases, it is desirable to avoid inhibition of other integrins. In some embodiments, the compound is a selective αvβ6 integrin inhibitor. In some embodiments, the compound does not substantially inhibit α4β1 integrin, αvβ8 integrin, and / or α2β3 integrin. In some embodiments, the compound inhibits αvβ6 integrin but does not substantially inhibit α4β1 integrin. In some embodiments, the compound inhibits αvβ6 integrin but does not substantially inhibit αvβ8 integrin. In some embodiments, the compound inhibits αvβ6 integrin but does not substantially inhibit αvβ3 integrin. In some embodiments, the compound inhibits αvβ6 integrin but does not substantially inhibit αvβ8 integrin and α4β1 integrin.

[0175] The present invention also contemplates isotopically labeled and / or isotopically enriched forms of the compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compounds are isotopically labeled, e.g., isotopically labeled compounds of formula (I) or variations thereof described herein, in which one or more atoms are replaced with an isotope of the same element. Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 O. 17 O. 32 P, 35 S, 18 F, 36 Cl. Deuterium ( 2 Incorporation of heavier isotopes, such as H or D, can provide certain therapeutic advantages due to improved metabolic stability, e.g., increased in vivo half-life, or reduced dosage requirements, and therefore may be preferred in some cases. As used herein, each example of replacing hydrogen with deuterium is also a disclosure of replacing that hydrogen with tritium. As used herein, each example of enrichment, substitution, or replacement of an atom with the atom's corresponding isotope encompasses one of the following isotopic enrichment levels, or a range between any two of the above percentages: about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 100%.

[0176] Isotopically labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art, or by procedures similar to those described in the accompanying Examples, substituting the appropriate isotopically labeled reagent for the corresponding unlabeled reagent.

[0177] In various embodiments, for each compound named or described herein, the corresponding isotopically substituted compounds are specifically disclosed according to the following description. For example, the structural variable R 1 and R 1a Corresponding isotopically substituted compounds are disclosed in which groups corresponding to 1 and R 1a can be perdeuterated, such that all hydrogens therein can be independently replaced with deuterium. 1a Structural variable R, not in 1 Corresponding isotopically substituted compounds are disclosed in which one or more hydrogens in the group corresponding to can be independently replaced with deuterium. For example, any substituent R 1a Not in R 1 Corresponding isotopically substituted compounds are disclosed in which all hydrogens attached to the ring in the group corresponding to R can be replaced with deuterium. 1a One or more hydrogens in may be independently replaced by deuterium, e.g., R 1a Also disclosed are corresponding isotopically substituted compounds in which all hydrogens in the group corresponding to: may be replaced with deuterium.

[0178] Also, for example, the structural variable R 2 and R 2a can be independently deuterated, e.g., the structural variable R 2 and R 2a The corresponding isotopically substituted compounds are disclosed in which R can be perdeuterated, such that all hydrogens therein can be independently replaced with deuterium. 2a Not in R 2 Also disclosed are corresponding isotopically substituted compounds in which one or more hydrogens in the group corresponding to R can be independently replaced with deuterium. 2 R is the carbon that bonds 2The corresponding isotopically substituted compounds are disclosed in which each hydrogen at the 1-position of R can be independently replaced with deuterium. 2 For the specified compound having -CH2CH2CH2F corresponding to R 2 Also disclosed are the corresponding isotopically substituted compounds where R is -CD2CH2CH2F; 2 For the designated compound having -CH2-cyclopropyl corresponding to R 2 Also disclosed are corresponding isotopically substituted compounds where R is -CD2-cyclopropyl; etc. 2a Corresponding isotopically substituted compounds are disclosed in which each hydrogen in the group corresponding to R can be independently replaced with deuterium. For example, 2a For each compound where is -OCH3, R 2a Also disclosed are corresponding isotopically substituted compounds where R 2a For each compound where is -N(CH3)2, R 2a Also disclosed are corresponding isotopically substituted compounds where R can be -N(CD3)2; etc. 2 The 1-position of R can be di-deuterated. 2a Compounds are disclosed in which each hydrogen in a group corresponding to: can be replaced with deuterium.

[0179] R 10 , R 11 , R 12 , R 13 , and each R 14 Also disclosed are the corresponding isotopically substituted compounds where R is independently deuterated. For example, 10 , R 11 is deuterium or R 12 , R 13 is deuterium or R 10 , R 11 , R 12 and R 13 The corresponding isotopically substituted compounds are disclosed in which R 14 is deuterium, and R 14is substituted with a tetrahydronaphthyridin-2-yl group at the 3-position, the 4-position, or the 3- and 4-positions. 14 is deuterium, and each R 14 independently replaces each hydrogen atom at the 5-position, 6-position, 7-position, 5- and 6-position, 5- and 7-position, 6- and 7-position, or 5-, 6- and 7-position in a tetrahydronaphthyridin-2-yl group, e.g., the 7-position can be substituted with two deuterium atoms.

[0180] In some embodiments, R 1 All ring hydrogens in R can be replaced by deuterium; 2 The 1-position of R can be di-deuterated; 2a The corresponding isotopically substituted compounds are disclosed in which R can be perdeuterated. 1 The corresponding isotopically substituted compounds are disclosed in which all ring hydrogens in R can be replaced by deuterium. 1 All ring hydrogens in R can be replaced by deuterium; 2 The 1-position of R can be di-deuterated; 2a can be perdeuterated; R 12 and R 13 can be deuterium; and the corresponding isotopically substituted compounds are disclosed in which the 7-position of the tetrahydronaphthyridin-2-yl group can be di-deuterated. 1 All ring hydrogens in R can be replaced by deuterium; 2a The corresponding isotopically substituted compounds are disclosed in which each hydrogen in R can be independently replaced by deuterium. 1 All ring hydrogens in R can be replaced by deuterium; 2 The 1-position of R can be di-deuterated; 2a can be perdeuterated; R 12 and R 13 The corresponding isotopically substituted compounds are disclosed in which R can be deuterium. 1 and R 1a can be perdeuterated; R 2 The 1-position of R can be di-deuterated; 2a can be perdeuterated; R 12 and R 13can be deuterium; and the corresponding isotopically substituted compounds are disclosed in which the 7-position of the tetrahydronaphthyridin-2-yl group can be di-deuterated. 1 All ring hydrogens in R can be replaced by deuterium; 2 The 1-position of R can be di-deuterated; 2a can be perdeuterated; R 12 and R 13 The corresponding isotopically substituted compounds are disclosed, in which:

[0181] In some embodiments of the named compounds, R 1 , R 1a , R 2 , R 2a , R 10 , R 11 , R 12 , R 13 , and R 14 Each hydrogen represented in may independently be tritium. For example, R 1 , R 1a , or R 1 and R 1a The corresponding isotopically substituted compounds are disclosed in which one or more hydrogens in R can be independently replaced by tritium. 1 , R 1a , or R 1 and R 1a The corresponding isotopically substituted compounds are disclosed in which one or more ring hydrogens in R can be independently replaced by tritium. 2 , R 2a , or R 2 and R 2a The corresponding isotopically substituted compounds are disclosed in which one or more hydrogens in R can be independently replaced by tritium. 2 , R 2a , or R 2 and R 2awherein one or more hydrogen atoms can be independently replaced by tritium. Corresponding isotopically substituted compounds are disclosed in which one of the 3- or 4-positions of the tetrahydronaphthyridin-2-yl group, e.g., the 3-position, can be tritiated. Corresponding isotopically substituted compounds are disclosed in which one of the 5-, 6-, or 7-positions of the tetrahydronaphthyridin-2-yl group can be monotritiated or ditritiated, e.g., the 7-position can be ditritiated.

[0182] In some embodiments of the named compounds, one or more carbons 13 The corresponding isotopically substituted compounds are disclosed, in which R 1 , R 1a , R 2 , R 2a wherein one or more carbons, such as those in the tetrahydronaphthyridin-2-yl ring shown in the structural formulas herein, 13 The corresponding isotopically substituted compounds are disclosed, in which R 1 , R 1a , R 2 , R 2a and / or the tetrahydronaphthyridin-2-yl group, one or more ring carbons are 13 C. For example, R 1 , R 1a , R 2 , R 2a and / or tetrahydronaphthyridin-2-yl groups, one or more ring carbons in the ring directly bonded to the remainder of the compound are 13 For example, in the tetrahydronaphthyridin-2-yl group, the ring directly attached to the rest of the compound is an aromatic heterocycle attached at the 2-position. 1 , R 1a , R 2 , R 2a In polycyclic rings in groups corresponding to13 For example, in a tetrahydronaphthyridin-2-yl ring, the non-aromatic heterocyclyl ring is fused to the ring that is attached to the remainder of the compound. 1 , R 1a , R 2 , R 2a and / or all ring carbons or all carbons in the tetrahydronaphthyridin-2-yl ring are 13 It can be replaced by C.

[0183] The present invention also encompasses any and all metabolites of any of the described compounds, which may include chemical species produced by biotransformation of any of the described compounds, such as intermediates and products of metabolism of the compounds.

[0184] An article of manufacture is provided comprising a compound of the invention or a salt or solvate thereof in a suitable container, which may be a vial, jar, ampoule, preloaded syringe, iv bag, or the like.

[0185] Preferably, the compounds detailed herein are orally bioavailable, however, they may also be formulated for parenteral (e.g., intravenous) administration.

[0186] One or more compounds described herein can be used to prepare a medicament by combining one or more compounds as active ingredients with a pharmacologically acceptable carrier known in the art. Depending on the therapeutic form of the medicament, the carrier can be in various forms.

[0187] General synthesis method The compounds of the present invention can be prepared by a number of methods, as generally described below and more specifically described in the Examples (such as the schemes provided in the Examples below). In the description of the preparation methods below, the symbols, when used in the formulae described, should be understood to represent the groups described above in connection with the formulae herein.

[0188] If it is desired to obtain a specific enantiomer of a compound, this can be achieved from the corresponding mixture of enantiomers by using suitable conventional methods for separating or resolving enantiomers.Thus, for example, a mixture of enantiomers, such as a racemate, can be prepared by reacting with a suitable chiral compound to produce a diastereomeric derivative.The diastereomers can then be separated by conventional means, such as crystallization, and the desired enantiomer is recovered.In another resolution method, chiral high performance liquid chromatography can be used to separate the racemate.Alternatively, if necessary, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the preparation methods described.

[0189] Chromatography, recrystallization, and other conventional separation methods can also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify the product of a reaction.

[0190] Solvates and / or polymorphs of the compounds provided herein or their pharmaceutically acceptable salts are also contemplated. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are often formed during crystallization. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Polymorphs include different crystalline packing arrangements of a compound with the same elemental composition. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and / or solubility. Various factors, such as the recrystallization solvent, crystallization rate, and storage temperature, can result in the predominance of a single crystal.

[0191] 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.

[0192] 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.

[0193] Compounds of formula 11A can be prepared according to general scheme A, where R 1 and R 2 can be prepared according to formula (I) or as defined for formula (I) or as applicable variations detailed herein). [ka]

[0194] Coupling of 1A with a compound of formula 2A in the presence of a suitable coupling agent gives a compound of formula 3A, which is reduced to give a compound of formula 4A. Reductive amination of a compound of formula 4A with compound 5A gives a compound of formula 6A. Removal of the N-Boc protecting group on a compound of formula 6A by exposure to a suitable acid gives a compound of formula 7A, which can be coupled with a compound of formula 8A to give a compound of formula 10A. Hydrolysis of a compound of formula 10A in the presence of a suitable hydroxide source gives a compound of formula 11A.

[0195] Reaction conditions for the transformations of General Scheme A are provided in the general procedures below, particularly General Procedures A, D, E, F, G, H and P.

[0196] General Scheme A may be modified to include the group R 2Variants of the compound of formula 11A can be prepared by starting with variants of 1A having five and six carbon linkers between the nitrogen bearing the 1A and the tetrahydronaphthyridine group. These variants of the compound of formula 11A can be synthesized by replacing 1A with 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid or 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid and using the route described in general Scheme A. 6-Oxoheptanoic acid and 7-oxooctanoic acid can be converted to 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid and 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid, respectively, by condensation with 2-aminonicotinaldehyde in the presence of a suitable catalyst, followed by hydrogenation of the resulting naphthyridine ring to the 5,6,7,8-tetrahydronaphthyridine ring using procedures known in the chemical literature.

[0197] Compounds of formula 11A can alternatively be prepared according to general scheme B, where R 1 and R 2 can be prepared according to formula (I) or as defined for formula (I) or as applicable variations detailed herein). [ka]

[0198] Introduction of the N-Boc group of 1B in the presence of a suitable base and di-tert-butyl dicarbonate gives a compound of formula 2B, which is reduced to give a compound of formula 3B. Oxidation of the compound of formula 3B with a suitable oxidizing agent gives a compound of formula 4B. Reductive amination of the compound of formula 4B with compound 2A gives a compound of formula 5B. Reductive amination of the compound of formula 5B with compound 5A gives a compound of formula 7B. Removal of the N-Boc protecting group on compound of formula 7B by exposure to a suitable acid gives a compound of formula 7A, which can be coupled with a compound of formula 8A to give a compound of formula 10A. Hydrolysis of the compound of formula 10A in the presence of a suitable hydroxide source gives a compound of formula 11A.

[0199] Reaction conditions for the transformations of General Scheme B are provided in the general procedures below, particularly General Procedures B, D, F, G, H and P.

[0200] General Scheme B may be modified to include the group R 2 Variants of the compound of formula 11A can be prepared by starting with variants of 1B having five and six carbon linkers between the nitrogen bearing the 1B and the tetrahydronaphthyridine group. These variants of the compound of formula 11A can be synthesized by replacing 1B with ethyl 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentanoate or ethyl 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexanoate and using the route described in general Scheme B. Ethyl 6-oxoheptanoate and ethyl 7-oxooctanoate can be converted to ethyl 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentanoate and ethyl 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexanoate, respectively, by condensation with 2-aminonicotinaldehyde in the presence of a suitable catalyst, followed by hydrogenation of the resulting naphthyridine ring to the 5,6,7,8-tetrahydronaphthyridin ring using procedures known in the chemical literature.

[0201] Compounds of formula 10C can be prepared according to general scheme C, where R is R 2a C1-C5 alkyl optionally substituted by R 1 and R 2a can be prepared according to formula (I) or as defined for formula (I) or as applicable variations detailed herein). [ka]

[0202] Coupling of 1C with a compound of formula 4C in the presence of a suitable coupling agent provides a compound of formula 2C, which is reduced to provide a compound of formula 3C. Reductive amination of a compound of formula 3C with compound 5A provides a compound of formula 5C. Global removal of the N-Boc protecting group from a compound of formula 5C by exposure to a suitable acid provides a compound of formula 6C, which can be coupled with a compound of formula 8A to provide a compound of formula 9C. Hydrolysis of a compound of formula 9C in the presence of a suitable hydroxide source provides a compound of formula 10C.

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

[0204] By modifying General Scheme C to start with variants of 1C having five and six carbon linkers between the nitrogen bearing the -CHR group and the tetrahydronaphthyridine group, variants of the compound of Formula 10C can be prepared. These variants of the compound of Formula 10C can be synthesized by replacing 1C with 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentan-1-amine or 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexan-1-amine and using the route described in General Scheme C. 6-Oxoheptanoic acid and 7-oxooctanoic acid can be converted to 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid and 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid, respectively, by condensation with 2-aminonicotinaldehyde in the presence of a suitable catalyst, followed by hydrogenation of the resulting naphthyridine ring to the 5,6,7,8-tetrahydronaphthyridine ring using procedures known in the chemical literature. The resulting carboxylic acids can be converted to primary amines by a two-step process involving coupling the carboxylic acid with a suitable ammonia source in the presence of a suitable coupling reagent, followed by reduction.

[0205] Compounds of formula 10C can alternatively be prepared according to general scheme D, where R is R 2aC1-C5 alkyl optionally substituted by R 1 and R 2a can be prepared according to formula (I) or as defined for formula (I) or as applicable variations detailed herein). [ka]

[0206] 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 a compound of formula 3C with compound 5A gives a compound of formula 5C. Removal of the N-Boc protecting group on a compound of formula 5C by exposure to a suitable acid gives a compound of formula 6C, which can be coupled with a compound of formula 9A to give a compound of formula 9C. Hydrolysis of a compound of formula 8A in the presence of a suitable hydroxide source gives a compound of formula 10C.

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

[0208] By modifying General Scheme D to start with variants of 1C having five and six carbon linkers between the nitrogen bearing the -CHR group and the tetrahydronaphthyridine group, compounds of Formula 10C can be prepared. These variants of the compound of Formula 10C can be synthesized by replacing 1C with 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentan-1-amine or 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexan-1-amine and using the route described in General Scheme D. 6-Oxoheptanoic acid and 7-oxooctanoic acid can be converted to 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid and 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid, respectively, by condensation with 2-aminonicotinaldehyde in the presence of a suitable catalyst and hydrogenation of the resulting naphthyridine ring to a 5,6,7,8-tetrahydronaphthyridine ring with water using procedures known in the chemical literature. The resulting carboxylic acids can be converted to primary amines by a two-step process involving coupling the carboxylic acid with a suitable ammonia source in the presence of a suitable coupling reagent, followed by reduction.

[0209] Compounds of formula 1f can be prepared according to general scheme E. It is understood that the ring bearing the Het designation can be an aromatic heterocycle. [ka]

[0210] Compounds of formula 1a can be hydrolyzed to give compounds of formula 1b, which can be alkylated with a suitable electrophile to give compounds of formula 1c. Compounds of formula 1c can be deprotected under reducing conditions to give compounds of formula 1d. Metal-catalyzed cross-coupling of halogenated arenes with compounds of formula 1d gives compounds of formula 1e, which can be hydrolyzed under acidic conditions to give compounds of formula 1f.

[0211] Reaction conditions for the transformations of General Scheme E are provided in the general procedures below, particularly General Procedures Q, R, S, T and U.

[0212] It is understood that the above schemes can be modified to arrive at a variety of compounds of the invention by selecting appropriate reagents and starting materials. For a general description of protecting groups and their use, see PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis 4" th edition, Wiley-Interscience, New York, 2006.

[0213] Additional methods for preparing compounds according to formula (I) and salts thereof are provided in the Examples. As one of ordinary skill in the art will recognize, the preparation methods taught herein can be adapted to provide additional compounds within the scope of formula (I), for example, by selecting starting materials that provide the desired compound.

[0214] Pharmaceutical Compositions and Formulations Pharmaceutical compositions of any of the compounds detailed herein, including compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) and (II-H) or a salt thereof, or any of the compounds of Figure 1 or a salt thereof, or mixtures thereof, are encompassed by the present invention. Pharmaceutical compositions of any of the compounds detailed herein, including compounds of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), or a salt thereof, or any of the compounds in Figure 1, or a salt thereof, or mixtures thereof, are encompassed by the present invention. Pharmaceutical compositions of compounds of Formula (A), or a salt thereof, or mixtures thereof, are encompassed by the present invention. Accordingly, the present invention encompasses pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions of the present invention may be in a form suitable for oral, buccal, parenteral, nasal, topical, or rectal administration, or in a form suitable for administration by inhalation. In one embodiment, the pharmaceutical composition is a controlled release composition of any of the compounds detailed herein.

[0215] In one aspect, the compounds detailed herein can be in purified form, and compositions comprising the compounds in purified form are described herein. In one embodiment, the compositions can have 35% or less impurities, where the impurities represent compounds other than the compound or a salt thereof that makes up the majority of the composition. For example, a composition of a compound selected from the compounds of Figure 1 can contain 35% or less impurities, where the impurities represent compounds other than the compound or a salt thereof that makes up the majority of the composition. For example, a composition comprising a compound selected from the compounds of Figure 1 can have 35% or less impurities, where the impurities represent compounds other than the compound or a salt thereof that makes up the majority of the composition. For example, a composition comprising a compound selected from the compounds of Figure 1 can have 35% or less impurities, where the impurities represent compounds other than the compound or a salt thereof that makes up the majority of the composition. In one embodiment, the compositions can contain 25% or less impurities. In one embodiment, the compositions can contain 20% or less impurities. In a further embodiment, a composition comprising a compound detailed herein or a salt thereof is provided as a composition of substantially pure compound. A "substantially pure" composition is one that contains 10% or less impurities, e.g., less than 9%, 7%, 5%, 3%, 1%, or 0.5% impurities. In some embodiments, a composition comprising a compound or salt thereof detailed herein is in substantially pure form. In yet another variation, a substantially pure composition of a compound or salt thereof is provided, the composition containing 10% or less impurities. In a further variation, a substantially pure composition of a compound or salt thereof is provided, the composition containing 9% or less impurities. In a further variation, a substantially pure composition of a compound or salt thereof is provided, the composition containing 7% or less impurities. In a further variation, a substantially pure composition of a compound or salt thereof is provided, the composition containing 5% or less impurities. In another variation, a substantially pure composition of a compound or salt thereof is provided, the composition containing 3% or less impurities. In yet another variation, a substantially pure composition of a compound or salt thereof is provided, the composition containing 1% or less impurities. In a further variation, a substantially pure composition of a compound or salt thereof is provided, the composition containing 0.5% or less impurities.In yet another variation, a composition of a substantially pure compound means that the composition contains no more than 10%, or preferably no more than 5%, or more preferably no more than 3%, or even more preferably no more than 1%, or most preferably no more than 0.5%, of impurities, which may be compounds of different stereochemical forms. For example, a composition of a substantially pure (S) compound means that the composition contains no more than 10%, or no more than 5%, or no more than 3%, or no more than 1%, or no more than 0.5% of the (R) form of the compound.

[0216] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual, such as a human. In another variation, compositions containing the compounds in substantially pure form are provided. In another variation, the invention encompasses pharmaceutical compositions comprising the compounds detailed herein and a pharmaceutically acceptable carrier or excipient. In another variation, methods of administering the compounds are provided. Purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for the compounds or forms detailed herein.

[0217] The compounds or salts thereof detailed herein can be formulated for available delivery routes, including oral, mucosal (e.g., intranasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. The compounds or salts thereof can be formulated with suitable carriers to provide delivery forms, including, but not limited to, tablets, caplets, capsules (e.g., hard or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, poultices, pastes, powders, dressings, creams, liquids, patches, aerosols (e.g., nasal sprays or inhalants), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, or elixirs.

[0218] One or more compounds described herein or their salts can be used to prepare formulations, e.g., pharmaceutical preparations, by combining one or more compounds or their salts as active ingredients with pharmaceutically acceptable carriers, such as those described above. Depending on the therapeutic dosage form of the system (e.g., transdermal patch vs. oral tablet), the carrier can take various forms. In addition, pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, colorants, regulators, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants. Formulations containing compounds can also contain other substances with useful therapeutic properties. Pharmaceutical preparations can be prepared by known pharmaceutical methods; suitable formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st ed. (2005), incorporated herein by reference.

[0219] The compounds described herein can be administered to individuals (e.g., humans) in the form of commonly accepted oral compositions, such as tablets, coated tablets, and hard or soft-shelled gel capsules, emulsions, or suspensions. Examples of carriers that may be required for preparing such compositions include lactose, corn starch or its derivatives, talc, stearates or their salts, etc. Acceptable carriers for soft-shelled gel capsules include vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. In addition, pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, colorants, adjusters, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants.

[0220] Any of the compounds described herein can be formulated into tablets in the dosage forms described, for example, a compound described herein or a pharmaceutically acceptable salt thereof can be formulated as a 10 mg tablet.

[0221] Compositions comprising the compounds provided herein are also described. In one variation, the composition comprises the compound and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided. In some embodiments, the composition is for use in human or veterinary medicine. In some embodiments, the composition is for use in the methods described herein. In some embodiments, the composition is for use in treating a disease or disorder described herein.

[0222] How to use The compounds and compositions of the invention, e.g., pharmaceutical compositions containing a compound of the formula provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, can be used in methods of administration and treatment as provided herein. The compounds and compositions can also be used in in vitro methods, such as in vitro methods in which the compound or composition is administered to cells for screening purposes and / or to perform quality control assays.

[0223] In one aspect, there is provided a method of treating a fibrotic disorder in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1-66 in FIG. 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 a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, there is provided a method of treating a fibrotic disease in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.In one aspect, a method of treating a fibrotic disorder in an individual in need thereof is provided, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, a method of treating a fibrotic disorder in an individual in need thereof is provided, comprising administering to the individual a therapeutically effective amount of a compound of Formula (A), or a variant thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, the individual is a human. The individual, eg, a human, can be one in need of treatment, such as one who has or is suspected of having a fibrotic disease.

[0224] In another aspect, a method is provided for delaying the onset and / or development of a fibrotic disease in an individual (e.g., a human) at risk of developing a fibrotic disease. It is understood that delaying onset can include prevention if the individual has not yet developed a fibrotic disease. In one aspect, an individual at risk of developing a fibrotic disease has or is suspected of having one or more risk factors for developing a fibrotic disease. Risk factors for fibrotic disease can include the individual's age (e.g., middle-aged or older adult), the presence of inflammation, having one or more genetic factors associated with the development of a fibrotic disease, a medical history such as treatment with a drug or method (e.g., radiology) believed to be associated with an increased susceptibility to fibrosis or a medical condition believed to be associated with fibrosis, a smoking history, or the presence of occupational and / or environmental factors such as exposure to pollutants associated with the development of a fibrotic disease. In some embodiments, an individual at risk of developing a fibrotic disease has or is suspected of having NAFLD, NASH, CKD, scleroderma, Crohn's disease, NSIP, PSC, PBC, or has had or is suspected of having had a myocardial infarction.

[0225] In some embodiments, the fibrotic disorder is fibrosis of a tissue such as the lung (pulmonary fibrosis), liver, skin, heart (cardiac fibrosis), kidney (renal fibrosis), or gastrointestinal tract (gastrointestinal fibrosis).

[0226] In some embodiments, the fibrotic disease is pulmonary fibrosis (e.g., IPF), liver fibrosis, skin fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis (e.g., PBC).

[0227] In some embodiments, the fibrotic disease is pulmonary fibrosis, e.g., idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis is, for example, interstitial lung disease, radiation-induced pulmonary fibrosis, or systemic sclerosis-associated interstitial lung disease.

[0228] 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.

[0229] In some embodiments, the fibrotic disease is fibrotic nonspecific interstitial pneumonia (NSIP).

[0230] In some embodiments, fibrotic disease is liver fibrosis, for example, infectious liver fibrosis (caused by pathogens such as HCV, HBV or parasites such as schistosomiasis), NASH, alcoholic fatty liver-induced liver fibrosis and liver cirrhosis.In some embodiments, liver fibrosis is non-alcoholic fatty liver disease (NAFLD).In some embodiments, liver fibrosis is NASH.

[0231] In some embodiments, the fibrotic disease is biliary fibrosis.

[0232] In some embodiments, the fibrotic disease is renal fibrosis, such as diabetic nephrosclerosis, hypertensive nephrosclerosis, focal segmental glomerulosclerosis ("FSGS"), and acute kidney injury due to contrast-induced nephropathy. In some embodiments, the fibrotic disease is diabetic nephropathy, diabetic kidney disease, or chronic kidney disease.

[0233] In some embodiments, the fibrotic disease is characterized by one or more of glomerulonephritis, end-stage renal disease, hearing loss, changes in the lens of the eye, hematuria, or proteinuria. In some embodiments, the fibrotic disease is Alport syndrome.

[0234] In some embodiments, the fibrotic disorder is systemic or localized sclerosis or scleroderma, keloids and hypertrophic scars, or post-surgical adhesions. In some embodiments, the fibrotic disorder is scleroderma or systemic sclerosis.

[0235] In some embodiments, the fibrotic disease is atherosclerosis or restenosis.

[0236] In some embodiments, the fibrotic disease is gastrointestinal fibrosis, eg, Crohn's disease.

[0237] In some embodiments, the fibrotic disease is cardiac fibrosis, such as post-myocardial infarction-induced fibrosis and hereditary cardiomyopathies.

[0238] In some embodiments, the method can include modulating the activity of at least one integrin in a subject in need thereof. For example, the method can include modulating the activity of α V The method can include regulating the activity of αβ. V The method can include regulating the activity of α V β1 and α V The method can include modulating the activity of β6. Modulating the activity of at least one integrin can include, for example, inhibiting at least one integrin. The method can include inhibiting at least one integrin, such as α6, in a subject. V β1 and α V The method can include administering to a subject an amount of the compound or its pharmaceutically acceptable salt that is effective for regulating the activity of at least one integrin in the subject that needs to be regulated.The subject that needs to regulate the activity of at least one integrin can have any of the fibrotic diseases or conditions described herein.For example, the fibrotic disease or condition can include idiopathic pulmonary fibrosis, interstitial lung disease, radiation-induced pulmonary fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease-induced fibrosis, Alport syndrome, primary sclerosing cholangitis, primary biliary cholangitis (also known as primary biliary cirrhosis), biliary atresia, systemic sclerosis-related interstitial lung disease, scleroderma (also known as systemic sclerosis), diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, or Crohn's disease.The method can include regulating the activity of at least one integrin, such as αβ, in a subject that needs to be treated with NASH. Vβ1 and α V The method may include administering to the subject an amount of the compound or a pharmaceutically acceptable salt thereof effective to modulate the activity of at least one integrin, such as α, β, or β6, in a subject in need of treatment for IPF. V β1 and α V The method may include administering to the subject an amount of the compound or a pharmaceutically acceptable salt thereof effective to modulate at least one activity of β6.

[0239] Fibrotic diseases are primarily caused by α V For example, the fibrotic disease may include idiopathic pulmonary fibrosis or renal fibrosis. Thus, the method may involve diseases that are primarily mediated by αβ, such as IPF. V α to treat conditions mediated by β6 V Fibrotic diseases are primarily caused by regulating the activity of α V For example, fibrotic diseases such as NASH can be mediated by β1. V α to treat β1-mediated conditions, such as NASH V Fibrotic diseases can be caused by regulating the activity of α V β1 and α V For example, the fibrotic disease may be mediated by β6, such as PSC or biliary atresia. V β1 and α V to treat conditions mediated by both α and β6 V β1 and α V Examples include regulating the activity of β6.

[0240] The compound is α V The compound may be a modulator, e.g., an inhibitor, of α V The compound may be a modulator, e.g., an inhibitor, of α V β1 and α VThe compound may be a dual modulator, e.g., a dual inhibitor, e.g., a dual selective inhibitor, of β6. For example, Table B-3 shows that some exemplary compounds are primarily selective for α V Alpha over Beta6 V Inhibiting β1; some exemplary compounds inhibit primarily α V α rather than β1 V β6; and some exemplary compounds inhibit α V β1 and α V It inhibits β6 equally well, e.g., "α V β1 / α V This indicates that it can be considered a "dual β6 inhibitor."

[0241] α V β1 integrin and α V Treating patients with fibrotic diseases by modulating or inhibiting the activity of one or both of the β6 integrins is a promising approach. V β1 integrin, α V β6 integrin, or α V β1 integrin and α V It is shown that β6 integrin is modulated or inhibited sufficiently to treat a fibrotic disorder in a subject.

[0242] In one aspect, there is provided a compound of Formula (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1 to 66 in FIG. 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a fibrotic disease.

[0243] In one aspect, there is provided a compound of Formula (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1 to 147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a fibrotic disease.

[0244] In one aspect, there is provided a compound of Formula (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1 to 665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a fibrotic disease.

[0245] In one aspect, there is provided a compound of Formula (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1 to 780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a fibrotic disease.

[0246] Also provided is the use of a compound of Formula (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1 to 66 in Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a fibrotic disease.

[0247] Also provided is the use of a compound of Formula (I), or a variant thereof, such as a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1 to 147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a fibrotic disease.

[0248] Also provided is the use of a compound of Formula (I), or a variant thereof, such as a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1 to 665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a fibrotic disease.

[0249] Also provided is the use of a compound of Formula (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1 to 780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a fibrotic disease.

[0250] In another aspect, there is provided a method of inhibiting αvβ6 integrin in an individual, comprising administering a compound of Formula (I), or a variant thereof, such as a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a stereoisomer thereof, or a compound selected from compound numbers 1-66 in FIG. 1 , or a pharmaceutically acceptable salt thereof.

[0251] In another aspect, there is provided a method of inhibiting αvβ6 integrin in an individual, comprising administering a compound of Formula (I), or a variant thereof, such as a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a stereoisomer thereof, or a compound selected from Compound Nos. 1-147, or a pharmaceutically acceptable salt thereof.

[0252] In another aspect, there is provided a method of inhibiting αvβ6 integrin in an individual, comprising administering a compound of Formula (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a stereoisomer thereof, or a compound selected from Compound Nos. 1-665, or a pharmaceutically acceptable salt thereof.

[0253] In another aspect, there is provided a method of inhibiting αvβ6 integrin in an individual, comprising administering a compound of Formula (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a stereoisomer thereof, or a compound selected from Compound Nos. 1-780, or a pharmaceutically acceptable salt thereof.

[0254] Also provided is a method of inhibiting TGFβ activation in a cell, comprising administering to the cell a compound of Formula (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1-66 in FIG. 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0255] Also provided is a method of inhibiting TGFβ activation in a cell, comprising administering to the cell a compound of Formula (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1 to 147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0256] Provided is a method of inhibiting TGFβ activation in a cell, the method comprising administering to the cell a compound of formula (I), or a variant thereof, e.g., a compound of formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1 to 665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0257] Provided is a method for inhibiting TGFβ activation in a cell, the method comprising administering to the cell a compound of formula (I), or a variant thereof, e.g., a compound of formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1 to 780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0258] Also provided is a method of inhibiting αvβ6 integrin in an individual in need thereof, comprising administering to the subject a compound of Formula (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compound numbers 1 to 66 in Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Also provided is a method of inhibiting αvβ6 integrin in an individual in need thereof, comprising administering to the subject a compound of Formula (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1 to 147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Also provided is a method for inhibiting αvβ6 integrin in an individual in need thereof, comprising administering to the subject a compound of Formula (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1 to 665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.Also provided are methods for inhibiting αvβ6 integrin in an individual in need thereof, comprising administering to the subject a compound of Formula (I), or a variant thereof, such as a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one such method, the compound is a selective αvβ6 integrin inhibitor. In another such method, the compound does not substantially inhibit α4β1, αvβ8, and / or α2β3 integrins. In yet another such method, the compound inhibits αvβ6 integrin but does not substantially inhibit α4β1 integrin. In yet another such method, the compound inhibits αvβ6 integrin but does not substantially inhibit αvβ8 integrin. In a further such method, the compound inhibits αvβ6 integrin but does not substantially inhibit α2β3 integrin. In one embodiment, a method is provided for inhibiting αvβ6 integrin and one or more of αvβ1, αvβ3, αvβ5, α2β1, α3β1, α6β1, α7β1, and α11β1 integrin in a subject in need thereof. In another embodiment, a method is provided for inhibiting αvβ6 integrin and αvβ1 integrin. In another embodiment, a method is provided for inhibiting αvβ6 integrin, αvβ3 integrin, and αvβ5 integrin. In another embodiment, a method is provided for inhibiting αvβ6 integrin and α2β1 integrin. In another embodiment, a method is provided for inhibiting αvβ6 integrin, α2β1 integrin, and α3β1 integrin. In another embodiment, a method is provided for inhibiting αvβ6 integrin and α6β1 integrin. In another embodiment, a method is provided for inhibiting αvβ6 integrin and α7β1 integrin.In another embodiment, a method is provided for inhibiting αvβ6 integrin and α11β1 integrin.In one aspect, in all such embodiments, 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 (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compound numbers 1-66 in FIG. 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, in all such embodiments, the method of 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 (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, in all such embodiments, the method of 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 (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.In one aspect, in all such embodiments, the method of 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 (I), or a variant thereof, e.g., a compound of Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0259] Compounds of formula (A) can be used in the compositions, methods and uses described herein for formula (I) and variations of formula (I).

[0260] In any of the described methods, in one embodiment, the individual is a human, e.g., a human in need of the method. The individual may be a human diagnosed with or suspected of having a fibrotic disease. The individual may be a human without detectable disease but with one or more risk factors for developing a fibrotic disease.

[0261] kit The present invention further provides a kit for carrying out the method of the present invention, comprising one or more compounds or salts thereof as described herein, or pharmaceutical compositions comprising the compounds as described herein.The kit can use any of the compounds disclosed herein.In one variation, the kit uses a compound as described herein or a pharmaceutically acceptable salt thereof.The kit can be used for one or more of the uses described herein, and therefore can contain instructions for use in treating fibrotic diseases.

[0262] The kit generally comprises a suitable package. The kit may comprise one or more containers containing the compounds described herein. Each component (if there are two or more components) can be packed in a separate container, or several components can be combined into one container if cross-reactivity and shelf life permit. One or more components of the kit may be sterile and / or contained in a sterile package.

[0263] The kits may be in unit dosage form, bulk packages (e.g., multi-dose packages), or sub-unit doses. For example, kits may be provided that contain a sufficient dosage of a compound as disclosed herein (e.g., a therapeutically effective amount) and / or a second pharmaceutically active compound useful for a disease detailed herein (e.g., fibrosis) to effectively treat an individual for an extended period of time, e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or longer. The kits may also include multiple unit doses of the compound and instructions for use, and may be packaged in a quantity sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0264] The kit may include a set of instructions, typically written instructions, although electronic storage media (e.g., magnetic or optical disks) containing instructions are also acceptable, regarding the use of the components of the methods of the invention. The instructions included in the kit generally include information regarding the components and their administration to an individual.

[0265] General Procedure The compounds provided herein can be prepared according to general schemes, as illustrated by the general procedures and examples. Even when the general procedures are followed, slight variations in temperature, concentration, reaction time, and other parameters can occur that do not substantially affect the outcome of the procedures.

[0266] In the following general procedures, where a specific stereoisomer, or an unspecified stereoisomer, or a mixture of stereoisomers is shown, it is understood that analogous chemical transformations can be carried out on other specific stereoisomers, or an unspecified stereoisomer, or a mixture thereof. For example, the hydrolysis reaction of methyl (S)-4-amino-butanoate to (S)-4-amino-butanoic acid can also be carried out on methyl (R)-4-amino-butanoate to produce (R)-4-amino-butanoic acid, or on a mixture of methyl (S)-4-amino-butanoate and methyl (R)-4-amino-butanoate to produce a mixture of (S)-4-amino-butanoic acid and (R)-4-amino-butanoic acid.

[0267] Some of the following general procedures use specific compounds to illustrate the general reaction (e.g., deprotection of a compound having a Boc-protected amine to a compound having a deprotected amine using an acid). The general reaction can be performed on other specific compounds having the same functional group (e.g., different compounds having a protected amine where the Boc-protecting group can be removed using an acid in the same manner) only if such other specific compounds do not contain additional functional groups susceptible to the general reaction (i.e., such other specific compounds do not contain acid-sensitive functional groups), or if the effect of the general reaction on these additional functional groups is desired (e.g., such other specific compounds have another group susceptible to acid, and the effect of acid on this other group is the desired reaction).

[0268] Where a particular reagent or solvent is specifically described for a reaction in a general procedure, one skilled in the art will recognize that other reagents or solvents can be substituted as needed. For example, where hydrochloric acid is used to remove the Boc group, trifluoroacetic acid can be used instead. As another example, where HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) is used as a coupling reagent, BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate) or PyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) can be used instead.

[0269] General Procedure A [ka]

[0270] N-Cyclopropyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide. To a mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanoic acid hydrochloride (5.0 g, 19.48 mmol) and cyclopropanamine (1.51 mL, 21.42 mmol) in CHCl (80 mL) was added DIPEA (13.57 mL, 77.9 mmol) at room temperature. HATU (8.1 g, 21.42 mmol) was then added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified by normal-phase silica gel chromatography to give N-cyclopropyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide.

[0271] General Procedure B [ka] N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide. To a mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (351 mg, 1.71 mmol) and formic acid (0.09 mL, 2.22 mmol) in THF / DMF (4:1) (5 mL) was added HATU (844 mg, 2.22 mmol), followed by DIPEA (0.89 mL, 5.13 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified by normal phase silica gel chromatography to give N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide.

[0272] General procedure C [ka] N-(2-Methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. A mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (300 mg, 1.46 mmol), 1-bromo-2-methoxyethane (0.11 mL, 1.17 mmol), and DIPEA (0.25 mL, 1.46 mmol) in i-PrOH (3 mL) was heated to 70° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, then concentrated in vacuo and purified by normal phase silica gel chromatography to give N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine.

[0273] General Procedure D [ka] N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. To a solution of N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide (200 mg, 0.86 mmol) in THF (2 mL) at room temperature was added dropwise a borane-tetrahydrofuran complex solution (1.0 M in THF, 4.0 mL, 4.0 mmol). The resulting mixture was then heated to 60° C. for 2 hours and then allowed to cool to room temperature. The reaction mixture was diluted with MeOH and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine.

[0274] General Procedure E [ka] N-(2-Methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (5). To a solution of N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide (15.5 g, 1.0 equiv.) in 1,4-dioxane (124 mL) at room temperature was slowly added LiAlH (1.0 M in THF, 123 mL, 2.2 equiv.), and the resulting mixture was heated to reflux for 20 hours and then cooled to 0° C. To this solution was added HO (4.7 mL), followed by 1 M NaOH (4.7 mL), followed by HO (4.7 mL), warmed to room temperature, and stirred for 30 minutes, at which point solid MgSO was added and stirred for an additional 30 minutes. The resulting mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated in vacuo to give N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine.

[0275] General Procedure F [ka] Methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. To a mixture of N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (5) (187 mg, 0.85 mmol) in MeOH (5 mL) at room temperature was added acetic acid (0.12 mL, 2.05 mmol), followed by the addition of methyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (217 mg, 0.94 mmol). The resulting mixture was stirred at room temperature for 15 minutes, at which time sodium cyanoborohydride (80 mg, 1.28 mmol) was added to the reaction mixture, stirred for 30 minutes, and then concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate.

[0276] General Procedure G [ka] Methyl (S)-2-amino-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (152 mg, 0.35 mmol) in 2 mL of CHCl at room temperature was added 4 N HCl in 1,4-dioxane (1 mL, 4 mmol), and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo to give methyl (S)-2-amino-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate as the trihydrochloride salt.

[0277] General Procedure H [ka] A solution of (S)-methyl 2-amino-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate trihydrochloride (80 mg, 0.16 mmol), 4-chloro-2-methyl-6-(trifluoromethyl)pyrimidine (64 mg, 0.33 mmol), and DIPEA (0.23 mL, 1.31 mmol) in i-PrOH (1 mL) was heated at 60 °C overnight. The reaction was allowed to cool to room temperature and then concentrated in vacuo. The resulting crude residue was purified by normal phase silica gel chromatography to give methyl (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)amino)butanoate.

[0278] General procedure P [ka] (S)-2-((2-chloro-3-fluorophenyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a solution of methyl (S)-2-((2-chloro-3-fluorophenyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate in THF / MeOH / HO (4:1:1) at room temperature was added lithium hydroxide (about 4 equivalents), and the resulting mixture was stirred for 30 minutes. The reaction mixture was concentrated in vacuo and the resulting crude residue was purified by reverse-phase HPLC to afford (S)-2-((2-chloro-3-fluorophenyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid as the trifluoroacetate salt.

[0279] General Procedure Q [ka] (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a mixture of methyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (1 g, 1.90 mmol) in HO (3 mL), THF (3 mL), and MeOH (3 mL) was added LiOH·HO (159.36 mg, 3.80 mmol), and the mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo. The mixture was adjusted to pH=6 with AcOH (2 mL) and the residue was concentrated in vacuo to give the compound (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. LCMS (ESI+): m / z = 513.5 (M+H) + . 1 H NMR (400 MHz, DMSO-d): δ ppm 7.25 - 7.37 (m, 5 H) 7.00 (d, J=7.28 Hz, 1 H) 6.81 (br d, J=7.50 Hz, 1 H) 6.22 (d, J=7.28 Hz, 1 H6) 4.93 - 5.05 (m, 2 H) 3.68 - 3.77 (m, 1 H) 3.25 - 3.34 (m, 1 H) 3.15 - 3.24 (m, 5 H) 2.58 (br t, J=6.06 Hz, 2 H) 2.29 - 2.49 (m, 8 H) 2.16 (br dd, J=12.90, 6.06Hz, 1H) 1.69 - 1.78 (m, 2 H) 1.58 - 1.68 (m, 1 H) 1.53 (quin, J=7.39 Hz, 2 H) 1.28 - 1.40 (m, 2 H) 1.00 (d, J=5.95 Hz, 3 H).

[0280] General Procedure R [ka] tert-butyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (300 mg, 523.84 μmol, HOAc salt) in DMA (4 mL) was added N-benzyl-N,N-diethylethanaminium chloride (119.32 mg, 523.84 μmol), K2CO3 (1.88 g, 13.62 mmol), 2-bromo-2-methylpropane (3.45 g, 25.14 mmol). The mixture was stirred at 55° C. for 18 hours and then allowed to cool to room temperature. The reaction mixture was concentrated in vacuo, and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative TLC to give tert-butyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. LCMS (ESI+): m / z = 569.3 (M+H) + .

[0281] General Procedures [ka] tert-Butyl (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. To a solution of tert-butyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (107 mg, 188.13 μmol) in i-PrOH (2 mL) was added Pd(OH) (26 mg) under N atmosphere. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (15 psi) at room temperature for 15 hours. The mixture was filtered and concentrated in vacuo to give tert-butyl (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. LCMS (ESI+): m / z = 435.5 (M+H) + . 1 H NMR (400 MHz, CDCl3): δ ppm 7.06 (d, J=7.34 Hz, 1 H) 6.34 (d, J=7.34 Hz, 1 H) 4.98 (br s, 1 H) 3.38 - 3.44 (m, 4 H) 3.34 (s, 3 H) 2.69 (t, J=6.30 Hz, 2 H) 2.51 - 2.59 (m, 5 H) 2.31 (dd, J=13.39, 5.56 Hz, 1 H) 1.86 - 1.94 (m, 5 H) 1.49 - 1.69 (m, 6 H) 1.47 (s, 9 H) 1.13 (d, J=6.11Hz, 3H).

[0282] General procedure T [ka] (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid tert-butyl ester. (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid tert-butyl ester. To a solution of tert-butyl (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (100 mg, 230.09 μmol) and 2-chloro-5-methyl-pyrimidine (24.65 mg, 191.74 μmol) in 2-methyl-2-butanol (2 mL) was added t-BuONa (2 M in THF, 191.74 μL) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (15.23 mg, 19.17 μmol), and the resulting mixture was stirred at 100° C. for 14 hours. The mixture was concentrated in vacuo to give tert-butyl (S)-4-(((S)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate. LCMS (ESI+): m / z = 527.3 (M+H) + .

[0283] General Procedure U [ka] (S)-4-(((R)-2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid. To a solution of tert-butyl (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate (80 mg, 151.89 μmol) in DCM (2 mL) was added TFA (254.14 mg, 2.23 mmol) at 0° C. The mixture was stirred at room temperature for 6 hours. The mixture was concentrated in vacuo and the resulting crude residue was purified by preparative HPLC to give the compound (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid. LCMS (ESI+): m / z = 471.2 (M+H) + . 1 H NMR (400 MHz, Methanol-d4) δ ppm 8.57 (br s, 2 H) 7.60 (d, J=7.28 Hz, 1 H) 6.67 (d, J=7.28 Hz, 1 H) 4.81 - 4.86 (m, 1 H) 3.86 (br s, 1 H) 3.41 - 3.59 (m, 4 H) 3.39 (s, 3 H) 3.33 - 3.38 (m, 1 H) 3.12 - 3.30 (m, 3 H) 2.76 - 2.86 (m, 4 H) 2.54 (br s, 1 H) 2.39 (br d, J=8.82 Hz, 1 H) 2.30 (s, 3H) 1.76 - 1.99 (m, 6 H) 1.22 (d, J=5.95 Hz, 3 H).

[0284] Enumeration of embodiments The embodiments listed below are representative of some aspects of the present invention. Embodiment 1. Formula (I): [ka] [In the formula, R 1 C6~C 14 aryl or 5- to 10-membered heteroaryl, wherein the C6 to C 14 Aryl and 5- to 10-membered heteroaryl are R 1a may be replaced by; R 2 is R 2a C1-C6 alkyl optionally substituted by R 2b C3-C6 cycloalkyl optionally substituted by R 2c 3- to 12-membered heterocyclyl optionally substituted by -S(O)R 2d and; Each R 1a are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-C 14 Aryl, deuterium, halogen, -CN, -OR 3 , -SR 3 , -NR 4 R 5 , -NO2, -C=NH(OR 3 ), -C(O)R 3 , -OC(O)R 3 , -C(O)OR 3 , -C(O)NR 4 R 5 , -NR 3 C(O)R 4 , -NR 3 C(O)OR 4 , -NR 3 C(O)NR 4 R 5 , -S(O)R 3 , -S(O)2R 3 , -NR 3 S(O)R 4 , -NR 3 S(O)2R 4 , -S(O)NR 4 R 5 , -S(O)NR 4 R 5 , or -P(O)(OR 4 )(OR5 ) where each R 1a are independently deuterium, halogen, oxo, -OR, if possible. 6 , -NR 6 R 7 , -C(O)R 6 , -CN, -S(O)R 6 , -S(O)2R 6 , -P(O)(OR 6 )(OR 7 ), C3-C8 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C6-C 14 optionally substituted by aryl or C1-C6 alkyl optionally substituted by deuterium, oxo, —OH or halogen; Each R 2a , R 2b , R 2c , R 2e and R 2f are independently oxo or R 1a and; R 2d is R 2e C1-C6 alkyl optionally substituted by, or R 2f C3-C5 cycloalkyl optionally substituted by R 3 are independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R 3 The C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C6 cycloalkyl, C6 to C 14 Aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from halogen, deuterium, oxo, -CN, -OR 8 , -NR 8 R 9 , -P(O)(OR 8 )(OR 9 ), or C1-C6 alkyl optionally substituted by deuterium, halogen, —OH or oxo; R 4 and R 5 are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R 4 and R 5 The C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C6 cycloalkyl, C6 to C 14 Aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from deuterium, halogen, oxo, -CN, -OR 8 , -NR 8 R 9 or C1-C6 alkyl optionally substituted by deuterium, halogen, —OH or oxo; or R 4 and R 5 together with the atom to which they are attached, deuterium, halogen, oxo, -OR 8 , -NR 8 R 9 or a 3- to 6-membered heterocyclyl optionally substituted by C1-C6 alkyl optionally substituted by deuterium, halogen, oxo or -OH; R 6 and R 7 are each independently hydrogen, deuterium, or C1-C6 alkyl optionally substituted with deuterium, halogen, or oxo, or C2-C6 alkenyl optionally substituted with deuterium, halogen, or oxo, or C2-C6 alkynyl optionally substituted with deuterium, halogen, or oxo; or R 6 and R 7 together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted by deuterium, halogen, or oxo; R 8and R 9 are each independently hydrogen, deuterium, or C1-C6 alkyl optionally substituted with deuterium, halogen, or oxo, or C2-C6 alkenyl optionally substituted with deuterium, halogen, or oxo, or C2-C6 alkynyl optionally substituted with deuterium, halogen, or oxo; or R 8 and R 9 together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, or C1-C6 alkyl optionally substituted by deuterium, oxo, or halogen; Each R 10 , R 11 , R 12 and R 13 are independently hydrogen or deuterium; R 14 is deuterium; q is 0, 1, 2, 3, 4, 5, 6, 7 or 8; p is 3, 4, 5, 6, 7, 8, or 9] or a salt thereof. Embodiment 2. R 1a , R 2a , R 2b , R 2c , R 2e , R 2f , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , or R 14 or a salt thereof. Embodiment 3. R 10 , R 11 , R 12 , R 13 , and R 14 is hydrogen; p is 3; and formula (II): [ka] or a salt thereof. Embodiment 4. R 1 But R 1a or a salt thereof. Embodiment 5. R 1 But R 1a or a salt thereof. Embodiment 6. R 1 But R 1a pyrimidin-4-yl optionally substituted by 1a is 5-10 membered heteroaryl, or C1-C6 alkyl optionally substituted with halogen; or a salt thereof. Embodiment 7. R 1 A compound of embodiment 1, 2 or 3, wherein is pyrimidin-4-yl optionally substituted by pyrazolyl, methyl, difluoromethyl or trifluoromethyl; or a salt thereof. Embodiment 8. R 1 A compound of embodiment 1, 2 or 3, wherein is pyrimidin-4-yl substituted with both methyl and trifluoromethyl; or a salt thereof. Embodiment 9. R 1 But R 1a or a salt thereof. Embodiment 10. R 1 The compound of embodiment 1, 2 or 3, wherein is quinazolin-4-yl optionally substituted by halogen, C1-C6 alkyl optionally substituted by halogen, or C1-C6 alkoxy, or a salt thereof. Embodiment 11. R 1A compound of embodiment 1, 2 or 3, wherein is quinazolin-4-yl optionally substituted by fluoro, chloro, methyl, trifluoromethyl or methoxy; or a salt thereof. Embodiment 12. R 2 But R 2a or a salt thereof. Embodiment 13. R 2 But R 2a C1-C6 alkyl optionally substituted by, where R 2a is halogen; C3-C8 cycloalkyl optionally substituted by halogen; 5-10 membered heteroaryl optionally substituted by C1-C6 alkyl; -NR 4 R 5 ;-NR 3 C(O)R 4 ;-S(O)2R 3 or oxo; or a salt thereof. Embodiment 14. R 2 But R 2a C1-C6 alkyl optionally substituted by, where R 2a 12. The compound of any one of embodiments 1-11, wherein is fluoro; cyclobutyl substituted with fluoro; pyrazolyl substituted with methyl; or —S(O) 2 CH 3 ; or a salt thereof. Embodiment 15. R 2 But, -OR 3 or a salt thereof. Embodiment 16. R 2 But, -OR 3 C1-C6 alkyl optionally substituted by R 3 is hydrogen; C1-C6 alkyl optionally substituted with halogen; C3-C6 cycloalkyl optionally substituted with halogen; C6-C 14aryl; or 5- to 6-membered heteroaryl optionally substituted by halogen or C1-C6 alkyl; or a salt thereof. Embodiment 17. R 2 But, -OR 3 C1-C6 alkyl optionally substituted by R 3 or a salt thereof. Embodiment 18. R 2 The compound of any one of embodiments 1-11, wherein is —CH 2 CH 2 OCH 3 . Embodiment 19. R 2 But halogen and -OR 3 and C1-C6 alkyl substituted with both R 3 or a salt thereof. Embodiment 20. R 2 But R 2b or a salt thereof. Embodiment 21. R 2 12. The compound of any one of embodiments 1-11, or a salt thereof, wherein is cyclopropyl. Embodiment 22. R 1 but, [ka] where m is 0, 1, 2, or 3, and each R 1a is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1aor a salt thereof. 4. The compound of embodiment 1, 2 or 3, wherein said alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl are independently optionally substituted with deuterium; Embodiment 23. R 1 but, [ka] where each R 1a 23. The compound of embodiment 22, wherein is independently deuterium, alkyl, haloalkyl, or heteroaryl; or a salt thereof. Embodiment 24. R 1 but, [ka] where m is 0, 1, 2, or 3, and each R 1a is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a or a salt thereof. 4. The compound of embodiment 1, 2 or 3, wherein said alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl are independently optionally substituted with deuterium; Embodiment 25. R 1 but, [ka] where m is 0, 1, 2, 3, 4, or 5, and each R 1a is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a or a salt thereof. 4. The compound of embodiment 1, 2 or 3, wherein said alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl are independently optionally substituted with deuterium; Embodiment 26. R 1 but, [ka] where each R1a is independently deuterium, halogen, alkyl, haloalkyl, or alkoxy; or a salt thereof. Embodiment 27. R 1 but, [ka] where m is 0, 1, 2, 3, 4, or 5, and each R 1a is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a or a salt thereof. 4. The compound of embodiment 1, 2 or 3, wherein said alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl are independently optionally substituted with deuterium; Embodiment 28. R 1 but, [ka] where m is 0, 1, 2, 3, or 4, and each R 1a is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a or a salt thereof. 4. The compound of embodiment 1, 2 or 3, wherein said alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl are independently optionally substituted with deuterium; Embodiment 29. R 1 but, [ka] 29. The compound of embodiment 28, selected from the group consisting of: Embodiment 30. R 1 but, [ka] where m is 0, 1, 2, 3, or 4, and each R 1ais, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a or a salt thereof. 4. The compound of embodiment 1, 2 or 3, wherein said alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl are independently optionally substituted with deuterium; Embodiment 31. R 1 but, [ka] 31. The compound of embodiment 30, selected from the group consisting of: Embodiment 32. R 1 but, [ka] where m is 0, 1, 2, 3, or 4, and each R 1a is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a or a salt thereof. 4. The compound of embodiment 1, 2 or 3, wherein said alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl are independently optionally substituted with deuterium; Embodiment 33. R 1 but, [ka] 33. The compound of embodiment 32, selected from the group consisting of: Embodiment 34. R 1 but, [ka] where 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 1aor a salt thereof. 4. The compound of embodiment 1, 2 or 3, wherein said alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl are independently optionally substituted with deuterium; Embodiment 35. R 1 but, [ka] where 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 1a or a salt thereof. 4. The compound of embodiment 1, 2 or 3, wherein said alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl are independently optionally substituted with deuterium; Embodiment 36. R 1 but, [ka] where m is 0, 1, or 2, and each R 1a is, where applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, —CN, or heteroaryl, where R 1a or a salt thereof. 4. The compound of embodiment 1, 2 or 3, wherein said alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl are independently optionally substituted with deuterium; Embodiment 37. R 1 but, [ka] and any of the above groups in which one or more hydrogen atoms are replaced by deuterium atoms; or a salt thereof. Embodiment 38. R 1 but, [ka] and any of the above groups in which one or more hydrogen atoms are replaced by deuterium atoms; or a salt thereof. Embodiment 39. R 1 but, [ka] and any of the above groups in which one or more hydrogen atoms are replaced by deuterium atoms; or a salt thereof. Embodiment 40. R 2 but, [ka] where n is 1, 2, 3, 4, 5, or 6; R 3 is C1-C2 alkyl optionally substituted with fluoro; phenyl optionally substituted with fluoro; pyridinyl optionally substituted with fluoro or methyl; or cyclopropyl optionally substituted with fluoro; or a salt thereof. Embodiment 41. R 2 but, [ka] and any of the above groups in which one or more hydrogen atoms are replaced by deuterium atoms; or a salt thereof. Embodiment 42. A compound or a salt thereof selected from compound numbers 1 to 66 in FIG. Embodiment 43. A compound or a salt thereof selected from Compound Nos. 1 to 147. Embodiment 44. A compound or a salt thereof selected from Compound Nos. 1 to 665. Embodiment 45. A pharmaceutical composition comprising a compound of any one of Embodiments 1 to 44, or a salt thereof, and a pharmaceutically acceptable carrier or excipient. Embodiment 46. A method of treating a fibrotic disease in an individual in need thereof, comprising administering a compound of any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof. Embodiment 47. The method of embodiment 46, wherein the fibrotic disease is pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis. Embodiment 48. A kit comprising a compound of any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof. Embodiment 49. The kit of embodiment 48, further comprising instructions for treating a fibrotic disorder. Embodiment 50. A method of inhibiting αvβ6 integrin in an individual, comprising administering a compound of any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof. Embodiment 51. A method for inhibiting TGFβ activation in a cell, comprising administering to the cell a compound of any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof. Embodiment 52. Use of a compound of any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a fibrotic disease. Embodiment 53. R 2

[0037] Embodiment 12. The compound of any one of embodiments 1-11, wherein is C3-C5 alkyl substituted with both fluorine and -OCH3; or a salt thereof. Embodiment 54. R 2 But, -OR 3 C1-C6 alkyl optionally substituted by R 3 12. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein is phenyl optionally substituted by fluorine. Embodiment 55. R 2 But, -OR 3 C1-C6 alkyl optionally substituted by R 3 12. The compound of any one of embodiments 1 to 11, wherein is pyridinyl optionally substituted by fluorine or methyl; or a salt thereof. Embodiment 56. R2 But R 2a C1-C6 alkyl substituted by, where R 2a 12. The compound of any one of embodiments 1-11, or a salt thereof, wherein is halogen. Embodiment 57. R 2 But R 2a C1-C6 alkyl substituted by, where R 2a 12. The compound of any one of embodiments 1-11, or a salt thereof, wherein is deuterium. Embodiment 58. R 2 But R 2a C1-C6 alkyl substituted by, where R 2a 12. The compound of any one of embodiments 1 to 11, wherein is 3- to 12-membered heterocyclyl optionally substituted by oxo; or a salt thereof. Embodiment 59. R 2 But R 2a C1-C6 alkyl substituted by, where R 2a 12. The compound of any one of embodiments 1 to 11, wherein is 4-5 membered heterocyclyl optionally substituted by oxo; or a salt thereof. Embodiment 60. R 2 But R 2a C1-C6 alkyl substituted by, where R 2a But halogen or -OR 6 C6 to C optionally substituted by 14 12. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein: Embodiment 61. R 2 But R 2a C1-C6 alkyl substituted by, where R 2a But halogen or -OR 6 or a salt thereof. Embodiment 62. R 2 But R 2a C1-C6 alkyl substituted by, where R 2a12. The compound of any one of embodiments 1-11, wherein is 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl; or a salt thereof. Embodiment 63. R 2 But R 2a C1-C6 alkyl substituted by, where R 2a 12. The compound of any one of embodiments 1-11, wherein is pyrazolyl optionally substituted by methyl; or a salt thereof. Embodiment 64. R 2 But R 2a C1-C6 alkyl substituted by, where R 2a -CN, halogen or -OR 6 or a salt thereof. Embodiment 65. R 2 But R 2a C1-C6 alkyl substituted by, where R 2a But -S(O)2R 3 or a salt thereof. Embodiment 66. R 1 But R 1a or a salt thereof. Embodiment 67. R 1 But R 1a or a salt thereof. Embodiment 68. R 1 But R 1a or a salt thereof. 4. The compound of embodiment 1, 2 or 3, wherein the compound is 1H-pyrrolopyridyl optionally substituted by: Embodiment 69. R 1 But R 1a or a salt thereof. Embodiment 70. R 1 But R 1aor a salt thereof. Embodiment 71. R 1 But R 1a or a salt thereof. [Example]

[0285] Synthesis Example The chemical reactions in the described synthetic examples can be easily adapted to prepare many other compounds of the present invention, and other methods for preparing compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds of the present invention can be successfully carried out with modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups or by utilizing other suitable reagents known in the art other than those described, or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or known in the art are recognized to have applicability for preparing other compounds of the present invention.

[0286] For the examples described herein, reference to a general procedure indicates that the reaction was prepared using similar reaction conditions and parameters to the general procedure described above.

[0287] procedure The compounds provided herein can be prepared according to the procedures and schemes as illustrated by the examples. When following the procedures, slight variations in temperature, concentration, reaction time and other parameters can occur that do not substantially affect the outcome of the procedures.

[0288] Step A [ka] N-Cyclopropyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide. To a mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanoic acid hydrochloride (5.0 g, 19.48 mmol) and cyclopropanamine (1.51 mL, 21.42 mmol) in CHCl (80 mL) was added DIPEA (13.57 mL, 77.9 mmol) at room temperature. HATU (8.1 g, 21.42 mmol) was then added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified by normal-phase silica gel chromatography to give N-cyclopropyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide.

[0289] Step B [ka] N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide. To a mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (351 mg, 1.71 mmol) and formic acid (0.09 mL, 2.22 mmol) in THF / DMF (4:1) (5 mL) was added HATU (844 mg, 2.22 mmol), followed by DIPEA (0.89 mL, 5.13 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified by normal phase silica gel chromatography to give N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide.

[0290] Step C [ka] N-(2-Methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. A mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (300 mg, 1.46 mmol), 1-bromo-2-methoxyethane (0.11 mL, 1.17 mmol), and DIPEA (0.25 mL, 1.46 mmol) in i-PrOH (3 mL) was heated to 70° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, then concentrated in vacuo and purified by normal phase silica gel chromatography to give N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine.

[0291] Step D [ka] N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. To a solution of N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide (200 mg, 0.86 mmol) in THF (2 mL) at room temperature was added dropwise a borane-tetrahydrofuran complex solution (1.0 M in THF, 4.0 mL, 4.0 mmol). The resulting mixture was then heated to 60° C. for 2 hours and then allowed to cool to room temperature. The reaction mixture was diluted with MeOH and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine.

[0292] Step E [ka] N-(2-Methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (5). To a solution of N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide (15.5 g, 1.0 equiv.) in 1,4-dioxane (124 mL) at room temperature was slowly added LiAlH (1.0 M in THF, 123 mL, 2.2 equiv.), and the resulting mixture was heated to reflux for 20 hours and then cooled to 0° C. To this solution was added HO (4.7 mL), followed by 1 M NaOH (4.7 mL), followed by HO (4.7 mL), warmed to room temperature, and stirred for 30 minutes, at which point solid MgSO was added and stirred for an additional 30 minutes. The resulting mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated in vacuo to give N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine.

[0293] Step F [ka] Methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. To a mixture of N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (5) (187 mg, 0.85 mmol) in MeOH (5 mL) at room temperature was added acetic acid (0.12 mL, 2.05 mmol), followed by the addition of methyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (217 mg, 0.94 mmol). The resulting mixture was stirred at room temperature for 15 minutes, at which time sodium cyanoborohydride (80 mg, 1.28 mmol) was added to the reaction mixture, stirred for 30 minutes, and then concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate.

[0294] Step G [ka] Methyl (S)-2-amino-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (152 mg, 0.35 mmol) in 2 mL of CHCl at room temperature was added 4 N HCl in 1,4-dioxane (1 mL, 4 mmol), and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo to give methyl (S)-2-amino-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate as the trihydrochloride salt.

[0295] Step H [ka] A solution of (S)-methyl 2-amino-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate trihydrochloride (80 mg, 0.16 mmol), 4-chloro-2-methyl-6-(trifluoromethyl)pyrimidine (64 mg, 0.33 mmol), and DIPEA (0.23 mL, 1.31 mmol) in i-PrOH (1 mL) was heated at 60 °C overnight. The reaction was allowed to cool to room temperature and then concentrated in vacuo. The resulting crude residue was purified by normal phase silica gel chromatography to give methyl (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)amino)butanoate.

[0296] Procedure P [ka] (S)-2-((2-chloro-3-fluorophenyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a solution of methyl (S)-2-((2-chloro-3-fluorophenyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate in THF / MeOH / HO (4:1:1) at room temperature was added lithium hydroxide (approximately 4 equivalents), and the resulting mixture was stirred for 30 minutes. The reaction mixture was concentrated in vacuo, and the resulting crude residue was purified by reverse-phase HPLC to give (S)-2-((2-chloro-3-fluorophenyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[0297] Step Q [ka] (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a mixture of methyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (1 g, 1.90 mmol) in HO (3 mL), THF (3 mL), and MeOH (3 mL) was added LiOH·HO (159.36 mg, 3.80 mmol), and the mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo. The mixture was adjusted to pH=6 with AcOH (2 mL) and the residue was concentrated in vacuo to give the compound (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. LCMS (ESI+): m / z = 513.5 (M+H) + . 11H NMR (400 MHz, DMSO-d6): δ ppm 7.25 - 7.37 (m, 5 H) 7.00 (d, J = 7.28 Hz, 1 H) 6.81 (br d, J = 7.50 Hz, 1 H) 6.22 (d, J = 7.28 Hz, 1 H6) 4.93 - 5.05 (m, 2 H) 3.68 - 3.77 (m, 1 H) 3.25 - 3.34 (m, 1 H) 3.15 - 3.24 (m, 5 H) 2.58 (br t, J = 6.06 Hz, 2 H) 2.29 - 2.49 (m, 8 H) 2.16 (br dd, J = 12.90, 6.06 Hz, 1 H) 1.69 - 1.78 (m, 2 H) 1.58 - 1.68 (m, 1 H) 1.53 (quin, J = 7.39 Hz, 2 H) 1.28 - 1.40 (m, 2 H) 1.00 (d, J = 5.95 Hz, 3 H).

[0298] Procedure R [Chemical formula] tert-butyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (300 mg, 523.84 μmol, HOAc salt) in DMA (4 mL) was added N-benzyl-N,N-diethylethanaminium chloride (119.32 mg, 523.84 μmol), K2CO3 (1.88 g, 13.62 mmol), 2-bromo-2-methylpropane (3.45 g, 25.14 mmol). The mixture was stirred at 55° C. for 18 hours and then allowed to cool to room temperature. The reaction mixture was concentrated in vacuo, and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative TLC to give tert-butyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. LCMS (ESI+): m / z = 569.3 (M+H) + .

[0299] Step S [ka] tert-Butyl (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. Under a N atmosphere, Pd(OH) (26 mg) was added to a solution of tert-butyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (107 mg, 188.13 μmol) in i-PrOH (2 mL). The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (15 psi) at room temperature for 15 hours. The mixture was filtered and concentrated in vacuo to give tert-butyl (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. LCMS (ESI+): m / z = 435.5 (M+H) + . 1 H NMR (400 MHz, CDCl3): δ ppm 7.06 (d, J=7.34 Hz, 1 H) 6.34 (d, J=7.34 Hz, 1 H) 4.98 (br s, 1 H) 3.38 - 3.44 (m, 4 H) 3.34 (s, 3 H) 2.69 (t, J=6.30 Hz, 2 H) 2.51 - 2.59 (m, 5 H) 2.31 (dd, J=13.39, 5.56 Hz, 1 H) 1.86 - 1.94 (m, 5 H) 1.49 - 1.69 (m, 6 H) 1.47 (s, 9 H) 1.13 (d, J=6.11Hz, 3H).

[0300] Procedure T [ka] (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid tert-butyl ester. (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid tert-butyl ester. To a solution of tert-butyl (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (100 mg, 230.09 μmol) and 2-chloro-5-methyl-pyrimidine (24.65 mg, 191.74 μmol) in 2-methyl-2-butanol (2 mL) was added t-BuONa (2 M in THF, 191.74 μL) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (15.23 mg, 19.17 μmol), and the resulting mixture was stirred at 100° C. for 14 hours. The mixture was concentrated in vacuo to give tert-butyl (S)-4-(((S)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate. LCMS (ESI+): m / z = 527.3 (M+H) + .

[0301] Step U [ka] (S)-4-(((R)-2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid. To a solution of tert-butyl (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate (80 mg, 151.89 μmol) in DCM (2 mL) was added TFA (254.14 mg, 2.23 mmol) at 0° C. The mixture was stirred at room temperature for 6 hours. The mixture was concentrated in vacuo and the resulting crude residue was purified by preparative HPLC to give the compound (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid. LCMS (ESI+): m / z = 471.2 (M+H) + . 1 H NMR (400 MHz, Methanol-d4) δ ppm 8.57 (br s, 2 H) 7.60 (d, J=7.28 Hz, 1 H) 6.67 (d, J=7.28 Hz, 1 H) 4.81 - 4.86 (m, 1 H) 3.86 (br s, 1 H) 3.41 - 3.59 (m, 4 H) 3.39 (s, 3 H) 3.33 - 3.38 (m, 1 H) 3.12 - 3.30 (m, 3 H) 2.76 - 2.86 (m, 4 H) 2.54 (br s, 1 H) 2.39 (br d, J=8.82 Hz, 1 H) 2.30 (s, 3H) 1.76 - 1.99 (m, 6 H) 1.22 (d, J=5.95 Hz, 3 H).

[0302] Synthesis Example The chemical reactions in the described synthetic examples can be easily adapted to prepare many other compounds of the present invention, and other methods for preparing compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds of the present invention can be successfully carried out with modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups or by utilizing other suitable reagents known in the art other than those described, or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or known in the art are recognized to have applicability for preparing other compounds of the present invention.

[0303] For the examples described herein, reference to a procedure indicates that the reaction was prepared using similar reaction conditions and parameters to the procedure described above.

[0304] Example A1 Synthesis of (S)-2-fluoro-3-methoxypropan-1-amine [ka] Methyl dibenzyl-D-serinate. To a mixture of methyl D-serinate hydrochloride (100 g, 642.76 mmol), K2CO3 (177.67 g, 1.29 mol), and KI (53.35 g, 321.38 mmol) in DMF (1.5 L) was added benzyl bromide (241.85 g, 1.41 mol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was quenched with H2O (3000 mL) and EtOAc (1 L × 3). The organic phase was washed with brine (1 L), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by normal phase silica gel chromatography to give methyl dibenzyl-D-serinate.

[0305] [ka] Methyl (S)-3-(dibenzylamino)-2-fluoropropanoate. To a solution of methyl dibenzyl-D-serinate (155 g, 517.77 mmol) in THF (1.2 L) was added DAST (102.65 g, 636.85 mmol, 84.14 mL) dropwise at 0 ° C., and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with saturated aqueous NaHCO (1 L) at 0 ° C. and extracted with EtOAc (500 mL × 3). The organic phase was dried over Na SO , filtered, and concentrated in vacuo. The crude product was purified by normal phase silica gel chromatography to give methyl (S)-3-(dibenzylamino)-2-fluoropropanoate.

[0306] [ka] (S)-3-(dibenzylamino)-2-fluoropropan-1-ol. To a solution of methyl (S)-3-(dibenzylamino)-2-fluoropropanoate (103 g, 341.79 mmol) in THF (1 L) was added LiBH (14.89 g, 683.58 mmol) at 0 ° C. The mixture was stirred at 40 ° C. for 12 hours. The mixture was poured into aqueous NH Cl (500 mL) at 0 ° C. The aqueous phase was extracted with ethyl acetate (300 mL × 3). The combined organic extracts were dried over Na SO , filtered, and concentrated in vacuo to give (S)-3-(dibenzylamino)-2-fluoropropan-1-ol, which was used without further purification.

[0307] [ka] (S)-N,N-Dibenzyl-2-fluoro-3-methoxypropan-1-amine. To a solution of (S)-3-(dibenzylamino)-2-fluoropropan-1-ol (51 g, 186.58 mmol) in THF (400 mL), NaH (60% dispersion in mineral oil, 11.19 g, 279.87 mmol) was added at 0 ° C., and the resulting mixture was stirred at 0 ° C. for 30 minutes. Then, iodomethane (18.58 mL, 298.52 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hours. The mixture was quenched with aqueous NH Cl solution (500 mL) at 0 ° C. The aqueous phase was extracted with EtOAc (500 mL × 3). The combined organic extracts were dried over Na SO , filtered, and concentrated in vacuo. The resulting crude residue was purified by normal phase silica gel chromatography to give (S)-N,N-dibenzyl-2-fluoro-3-methoxypropan-1-amine.

[0308] [ka] (S)-2-Fluoro-3-methoxypropan-1-amine. To a solution of (S)-N,N-dibenzyl-2-fluoro-3-methoxypropan-1-amine (15 g, 52.20 mmol) in MeOH (200 mL) was added Pd / C (3 g). The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (50 psi) at 50 °C for 12 h. The reaction mixture was filtered through a Celite pad, and the filtrate was treated with HCl / EtOAc (50 mL) and then concentrated in vacuo to give (S)-2-fluoro-3-methoxypropan-1-amine hydrochloride, which was used without further purification.

[0309] Example A2 Synthesis of tert-butyl 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

[0310] [ka] tert-Butyl 7-(4-ethoxy-4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate. To a solution of ethyl 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanoate (5.25 g, 21.1 mmol) and di-tert-butyl dicarbonate (5.89 mL, 25.4 mmol) in THF (70 mL) was added lithium bis(trimethylsilyl)amide (25.4 mL, 25.4 mmol) at 0 ° C. After 2 hours, the reaction was diluted with EtOAc (50 mL) and quenched with saturated NH Cl (50 mL). After stirring for 30 minutes, the layers were separated, and the organic phase was washed with brine (20 mL), dried over Na SO , and concentrated in vacuo. The resulting crude residue was purified by normal phase silica gel chromatography to give tert-butyl 7-(4-ethoxy-4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate.

[0311] [ka] tert-Butyl 7-(4-hydroxybutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate. To a solution of tert-butyl 7-(4-ethoxy-4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (6.81 g, 19.5 mmol) in THF (50 mL) was added LiBH (1.0 M in THF, 19.5 mL, 19.5 mmol) at room temperature. The mixture was stirred overnight, then quenched with saturated NH Cl and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with H O, dried over Na SO , filtered, and concentrated in vacuo. The resulting crude residue was purified by normal phase silica gel chromatography to give tert-butyl 7-(4-hydroxybutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate.

[0312] [ka] tert-Butyl 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate. A solution of oxalyl chloride (2.57 mL, 29.3 mmol) in CHCl (69 mL) was cooled to −78° C. for 5 minutes, at which point dimethyl sulfoxide (4.2 mL, 58.6 mmol) was added and the mixture was stirred for 30 minutes. A solution of tert-butyl 7-(4-hydroxybutyl)-3,4-dihydro-2H-1,8-naphthyridine-1-carboxylate (6.9 g, 22.6 mmol) in CHCl (10.5 mL) was added and stirred at −78° C. for 1 hour. Triethylamine (10.5 mL, 75.1 mmol) was then added to the reaction mixture and stirred for 30 minutes. The reaction was quenched with water and extracted with CHCl. The organic phase was collected and dried over sodium sulfate. The organic phase was concentrated to give tert-butyl 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate, which was used without further purification.

[0313] Example A3 Synthesis of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinolin-4-ylamino)butanoate

[0314] [ka] Methyl (S)-2-amino-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. Prepared according to Scheme A using 2-methoxyethylamine using Procedure A, then Procedure E, Procedure F and Procedure G to give methyl (S)-2-amino-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate.

[0315] [ka] Methyl (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinolin-4-ylamino)butanoate. 4-Bromoquinoline (65 mg, 0.3 mmol), Pd(OAc) (6.3 mg, 0.03 mmol), rac-BINAP (35 mg, 0.6 mmol), and KPO (210 mg, 1.0 mmol) were added to a microwave vial containing methyl (S)-2-amino-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (125 mg, 0.3 mmol), and then diluted with dioxane (2 mL). The mixture was degassed, sealed, and heated to 100 °C for 1 hour. The reaction mixture was allowed to cool to room temperature, then filtered and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give methyl (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinolin-4-ylamino)butanoate.

[0316] Example A4 Synthesis of methyl (S)-2-(isoquinolin-1-ylamino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate

[0317] [ka] Methyl (S)-2-(isoquinolin-1-ylamino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. 1-Bromoisoquinoline (65 mg, 0.3 mmol), Pd(OAc) (6.3 mg, 0.03 mmol), rac-BINAP (35 mg, 0.6 mmol), and KPO (210 mg, 1.0 mmol) were added to a microwave vial containing methyl (S)-2-amino-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (125 mg, 0.3 mmol), and then diluted with dioxane (2 mL). The mixture was degassed, sealed, and heated to 100 °C for 1 h. The reaction mixture was allowed to cool to room temperature, then filtered and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give methyl (S)-2-(isoquinolin-1-ylamino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate.

[0318] In the following examples, compounds without specific synthetic descriptions can be synthesized by procedures described herein similar to those for, for example, compound 2, Scheme 1; compound 81, Scheme 5; and compound 213, Scheme 24.

[0319] For example, (S)-2-((3-cyanopyrazin-2-yl)amino)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (compound 597) can be prepared by slightly modifying the procedure in Scheme 1. Using 2-(3,5-difluorophenoxy)ethan-1-amine instead of cyclopropylamine in step 1, the analogous amine product can be obtained. The amine product can then be Boc-deprotected as in step 2, followed by reductive amination as in step 3, to obtain the analogous tertiary amine product. This tertiary amine can then be base-mediated hydrolyzed as in step 4, followed by deprotection of the benzyl carbamate under reducing conditions as in step 5, to obtain the analogous amino acid product. This amino acid can then be converted to S N The compound can be reacted with a suitably activated heterocycle, such as 3-chloropyrazine-2-carbonitrile, in an Ar reaction to give the described compounds. Similarly, the analogous free amino acid product from step 5 can be reacted with an analogous activated heterocycle, as described in step 6, and then subjected to reduction conditions as shown in step 7 of Scheme 1 or cross-coupling conditions as shown in step 2 of Scheme 5, to give further described prophetic compounds.

[0320] Alternatively, if another amine is used in place of cyclopropylamine, the tertiary amine product resulting from step 3 in Scheme 1 can be hydrolyzed as shown in step 1 of Scheme 24, and the acid product can then be t-butylated with t-butyl bromide under basic conditions as shown in step 2 of Scheme 24. The resulting t-butyl ester product can be deprotected under reductive conditions as in step 3 of Scheme 24 to provide the amino ester product, which can then undergo palladium-catalyzed cross-coupling with an appropriate aryl or heteroaryl halide as in step 4 of Scheme 24 to provide the ester product, which can be exposed to acid as in step 5 of Scheme 24 to provide the final compound.

[0321] For example, (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-indazol-3-yl)amino)butanoic acid (Compound 624) can be prepared by slightly modifying the procedure of Scheme 1. Using 2-(3,5-difluorophenoxy)ethan-1-amine instead of cyclopropylamine in Step 1 provides the analogous amine product. This amine product can then be Boc-deprotected as in Step 2 and then reductively aminated as in Step 3 to provide the analogous tertiary amine product. The tertiary amine product can be hydrolyzed as shown in Step 1 of Scheme 24, and the acid product can then be t-butylated with t-butyl bromide under basic conditions as shown in Step 2 of Scheme 24. The resulting t-butyl ester product can be deprotected under reducing conditions as in step 3 of Scheme 24 to give the amino ester product, which can then undergo a palladium-catalyzed cross-coupling in step 4 of Scheme 24 using 3-bromo-1-methyl-1H-indazole in place of 6-chloro-N,N-dimethylpyrimidin-4-amine to give the ester product, which can be exposed to acid to give the described compound.

[0322] Compound 1: (S)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-(difluoromethyl)pyrimidin-4-yl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with cyclopropylamine and Procedure H with 4-chloro-6-(difluoromethyl)pyrimidine. LCMS theoretical m / z = 475.3. [M+H]+, observed 475.2.

[0323] Compound 1: (S)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-(difluoromethyl)pyrimidin-4-yl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with cyclopropylamine and Procedure H with 4-chloro-6-(difluoromethyl)pyrimidine. LCMS theoretical m / z = 475.3. [M+H]+, observed 475.2.

[0324] Scheme 1, Compound 2: [ka] Step 1: tert-butyl 7-(4-(cyclopropylamino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate. To a solution of cyclopropanamine (22.8 mL, 328.5 mmol), AcOH (18.8 mL, 328.5 mmol) and NaBHCN (4.13 g, 65.7 mmol) in MeOH (100 mL) was added a solution of tert-butyl 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (10.0 g, 32.9 mmol) in MeOH (100 mL) at 0 ° C., and the resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with saturated NaHCO and stirred until gas evolution ceased, then concentrated in vacuo to remove volatiles. The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative HPLC to give the title compound. LCMS theoretical m / z = 346.3. [M+H]+, observed value 346.5.

[0325] Step 2: N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)cyclopropanamine. To a solution of tert-butyl 7-(4-(cyclopropylamino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (2.5 g, 7.24 mmol) in 10 mL of EtOAc was added 1.8 mL of 4 M HCl in EtOAc, and the resulting mixture was stirred at room temperature for 12 hours and then concentrated in vacuo. The crude residue was used without further purification. LCMS theoretical m / z = 246.2. [M+H]+, observed 246.0.

[0326] Step 3: (S)-2-(((benzyloxy)carbonyl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. To a mixture of (S)-2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (2.59 g, 9.8 mmol) and N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)cyclopropanamine hydrochloride (2.5 g, 8.9 mmol) in DCE (40 mL) was added AcOH (761 μL, 13.3 mmol) at 0 °C, and NaBH(OAc) (2.82 g, 13.3 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with saturated aqueous NaHCO3 and stirred until gas evolution ceased, then extracted with CH2Cl2. The combined organic extracts were washed with brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give the title compound. LCMS theoretical m / z = 495.3. [M+H]+, observed value 495.4.

[0327] Step 4: (S)-2-(((benzyloxy)carbonyl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a solution of methyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (4 g, 7.9 mmol) in THF / MeOH / HO (1:1:1) (36 mL) was added LiOH·HO (664 mg, 15.8 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then adjusted to pH=6 by careful addition of 1 N HCl and then concentrated in vacuo to provide the title compound. LCMS theoretical m / z = 480.3 [M]+, measured 480.1.

[0328] Step 5: (S)-2-Amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a flask containing (S)-2-(((benzyloxy)carbonyl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (4.5 g, 9.4 mmol) was added 20 wt % Pd(OH) / C (4.5 g), which was then diluted with i-PrOH (300 mL) and stirred at room temperature under 50 psi H atmosphere for 48 hours. The reaction mixture was filtered through a pad of CELITE®, rinsed with MeOH, and then concentrated in vacuo. The crude residue was purified by preparative reverse-phase HPLC to give the title compound. LCMS theoretical m / z = 347.2. [M+H]+, measured 347.2.

[0329] Step 6: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a solution of (S)-2-amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid trifluoroacetate (150 mg, 0.3 mmol) in THF / HO (4:1) (3 mL) was added 5-bromo-4-chloro-pyrimidine (69 mg, 0.4 mmol) and NaHCO (137 mg, 1.63 mmol), followed by stirring at 70 °C for 2 h, then cooled to room temperature and concentrated in vacuo. The crude residue was used without further purification.

[0330] Step 7: (S)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid. To a flask containing (S)-2-((5-bromopyrimidin-4-yl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (157 mg, 0.3 mmol) was added 20 wt % Pd / C (200 mg), which was then diluted with MeOH (20 mL). The resulting mixture was stirred under an atmosphere of H at room temperature for 4 hours, then filtered and concentrated in vacuo. The crude residue was purified by preparative reverse-phase HPLC to give the title compound. LCMS (ESI+): m / z = 425.2 (M+H) + . 1H NMR (400 MHz, Methanol-d4): δ ppm 8.34 (s, 1 H) 7.96 (br s, 1 H) 7.18 (d, J=7.21 Hz, 1 H) 6.52 (br s, 1 H) 6.39 (d, J=7.21 Hz, 1 H) 3.87 - 4.65 (m, 1 H) 3.34 - 3.42 (m, 2 H) 2.76 - 2.96 (m, 2 H) 2.70 (br t, J=6.11 Hz, 4 H) 2.54 (br t, J=7.03 Hz, 2 H) 2.14 - 2.26 (m, 1 H) 1.96 - 2.08 (m, 1 H) 1.87 (q, J=5.87 Hz, 3 H) 1.62 (br d, J=4.40 Hz, 4 H) 0.37 - 0.59 (m, 4 H). LCMS theoretical m / z = 425.3. [M+H]+, measured 425.2.

[0331] Compound 3: (S)-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. To a mixture of (S)-2-amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (170 mg, 0.4 mmol) in THF / HO (4:1) (2.5 mL) was added 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (75 mg, 0.4 mmol) and NaHCO (112 mg, 1.33 mmol), and the resulting mixture was stirred at 70 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting crude residue was purified by preparative reverse phase HPLC to afford the title compound as the trifluoroacetic acid salt. 1H NMR (400 MHz, D2O): δ ppm 8.32 - 8.47 (m, 2 H) 7.51 (br d, J=6.60 Hz, 1 H) 6.56 (br s, 1 H) 4.85 (br s, 1 H) 4.03 (br s, 3 H) 3.29 - 3.63 (m, 6 H) 2.38 - 2.91 (m, 7 H) 1.64 - 1.95 (m, 6 H) 0.90 - 1.09 (m, 4 H). LCMS theoretical m / z = 479.3. [M+H]+, measured 479.2.

[0332] Compound 4: (S)-4-((2-hydroxy-2-methylpropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid. Prepared according to Scheme A using Procedure A with 1-amino-2-methylpropan-2-ol, Procedure H with 4-chloropyrimidine, and Procedure P. LCMS theoretical m / z = 457.3. [M+H]+, Found 457.2.

[0333] Compound 5: (S)-4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m / z = 493.1. [M+H]+, Found 493.1.

[0334] Compound 6: (S)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme A using Procedure A with cyclopropylamine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m / z = 475.3. [M+H]+, Found 475.3

[0335] Compound 7: (S)-2-((7-fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 4-chloro-7-fluoroquinazoline, and Procedure P. LCMS theoretical m / z = 511.3. [M+H]+, Found 511.3.

[0336] Compound 8: (S)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme A using Procedure A with 2,2-difluoroethan-1-amine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m / z = 499.3. [M+H]+, Found 499.3.

[0337] Compound 9: (S)-4-((3,3-Difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme A using Procedure A with 3,3-difluorocyclobutan-1-amine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m / z = 523.3. [M+H]+, Found 525.3.

[0338] Compound 10: (S)-4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 4-chloro-2-methylquinazoline, and Procedure P. LCMS theoretical m / z = 507.3. [M+H]+, Found 507.3.

[0339] Compound 11: (S)-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. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 4-chloropyrido[2,3-d]pyrimidine, and Procedure P. LCMS theoretical m / z = 494.3. [M+H]+, Found 494.3.

[0340] Compound 12: (S)-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. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 4-chloro-7-fluoro-2-methylquinazoline, and Procedure P. LCMS theoretical m / z = 525.3. [M+H]+, Found 525.3.

[0341] Compound 13: (S)-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. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 4-chloro-7-(trifluoromethyl)quinazoline, and Procedure P. LCMS theoretical m / z = 561.3. [M+H]+, Found 561.3.

[0342] Compound 14: (S)-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. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 4-chloro-2-(trifluoromethyl)quinazoline, and Procedure P. LCMS theoretical m / z = 561.3. [M+H]+, observed 561.3.

[0343] Compound 15: (S)-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. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 4-chloro-8-(trifluoromethyl)quinazoline, and Procedure P. LCMS theoretical m / z = 561.3. [M+H]+, Found 561.3.

[0344] Compound 16: (S)-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. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 4-chloropyrido[3,2-d]pyrimidine, and Procedure P. LCMS theoretical m / z = 494.3. [M+H]+, Found 494.3.

[0345] Compound 17: (S)-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. Prepared according to Scheme A using Procedure A with 2-metho...

Claims

1. Formula (A): 【Chemistry 1】 [In the formula, R 1 is C 6 ~C 14 aryl or 5-10 membered heteroaryl, 6 ~C 14 Aryl and 5- to 10-membered heteroaryl are R 1a may be substituted by; R 2 is hydrogen; deuterium; R 2a C which may be substituted by 1 ~C 6 Alkyl; -OH; R 2a -O-C 1 ~C 6 Alkyl; R 2b C which may be substituted by 3 ~C 6 Cycloalkyl; R 2b -O-C 3 ~C 6 Cycloalkyl; R 2c 3- to 12-membered heterocyclyl optionally substituted by -S(O) 2 R 2d provided that the carbon atom directly bonded to the nitrogen atom is R other than halogen. 2a may be substituted with a moiety; Each R 1a is independently 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 ~C 14 Aryl, deuterium, halogen, -CN, -OR 3 , -SR 3 , -NR 4 R 5 , -NO 2 , -C=NH(OR 3 ), -C(O)R 3 , -OC(O)R 3 , -C(O)OR 3 , -C(O)NR 4 R 5 , -NR 3 C(O)R 4 , -NR 3 C(O)OR 4 , -NR 3 C(O)NR 4 R 5 , -S(O)R 3 , -S(O) 2 R 3 , -NR 3 S(O)R 4 , -NR 3 S (O) 2 R 4 , -S(O)NR 4 R 5 , -S(O) 2 N.R. 4 R 5 or -P(O)(OR 4 )(OR 5 ), where each R 1a are independently deuterium, halogen, oxo, -OR 6 , -NR 6 R 7 , -C(O)R 6 , -CN, -S(O)R 6 , -S(O) 2 R 6 , -P(O)(OR 6 )(OR 7 ), C 3 ~C 8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 ~C 14 Aryl or C optionally substituted by deuterium, oxo, -OH or halogen 1 ~C 6 may be substituted with alkyl; Each R 2a , R 2b , R 2c , R 2e and R 2f are independently oxo or R 1a and R 2d is R 2e C which may be substituted by 1 ~C 6 Alkyl, or R 2f C which may be substituted by 3 ~C 5 is cycloalkyl; R 3 are independently hydrogen, deuterium, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, C 6 ~C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, where R 3 The C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, C 6 ~C 14 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are independently selected from halogen, deuterium, oxo, —CN, —OR 8 , -NR 8 R 9 , -P(O)(OR 8 )(OR 9 ), or C optionally substituted by deuterium, halogen, —OH or oxo 1 ~C 6 may be substituted with alkyl; R 4 and R 5 are each independently hydrogen, deuterium, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, C 6 ~C 14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R 4 and R 5 The C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, C 6 ~C 14 Aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from deuterium, halogen, oxo, —CN, —OR 8 , -NR 8 R 9 or C optionally substituted by deuterium, halogen, —OH or oxo 1 ~C 6 optionally substituted by alkyl; or R 4 and R 5 together with the atom to which they are attached, deuterium, halogen, oxo, -OR 8 , -NR 8 R 9 or C optionally substituted by deuterium, halogen, oxo or -OH 1 ~C 6 forming a 3- to 6-membered heterocyclyl optionally substituted by alkyl; R 6 and R 7 are each independently hydrogen, deuterium, or C optionally substituted by deuterium, halogen, or oxo. 1 ~C 6 C optionally substituted by alkyl, deuterium, halogen or oxo 2 ~C 6 Alkenyl, or C optionally substituted by deuterium, halogen or oxo 2 ~C 6 is alkynyl; or R 6 and R 7 are, together with the atom to which they are attached, deuterium, halogen, oxo, or C which may be substituted by deuterium, halogen, or oxo. 1 ~C 6 forming a 3- to 6-membered heterocyclyl optionally substituted by alkyl; R 8 and R 9 are each independently hydrogen, deuterium, or C optionally substituted by deuterium, halogen, or oxo. 1 ~C 6 C optionally substituted by alkyl, deuterium, halogen or oxo 2 ~C 6 Alkenyl, or C optionally substituted by deuterium, halogen or oxo 2 ~C 6 is alkynyl; or R 8 and R 9 are, together with the atom to which they are attached, deuterium, halogen, oxo, or C which may be substituted by deuterium, oxo or halogen. 1 ~C 6 forming a 3- to 6-membered heterocyclyl optionally substituted by alkyl; Each R 10 , R 11 , R 12 and R 13 is independently hydrogen or deuterium; R 14 is deuterium; q is 0, 1, 2, 3, 4, 5, 6, 7 or 8; Each R 15 is independently selected from hydrogen, deuterium, or a halogen; Each R 16 is independently selected from hydrogen, deuterium, or a halogen; p is 3, 4, 5, 6, 7, 8 or 9. or a salt thereof.

2. R 2 But, R 2a C which may be substituted by 1 ~C 6 Alkyl; R 2b C which may be substituted by 3 ~C 6 Cycloalkyl; R 2c 3- to 12-membered heterocyclyl optionally substituted by -S(O) 2 R 2d and R 3 are independently hydrogen, deuterium, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, C 6 ~C 14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R 3 The C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, C 6 ~C 14 Aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are independently selected from halogen, deuterium, oxo, —CN, —OR 8 , -NR 8 R 9 , -P(O)(OR 8 )(OR 9 ), or C optionally substituted by deuterium, halogen, —OH or oxo 1 ~C 6 may be substituted with alkyl; Each R 15 is hydrogen; Each R 16 is hydrogen; Formula (I): 【Chemistry 2】 Denoted by The compound according to claim 1.

3. R 1a , R 2a , R 2b , R 2c , R 2e , R 2f , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , or R 14 3. The compound according to claim 1 or 2, or a salt thereof, wherein at least one of:

4. R 10 , R 11 , R 12 , R 13 , and R 14 is hydrogen; p is 3; and formula (II): 【Chemistry 3】 As represented by the compound 3. The compound according to claim 1 or 2, or a salt thereof.

5. R 1 But, R 1a The compound according to any one of claims 1 to 4, which is a 5- to 10-membered heteroaryl optionally substituted by:

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

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

8. R 1 But, R 1a The compound according to any one of claims 1 to 4, which is pyrimidin-4-yl optionally substituted by:

9. R 1 But, R 1a pyrimidin-4-yl optionally substituted by 1a is a 5- to 10-membered heteroaryl optionally substituted by halogen or C 1 ~C 6 The compound according to any one of claims 1 to 4, or a salt thereof, which is alkyl.

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

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

12. R 1 But, R 1a The compound according to any one of claims 1 to 4, which is quinazolin-4-yl optionally substituted by: or a salt thereof.

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

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

15. R 2 but, hydrogen; deuterium; Hydroxy; or Deuterium, halogens, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Alkoxyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Halocycloalkyl, C 3 ~C 8 Cycloalkoxyl, C 6 ~C 14 Aryl, C 6 ~C 14 Aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy, 3- to 12-membered heterocyclyl optionally substituted by oxo, —C(O)NR 4 R 5 , -NR 3 C(O)R 4 , or -S(O) 2 R 3 Optionally substituted with C 1 ~C 6 Alkyl or C 1 ~C 6 Alkoxyl 15. The compound according to claim 1 or 3, or a salt thereof,

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

17. R 2 But, R 2a C which may be substituted by 1 ~C 6 The compound according to any one of claims 1 to 14, or a salt thereof, which is alkyl.

18. R 2 But, R 2a C which may be substituted by 1 ~C 6 alkyl, where R 2a is halogen; C optionally substituted by halogen 3 ~C 8 Cycloalkyl; C 1 ~C 6 5-10 membered heteroaryl optionally substituted by alkyl; -NR 4 R 5 ;-NR 3 C(O)R 4 ;-S(O) 2 R 3 or oxo, or a salt thereof.

19. R 2 But, R 2a C which may be substituted by 1 ~C 6 alkyl, where R 2a is fluoro; cyclobutyl substituted by fluoro; pyrazolyl substituted by methyl; or -S(O) 2 CH 3 The compound according to any one of claims 1 to 14, or a salt thereof.

20. R 2 But, -OR 3 C which may be substituted by 1 ~C 6 The compound according to any one of claims 1 to 14, or a salt thereof, which is alkyl.

21. R 2 But, -OR 3 C which may be substituted by 1 ~C 6 alkyl, R 3 is hydrogen; C optionally substituted by halogen 1 ~C 6 Alkyl; C optionally substituted with halogen 3 ~C 6 Cycloalkyl; C optionally substituted by halogen 6 ~C 14 aryl; or halogen or C 1 ~C 6 The compound according to any one of claims 1 to 14, which is a 5- to 6-membered heteroaryl optionally substituted by alkyl, or a salt thereof.

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

23. R 2 But -CH 2 CH 2 OCH 3 The compound according to any one of claims 1 to 14, or a salt thereof.

24. R 2 is halogen and -OR 3 C is substituted by both 1 ~C 6 alkyl, where R 3 But, C 1 ~C 6 The compound according to any one of claims 1 to 14, or a salt thereof, which is alkyl.

25. R 2 But, R 2b C which may be substituted by 3 ~C 6 The compound according to any one of claims 1 to 14, or a salt thereof, which is cycloalkyl.

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

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

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

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

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

31. R 1 but, 【Chemistry 8】 where each R 1a is independently deuterium, halogen, alkyl, haloalkyl or alkoxy; or a salt thereof, according to claim 30.

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

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

34. R 1 but, 【Chemistry 11】 31. The compound of claim 30, selected from the group consisting of:

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

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

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

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

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

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

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

42. R 1 but, 【Chemistry 19】 and any one of the above groups in which one or more hydrogen atoms are replaced by deuterium atoms, or a salt thereof, according to any one of claims 1 to 4.

43. R 1 but, 【Chemistry 20】 and any one of the above groups in which one or more hydrogen atoms are replaced by deuterium atoms, or a salt thereof, according to any one of claims 1 to 4.

44. R 1 but, 【Chemistry 21】 and any one of the above groups in which one or more hydrogen atoms are replaced by deuterium atoms, or a salt thereof, according to any one of claims 1 to 4.

45. R 1 but, 【Chemical 22】 and any one of the above groups in which one or more hydrogen atoms are replaced by deuterium atoms, or a salt thereof, according to any one of claims 1 to 4.

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

47. R 2 but, 【Chemistry 24】 and any of the above groups in which one or more hydrogen atoms are replaced by deuterium atoms, or a salt thereof, according to any one of claims 1 to 14 or 27 to 45.

48. R 2 but, 【Chemistry 25】 and any of the above groups in which one or more hydrogen atoms are replaced by deuterium atoms, or a salt thereof, according to any one of claims 1 to 14 or 27 to 45.

49. R 2 Fluorine and -OCH 3 C is substituted by both 3 ~C 5 The compound according to any one of claims 1 to 11, or a salt thereof, which is alkyl.

50. R 2 But, -OR 3 C which may be substituted by 1 ~C 6 alkyl, R 3 The compound according to any one of claims 1 to 14 or 27 to 45, wherein is phenyl optionally substituted by fluorine, or a salt thereof.

51. R 2 But, -OR 3 C which may be substituted by 1 ~C 6 alkyl, R 3 The compound according to any one of claims 1 to 14 or 27 to 45, wherein is pyridinyl optionally substituted by fluorine or methyl, or a salt thereof.

52. R 2 But, R 2a C substituted by 1 ~C 6 alkyl, where R 2a The compound according to any one of claims 1 to 14 or 27 to 45, or a salt thereof, wherein is halogen.

53. R 2 But, R 2a C substituted by 1 ~C 6 alkyl, where R 2a The compound according to any one of claims 1 to 14 or 27 to 45, or a salt thereof, wherein is deuterium.

54. R 2 But, R 2a C substituted by 1 ~C 6 alkyl, where R 2a The compound according to any one of claims 1 to 14 or 27 to 45, wherein is 3- to 12-membered heterocyclyl optionally substituted by oxo, or a salt thereof.

55. R 2 But, R 2a C substituted by 1 ~C 6 alkyl, where R 2a The compound according to any one of claims 1 to 14 or 27 to 45, wherein is 4- to 5-membered heterocyclyl optionally substituted by oxo, or a salt thereof.

56. R 2 But, R 2a C substituted by 1 ~C 6 alkyl, where R 2a is halogen or -OR 6 C which may be substituted by 6 ~C 14 The compound according to any one of claims 1 to 14 or 27 to 45, or a salt thereof, which is aryl.

57. R 2 But, R 2a C substituted by 1 ~C 6 alkyl, where R 2a is halogen or -OR 6 The compound according to any one of claims 1 to 14 or 27 to 45, which is phenyl optionally substituted by

58. R 2 But, R 2a C substituted by 1 ~C 6 alkyl, where R 2a But, C 1 ~C 6 The compound according to any one of claims 1 to 14 or 27 to 45, which is a 5- to 10-membered heteroaryl optionally substituted by alkyl, or a salt thereof.

59. R 2 But, R 2a C substituted by 1 ~C 6 alkyl, where R 2a The compound according to any one of claims 1 to 14 or 27 to 45, wherein is pyrazolyl optionally substituted by methyl, or a salt thereof.

60. R 2 But, R 2a C substituted by 1 ~C 6 alkyl, where R 2a is -CN, halogen or -OR 6 C which may be substituted by 3 ~C 8 The compound according to any one of claims 1 to 14 or 27 to 45, or a salt thereof, which is cycloalkyl.

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

62. R 1 But, R 1a The compound according to any one of claims 1 to 4, which is pyridyl optionally substituted by: or a salt thereof.

63. R 1 But, R 1a The compound according to any one of claims 1 to 4, which is indazolyl optionally substituted by: or a salt thereof.

64. R 1 But, R 1a The compound according to any one of claims 1 to 4, which is 1H-pyrrolopyridyl optionally substituted by:

65. R 1 But, R 1a The compound according to any one of claims 1 to 4, which is quinolinyl optionally substituted by: or a salt thereof.

66. R 1 But, R 1a The compound according to any one of claims 1 to 4, which is phenyl optionally substituted by: or a salt thereof.

67. R 1 But, R 1a The compound according to any one of claims 1 to 4, which is indanyl optionally substituted by: or a salt thereof.

68. A compound selected from compound numbers 1 to 66 in FIG. 1, or a salt thereof.

69. A compound selected from compound numbers 1 to 147, or a salt thereof.

70. A compound selected from compound numbers 1 to 665, or a salt thereof.

71. A compound selected from compound numbers 1 to 780, or a salt thereof.

72. 72. A pharmaceutical composition comprising a compound according to any one of claims 1 to 71 or a salt thereof, and a pharma- ceutically acceptable carrier or excipient.

73. 72. A method for treating a fibrotic disease in an individual in need thereof, comprising administering a compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof.

74. 74. The method of claim 73, wherein the fibrotic disease is pulmonary fibrosis, hepatic fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis or biliary fibrosis.

75. 74. The method of claim 73, wherein the fibrotic disease is liver fibrosis, cardiac fibrosis, primary sclerosing cholangitis or biliary fibrosis.

76. 72. A kit comprising a compound according to any one of claims 1 to 71 or a pharma- ceutically acceptable salt thereof.

77. 77. The kit of claim 76, further comprising instructions for treating a fibrotic disorder.

78. 72. A method of inhibiting αvβ6 integrin in an individual, comprising administering a compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof.

79. 72. A method of inhibiting TGFβ activation in a cell, comprising administering to said cell a compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof.

80. 72. Use of a compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a fibrotic disease.

81. α V β 6 A compound or salt thereof according to any one of claims 1 to 71 for use in inhibiting integrins, said use comprising administering to said subject a V β 6 Integrins and α V β 6 contacting said compound or a salt thereof with an effective amount of said compound to inhibit an integrin.

82. A method of modulating the activity of at least one integrin in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1 to 71, or a pharma- ceutically acceptable salt thereof, in an amount effective to modulate the activity of at least one integrin in the subject, wherein the at least one integrin comprises at least one of αvβ1 integrin and αvβ6 integrin.

83. 83. The method of claim 82, comprising inhibiting the activity of one or both of αvβ1 integrin and αvβ6 integrin in the subject.

84. The subject has or is at risk for a fibrotic disease selected from the group consisting of idiopathic pulmonary fibrosis (IPF), interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease-induced fibrosis, Alport syndrome, primary sclerosing cholangitis (PSC), primary biliary cholangitis, biliary atresia, systemic sclerosis-associated interstitial lung disease, scleroderma, diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn's disease; The method includes treating a fibrotic disease in a subject by inhibiting activity of one or both of αvβ1 integrin and αvβ6 integrin in the subject.

84. The method of claim 82 or 83.

85. 84. The method of claim 82 or 83, wherein the subject is in need of treatment for NASH, and the amount of the compound or a pharma- ceutically acceptable salt thereof administered to the subject is effective to inhibit activity of at least αvβ1 integrin, thereby treating NASH in the subject.

86. The method of claim 82 or 83, wherein the subject is in need of treatment for IPF and the amount of the compound or a pharmacologic acceptable salt thereof administered to the subject is effective to at least inhibit activity of αvβ6 integrin, thereby treating IPF in the subject.

87. The method of claim 82 or 83, wherein the subject is in need of treatment for PSC, and the amount of the compound or a pharma- ceutically acceptable salt thereof administered to the subject is effective to inhibit the activity of at least one of αvβ6 integrin and αvβ1 integrin, thereby treating the PSC in the subject.

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