BR122024019819A2 - AMINO ACID COMPOUNDS, THEIR USES AND PHARMACEUTICAL COMPOSITION OF THEM - Google Patents

Abstract

The invention relates to compounds of formula (A) and formula (I): or a salt thereof, wherein R1, R2, R10, R11, R12, R13, R14, R15, R16, q and p are as described herein. The compounds of formula (A), formula (I) and pharmaceutical compositions thereof are inhibitors of integrin αvβ6 that are useful for the treatment of fibrosis, such as idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP).

Description

CROSS-REFERENCE TO RELATED ORDERS

[001] This application claims the priority benefit of United States Provisional Patent Application Nos. 62/639,988, filed March 7, 2018, and 62/690,933, filed June 27, 2018. The disclosures of those applications are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

[002] Fibrosis, a pathological feature of many diseases, is caused by a dysfunction in the body's natural ability to repair damaged tissue. If left untreated, fibrosis can result in scarring of vital organs, causing irreparable damage and eventual organ failure.

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

[004] Renal fibrosis, characterized by glomerulosclerosis and tubulointerstitial fibrosis, is the final common manifestation of a wide variety of chronic kidney diseases (CKD). Regardless of the initial causes, progressive CKD often results in widespread tissue scarring that leads to destruction of the renal parenchyma and end-stage renal failure, a devastating condition requiring dialysis or renal replacement.

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

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

[007] Crohn's disease is a chronic disease of unknown etiology that tends to progress even in the context of medical or surgical treatment. Intestinal fibrosis is among the most common complications of Crohn's disease, resulting in the formation of strictures in the small intestine and colon.

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

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

[0010] Nonspecific interstitial pneumonia (NSIP) is a rare disease that affects the tissue that surrounds and separates the tiny air sacs of the lungs. These air sacs, called alveoli, are where the exchange of oxygen and carbon dioxide between the lungs and the bloodstream takes place. Interstitial pneumonia is a disease in which the mesh-like walls of the alveoli become inflamed. The pleura (a thin covering that protects and cushions the lungs and the individual lobes of the lungs) can also become inflamed. There are two primary forms of NSIP - cellular and fibrotic. The cellular form is defined primarily by inflammation of the cells of the interstitium. The fibrotic form is defined by thickening and scarring of the lung tissue. This scarring is known as fibrosis and is irreversible. When lung tissue becomes thickened or scarred, it does not function as well. Breathing becomes less efficient and there are lower levels of oxygen in the blood. (Kim et al., Proc. Am. Thorac. Soc. (2006) 3: 285 to 292; Lynch, D., Radiology (2001) 221: 583 to 584; Kinder et al., Am. J. Respir. Crit. Care Med. (2007) 176: 691 to 697).

[0011] Available treatment courses are scarce, as there are currently no options on the market that have been proven to affect patient survival or symptoms in the long term. The need for treatment of fibrotic diseases remains.

[0012] Integrin αvβ6 is expressed on epithelial cells and binds to the latency-associated peptide of transforming growth factor-β1 (TGFβ1) and mediates TGFβ1 activation. Its expression level is significantly increased after lung and cholangiocyte injury, and plays a critical role in vivo in tissue fibrosis. Elevated 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 obliterates the bile ducts. The resulting impediment to the flow of bile into the intestines can lead to cirrhosis of the liver and subsequent complications such as liver failure and liver cancer. Expression of αvβ6 is elevated in the liver and bile duct of patients with PSC.

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

BRIEF SUMMARY OF THE INVENTION

[0015] Disclosed are amino acid compounds that are inhibitors of αvβ6 integrin, compositions containing these compounds, and methods for treating diseases mediated by αvβ6 integrin, such as a fibrotic disease.

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

[0017] Further provided is a pharmaceutical composition comprising a compound of formula (A), or any variation thereof detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier or excipient.

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

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

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

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

[0022] Further provided is a kit comprising a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises instructions for use in accordance with a method described herein, such as a method of treating a fibrotic disease in a subject.

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

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

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

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

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

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

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

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

[0031] In another aspect, a method is provided for preparing a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof. Also provided are intermediate compounds useful in the synthesis of a compound of formula (I), or any variation thereof.

BRIEF DESCRIPTION OF THE FIGURES

[0032] Figure 1 shows compounds 1-780 as disclosed herein.

[0033] Figure 2 shows Table B-3, with biological data for several compounds disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

[0034] The present disclosure provides, inter alia, compounds of formula (A) and variations thereof, or a salt thereof, pharmaceutical compositions comprising compounds of formula (A) or a salt thereof, and methods of using such compounds and compositions in the treatment of fibrotic diseases.

[0035] The present disclosure provides, inter alia, compounds of formula (I) and variations thereof, or a salt thereof, pharmaceutical compositions comprising compounds of formula (I) or a salt thereof, and methods of using such compounds and compositions in the treatment of fibrotic diseases.

DEFINITIONS

[0036] For use herein, unless otherwise clearly indicated, the use of the terms "a", "an" and the like refers to one or more.

[0037] Reference to "about" a value or parameter in this document includes (and describes) embodiments that are directed to that value or parameter per se. For example, the description referring to "about X" includes the description of "X".

[0038] "Alkyl", as used herein, refers to and includes, unless otherwise indicated, a linear (i.e., unbranched) or branched saturated univalent hydrocarbon chain or a combination thereof, having the designated number of carbon atoms (i.e., C1-C10 means one to ten carbon atoms). Particular alkyl groups are those that have 1 to 20 carbon atoms (a "C1-C20 alkyl"), that have 1 to 10 carbon atoms (a "C1-C10 alkyl"), that have 6 to 10 carbon atoms (a "C6-C10 alkyl"), that have 1 to 6 carbon atoms (a "C1-C6 alkyl"), that have 2 to 6 carbon atoms (a "C2-C6 alkyl"), or that have 1 to 4 carbon atoms (a "C1-C4 alkyl"). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0039] "Alkylene", as used herein, refers to the same residues as alkyl, but with bivalence. Particular alkylene groups are those having 1 to 20 carbon atoms (a "C1-C20 alkylene"), having 1 to 10 carbon atoms (a "C1C10 alkylene"), having 6 to 10 carbon atoms (a "C6-C10 alkylene"), having 1 to 6 carbon atoms (a "C1-C6 alkylene"), 1 to 5 carbon atoms (a "C1-C5 alkylene"), 1 to 4 carbon atoms (a "C1-C4 alkylene"), or 1 to 3 carbon atoms (a "C1-C3 alkylene"). Examples of alkylene include, but are not limited to, gru- (-CH2(CH2)5CH2-), octylene (-CH2(CH2)6CH2-), and the like.

[0040] "Alkenyl", as used herein, refers to and includes, unless otherwise indicated, a linear (i.e., unbranched) or branched univalent unsaturated hydrocarbon chain or a combination thereof, that has at least one site of olefinic unsaturation (i.e., that has at least one chemical moiety of the formula C=C) and that has the designated number of carbon atoms (i.e., C2-C10 means two to ten carbon atoms). An alkenyl group may have "cis" or "trans" configurations or, alternatively, "E" or "Z" configurations. Particular alkenyl groups are those that have 2 to 20 carbon atoms (a "C2-C20 alkenyl"), that have 6 to 10 carbon atoms (a "C6-C10 alkenyl"), that have 2 to 8 carbon atoms (a "C2-C8 alkenyl"), that have 2 to 6 carbon atoms (a "C2-C6 alkenyl"), or that have 2 to 4 carbon atoms (a "C2-C4 alkenyl"). Examples of alkenyl groups include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl and the like.

[0041] "Alkenylene", as used herein, refers to the same residues as alkenyl but which have bivalence. Particular alkenylene groups are those having 2 to 20 carbon atoms (a "C2-C20 alkenylene"), having 2 to 10 carbon atoms (a "C2-C10 alkenylene"), having 6 to 10 carbon atoms (a "C6-C10 alkenylene"), having 2 to 6 carbon atoms (a "C2C6 alkenylene"), 2 to 4 carbon atoms (a "C2-C4 alkenylene") or 2 to 3 carbon atoms (a "C2-C3 alkenylene"). Examples of alkenylene include, but are not limited to, groups such as ethenylene (or vinylene) (-CH=CH-), propenylene (-CH=CHCH2-), 1,4-but-1-enylene (-CH=CH-CH2CH2-), 1,4-but-2-enylene (-CH2CH=CHCH2-), 1,6-hex-1-enylene (-CH=CH-(CH2)3CH2-) and the like.

[0042] "Alkynyl", as used herein, refers to and includes, unless otherwise indicated, a univalent unsaturated (i.e., unbranched) or branched hydrocarbon chain or a combination thereof, that has at least one site of acetylenic unsaturation (i.e., that has at least one chemical moiety of the formula C=C) and that has the designated number of carbon atoms (i.e., C2-C10 means two to ten carbon atoms). Particular alkynyl groups are those that have 2 to 20 carbon atoms (a "C2-C20 alkynyl"), that have 6 to 10 carbon atoms (a "C6-C10 alkynyl"), that have 2 to 8 carbon atoms (a "C2-C8 alkynyl"), that have 2 to 6 carbon atoms (a "C2-C6 alkynyl"), or that have 2 to 4 carbon atoms (a "C2-C4 alkynyl"). Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.

[0043] "Alkynylene", as used herein, refers to the same residues as alkynyl, but with bivalence. Particular alkynylene groups are those having 2 to 20 carbon atoms (a "C2-C20 alkynylene"), having 2 to 10 carbon atoms (a "C2-C10 alkynylene"), having 6 to 10 carbon atoms (a "C6C10 alkynylene"), having 2 to 6 carbon atoms (a "C2-C6 alkynylene"), 2 to 4 carbon atoms (a "C2-C4 alkynylene"), or 2 to 3 carbon atoms (a "C2-C3 alkynylene"). Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetynylene) (-C=C-), propynylene (-C=CCH2-), and the like.

[0044] "Cycloalkyl" as used herein refers to and includes, unless otherwise indicated, univalent saturated cyclic hydrocarbon structures having the designated number of carbon atoms (i.e., C3-C10 means three to ten carbon atoms). The cycloalkyl may consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms. A preferred cycloalkyl is a cyclic hydrocarbon that has 3 to 8 ring carbon atoms (a "C3-C8 cycloalkyl"), that has 3 to 6 ring carbon atoms (a "C3-C6 cycloalkyl"), or that has 3 to 4 ring carbon atoms (a "C3-C4 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0045] "Cycloalkylene", as used herein, refers to the same residues as cycloalkyl, but with bivalence. Cycloalkylene may consist of one ring or multiple rings which may be fused, spiro or bridged, or combinations thereof. Particular cycloalkylene groups are those having from 3 to 12 annular carbon atoms. A preferred cycloalkylene is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkylene"), having from 3 to 6 carbon atoms (a "C3-C6 cycloalkylene"), or having from 3 to 4 annular carbon atoms (a "C3-C4 cycloalkylene"). Examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, and the like. A cycloalkylene may bond to the remaining structures through the same ring carbon atom or different ring carbon atoms. When a cycloalkylene bonds to the remaining structures through two different ring carbon atoms, the connecting bonds may be cis or trans to each other. For example, cyclopropylene may include 1,1-cyclopropylene and 1,2-cyclopropylene (e.g., cis-1,2-cyclopropylene or trans-1,2-cyclopropylene) or a mixture thereof.

[0046] "Cycloalkenyl" refers to and includes, unless otherwise indicated, an unsaturated non-aromatic cyclic univalent hydrocarbon structure having at least one site of olefinic unsaturation (i.e., having at least one chemical moiety of the formula C=C) and having the designated number of carbon atoms (i.e., C3-C10 means three to ten carbon atoms). Cycloalkenyl may consist of one ring, such as cyclohexenyl, or multiple rings, such as norbornenyl. A preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having 3 to 8 ring carbon atoms (a "C3-C8 cycloalkenyl"). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like.

[0047] "Cycloalkenylene", as used herein, refers to the same residues as cycloalkenyl, but with bivalence.

[0048] "Aryl" or "Ar", as used herein, refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) whose condensed rings may or may not be aromatic. Particular aryl groups are those having 6 to 14 annular carbon atoms (a "C6-C14 aryl"). An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.

[0049] "Arylene", as used herein, refers to the same residues as aryl, but with bivalence. Particular arylene groups are those having 6 to 14 ring carbon atoms (a "C6-C14 arylene").

[0050] "Heteroaryl", as used herein, refers to an unsaturated aromatic cyclic group having from 1 to 14 ring carbon atoms and at least one ring heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur. A heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl) which condensed rings may or may not be aromatic. Particular heteroaryl groups are 5- to 14-membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-, 6-, or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur. In a variation, specific heteroaryl groups are 5-, 6-, or 7-membered monocyclic aromatic rings having 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, particular heteroaryl groups are polycyclic aromatic rings that have 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. A heteroaryl group that has more than one ring in which at least one ring is nonaromatic may be connected to the parent structure at an aromatic ring position or at a nonaromatic ring position. In one variation, a heteroaryl group that has more than one ring in which at least one ring is nonaromatic is connected to the parent structure at an aromatic ring position. A heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom.

[0051] "Heteroarylene", as used herein, refers to the same residues as heteroaryl, but with bivalence.

[0052] "Heterocycle", "heterocyclic" or "heterocyclyl", as used herein, refers to a saturated or unsaturated non-aromatic cyclic group having a single ring or multiple condensed rings and having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur or oxygen and the like. A heterocycle comprising more than one ring may be fused, bridged or spiro, or any combination thereof, but excludes heteroaryl groups. The heterocyclyl group may be optionally substituted independently by one or more substituents described herein. Particular heterocyclic groups are 3- to 14-membered rings having 1 to 13 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 12-membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 10-membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 8-membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 3- to 6-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from from nitrogen, oxygen, and sulfur. In one variation, heterocyclyl includes 3-, 4-, 5-, 6-, or 7-membered monocyclic rings having 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3, or 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, heterocyclyl includes nonaromatic polycyclic rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0053] "Heterocyclylene", as used herein, refers to the same residues as heterocyclyl, but with bivalence.

[0054] "Halo" or "halogen" refers to elements in the Group 17 series with atomic numbers from 9 to 85. Preferred halo groups include the fluorine, chlorine, bromine, and iodine radicals. When a residue is substituted by more than one halogen, it may be referred to using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl substituted by two ("di") or three ("tri") halo groups, which may be, but are not necessarily, 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 takes the place of each H in the hydrocarbon that constitutes the alkyl chemical portion of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

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

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

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

[0058] "D" refers to deuterium (2H).

[0059] "T" refers to tritium (3H).

[0060] An alkyl group in which each hydrogen is replaced by deuterium is referred to as "perdeuterated". An alkyl group in which each hydrogen is replaced by tritium is referred to as "pertritiated".

[0061] "Optionally substituted", unless otherwise specified, means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group wherein the substituents may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, an optionally substituted group is unsubstituted.

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

[0063] Unless otherwise clearly indicated, "an individual" as used herein refers to a mammal, including but not limited to a primate, human, bovine, horse, feline, canine, or rodent. In one variation, the individual is a human being.

[0064] As used herein, "treatment" or "treating" is an approach to achieving beneficial or desired results, including clinical results. Beneficial or desired results include, but are not limited to, one or more of the following: further decreasing one of the symptoms resulting from the disease, decreasing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, delaying the occurrence or recurrence of the disease, delaying or delaying the progression of the disease, improving the status of the disease, providing a remission (whether partial or complete) of the disease, decreasing the dose of one or more drugs needed to treat the disease, potentiating the effect of another drug, slowing the progression of the disease, increasing the quality of life, and/or prolonging survival. Also encompassed by "treatment" is reducing the pathological consequences of fibrosis. The methods of the invention contemplate any one or more of these aspects of treatment.

[0065] As used herein, the term "effective amount" means such an amount of a compound of the invention as is expected to be effective in a given therapeutic manner. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of the administration of one or more therapeutic agents (e.g., a compound, or a pharmaceutically acceptable salt thereof), and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result can be or is achieved. Appropriate doses of any of the co-administered compounds may optionally be reduced due to the combined action (e.g., additive or synergistic effects) of the compounds.

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

[0067] As used herein, "unit dosage form" refers to physically discrete units, suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may contain a single or combination therapy.

[0068] As used herein, the term “controlled release” refers to a formulation containing drug or a fraction thereof in which the release of the drug is not immediate, i.e., with a “controlled release” formulation, administration does not result in the immediate release of the drug into an absorption pool. The term encompasses depot formulations designed to gradually release the drug compound over an extended period of time. Controlled release formulations can include a wide variety of drug delivery systems, typically involving mixing the drug compound with carriers, polymers, or other compounds having the desired release characteristics (e.g., pH-dependent or pH-independent solubility, varying degrees of water solubility, and the like) and formulating the mixture according to the desired route of delivery (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, and the like).

[0069] As used herein, "pharmaceutically acceptable" or "pharmacologically acceptable" means a material that is not biologically or otherwise undesirable; for example, the material can be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting detrimentally with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required toxicological and manufacturing testing standards and/or are included in the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration.

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

[0071] The term "excipient" as used herein means an inert or inactive substance that can be used in the production of a drug or pharmaceutical product, such as a tablet containing a compound of the invention as an active ingredient. Various substances may be encompassed by the term excipient, including, without limitation, any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, chewable tablet materials, sweetener or flavoring, suspension/gelling agent, or wet granulating agent. Binders include, for example, carbomers, 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, dc fructose (dc = "directly compressible"), dc honey, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose or microcrystalline cellulose), dc starch, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, maltodextrin, carrageenans, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable tablet materials include, for example, dextrose, dc fructose, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0072] Unless otherwise indicated, "substantially pure" means a composition that contains no more than 10% impurity, such as a composition comprising less than 9%, 7%, 5%, 3%, 1%, 0.5% impurity.

[0073] It is understood that aspects and embodiments described herein as "comprising" include "consisting of" and "consisting essentially of" embodiments.

[0074] COMPOUNDS

[0075] In one aspect, there is provided a compound of formula (A):

[0076] or a salt thereof, wherein:

[0077] R1is C6-C14 aryl or 5- to 10-membered heteroaryl wherein the C6-C14 aryl and the 5- to 10-membered heteroaryl are optionally substituted by R1a;

[0078] R2is hydrogen; deuterium; C1-C6 alkyl optionally substituted by R2a; -OH; -O-C1-C6 alkyl optionally substituted by R2a; C3-C6 cycloalkyl optionally substituted by R2b; -O-C3-C6 cycloalkyl optionally substituted by R2b; 3- to 12-membered heterocyclyl optionally substituted by R2c; or -S(O)2R2d; with the proviso that any carbon atom bonded directly to a nitrogen atom is optionally substituted with a R2a chemical moiety other than halogen;

[0079] each R1a is 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-C14 aryl, deuterium, halogen, -CN, -OR3, -SR3, -NR4R5, -NO2, -C=NH(OR3), -C(O)R3, -OC(O)R3, -C(O)OR3, -C(O)NR4R5, -NR3C(O)R4, - NR3C(O)OR4, -NR3C(O)NR4R5, -S(O)R3, -S(O)2R3, -NR3S(O)R4, -NR3S(O)2R4, -S(O)NR4R5, -S(O)2NR4R5 or -P(O)(OR4)(OR5), where each R1a is, whenever possible, independently optionally substituted by deuterium, halogen, oxo, -OR6, -NR6R7 , -C(O)R6, -CN, -S(O)R6, -S(O)2R6, -P(O)(OR6)(OR7), C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, heteroaryl 5- to 10-membered C6-C14 aryl or C1-C6 alkyl optionally substituted by deuterium, oxo, -OH or halogen;

[0080] each R2a, R2b, R2c, R2e and R2f is, independently, oxo or R1a;

[0081] R2 is C1-C6 alkyl optionally substituted by R2e or C3 C5 cycloalkyl optionally substituted by R2f;

[0082] R3is independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of R3are independently optionally substituted by halogen, deuterium, oxo, -CN, -OR8, -NR8R9, -P(O)(OR8)(OR9) or C1C6 alkyl optionally substituted by deuterium, halogen, OH or oxo;

[0083] R4 and R5 are each, independently, hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl of R4 and R5 are, independently, optionally substituted by deuterium, halogen, oxo, -CN, -OR8, -NR8R9, or C1-C6 alkyl optionally substituted by deuterium, halogen, -OH, or oxo;

[0084] or R4 and R5are taken together with the atom to which they are attached to form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, -OR8, -NR8R9 or C1C6 alkyl optionally substituted by deuterium, halogen, oxo or -OH;

[0085] R6 and R7 are each, independently, hydrogen, deuterium, C1-C6 alkyl optionally substituted by deuterium, halogen or oxo, C2-C6 alkenyl optionally substituted by deuterium, halogen or oxo, or C2-C6 alkynyl optionally substituted by deuterium, halogen or oxo;

[0086] or R6 and R7are taken together with the atom to which they are attached to form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo or C1-C6 alkyl optionally substituted by deuterium, halogen or oxo;

[0087] R8 and R9 are each, independently, hydrogen, deuterium, C1-C6 alkyl optionally substituted by deuterium, halogen or oxo, C2-C6 alkenyl optionally substituted by deuterium, halogen or oxo, or C2-C6 alkynyl optionally substituted by deuterium, halogen or oxo;

[0088] or R8 and R9 are taken together with the atom to which they are attached to form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo or C1-C6 alkyl optionally substituted by deuterium, oxo or halogen;

[0089] each of R10, R11, R12 and R13 are, independently, hydrogen or deuterium;

[0090] R14 is deuterium;

[0091] q is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0092] each R15 is independently selected from hydrogen, deuterium or halogen;

[0093] each R16 is independently selected from hydrogen, deuterium, or halogen; and

[0094] p is 3, 4, 5, 6, 7, 8 or 9.

[0095] In one variation, there is provided a compound of formula (A), or a salt thereof, wherein the carbon bearing the CO2H and NHR1 chemical moieties is in the "S" configuration. In another variation, there is provided a compound of formula (A), or a salt thereof, wherein the carbon bearing the CO2H and NHR1 chemical moieties is in the "R" configuration. Mixtures of a compound of formula (A) are also encompassed, including racemic or non-racemic mixtures of a given compound and mixtures of two or more compounds of different chemical formulas.

[0096] In a variation of formula (A), R2 has the proviso that any carbon atom bonded directly to a nitrogen atom is either unsubstituted or replaced with deuterium.

[0097] In the descriptions herein, it is understood that each description, variation, embodiment or aspect of a chemical moiety may be combined with each description, variation, embodiment or aspect of other chemical moieties in the same manner as if each combination of descriptions were specifically and individually listed. For example, each description, variation, embodiment or aspect provided herein with respect to R1 of formula (A) may be combined with each description, variation, embodiment or aspect of R2 in the same manner as if each combination were specifically and individually listed.

[0098] In one aspect, there is provided a compound of formula (I)

[0099] or a salt thereof, wherein:

[00100] R1is C6-C14 aryl or 5- to 10-membered heteroaryl wherein the C6-C14 aryl and the 5- to 10-membered heteroaryl are optionally substituted by R1a;

[00101] R2is C1-C6 alkyl optionally substituted by R2a; C3-C6 cycloalkyl optionally substituted by R2b; 3- to 12-membered heterocyclyl optionally substituted by R2c; or -S(O)2R2d;

[00102] each R1a is 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-C14 aryl, deuterium, halogen, -CN, -OR3, -SR3, -NR4R5, -NO2, -C=NH(OR3), - C(O)R3, -OC(O)R3, -C(O)OR3, -C(O)NR4R5, -NR3C(O) R4, - NR3C(O)OR4, -NR3C(O)NR4R5, -S(O)R3, -S(O)2R3, -NR3S(O)R4, - NR3S(O)2R4, -S(O)NR4R5, -S(O)2NR4R5 or -P(O)(OR4)(OR5), where each R1a is, whenever possible, independently optionally substituted by deuterium, halogen, oxo, -OR6, -NR6R7 , -C(O)R6, -CN, -S(O)R6, -S(O)2R6, -P(O)(OR6)(OR7), C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, heteroaryl 5- to 10-membered C6-C14 aryl or C1-C6 alkyl optionally substituted by deuterium, oxo, -OH or halogen;

[00103] each R2a, R2b, R2c, R2e and R2f is, independently, oxo or R1a;

[00104] R2 is C1-C6 alkyl optionally substituted by R2e or C3 C5 cycloalkyl optionally substituted by R2f;

[00105] R3is independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of R3are independently optionally substituted by halogen, deuterium, oxo, -CN, -OR8, -NR8R9, -P(O)(OR8)(OR9) or C1C6 alkyl optionally substituted by deuterium, halogen, OH or oxo;

[00106] R4 and R5 are each, independently, hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl of R4 and R5 are, independently, optionally substituted by deuterium, halogen, oxo, -CN, -OR8, -NR8R9, or C1-C6 alkyl optionally substituted by deuterium, halogen, -OH, or oxo;

[00107] or R4 and R5are taken together with the atom to which they are attached to form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, -OR8, -NR8R9 or C1C6 alkyl optionally substituted by deuterium, halogen, oxo or -OH;

[00108] R6 and R7 are each, independently, hydrogen, deuterium, C1-C6 alkyl optionally substituted by deuterium, halogen or oxo, C2-C6 alkenyl optionally substituted by deuterium, halogen or oxo, or C2-C6 alkynyl optionally substituted by deuterium, halogen or oxo;

[00109] or R6 and R7are taken together with the atom to which they are attached to form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo or C1-C6 alkyl optionally substituted by deuterium, halogen or oxo;

[00110] R8 and R9 are each, independently, hydrogen, deuterium, C1-C6 alkyl optionally substituted by deuterium, halogen or oxo, C2-C6 alkenyl optionally substituted by deuterium, halogen or oxo, or C2-C6 alkynyl optionally substituted by deuterium, halogen or oxo;

[00111] or R8 and R9are taken together with the atom to which they are attached to form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo or C1-C6 alkyl optionally substituted by deuterium, oxo or halogen;

[00112] each of R10, R11, R12, and R13 are independently hydrogen or deuterium; R14 is deuterium; q is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and

[00113] p is 3, 4, 5, 6, 7, 8 or 9.

[00114] In one variation, there is provided a compound of formula (I), or a salt thereof, wherein the carbon bearing the chemical moieties CO2H and NHR1 is in the "S" configuration. In another variation, there is provided a compound of formula (I), or a salt thereof, wherein the carbon bearing the chemical moieties CO2H and NHR1 is in the "R" configuration. Mixtures of a compound of formula (I) are also encompassed, including racemic or non-racemic mixtures of a given compound and mixtures of two or more compounds of different chemical formulas.

[00115] In a variation of formula (I), R2 includes the proviso that any carbon atom bonded directly to a nitrogen atom is optionally substituted by a chemical moiety R2a other than halogen. In a variation of formula (I), R2 includes the proviso that any carbon atom bonded directly to a nitrogen atom is either unsubstituted or is replaced by deuterium.

[00116] In the descriptions herein, it is understood that each description, variation, embodiment or aspect of a chemical moiety may be combined with each description, variation, embodiment or aspect of other chemical moieties in the same manner as if each combination of descriptions were specifically and individually listed. For example, each description, variation, embodiment or aspect provided herein with respect to R1 of formula (I) may be combined with each description, variation, embodiment or aspect of R2 in the same manner as if each combination were specifically and individually listed.

[00117] In some embodiments of the compound of formula (I), or a salt thereof, at least one of R1a, R2a, R2b, R2c, R2e, R2f, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, or R16 is deuterium.

[00118] In some embodiments of the compound of formula (I), or a salt thereof, R1 is 5- to 10-membered heteroaryl optionally substituted by R1a. In some embodiments, R1 is pyrimidin-4-yl optionally substituted by R1a. In some embodiments, R1 is pyrimidin-4-yl optionally substituted by R1a, wherein R1a is a 5- to 10-membered heteroaryl (e.g., pyrazolyl) or C1-C6 alkyl optionally substituted by halogen (e.g., methyl, difluoromethyl, and trifluoromethyl). In some embodiments, R1 is pyrimidin-4-yl optionally substituted by R1a, wherein R1a is 5- to 10-membered heteroaryl (e.g., pyrazolyl or pyridinyl) or C1-C6 alkyl optionally substituted by halogen (e.g., methyl, difluoromethyl, and trifluoromethyl). In some embodiments, R1 is pyrimidin-4-yl substituted by methyl and trifluoromethyl. In some embodiments, R1 is pyrimidin-4-yl substituted by methyl and pyridinyl. In some embodiments, R1 is pyrimidin-4-yl optionally substituted by R1a, wherein R1a is C6-C14 aryl (e.g., phenyl). In some embodiments, R1 is pyrimidin-4-yl optionally substituted by R1a, wherein R1a is -CN. In some embodiments, R1 is pyrimidin-2-yl optionally substituted by R1a. In some embodiments, R1 is pyrimidin-2-yl optionally substituted by R1a, wherein R1a is halogen, C1-C6 alkyl optionally substituted by halogen (e.g., methyl or trifluoromethyl), -CN, or C3-C8 cycloalkyl (e.g., cyclopropyl). In some embodiments of the compound of formula (I), or a salt thereof, R1 is quinazolin-4-yl optionally substituted by R1a. In some embodiments, R1 is quinazolin-4-yl optionally substituted by R1a, wherein R1a is halogen (e.g., fluorine and chlorine), C1-C6 alkyl optionally substituted by halogen (e.g., methyl or trifluoromethyl), or C1-C6 alkoxy (e.g., methoxy). In some embodiments, R1 is quinazolin-4-yl optionally substituted by R1a, wherein R1a is 5- to 10-membered heteroaryl (e.g., pyridinyl). In some embodiments, R1 is pyrazolopyrimidinyl optionally substituted by R1a. In some embodiments, R1 is pyrazolopyrimidinyl optionally substituted by R1a, wherein R1a is C1-C6 alkyl (e.g., methyl). In some embodiments wherein R1 is indicated as optionally substituted by R1a, the R1 moiety is unsubstituted. In some embodiments wherein R1 is indicated as optionally substituted by R1a, the R1 moiety is replaced by an R1a. In some embodiments where R1 is indicated as optionally substituted by R1a, the R1 moiety is substituted by 2 to 6, or 2 to 5, or 2 to 4, or 2 to 3 R1a moieties, which may be the same or different.

[00119] In some embodiments of formula (I), including embodiments describing variable R1, each of R10, R11, R12, and R13 is hydrogen. In some embodiments of formula (I), including embodiments describing variable R1 and/or variables R10, R11, R12, and R13, q is 0. In some embodiments, including embodiments describing variable R1 and/or variables R10, R11, R12, and R13 and/or variable q, p is 3, 4, or 5.

[00120] In some embodiments of formula (I), R10, R11, R12, and R13 are hydrogen, p is 3, q is 0, and the compound is of formula (II): (II) or a salt thereof, wherein R1 and R2are as defined for formula (I).

[00121] In some embodiments of the compound of formula (I), wherein R1 is a 5- to 10-membered heteroaryl optionally substituted by R1a, the compound has the formula (IA):

[00122] (I-A

[00123] or a salt thereof, wherein R1a, R2, R10, R11, R12, R13, R14, q and p are as defined for formula (I), m is 0, 1, 2 or 3, and the positions on the pyrimidine ring and tetrahydronaphthyridine ring are as indicated.

[00124] In one embodiment, there is provided a compound of formula (IA), or a salt thereof, wherein the carbon bearing the CO2H and NH chemical moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-A), or a salt thereof, wherein the carbon bearing the CO2H and NH chemical moieties is in the "R" configuration. Mixtures of a compound of formula (IA) are also encompassed, including racemic or non-racemic mixtures of a given compound and mixtures of two or more compounds of different chemical formulas.

[00125] In some embodiments of the compound of formula (IA), m is 0, 1, 2, or 3, and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R1a are, independently, optionally substituted by deuterium. In another embodiment of the compound of formula (I-A), m is 0, 1, 2, or 3, and each R1a is, where applicable, independently, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in a variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, -CN or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and 5- to 10-membered heteroaryl of R1a are, independently, optionally substituted by deuterium. In some embodiments of formula (I-A), m is 1, 2 or 3.

[00126] In some embodiments of the compound of formula (I-A), m is 0. In some embodiments of the compound of formula (I-A), m is 1 and R1a is in the 2 position. In some embodiments of the compound of formula (I-A), m is 1 and R1a is in the 5 position. In some embodiments of the compound of formula (I-A), m is 1 and R1a is in the 6 position. In some embodiments of the compound of formula (I-A), m is 2 and the R1a groups are in the 2 position and the 5 position. In some embodiments of the compound of formula (I-A), m is 2 and the R1a groups are in the 2 position and the 6 position. In some embodiments of the compound of formula (I-A), m is 2 and the R1a groups are in the 5 position and the 6 position. In some embodiments of the compound of formula (I-A), m is 3 and the R1a groups are in the 2 position and the 6 position. 2, position 5 and position 6. Whenever more than one R1a group is present, the R1a groups may be chosen independently. In any of these embodiments of the compound of formula (I-A), or a salt thereof, the carbon bearing the chemical moieties CO2H and NH may be in the "S" configuration or in the "R" configuration.

[00127] In some embodiments of formula (I-A), including embodiments describing the variables R1a and m, each of R10, R11, R12, and R13 are hydrogen. In some embodiments of formula (I-A), including embodiments describing the variables R1a and m and/or the variables R10, R11, R12 and R13, q is 0. In some embodiments of formula (I-A), including embodiments describing the variables R1a and m and/or the variables R10, R11, R12, and R13 and/or the variable q, p is 3, 4, or 5.

[00128] In some embodiments of formula (IA), R10, R11, R12, and R13 are hydrogen, p is 3, q is 0, and the compound is of formula (II-A):

[00129] or a salt thereof, wherein R1a and R2 are as defined for formula (I), m is 0, 1, 2 or 3 and the positions on the pyrimidine ring are as indicated. All descriptions of R1a, R2 and m with reference to formula (I) apply equally to formulae (I-A) and (II-A).

[00130] In some embodiments of the compound of formula (I), wherein R1 is 5- to 10-membered heteroaryl optionally substituted by R1a, the compound has the formula (IB):

[00131] or a salt thereof, wherein R1a, R2, R10, R11, R12, R13, R14, q and p are as defined for formula (I), m is 0, 1, 2, 3, 4, or 5, and the positions on the quinazoline ring are as indicated.

[00132] In one embodiment, there is provided a compound of formula (IB), or a salt thereof, wherein the carbon bearing the CO2H and NH chemical moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-B), or a salt thereof, wherein the carbon bearing the CO2H and NH chemical moieties is in the "R" configuration. Mixtures of a compound of formula (I-B) are also encompassed, including racemic or non-racemic mixtures of a given compound and mixtures of two or more compounds of different chemical formulas.

[00133] In some embodiments of the compound of formula (I-B), m is 0, 1, 2, 3, 4, or 5, and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R1a are, independently, optionally substituted by deuterium. In another embodiment of the compound of formula (I-B), m is 0, 1, 2, 3, 4, or 5, and each R1a is, when applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in a variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R1a are, independently, optionally substituted by deuterium. In some embodiments of the compound of formula (I-B), m is 1, 2, 3, 4, or 5.

[00134] In some embodiments of the compound of formula (I-B), m is 0. In some embodiments of the compound of formula (I-B), m is 1 and R1a is at position 2. In some embodiments of the compound of formula (I-B), m is 1 and R1a is at position 5. In some embodiments of the compound of formula (I-B), m is 1 and R1a is at position 6. In some embodiments of the compound of formula (I-B), m is 1 and R1a is at position 7. In some embodiments of the compound of formula (I-B), m is 1 and R1a is at position 8. In some embodiments of the compound of formula (I-B), m is 2 and the R1a groups are at position 2 and position 5. In some embodiments of the compound of formula (I-B), m is 2 and the R1a groups are at position 2 and position 6. In some embodiments of the compound of formula (I-B), m is 2, and the R1a groups are at the 2-position and the 7-position. In some embodiments of the compound of formula (I-B), m is 2, and the R1a groups are at the 2-position and the 8-position. In some embodiments of the compound of formula (I-B), m is 2, and the R1a groups are at the 5-position and the 6-position. In some embodiments of the compound of formula (I-B), m is 2, and the R1a groups are at the 5-position and the 7-position. In some embodiments of the compound of formula (I-B), m is 2, and the R1a groups are at the 5-position and the 8-position. In some embodiments of the compound of formula (I-B), m is 2, and the R1a groups are at the 6-position and the 7-position. In some embodiments of the compound of formula (I-B), m is 2, and the R1a groups are at the 6-position and the 8-position. In some embodiments of the compound of formula (I-B), m is 2 and the R1a groups are at the 7-position and 8-position. In some embodiments of the compound of formula (I-B), m is 3 and the R1a groups are at the 2-position, 5-position, and 6-position. In some embodiments of the compound of formula (I-B), m is 3 and the R1a groups are at the 2-position, 5-position, and 7-position. In some embodiments of the compound of formula (I-B), m is 3 and the R1a groups are at the 2-position, 5-position, and 8-position. In some embodiments of the compound of formula (I-B), m is 3 and the R1a groups are at the 2-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-B), m is 3 and the R1a groups are at the 2-position, position 7 and position 8. In some embodiments of the compound of formula (I-B), m is 3 and the R1a groups are at the 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-B), m is 3 and the R1a groups are at the 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-B), m is 3 and the R1a groups are at the 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-B), m is 3 and the R1a groups are at the 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-B), m is 4 and the R1a groups are at the 2-position, 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-B), m is 4 and the R1a groups are at the 2-position, 5-position, 6-position and position 8. In some embodiments of the compound of formula (I-B), m is 4 and the R1a groups are at position 2, position 5, position 7, and position 8. In some embodiments of the compound of formula (I-B), m is 4 and the R1a groups are at position 2, position 6, position 7, and position 8. In some embodiments of the compound of formula (I-B), m is 4 and the R1a groups are at position 5, position 6, position 7, and position 8. In some embodiments of the compound of formula (I-B), m is 5 and the R1a groups are at position 2, position 5, position 6, position 7, and position 8. Whenever more than one R1a group is present, the R1a groups can be chosen independently. In any of these embodiments of the compound of formula (IB), or a salt thereof, the carbon carrying the chemical moieties CO2H and NH may be in the "S" configuration or in the "R" configuration.

[00135] In some embodiments of formula (I-B), including embodiments describing variables R1a and m, each of R10, R11, R12, and R13 are hydrogen. In some embodiments of formula (IB), including embodiments describing variables R1a and m and/or variables R10, R11, R12, and R13, q is 0. In some embodiments of formula (I-B), including embodiments describing variables R1a and m and/or variables R10, R11, R12, and R13 and/or variable q, p is 3, 4, or 5.

[00136] In some embodiments of formula (IB), R10, R11, R12, and R13 are hydrogen, p is 3, q is 0, and the compound is of formula (II-B):

[00137] or a salt thereof, wherein R1a and R2 are as defined for formula (I), m is 0, 1, 2, 3, 4 or 5 and the positions on the quinazoline ring are as indicated. All descriptions of R1a, R2 and m with reference to formula (I) apply equally to formulae (I-B) and (II-B).

[00138] In some embodiments of the compound of formula (I), wherein R1 is a 5- to 10-membered heteroaryl optionally substituted by R1a, the compound has the formula (IC):

[00139] or a salt thereof, wherein R1a, R2, R10, R11, R12, R13, R14, q and p are as defined for formula (I), m is 0, 1, 2, 3 or 4, and the positions on the pyrido[3,2-d]pyrimidine ring are as indicated.

[00140] In one embodiment, there is provided a compound of formula (I-C), or a salt thereof, wherein the carbon bearing the chemical moieties CO2H and NH is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-C), or a salt thereof, wherein the carbon bearing the chemical moieties CO2H and NH is in the "R" configuration. Mixtures of a compound of formula (I-C) are also encompassed, including racemic or non-racemic mixtures of a given compound and mixtures of two or more compounds of different chemical formulas.

[00141] In some embodiments of the compound of formula (I-C), m is 0, 1, 2, 3, or 4, and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R1a are, independently, optionally substituted by deuterium. In another embodiment of the compound of formula (I-C), m is 0, 1, 2, 3, or 4, and each R1a is, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in a variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, -CN or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and 5- to 10-membered heteroaryl of R1a are, independently, optionally substituted by deuterium. In some embodiments of the compound of formula (I-C), m is 1, 2, 3 or 4.

[00142] In some embodiments of the compound of formula (I-C), m is 0. In some embodiments of the compound of formula (I-C), m is 1 and R1a is at position 2. In some embodiments of the compound of formula (I-C), m is 1 and R1a is at position 6. In some embodiments of the compound of formula (I-C), m is 1 and R1a is at position 7. In some embodiments of the compound of formula (I-C), m is 1 and R1a is at position 8. In some embodiments of the compound of formula (I-C), m is 2 and the R1a groups are at position 2 and position 6. In some embodiments of the compound of formula (I-C), m is 2 and the R1a groups are at position 2 and position 7. In some embodiments of the compound of formula (I-C), m is 2 and the R1a groups are at position 2 and position 8. In In some embodiments of the compound of formula (I-C), m is 2 and the R1a groups are at the 6-position and the 7-position. In some embodiments of the compound of formula (I-C), m is 2 and the R1a groups are at the 6-position and the 8-position. In some embodiments of the compound of formula (I-C), m is 2 and the R1a groups are at the 7-position and the 8-position. In some embodiments of the compound of formula (I-C), m is 3 and the R1a groups are at the 2-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-C), m is 3 and the R1a groups are at the 2-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-C), m is 3 and the R1a groups are at the 2-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-C), m is 3 and the R1a groups are at the 2-position, 7-position, and 8-position. at the 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-C), m is 4 and the R1a groups are at the 2-position, 6-position, 7-position, and 8-position. Whenever more than one R1a group is present, the R1a groups may be chosen independently. In any of these embodiments of the compound of formula (I-C), or a salt thereof, the carbon with the chemical moieties CO2H and NH can be in the "S" configuration or in the "R" configuration.

[00143] In some embodiments of formula (I-C), including embodiments describing variables R1a and m, each of R10, R11, R12, and R13 are hydrogen. In some embodiments of formula (IC), including embodiments describing variables R1a and m and/or variables R10, R11, R12, and R13, q is 0. In some embodiments of formula (I-C), including embodiments describing variables R1a and m and/or variables R10, R11, R12, and R13 and/or variable q, p is 3, 4, or 5.

[00144] In some embodiments of formula (IC), R10, R11, R12, and R13 are hydrogen, p is 3, q is 0, and the compound is of formula (II-C):

[00145] or a salt thereof, wherein R1a and R2are as defined for formula (I), m is 0, 1, 2, 3 or 4, and the positions on the pyrido[3,2-d]pyrimidine ring are as indicated. All descriptions of R1a, R2 and m with reference to formula (I) apply equally to formulae (IC) and (II-C).

[00146] In some embodiments of the compound of formula (I), wherein R1 is a 5- to 10-membered heteroaryl optionally substituted by R1a, the compound has the formula (ID):

[00147] or a salt thereof, wherein R1a, R2, R10, R11, R12, R13, R14, q and p are as defined for formula (I), m is 0, 1, 2, 3 or 4, and the positions on the pyrido[3,4-d]pyrimidine ring are as indicated.

[00148] In one embodiment, a compound of formula (I-D), or a salt thereof, is provided, wherein the carbon bearing the CO2H and NH chemical moieties is in the "S" configuration. In another embodiment, a compound of formula (I-D), or a salt thereof, is provided, wherein the carbon bearing the CO2H and NH chemical moieties is in the "R" configuration. Mixtures of a compound of formula (I-D) are also encompassed, including racemic or non-racemic mixtures of a given compound and mixtures of two or more compounds of different chemical formulas.

[00149] In some embodiments of the compound of formula (I-D), m is 0, 1, 2, 3, or 4, and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R1a are, independently, optionally substituted by deuterium. In another embodiment of the compound of formula (I-D), m is 0, 1, 2, 3, or 4, and each R1a is, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in a variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R1a are, independently, optionally substituted by deuterium. In some embodiments of the compound of formula (I-D), m is 1, 2, 3, or 4.

[00150] In some embodiments of the compound of formula (I-D), m is 0. In some embodiments of the compound of formula (I-D), m is 1 and R1a is at position 2. In some embodiments of the compound of formula (I-D), m is 1 and R1a is at position 5. In some embodiments of the compound of formula (I-D), m is 1 and R1a is at position 6. In some embodiments of the compound of formula (I-D), m is 1 and R1a is at position 8. In some embodiments of the compound of formula (I-D), m is 2 and the R1a groups are at position 2 and position 5. In some embodiments of the compound of formula (I-D), m is 2 and the R1a groups are at position 2 and position 6. In some embodiments of the compound of formula (I-D), m is 2 and the R1a groups are at position 2 and position 8. In In some embodiments of the compound of formula (I-D), m is 2 and the R1a groups are at the 5-position and the 6-position. In some embodiments of the compound of formula (I-D), m is 2 and the R1a groups are at the 5-position and the 8-position. In some embodiments of the compound of formula (I-D), m is 2 and the R1a groups are at the 6-position and the 8-position. In some embodiments of the compound of formula (I-D), m is 3 and the R1a groups are at the 2-position, 5-position, and the 6-position. In some embodiments of the compound of formula (I-D), m is 3 and the R1a groups are at the 2-position, 5-position, and the 8-position. In some embodiments of the compound of formula (I-D), m is 3 and the R1a groups are at the 2-position, 6-position, and the 8-position. 5, at the 6-position and at the 8-position. In some embodiments of the compound of formula (I-D), m is 4 and the R1a groups are at the 2-position, 5-position, 6-position and 8-position. Whenever more than one R1a group is present, the R1a groups may be chosen independently. In any such embodiment of the compound of formula (I-D), or a salt thereof, the carbon bearing the CO2H and NH chemical moieties may be in the "S" configuration or in the "R" configuration.

[00151] In some embodiments of formula (ID), including embodiments describing variables R1a and m, each of R10, R11, R12, and R13 is hydrogen. In some embodiments of formula (I-D), including embodiments describing variables R1a and m and/or variables R10, R11, R12, and R13, q is 0. In some embodiments of formula (I-D), including embodiments describing variables R1a and m and/or variables R10, R11, R12 and R13 and/or variable q, p is 3, 4, or 5.

[00152] In some embodiments of formula (ID), R10, R11, R12, and R13 are hydrogen, p is 3, q is 0, and the compound is of formula (II-D):

[00153] or a salt thereof, wherein R1a and R2are as defined for formula (I), m is 0, 1, 2, 3 or 4, and the positions on the pyrido[3,4-d]pyrimidine ring are as indicated. All descriptions of R1a, R2 and m with reference to formula (I) apply equally to formulae (ID) and (II-D).

[00154] In some embodiments of the compound of formula (I), wherein R1 is 5- to 10-membered heteroaryl optionally substituted by R1a, the compound has the formula (IE):

[00155] or a salt thereof, wherein R1a, R2, R10, R11, R12, R13, R14, q and p are as defined for formula (I), m is 0, 1, 2, 3 or 4, and the positions on the pyrido[2,3-d]pyrimidine ring are as indicated.

[00156] In one embodiment, there is provided a compound of formula (I-E), or a salt thereof, wherein the carbon bearing the CO2H and NH chemical 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 CO2H and NH chemical moieties is in the "R" configuration. Mixtures of a compound of formula (I-E) are also encompassed, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[00157] In some embodiments of the compound of formula (I-E), m is 0, 1, 2, 3, or 4, and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R1a are, independently, optionally substituted by deuterium. In another embodiment of the compound of formula (I-E), m is 0, 1, 2, 3, or 4, and each R1a is, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in a variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, -CN or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and 5- to 10-membered heteroaryl of R1a are, independently, optionally substituted by deuterium. In some embodiments of the compound of formula (I-E), m is 1, 2, 3 or 4.

[00158] In some embodiments of the compound of formula (I-E), m is 0. In some embodiments of the compound of formula (I-E), m is 1 and R1a is at position 2. In some embodiments of the compound of formula (I-E), m is 1 and R1a is at position 5. In some embodiments of the compound of formula (I-E), m is 1 and R1a is at position 6. In some embodiments of the compound of formula (I-E), m is 1 and R1a is at position 7. In some embodiments of the compound of formula (I-E), m is 2 and the R1a groups are at position 2 and position 5. In some embodiments of the compound of formula (I-E), m is 2 and the R1a groups are at position 2 and position 6. In some embodiments of the compound of formula (I-E), m is 2 and the R1a groups are at position 2 and position 7. In In some embodiments of the compound of formula (I-E), m is 2 and the R1a groups are at the 5-position and the 6-position. In some embodiments of the compound of formula (I-E), m is 2 and the R1a groups are at the 5-position and the 7-position. In some embodiments of the compound of formula (I-E), m is 2 and the R1a groups are at the 6-position and the 7-position. In some embodiments of the compound of formula (I-E), m is 3 and the R1a groups are at the 2-position, 5-position, and the 6-position. In some embodiments of the compound of formula (I-E), m is 3 and the R1a groups are at the 2-position, 5-position, and the 7-position. In some embodiments of the compound of formula (I-E), m is 3 and the R1a groups are at the 2-position, 6-position, and the 7-position. 5, position 6 and position 7. In some embodiments of the compound of formula (I-E), m is 4 and the R1a groups are in the 2-position, 5-position, 6-position and 7-position. Whenever more than one R1a group is present, the R1a groups may be chosen independently. In any such embodiment of the compound of formula (I-E), or a salt thereof, the carbon bearing the CO2H and NH chemical moieties may be in the "S" configuration or the "R" configuration.

[00159] In some embodiments of formula (I-E), including embodiments describing variables R1a and m, each of R10, R11, R12, and R13 is hydrogen. In some embodiments of formula (I-E), including embodiments describing variables R1a and m and/or variables R10, R11, R12, and R13, q is 0. In some embodiments of formula (I-E), including embodiments describing variables R1a and m and/or variables R10, R11, R12, and R13 and/or variable q, p is 3, 4, or 5.

[00160] In some embodiments of formula (IE), R10, R11, R12, and R13 are hydrogen, p is 3, q is 0, and the compound is of formula (II-E):

[00161] or a salt thereof, wherein R1a and R2are as defined for formula (I), m is 0, 1, 2, 3 or 4, and the positions on the pyrido[2,3-d]pyrimidine ring are as indicated. All descriptions of R1a, R2and m with reference to formula (I) apply equally to formulae (I-E) and (II-E).

[00162] In some embodiments of the compound of formula (I), wherein R1 is a 5- to 10-membered heteroaryl optionally substituted by R1a, the compound has the formula (IF):

[00163] or a salt thereof, wherein R1a, R2, R10, R11, R12, R13, R14, q and p are as defined for formula (I), m is 0, 1, 2, 3, 4, 5 or 6 and the positions on the quinoline ring are as indicated.

[00164] In one embodiment, a compound of formula (I-F), or a salt thereof, is provided, wherein the carbon bearing the CO2H and NH chemical moieties is in the "S" configuration. In another embodiment, a compound of formula (I-F), or a salt thereof, is provided, wherein the carbon bearing the CO2H and NH chemical moieties is in the "R" configuration. Mixtures of a compound of formula (I-F) are also encompassed, including racemic or non-racemic mixtures of a given compound and mixtures of two or more compounds of different chemical formulas.

[00165] In some embodiments of the compound of formula (I-F), m is 0, 1, 2, 3, 4, 5, or 6 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R1a are, independently, optionally substituted by deuterium. In another embodiment of the compound of formula (I-F), m is 0, 1, 2, 3, 4, 5, or 6, and each R1a is, where applicable, independently, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which, in a variation, may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R1a are, independently, optionally substituted by deuterium. In some embodiments of the compound of formula (I-F), m is 1, 2, 3, 4, 5, or 6.

[00166] In some embodiments of the compound of formula (I-F), m is 0. In some embodiments of the compound of formula (I-F), m is 1 and R1a is at position 2. In some embodiments of the compound of formula (I-F), m is 1 and R1a is at position 3. In some embodiments of the compound of formula (I-F), m is 1 and R1a is at position 5. In some embodiments of the compound of formula (I-F), m is 1 and R1a is at position 6. In some embodiments of the compound of formula (I-F), m is 1 and R1a is at position 7. In some embodiments of the compound of formula (I-F), m is 1 and R1a is at position 8. In some embodiments of the compound of formula (I-F), m is 2 and the R1a groups are at position 2 and position 3. In some embodiments of the compound of formula (I-F), m is 2 and the R1a groups are at the 2-position and the 5-position. In some embodiments of the compound of formula (I-F), m is 2 and the R1a groups are at the 2-position and the 6-position. In some embodiments of the compound of formula (I-F), m is 2 and the R1a groups are at the 2-position and the 7-position. In some embodiments of the compound of formula (I-F), m is 2 and the R1a groups are at the 2-position and the 8-position. In some embodiments of the compound of formula (I-F), m is 2 and the R1a groups are at the 3-position and the 5-position. In some embodiments of the compound of formula (I-F), m is 2 and the R1a groups are at the 3-position and the 6-position. In some embodiments of the compound of formula (I-F), m is 2 and the R1a groups are at the 3-position and the 7-position. In some embodiments of the compound of formula (I-F), m is 2 and the R1a groups are at the 3-position and the 8-position. In some embodiments of the compound of formula (I-F), m is 2 and the R1a groups are at the 5-position and the 6-position. In some embodiments of the compound of formula (I-F), m is 2 and the R1a groups are at the 5-position and the 7-position. In some embodiments of the compound of formula (I-F), m is 2 and the R1a groups are at the 5-position and the 8-position. In some embodiments of the compound of formula (I-F), m is 2 and the R1a groups are at the 6-position and the 7-position. In some embodiments of the compound of formula (I-F), m is 2 and the R1a groups are at the 6-position and the 8-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are in the 2-position, 3-position, and 5-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are in the 2-position, 3-position, and 6-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are in the 2-position, 3-position, and 7-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are in the 2-position, 3-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are in the 2-position, 5-position, and 6-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are in the 2-position, 5-position, and 7-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are in the 2-position, 5-position, and 7-position. and position 8. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are at the 2-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are at the 2-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are at the 2-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are at the 3-position, 5-position, and 6-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are at the 3-position, 5-position, and 7-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are at the 3-position, 5-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are at the 3-position, the 6-position, and the 7-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are at the 3-position, the 6-position, and the 8-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are at the 3-position, the 7-position, and the 8-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are at the 5-position, the 6-position, and the 7-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are at the 5-position, the 6-position, and the 8-position. In some embodiments of the compound of formula (I-F), m is 3 and the R1a groups are at the 5-position, the 7-position, and the 8-position. R1a are at position 6, position 7, and position 8. In some embodiments of the compound of formula (I-F), m is 4 and the R1a groups are at position 2, position 3, position 5, and position 6. In some embodiments of the compound of formula (I-F), m is 4 and the R1a groups are at position 2, position 3, position 5, and position 7. In some embodiments of the compound of formula (I-F), m is 4 and the R1a groups are at position 2, position 3, position 5, and position 8. In some embodiments of the compound of formula (I-F), m is 4 and the R1a groups are at position 2, position 3, position 6, and position 7. In some embodiments of the compound of formula (I-F), m is 4 and the R1a groups are at position 2, position 3, position 6, and position 8. In some embodiments of the compound of formula (I-F), m is 4 and the R1a groups are at the 2-position, 3-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4 and the R1a groups are at the 2-position, 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-F), m is 4 and the R1a groups are at the 2-position, 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4 and the R1a groups are at the 2-position, 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4 and the R1a groups are at the 2-position, 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4 and the R1a groups are at the 3-position, 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4 and the R1a groups are at the 3-position, 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4 and the R1a groups are at the 3-position, 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4 and the R1a groups are at the 5-position, 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 5 and the R1a groups are at the 2-position, 3-position, 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-F), m is 5 and the R1a groups are at the 2-position, 3-position, 5-position, 6-position, and 7-position. 5, position 6, and position 8. In some embodiments of the compound of formula (I-F), m is 5 and the R1a groups are at the 2-position, 3-position, 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 5 and the R1a groups are at the 2-position, 3-position, 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 5 and the R1a groups are at the 2-position, 5-position, 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 5 and the R1a groups are at the 3-position, 5-position, 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 6 and the R1a groups are at the 2-position, 3-position, 5-position, 6-position, 7-position, and 8-position. Always that more than one R1a group is present, the R1a groups may be chosen independently. In any of these embodiments of the compound of formula (I-F), or a salt thereof, the carbon with the chemical moieties CO2H and NH may be in the "S" configuration or in the "R" configuration.

[00167] In some embodiments of formula (I-F), including embodiments describing variables R1a and m, each of R10, R11, R12, and R13 are hydrogen. In some embodiments of formula (I-F), including embodiments describing variables R1a and m and/or variables R10, R11, R12, and R13, q is 0. In some embodiments of formula (I-F), including embodiments describing variables R1a and m and/or variables R10, R11, R12, and R13 and/or variable q, p is 3, 4, or 5.

[00168] In some embodiments of formula (IF), R10, R11, R12, and R13 are hydrogen, p is 3, q is 0, and the compound is of formula (II-F):

[00169] or a salt thereof, wherein R1a and R2 are as defined for formula (I), m is 0, 1, 2, 3, 4, 5 or 6 and the positions on the quinoline ring are as indicated. All descriptions of R1a, R2 and m with reference to formula (I) apply equally to formulae (I-F) and (II-F).

[00170] In some embodiments of the compound of formula (I), wherein R1 is a 5- to 10-membered heteroaryl optionally substituted by R1a, the compound has the formula (IG):

[00171] or a salt thereof, wherein R1a, R2, R10, R11, R12, R13, R14, q and p are as defined for formula (I), m is 0, 1, 2, 3, 4, 5 or 6 and the positions on the isoquinoline ring are as indicated.

[00172] In one embodiment, a compound of formula (I-G), or a salt thereof, is provided, wherein the carbon bearing the CO2H and NH chemical moieties is in the "S" configuration. In another embodiment, a compound of formula (I-G), or a salt thereof, is provided, wherein the carbon bearing the CO2H and NH chemical moieties is in the "R" configuration. Mixtures of a compound of formula (I-G) are also encompassed, including racemic or non-racemic mixtures of a given compound and mixtures of two or more compounds of different chemical formulas.

[00173] In some embodiments of the compound of formula (I-G), m is 0, 1, 2, 3, 4, 5, or 6 and each R1a is, when applicable, independently, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R1a are, independently, optionally substituted by deuterium. In another embodiment of the compound of formula (I-G), m is 0, 1, 2, 3, 4, 5, or 6, and each R1a is, where applicable, independently, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which in a variation may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R1a are, independently, optionally substituted by deuterium. In some embodiments of the compound of formula (I-G), m is 1, 2, 3, 4, 5, or 6.

[00174] In some embodiments of the compound of formula (I-G), m is 0. In some embodiments of the compound of formula (I-G), m is 1 and R1a is at position 3. In some embodiments of the compound of formula (I-G), m is 1 and R1a is at position 4. In some embodiments of the compound of formula (I-G), m is 1 and R1a is at position 5. In some embodiments of the compound of formula (I-G), m is 1 and R1a is at position 6. In some embodiments of the compound of formula (I-G), m is 1 and R1a is at position 7. In some embodiments of the compound of formula (I-G), m is 1 and R1a is at position 8. In some embodiments of the compound of formula (I-G), m is 2 and the R1a groups are at position 3 and position 4. In some embodiments of the compound of formula (I-G), m is 2 and the R1a groups are at the 4-position and the 5-position. In some embodiments of the compound of formula (I-G), m is 2 and the R1a groups are at the 4-position and the 6-position. In some embodiments of the compound of formula (I-G), m is 2 and the R1a groups are at the 4-position and the 7-position. In some embodiments of the compound of formula (I-G), m is 2 and the R1a groups are at the 4-position and the 8-position. In some embodiments of the compound of formula (I-G), m is 2 and the R1a groups are at the 3-position and the 5-position. In some embodiments of the compound of formula (I-G), m is 2 and the R1a groups are at the 3-position and the 6-position. In some embodiments of the compound of formula (I-G), m is 2 and the R1a groups are at the 3-position and the 7-position. In some embodiments of the compound of formula (I-G), m is 2, and the R1a groups are at the 3-position and the 8-position. In some embodiments of the compound of formula (I-G), m is 2 and the R1a groups are at the 5-position and the 6-position. In some embodiments of the compound of formula (I-G), m is 2 and the R1a groups are at the 5-position and the 7-position. In some embodiments of the compound of formula (I-G), m is 2 and the R1a groups are at the 5-position and the 8-position. In some embodiments of the compound of formula (I-G), m is 2 and the R1a groups are at the 6-position and the 7-position. In some embodiments of the compound of formula (I-G), m is 2 and the R1a groups are at the 6-position and the 8-position. In some embodiments of the compound of formula (I-G), m is 2 and the R1a groups are at the 7-position and the 8-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are in the 3-position, the 4-position, and the 5-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are in the 3-position, the 4-position, and the 6-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are in the 3-position, the 4-position, and the 7-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are in the 3-position, the 4-position, and the 8-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are in the 4-position, the 5-position, and the 6-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are in the 4-position, the 5-position, and the 7-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are in the 4-position, the 5-position, and the 7-position. R1a are at the 4-position, 5-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are at the 4-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are at the 4-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are at the 4-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are at the 3-position, 5-position, and 6-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are at the 3-position, 5-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are at the 3-position, 5-position, and 7-position. and position 8. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are at the 3-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are at the 3-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are at the 3-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are at the 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are at the 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are at the 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 3 and the R1a groups are at the 5-position, 7-position, and 8-position. formula (I-G), m is 3 and the R1a groups are at the 6-position, the 7-position, and the 8-position. In some embodiments of the compound of formula (I-G), m is 4 and the R1a groups are at the 3-position, the 4-position, the 5-position, and the 6-position. In some embodiments of the compound of formula (I-G), m is 4 and the R1a groups are at the 3-position, the 4-position, the 5-position, and the 7-position. In some embodiments of the compound of formula (I-G), m is 4 and the R1a groups are at the 3-position, the 4-position, the 5-position, and the 8-position. In some embodiments of the compound of formula (I-G), m is 4 and the R1a groups are at the 3-position, the 4-position, the 6-position, and the 7-position. In some embodiments of the compound of formula (I-G), m is 4 and the R1a groups are at the 4-position, the 3-position, the 6-position, and the 8-position. In some embodiments of the compound of formula (I-G), m is 4 and the R1a groups are at the 3-position, 4-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 4 and the R1a groups are at the 4-position, 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 4 and the R1a groups are at the 4-position, 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 4 and the R1a groups are at the 4-position, 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 4 and the R1a groups are at the 4-position, 5-position, 7-position, and 8-position. position 7. In some embodiments of the compound of formula (I-G), m is 4 and the R1a groups are at the 3-position, 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 4 and the R1a groups are at the 3-position, 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 4 and the R1a groups are at the 3-position, 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 4 and the R1a groups are at the 5-position, 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 5 and the R1a groups are at the 3-position, 4-position, 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 5 and the R1a groups are at the 3-position, 4-position, 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 5 and the R1a groups are at the 3-position, 4-position, 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 5 and the R1a groups are at the 3-position, 4-position, 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 5 and the R1a groups are at the 4-position, 5-position, 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 5 and the R1a groups are at the 3-position, 5-position, 6-position, 7-position, and 8-position. 6, position 7 and position 8. Whenever more than one R1a group is present, the R1a groups may be chosen independently. In any of these embodiments of the compound of formula (I-G), or a salt thereof, the carbon with the chemical moieties CO2H and NH may be in the "S" configuration or in the "R" configuration.

[00175] In some embodiments of formula (I-G), including embodiments describing variables R1a and m, each of R10, R11, R12, and R13 is hydrogen. In some embodiments of formula (I-G), including embodiments describing variables R1a and m and/or variables R10, R11, R12, and R13, q is 0. In some embodiments of formula (I-G), including embodiments describing variables R1a and m and/or variables R10, R11, R12, and R13 and/or variable q, p is 3, 4, or 5.

[00176] In some embodiments of formula (IG), R10, R11, R12, and R13 are hydrogen, p is 3, q is 0, and the compound is of formula (II-G):

[00177] or a salt thereof, wherein R1a and R2 are as defined for formula (I), m is 0, 1, 2, 3, 4, 5 or 6 and the positions on the isoquinoline ring are as indicated. All descriptions of R1a, R2 and m with reference to formula (I) apply equally to formulae (I-G) and (II-G).

[00178] In some embodiments of the compound of formula (I), wherein R1 is a 5- to 10-membered heteroaryl optionally substituted by R1a, the compound has the formula (IH):

[00179] or a salt thereof, wherein R1a, R2, R10, R11, R12, R13, R14, q and p are as defined for formula (I), m is 0, 1 or 2, and the positions on the 1-methyl-1H-pyrazolo[3,4-d]pyrimidine ring are as indicated.

[00180] In one embodiment, there is provided a compound of formula (I-H), or a salt thereof, wherein the carbon bearing the CO2H and NH chemical moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-H), or a salt thereof, wherein the carbon bearing the CO2H and NH chemical moieties is in the "R" configuration. Mixtures of a compound of formula (I-H) are also encompassed, including racemic or non-racemic mixtures of a given compound and mixtures of two or more compounds of different chemical formulas.

[00181] In some embodiments of the compound of formula (I-H), m is 0, 1, or 2, and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R1a are, independently, optionally substituted by deuterium. In another embodiment of the compound of formula (I-H), m is 0, 1, or 2, and each R1a is, where applicable, independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which, in a variation, may be C1-C6 perhaloalkyl), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R1a are, independently, optionally substituted by deuterium. In some embodiments of the compound of formula (I-H), m is 1 or 2.

[00182] In some embodiments of the compound of formula (I-H), m is 0. In some embodiments of the compound of formula (I-H), m is 1 and R1a is in the 3 position. In some embodiments of the compound of formula (I-H), m is 1 and R1a is in the 6 position. In some embodiments of the compound of formula (I-H), m is 2 and the R1a groups are in the 3 position and the 6 position. Whenever more than one R1a group is present, the R1a groups may be chosen independently. In any such embodiment of the compound of formula (I-H), or a salt thereof, the carbon bearing the CO2H and NH chemical moieties may be in the "S" configuration or in the "R" configuration.

[00183] In some embodiments of formula (I-H), including embodiments describing variables R1a and m, each of R10, R11, R12, and R13 is hydrogen. In some embodiments of formula (I-H), including embodiments describing variables R1a and m and/or variables R10, R11, R12, and R13, q is 0. In some embodiments of formula (I-H), including embodiments describing variables R1a and m, and/or variables R10, R11, R12, and R13, and/or variable q, p is 3, 4, or 5.

[00184] In some embodiments of formula (IH), R10, R11, R12, and R13 are hydrogen, p is 3, q is 0, and the compound is of formula (II-H):

[00185] or a salt thereof, wherein R1a and R2are as defined for formula (I), m is 0, 1 or 2 and the positions on the 1-methyl-1H-pyrazolo[3,4-d]pyrimidine ring are as indicated. All descriptions of R1a, R2 and m with reference to formula (I) apply equally to formulae (I-H) and (II-H).

[00186] Also provided is a compound of formula (I) or (II), or a salt thereof, wherein R1 is a 5- to 10-membered heteroaryl optionally substituted by R1a. In some embodiments, R1 is an unsubstituted 5- to 10-membered heteroaryl (e.g., pyridinyl, pyrimidinyl, quinoxalinyl, quinazolinyl, pyrazolopyrimidinyl, quinolinyl, pyridopyrimidinyl, thienopyrimidinyl, pyridinyl, pyrrolopyrimidinyl, benzothiazolyl, isoquinolinyl, purinyl, or benzooxazolyl). In some embodiments, R1 is a 5- to 10-membered heteroaryl substituted by 1, 2, 3, 4, or 5 R1a groups, which may be the same or different, wherein each R1a is independently selected from halogen (e.g., fluorine, chlorine, or bromine), 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-C14 aryl (e.g., phenyl), -CN, -OR3 (e.g., -OCH3), and -NR4R5 (e.g., -N(CH3)2). In some embodiments, R1 is a 5-membered heteroaryl (e.g., pyrazolyl) substituted with 1, 2, 3, or 4 R1a groups which may be the same or different and is selected from -CH3, -CH2F, -CHF2, and -CF3. In some embodiments, R1 is 6-membered heteroaryl (e.g., pyridinyl, pyrimidinyl, or pyrazinyl) substituted by 1, 2, 3, 4, or 5 R1a groups which may be the same or different and is selected from halogen (e.g., fluorine, chlorine, or bromine), C3-C6 cycloalkyl (e.g., cyclopropyl), 5- to 6-membered heteroaryl (e.g., pyridinyl or pyrazolyl), C6-C10 aryl (e.g., phenyl), C1-C4 alkyl optionally substituted by halogen (e.g., -CH3, -CF3, or C(CH3)3), -CN, -OR3 (e.g., -OCH3), and -NR4R5 (e.g., -N(CH3)2). In some embodiments, R1 is 9-membered heteroaryl (e.g., pyrazolopyrimidinyl, pyrrolopyrimidinyl, thienopyrimidinyl, indazolyl, indolyl, or benzoimidazolyl) substituted by 1, 2, 3, 4, or 5 R1a groups which may be the same or different and is selected from -CH3, -CH2F, -CHF2, and -CF3. In some embodiments, R1 is 10-membered heteroaryl (e.g., quinazolinyl) substituted by 1, 2, 3, 4, or 5 R1a groups which may be the same or different and is selected from halogen (e.g., fluorine or chlorine), 5- to 6-membered heteroaryl (e.g., pyridinyl), C1 alkyl optionally substituted by halogen (e.g., -CH3 or -CF3), and -OR3 (e.g., -OCH3).

[00187] Also provided is a compound of formula (I) or (II), or a salt thereof, wherein R1 is selected from the group consisting of and any of the preceding groups, wherein any one or more hydrogen atoms are replaced by deuterium atom (or atoms). Also provided is a compound of formula (I) or (II), or a salt thereof, wherein R1 is selected from any of the preceding groups wherein any one or more hydrogen atoms are replaced by tritium atom (or atoms). For example, in some embodiments, each hydrogen bonded to a ring carbon in the preceding groups can be replaced by a corresponding isotope, e.g., deuterium or tritium. Each hydrogen bonded to an acyclic carbon in the preceding groups, e.g., methyl or methoxy carbons, can be replaced by a corresponding isotope, e.g., deuterium or tritium. Further, for example, the preceding groups can be percaterated, wherein all hydrogen is replaced by deuterium, or pertritiated, wherein all hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the preceding groups may be replaced with 13C. For example, in polycyclic rings between the preceding groups, one or more ring carbons in the ring directly attached to the rest of the compound may be replaced with 13C. In polycyclic rings between the preceding groups, one or more ring carbons may be replaced with 13C in the ring that replaces or is fused to the ring attached to the rest of the compound. Further, for example, each ring carbon in the preceding groups may be replaced with 13C.

[00188] Also provided is a compound of formula (I) or (II), or a salt thereof, wherein R 1 is selected from the group consisting of , and any of the preceding groups, wherein any one or more hydrogen atoms are replaced by deuterium atom (or atoms). Also provided is a compound of formula (I) or (II), or a salt thereof, wherein R1 is selected from any of the preceding groups wherein any one or more hydrogen atoms are replaced by tritium atom (or atoms). For example, in some embodiments, each hydrogen bonded to a ring carbon in the preceding groups can be replaced by a corresponding isotope, e.g., deuterium or tritium. Each hydrogen bonded to an acyclic carbon in the preceding groups, e.g., methyl or methoxy carbons, can be replaced by a corresponding isotope, e.g., deuterium or tritium. Further, for example, the preceding groups can be percaterated, wherein all hydrogen is replaced by deuterium, or pertritiated, wherein all hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the preceding groups may be replaced by 13C. For example, in polycyclic rings between the preceding groups, one or more ring carbons in the ring directly attached to the rest of the compound may be replaced by 13C. In polycyclic rings between the preceding groups, one or more ring carbons may be replaced by 13C in the ring that replaces or is fused to the ring attached to the rest of the compound. Further, for example, each ring carbon in the preceding groups may be replaced by 13C.

[00189] Also provided is a compound of formula (I) or (II), or a salt thereof, wherein R 1 is selected from the group consists of either one of the preceding groups, wherein any one or more hydrogen atoms are replaced by deuterium atom (or atoms). Also provided is a compound of formula (I) or (II), or a salt thereof, wherein R 1 is selected from any of the preceding groups wherein any one or more hydrogen atoms are replaced by tritium atom (or atoms). For example, in some embodiments, each hydrogen bonded to a ring carbon in the preceding groups can be replaced by a corresponding isotope, e.g., deuterium or tritium. Each hydrogen bonded to an acyclic carbon in the preceding groups, e.g., methyl or methoxy carbons, can be replaced by a corresponding isotope, e.g., deuterium or tritium. Further, for example, the preceding groups can be per-teritated, wherein all hydrogen is replaced by deuterium, or per-tritiated, wherein all hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the preceding groups may be replaced with 13C. For example, in polycyclic rings between the preceding groups, one or more ring carbons in the ring directly attached to the remainder of the compound may be replaced with 13C. In polycyclic rings between the preceding groups, one or more ring carbons may be replaced with 13C in the ring that replaces or is fused to the ring attached to the remainder of the compound. Further, for example, each ring carbon in the preceding groups may be replaced with 13C.

[00190] Also provided is a compound of formula (I) or (II), or a salt thereof, wherein R 1 is selected from the group consisting of and any of the preceding groups, wherein any one or more hydrogen atoms are replaced by deuterium atom (or atoms). Also provided is a compound of formula (I) or (II), or a salt thereof, wherein R 1 is selected from any of the preceding groups wherein any one or more hydrogen atoms are replaced by tritium atom (or atoms). For example, in some embodiments, each hydrogen bonded to a ring carbon in the preceding groups can be replaced by a corresponding isotope, e.g., deuterium or tritium. Each hydrogen bonded to an acyclic carbon in the preceding groups, e.g., methyl or methoxy carbons, can be replaced by a corresponding isotope, e.g., deuterium or tritium. Further, for example, the preceding groups can be percaterated, wherein all hydrogen is replaced by deuterium, or pertritiated, wherein all hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the preceding groups may be replaced with 13C. For example, in polycyclic rings between the preceding groups, one or more ring carbons in the ring directly attached to the remainder of the compound may be replaced with 13C. In polycyclic rings between the preceding groups, one or more ring carbons may be replaced with 13C in the ring that replaces or is fused to the ring attached to the remainder of the compound. Further, for example, each ring carbon in the preceding groups may be replaced with 13C.

[00191] Also provided is a compound of formula (I) or (II), or a salt thereof, wherein R1 is selected from the group consisting of or more hydrogen atoms are replaced by deuterium atom (or atoms). Also provided is a compound of formula (I) or (II), or a salt thereof, wherein R1 is selected from any of the preceding groups in which any one or more hydrogen atoms are replaced by tritium atom (or atoms). For example, in some embodiments, each hydrogen bonded to a ring carbon in the preceding groups can be replaced by a corresponding isotope, e.g., deuterium or tritium. Each hydrogen bonded to an acyclic carbon in the preceding groups, e.g., methyl or methoxy carbons, can be replaced by a corresponding isotope, e.g., deuterium or tritium. Further, for example, the preceding groups can be percaterated, in which all hydrogen is replaced by deuterium, or pertritiated, in which all hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the preceding groups can be replaced by 13C. For example, in polycyclic rings between the preceding groups, one or more ring carbons in the ring directly attached to the rest of the compound may be replaced by 13C. In polycyclic rings between the preceding groups, one or more ring carbons may be replaced by 13C in the ring that replaces or is fused to the ring attached to the rest of the compound. Furthermore, for example, each ring carbon in the preceding groups may be replaced by 13C.

[00192] The R1 groups described herein as chemical moieties (shown with a ^wv* symbol) are shown as attached at specific positions (e.g., pyrimid-4-yl, quinazolin-4-yl, isoquinolin-1-yl), but they may also be attached through any other available valence (e.g., pyrimid-2-yl). In some embodiments of the compound of formula (I) or (II), or a salt thereof, or X , wherein m is 0, 1, 2 or 3 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are, independently, optionally substituted by deuterium. In another embodiment the N^N compound of formula (I) or (II), or a salt thereof wherein m is 1, 2, or 3 and each R1a is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R1a are independently optionally substituted by deuterium. In another embodiment, R1 is wherein m is 0, 1, 2, 3, 4 or 5 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are, independently, optionally substituted by deuterium. In another embodiment of the compound of formula (I) or (II), or a salt thereof, R1 is where m is 1, 2, 3, 4, or 5 and each R1a is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R1a are independently optionally substituted by deuterium. In a further variation of such embodiments, each R1a is, 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- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of R1a are, independently, optionally substituted by deuterium.

[00193] In some embodiments of the compound of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H), or (II-H), or a salt thereof, R2 is C1-C6 alkyl optionally substituted by R2a. In some embodiments, R2 is C1-C6 alkyl optionally substituted by R2a, wherein R2a is: halogen (e.g., fluorine); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluorine); 5- to 10-membered heteroaryl optionally substituted by C1C6 alkyl (e.g., pyrazolyl optionally substituted by methyl); -S(O)2R3; -NR4R5; -NR3C(O)R4; oxo; or -OR3. In some embodiments, R2 is C1-C6 alkyl optionally substituted by R2a, wherein R2a is: halogen (e.g., fluorine); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluorine); 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., pyrazolyl optionally substituted by methyl); 3- to 12-membered heterocyclyl optionally substituted by halogen (e.g., oxetanyl optionally substituted by fluorine), -S(O)2R3; -NR4R5; -NR3C(O)R4; oxo; or -OR3. In some embodiments, R2 is C1-C6 alkyl optionally substituted by -OR3, wherein R3 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 fluorine); C6-C14 aryl optionally substituted by halogen (e.g., phenyl optionally substituted by fluorine); or 5- to 6-membered heteroaryl optionally substituted by halogen or C1-C6 alkyl (e.g., pyridinyl optionally substituted by fluorine or methyl). In some embodiments, R2 is -CH2CH2OCH3. In some embodiments, R2 is C1-C6 alkyl substituted by halogen and OR3. In some embodiments, R2 is n-propyl substituted by halogen and alkoxy (e.g., -CH2CH(F)CH2OCH3). In some embodiments wherein R2 is indicated as optionally substituted by R2a, the R2 moiety is unsubstituted. In some embodiments wherein R2 is indicated as optionally substituted by R2a, the R2 moiety is replaced by one R2a. In some embodiments wherein R2 is indicated as optionally substituted by R2a, the R2 moiety is substituted by 2 to 6, or 2 to 5, or 2 to 4, or 2 to 3 R2a moieties, which may be the same or different.

[00194] In some embodiments of the compound of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H), or (II-H), or a salt thereof, R2 is C1-C6 alkyl optionally substituted by R2a. In some embodiments, R2 is C1-C6 alkyl optionally substituted by R2a, wherein R2a is: halogen (e.g., fluorine); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluorine); 5- to 10-membered heteroaryl optionally substituted by C1C6 alkyl (e.g., pyrazolyl optionally substituted by methyl); -S(O)2R3; -NR4R5; -NR3C(O)R4; oxo; or -OR3. In some embodiments, R2 is C1-C6 alkyl optionally substituted by R2a, wherein R2a is: halogen (e.g., fluorine); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluorine); 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., pyrazolyl optionally substituted by methyl); 3- to 12-membered heterocyclyl optionally substituted by halogen (e.g., oxetanyl optionally substituted by fluorine); -S(O)2R3; -NR4R5; -NR3C(O)R4; oxo; or -OR3. In some embodiments, R2 is C1-C6 alkyl optionally substituted by R2a, wherein R2a is: halogen (e.g., fluorine); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluorine); C6-C14 aryl (e.g., phenyl); 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., thiazolyl or pyrazolyl optionally substituted by methyl); 3- to 12-membered heterocyclyl optionally substituted by halogen or oxo (e.g., R2a is: oxetanyl optionally substituted by fluorine; tetrahydrofuranyl; pyrrolidinyl optionally substituted by oxo; morpholinyl optionally substituted by oxo; or dioxanyl); -S(O)2R3; -NR4R5; -NR3C(O)R4; oxo; -OR3; or -CN. In some embodiments, R2 is C1-C6 alkyl optionally substituted by -OR3, wherein R3 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 fluorine); C6-C14 aryl optionally substituted by halogen (e.g., phenyl optionally substituted by fluorine); or 5- to 6-membered heteroaryl optionally substituted by halogen or C1-C6 alkyl (e.g., pyridinyl optionally substituted by fluorine or methyl). In some embodiments, R2 is -CH2CH2OCH3. In some embodiments, R2 is C1-C6 alkyl substituted by halogen and OR3. In some embodiments, R2 is n-propyl substituted by halogen and alkoxy (e.g., -CH2CH(F)CH2OCH3). In some embodiments where R2 is indicated as optionally substituted by R2a, the R2 moiety is unsubstituted. In some embodiments where R2 is indicated as optionally substituted by R2a, the R2 moiety is substituted by one R2a. In some embodiments where R2 is indicated as optionally substituted by R2a, the R2 moiety is substituted by 2 to 6, or 2 to 5, or 2 to 4, or 2 to 3 R2a moieties, which may be the same or different. In some embodiments, R2 is C1-C6 alkyl substituted by two halogen groups, which may be the same or different (e.g., two fluorine groups). In some embodiments, R2 is C1-C6 alkyl substituted with two -OR3 groups, which can be the same or different (e.g., two -OH groups, one -OH group and one -OCH3 group, or two -OCH3 groups). In some embodiments, R2 is C1-C6 alkyl substituted with one halogen group (e.g., fluorine) and one -OR3 group (e.g., -OH or -OCH3). In some embodiments, R2 is C1-C6 alkyl substituted with two halogen groups, which can be the same or different (e.g., two fluorine groups) and one -OR3 group (e.g., -OH or -OCH3). In some embodiments, R2 is C1-C6 alkyl substituted with one halogen group (e.g., fluorine) and two -OR3 groups, which can be the same or different (e.g., two -OH groups, one -OH group and one -OCH3 group, or two -OCH3 groups).

[00195] In some embodiments of the compound of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H), or (II-H), or a salt thereof, R2 is C3-C6 cycloalkyl optionally substituted by R2b. In some embodiments, R2 is C3-C6 cycloalkyl substituted by 1 or 2 R2b moieties which may be the same or different. In some embodiments, R2 is C3-C4 cycloalkyl optionally substituted by halogen (e.g., unsubstituted cyclopropyl or cyclobutyl optionally substituted by fluorine). In some embodiments, R2 is C3-C4 cycloalkyl optionally substituted with deuterium or tritium atom(s). For example, in some embodiments, each hydrogen bonded to a ring carbon in the preceding groups can be replaced with a corresponding isotope, e.g., deuterium or tritium. Each hydrogen bonded to an acyclic carbon in the preceding groups, e.g., methyl or methoxy carbons, can be replaced with a corresponding isotope, e.g., deuterium or tritium. Further, for example, the preceding groups can be percaterated, in which every hydrogen is replaced with deuterium, or pertritiated, in which every hydrogen is replaced with tritium. In some embodiments, one or more ring carbons in the preceding groups can be replaced with 13C. For example, in polycyclic rings between the preceding groups, one or more ring carbons in the ring directly attached to the rest of the compound can be replaced with 13C. In polycyclic rings between the preceding groups, one or more ring carbons may be replaced by 13C in the ring that replaces or is fused to the ring attached to the rest of the compound. In addition, for example, each ring carbon in the preceding groups may be replaced by 13C.

[00196] In some embodiments of the compound of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H), or (II-H), or a salt thereof, R2 is hydrogen.

[00197] In some embodiments of the compound of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H), or (II-H), a salt thereof, R2 is -O-C1-C6 alkyl optionally substituted by R2a. In some embodiments, R2 is -OCH3.

[00198] Also provided is 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, wherein R2 is selected from the group consisting of and any of the preceding groups in which any one or more hydrogen atoms are replaced by an atom (or atoms) of deuterium.

[00199] Also provided is 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, wherein R2 is selected from the group consisting of , and any of the preceding groups in which any one or more hydrogen atoms are replaced by a deuterium atom (or atoms).

[00200] Also provided is 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, wherein, where R3 and each R2a are as defined for formula (I).

[00201] Also provided is 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, wherein R2is - , where each R2a is as defined for formula (I).

[00202] Also provided is 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), O'R3 (II-G), (IH) or (II-H), or a salt thereof, wherein R2 is , where R3 is as defined for formula (I).

[00203] In one embodiment of formula (I), the tetrahydronaphthyridine group is disubstituted with deuterium at position 2.

[00204] In one aspect, there is provided a compound of formula (I), or a salt thereof (including a pharmaceutically acceptable salt thereof), wherein the compound or salt thereof has any one or more of the following structural features ("SF"):

[00205] (SFI) p is 3;

[00206] (SFII) each R10, R11, R12, R13 is hydrogen;

[00207] (SFIII) R1 is:

[00208] (A) unsubstituted 5- to 10-membered heteroaryl;

[00209] (B) 5- to 10-membered heteroaryl substituted by 1, 2, 3, 4 or 5 R1a groups that can be the same or different; wherein the 5- to 10-membered heteroaryl of (III) (A) and (III) (B) is: (i) pyridinyl; (ii) pyrimidinyl; (iii) quinoxalinyl; (iv) quinazolinyl; (v) pyrazolopyrimidinyl; (vi) quinolinyl; (vii) pyridopyrimidinyl; (viii) thienopyrimidinyl; (ix) purinyl; (x) pyrrolopyrimidinyl; (xi) benzooxazolyl; (xii) benzothiazolyl; (xiii) isoquinolinyl; (xiv) indolyl; (xv) benzoimidazolyl; (xvi) pyrazinyl; (xvii) indazolyl; or (xviii) pyrazolyl; (C) unsubstituted naphthalenyl; or (D) naphthalenyl substituted by 1, 2, 3, 4 or 5 R1a groups which may be the same or different; (SFIV) each R1a is: (A) halogen, as fluorine, chlorine or bromine; (B) C1-C6 alkyl optionally substituted by halogen, such as -CH3, -CHF2, -CF3 or C(CH3)3; (C) C3-C6 cycloalkyl, such as cyclopropyl; (D) 5- to 10-membered heteroaryl, such as pyridinyl or pyrazolyl; (E) C6-C14 aryl, such as phenyl; (F) -CN; (G) -OR3, such as -OCH3; or (H) -NR4R5, such as -N(CH3)2; (SFV) R2is: (A) unsubstituted C1-C6 alkyl, such as C1-C2 alkyl; (B) C1-C6 alkyl, such as C1-C2 alkyl, each of which is substituted by 1, 2, 3, 4 or 5 R2a groups which may be the same or different; (C) -O-C1-C6 unsubstituted alkyl, such as -O-C1-C2 alkyl; (D) -O-C1-C6 alkyl, such as -O-C1-C2 alkyl each of which is substituted by 1, 2, 3, 4 or 5 R2a groups which may be the same or different; (E) unsubstituted C3-C6 cycloalkyl such as cyclopropyl or cyclobutylene; there; or (F) C3-C6 cycloalkyl, such as cyclopropyl or cyclobutyl, each of which is substituted by 1, 2, 3, 4 or 5 R2b groups, which may be the same or different; and (SFVI) R2ais: (A) halogen, such as fluorine; (B) C3-C8 cycloalkyl, such as cyclopropyl or cyclobutyl, each of which is optionally substituted by halogen; (C) 5- to 10-membered heteroaryl optionally substituted by C1C6 alkyl, such as methyl-substituted pyrazolyl ; (D) 3- to 12-membered heterocyclyl optionally substituted by halogen or oxo, such as oxetanyl optionally substituted by fluorine, unsubstituted tetrahydrofuranyl, oxo-substituted pyrrolidinyl, unsubstituted morpholinyl, oxo-substituted morpholinyl, or dioxanyl ; (E) -S(O)2R3, such as -S(O)2CH3; (F) -C(O)NR4R5, such as -C(O)N(CH3)2; (G) -NR3C(O)R4 , such as -NHC(O)CH3; or (H) -OR3, where R3 is: (i) hydrogen; (ii) -CH3; (iii) -CH2CH3; (iv) -CH2CHF2; (v) -CH2CF3; ( vi) phenyl substituted by 0 to 2 fluorine groups; or (vii) pyridinyl substituted by 0 to 1 methyl group.

[00210] It is understood that compounds of formula (I) or any variation thereof described herein, or a salt thereof, may, in an embodiment, have any one or more of the structural features as noted above. For example, compounds of formula (I) or any variation thereof described herein, or a salt thereof, may, in an embodiment, have the following structural features: one or two or three or all of (SFI), (SFII), (SFIII), and (SFV). In an example, a compound of formula (I) or any variation thereof described herein, or a salt thereof, may, in an embodiment, have the following structural features: (SFI) and any one or two or all of (SFII), (SFIII), and (SFV) or any sub-embodiment thereof. In one example, a compound of formula (I) or any variation thereof described herein, or a salt thereof, can, in one embodiment, have the following structural features: (SFII) and any one or two or all of (SFI), (SFIII), and (SFV) or any submodality thereof. In one example, a compound of formula (I) or any variation thereof described herein, or a salt thereof, can, in one embodiment, have the following structural features: (SFIII) and any one or two or all of (SFI), (SFII), and (SFV) or any submodality thereof. In one example, a compound of formula (I) or any variation thereof described herein, or a salt thereof, can, in one embodiment, have the following structural features: (SFV) and any one or two or all of (SFI), (SFII), and (SFIII), or any submodality thereof. It is understood that the submodalities of structural features can likewise be combined in any manner. Although specific combinations of structural features are specifically noted below, it is understood that any and all combinations of features are covered. 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, (SFI), (SFIII), and (SFV) apply. In another variation, (SFII), (SFIII), and (SFV) apply. It is understood that each submodality of the structural features applies. For example, (SFIII) is (SFIII)(A)(i), (SFIII)(A)(ii), (SFIII)(A)(iii), (SFIII)(A)(iv), (SFIII)(A)(v), (SFIII)(A)(vi), (SFIII)(A)(vii), (SFIII)(A)(viii), (SFIII)(A)(ix), (SFIII)(A)(x), (SFIII)(A)(xi), (SFIII)(A)(xii), (SFIII)(A)(xiii), (SFIII)(A)(xiv), (SFIII)(A)(xv), (SFIII)(A)(xvi), (SFIII)(A)(xvii), (SFIII)(A)(xviii), (SFIII)(B)(i), (SFIII)(B)(ii), (SFIII)(B)(iii), (SFIII)(B)(iv), (SFIII)(B)(v), (SFIII)(B)(vi), (SFIII)(B)(vii) (SFIII)(B)(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).

[00211] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply.

[00212] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply.

[00213] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply.

[00214] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply.

[00215] 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 other 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 other 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 other 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 other 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 other 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.

[00216] Any variations or combinations cited herein for compounds of formula (I) also apply to formula (A), with the addition of any possible combinations of R15 and R16.

[00217] Representative compounds are listed in Figure 1.

[00218] In some embodiments, provided is a compound selected from Compounds 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 compound is a salt of a compound selected from Compounds Nos. 1-66 in Figure 1, or a stereoisomer thereof.

[00219] In some embodiments, provided is a compound selected from Compounds Nos. 1-147, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the compound is a salt of a compound selected from Compounds Nos. 1-147, or a stereoisomer thereof.

[00220] In some embodiments, provided is a compound selected from Compounds 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 salt of a compound selected from Compounds Nos. 1-665, or a stereoisomer thereof.

[00221] In some embodiments, provided is a compound selected from Compounds 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 salt of a compound selected from Compounds Nos. 1-780, or a stereoisomer thereof.

[00222] In a variation, the compound detailed in this document is 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-pyrazol[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.

[00223] In another variation, the compound detailed in this document is 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-pyrazol[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-pyrazol[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-pyrazol[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-pyrazol[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-pyrazol[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-pyrazol[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-pyrazol[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-pyrazol[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-pyrazol[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-pyrazol[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-pyrazol[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-naphthyridin2-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-pyrazol[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-pyrazol[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-pyrazol[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-pyrazol[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.

[00224] In some embodiments, a composition is provided, such as a pharmaceutical composition, wherein the composition comprises a compound selected from the group consisting of one or more of Compounds Nos. 1-66 in Figure 1, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of a salt of one or more of Compounds Nos. 1-66. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[00225] In some embodiments, a composition, such as a pharmaceutical composition, is provided wherein the composition comprises a compound selected from the group consisting of one or more of Compounds Nos. 1-147, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of a salt of one or more of Compounds Nos. 1-147. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[00226] In some embodiments, a composition is provided, such as a pharmaceutical composition, wherein the composition comprises a compound selected from the group consisting of one or more of Compounds Nos. 1-665, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of a salt of one or more of Compounds Nos. 1-665. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[00227] In some embodiments, a composition, such as a pharmaceutical composition, is provided wherein the composition comprises a compound selected from the group consisting of one or more of Compounds Nos. 1-780, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of a salt of one or more of Compounds Nos. 1-780. In one aspect, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[00228] The invention also includes all salts of the compounds referred to herein, such as pharmaceutically acceptable salts. The invention also includes any or all stereochemical forms, including any enantiomeric or diastereomeric forms and any tautomers or other forms of the compounds described. Unless the stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to encompass all possible stereoisomers of a depicted compound. Furthermore, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also described and encompassed by the invention. All forms of the compounds are also encompassed by the invention, such as the crystalline or non-crystalline forms of the compounds. It is also understood that prodrugs, solvates and metabolites of the compounds are encompassed by this disclosure. Compositions comprising a compound of the invention are also intended, such as a composition of a substantially pure compound including a specific stereochemical form thereof. Compositions comprising a mixture of compounds of the invention in any ratio are also encompassed by the invention, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced. When one or more tertiary amine moieties are present in the compound, the N-oxides are also provided and described.

[00229] The compounds described herein are inhibitors of integrin αvβ6. In some cases, it is desirable for the compound to inhibit integrins other than integrin αvβ6. In some embodiments, the compound inhibits integrin αvβ6 and one or more of integrin αvβ1, αvβ3, αvβ5, α2β1, α3β1, α6β1, α7β1, and α11β1. In some embodiments, the compound inhibits integrin αvβ6 and integrin αvβ1. In some embodiments, the compound inhibits integrin αvβ6, integrin αvβ3, and integrin αvβ5. In some embodiments, the compound inhibits integrin αvβ6 and integrin α2β1. In some embodiments, the compound inhibits integrin αvβ6, integrin α2β1, and integrin α3β1. In some embodiments, the compound inhibits integrin αvβ6 and integrin α6β1. In some embodiments, the compound inhibits integrin αvβ6 and integrin α7β1. In some embodiments, the compound inhibits integrin αvβ6 and integrin α11β1.

[00230] In some cases, it is desirable to avoid inhibition of other integrins. In some embodiments, the compound is a selective inhibitor of integrin αvβ6. In some embodiments, the compound does not substantially inhibit integrin α4β1, αvβ8, and/or α2β3. In some embodiments, the compound inhibits integrin αvβ6 but does not substantially inhibit integrin α4β1. In some embodiments, the compound inhibits integrin αvβ6 but does not substantially inhibit integrin αvβ8. In some embodiments, the compound inhibits integrin αvβ6 but does not substantially inhibit integrin α2β3. In some embodiments, the compound inhibits αvβ6 integrin, but does not substantially inhibit αvβ8 integrin and α4β1 integrin.

[00231] The invention also envisages isotopically labeled and/or isotopically enriched forms of compounds described herein. Compounds herein may contain unnatural proportions of atomic isotopes in one or more of the atoms constituting such compounds. In some embodiments, the compound is isotopically labeled, such as an isotopically labeled compound of formula (I) or variations thereof described herein, wherein one or more atoms are replaced by an isotope of the same element. Exemplary isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2H, 3H, 11C, 13C, 14C 13N, 15O, 17O, 32P, 35S, 18F, 36Cl. The incorporation of heavier isotopes, such as deuterium (2H or D), may provide certain therapeutic advantages resulting from increased metabolic stability, e.g., increased in vivo half-life, or reduced dosage requirements, and therefore may be preferred in some instances. As used herein, each instance of replacing a hydrogen with deuterium is also a disclosure of replacing that hydrogen with tritium. As used herein, each instance of enriching, substituting, or replacing an atom with the corresponding isotope of that atom encompasses isotopic enrichment levels of one of about: 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%, or a range between any two of the foregoing percentages.

[00232] The isotopically labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples, substituting appropriate isotopically labeled reagents in place of the corresponding unlabeled reagent.

[00233] In various embodiments, for each of the compounds named or depicted herein, corresponding isotopically substituted compounds are specifically disclosed according to the following description. For example, corresponding isotopically substituted compounds are disclosed in which the groups corresponding to the structural variables R1 and R1a can be independently deuterated, e.g., the structural variables R1 and R1a can be deuterated such that all hydrogen therein can be independently replaced with deuterium. Further, corresponding isotopically substituted compounds are disclosed in which one or more hydrogens in the group corresponding to the structural variable R1, but not in the optional substituent R1a, can be independently replaced with deuterium. For example, corresponding isotopically substituted compounds are disclosed in which all hydrogen attached to a ring in the group corresponding to R1, but not in the optional substituent R1a, can be replaced with deuterium. Also disclosed are corresponding isotopically substituted compounds in which one or more hydrogens in R1a can be independently replaced by deuterium, e.g., each hydrogen in the group corresponding to R1a can be replaced by deuterium.

[00234] Further disclosed are, for example, corresponding isotopically substituted compounds in which the groups corresponding to the structural variables R2 and R2a can be independently deuterated, e.g., the structural variables R2 and R2a can be deuterated such that every hydrogen therein can be independently replaced with deuterium. Also disclosed are corresponding isotopically substituted compounds in which one or more hydrogens in the group corresponding to R2, but not in the optional substituent R2a, can be independently replaced with deuterium. Further disclosed are corresponding isotopically substituted compounds in which each hydrogen at position 1 of R2, the carbon that links R2 to the rest of the compound, can be independently replaced with deuterium. For example, for named compounds that have -CH2CH2CH2F corresponding to R2, also disclosed are corresponding isotopically substituted compounds in which R2 is -CD2CH2CH2F; For named compounds having -CH2-cyclopropyl corresponding to R2, also disclosed are corresponding isotopically substituted compounds wherein R2 is -CD2-cyclopropyl; and the like. Also disclosed are corresponding isotopically substituted compounds wherein each hydrogen in the group corresponding to R2a can be independently replaced by deuterium. For example, for each compound wherein R2a is -OCH3, also disclosed are corresponding isotopically substituted compounds wherein R2a can be -OCD3; for each compound wherein R2a is -N(CH3)2, also disclosed are corresponding isotopically substituted compounds wherein R2a can be -N(CD3)2; and the like. Further disclosed are compounds in which the 1-position of R2 can be di-deuterated and each hydrogen in the group corresponding to R2a can be replaced by deuterium.

[00235] Also disclosed are corresponding isotopically substituted compounds in which R10, R11, R12, R13, and each R14 are independently deuterated. For example, disclosed are corresponding isotopically substituted compounds in which R10, R11 are deuterium, or R12, R13 are deuterium, or R10, R11, R12, and R13 are all deuterium. Further disclosed are compounds wherein R14 is deuterium and R14 replaces the tetrahydronaphthyridin-2-yl group at the 3-position, the 4-position, or both the 3 and 4 positions. Also disclosed are compounds wherein R14 is deuterium and each R14 independently replaces each hydrogen on the tetrahydronaphthyridin-2-yl group at the 5-position, the 6-position, the 7-position, both the 5 and 6 positions, the 5 and 7 positions, the 6 and 7 positions, or the 5, 6, and 7 positions, e.g., the 7-position may be replaced by two deuterium atoms.

[00236] In some embodiments, corresponding isotopically substituted compounds are disclosed in which: every ring hydrogen in R1 can be replaced with deuterium; position 1 of R2 can be di-deuterated; and R2a can be percaterated. Corresponding isotopically substituted compounds are disclosed in which every ring hydrogen in R1 can be replaced with deuterium. Corresponding isotopically substituted compounds are disclosed in which: every ring hydrogen in R1 can be replaced with deuterium; position 1 of R2 can be di-deuterated; R2a can be percaterated; R12 and R13 can be deuterium; and position 7 of the tetrahydronaphthyridin-2-yl group can be di-deuterated. Corresponding isotopically substituted compounds are disclosed in which: every ring hydrogen in R1 can be replaced with deuterium; and each hydrogen in R2a can be independently replaced with deuterium. Disclosed are corresponding isotopically substituted compounds in which: all ring hydrogen in R1 can be replaced by deuterium; position 1 of R2 can be dideuterated; R2a can be percaterated; and R12 and R13 can be deuterium. Disclosed are corresponding isotopically substituted compounds in which: R1 and R1a can be percaterated; position 1 of R2 can be dideuterated; R2a can be percaterated; R12 and R13 can be deuterium; and position 7 of the tetrahydronaphthyridin-2-yl group can be dideuterated. Disclosed are corresponding isotopically substituted compounds in which: all ring hydrogen in R1 can be replaced by deuterium; position 1 of R2 can be dideuterated; R2a can be percaterated; and R12 and R13 can be deuterium.

[00237] In some embodiments of the named compounds, each hydrogen represented in R1, R1a, R2, R2a, R10, R11, R12, R13, and R14 can independently be tritium. For example, corresponding isotopically substituted compounds are disclosed in which one or more hydrogens in R1, R1a, or R1 and R1a can be independently replaced with tritium. Corresponding isotopically substituted compounds are disclosed in which one or more ring hydrogens in R1, R1a, or R1 and R1a can be independently replaced with tritium. Corresponding isotopically substituted compounds are disclosed in which one or more hydrogens in R2, R2a, or R2 and R2a can be independently replaced with tritium. Disclosed are corresponding isotopically substituted compounds in which one or more hydrogens in R2, R2a, or R2 and R2a may be independently replaced by tritium. Disclosed are corresponding isotopically substituted compounds in which one of the 3- or 4-positions of the tetrahydronaphthyridin-2-yl group may be tritiated, e.g., the 3-position. Disclosed are corresponding isotopically substituted compounds in which one of the 5-, 6-, or 7-positions of the tetrahydronaphthyridin-2-yl group may be mono- or di-tritiated, e.g., the 7-position may be di-tritiated.

[00238] In some embodiments of the named compounds, corresponding isotopically substituted compounds are disclosed in which one or more carbons can be replaced by 13C. For example, corresponding isotopically substituted compounds are disclosed in which one or more carbons can be replaced by 13C, such as carbons in R1, R1a, R2, R2a, the tetrahydronaphthyridin-2-yl ring depicted in the structural formulas herein, and the like. For example, in rings represented by R1, R1a, R2, R2a, and/or the tetrahydronaphthyridin-2-yl group, one or more ring carbons can be replaced by 13C. For example, in the polycyclic rings represented by R1, R1a, R2, R2a, and/or the tetrahydronaphthyridin-2-yl group, one or more ring carbons in the ring directly attached to the rest of the compound may be replaced by 13C; for example, in the tetrahydronaphthyridin-2-yl group, the ring directly attached to the rest of the compound is a heteroaromatic ring attached in the 2-position. In polycyclic rings in the groups corresponding to R1, R1a, R2, R2a, and/or the tetrahydronaphthyridin-2-yl group, one or more ring carbons may be replaced by 13C in a ring that replaces or is fused to the ring attached to the rest of the compound. For example, in the tetrahydronaphthyridin-2-yl ring, the nonaromatic heterocyclic ring is fused to the ring attached to the rest of the compound. Furthermore, for example, each carbon of the ring, or each carbon in the group corresponding to R1, R1a, R2, R2a and/or the tetrahydronaphthyridin-2-yl ring may be replaced by 13C.

[00239] The invention also includes any or all metabolites of any of the described compounds. Metabolites may include any chemical species generated by a biotransformation of any of the described compounds, such as intermediates and products of the metabolism of the compound.

[00240] Articles of manufacture comprising a compound of the invention, or a salt or solvate thereof, in a suitable container are provided. The container may be a vial, jar, ampoule, pre-filled syringe, i.v. bag, and the like.

[00241] Preferably, the compounds detailed herein are orally bioavailable. However, the compounds may also be formulated for parenteral (e.g., intravenous) administration.

[00242] One or more compounds described herein may be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art. Depending on the therapeutic form of the medicament, the carrier may take various forms.

[00243] GENERAL SYNTHETIC METHODS

[00244] The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the following Examples (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used in the formulas depicted are to be understood as representing those groups described above in connection with the formulas herein.

[00245] Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by the reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, e.g., by crystallization, and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral high-performance liquid chromatography. Alternatively, if desired, a particular enantiomer may be obtained using an appropriate chiral intermediate in one of the processes described.

[00246] Chromatography, recrystallization, and other conventional separation procedures may also be used with intermediates or end products where it is desired to obtain a particular isomer of a compound or otherwise purify a product of a reaction.

[00247] Solvates and/or polymorphs of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated. Solvates contain stoichiometric or non-stoichiometric amounts of a solvent and are often formed during the crystallization process. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs generally 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 cause a single crystal form to dominate.

[00248] 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.

[00249] 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.

[00250] Compounds of formula 11A may be prepared according to General Scheme A, wherein R1 and R2 are as defined for formula (I) or any applicable variations detailed herein. GENERAL SCHEME A

[00251] Coupling of 1A with a compound of formula 2A in the presence of a suitable coupling agent produces a compound of formula 3A, which is reduced to produce 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 with a compound of formula 6A by exposure to an appropriate 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 compounds of formula 11A.

[00252] The reaction conditions for the transformations of General Scheme A are given in the General Procedures that follow, in particular General Procedures A, D, E, F, G, H, and P.

[00253] General Scheme A may be modified to prepare variants of compounds of formula 11A, starting with variants of 1A having 5 and 6 carbon ligands between the nitrogen atom bearing the R2 group and the tetrahydronaphthyridine group. These variants of compounds of formula 11A may be synthesized using the pathway described in General Scheme A by substituting 1A with 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid or 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid. 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 an appropriate catalyst followed by hydrogenation of the resulting naphthyridine ring to the 5,6,7,8-tetrahydronaphthyridine ring using procedures known in the chemical literature.

[00254] Compounds of formula 11A may alternatively be prepared according to General Scheme B wherein R1 and R2 are as defined for formula (I) or any applicable variations detailed herein. GENERAL SCHEME B

[00255] Installation of an N-Boc group from 1B in the presence of a suitable base and di-tert-butyl decarbonate yields a compound of formula 2B, which is reduced to yield a compound of formula 3B. Oxidation of a compound of formula 3B with a suitable oxidizing agent gives a compound of formula 4B. Reductive amination of a compound of formula 4B with compound 2A gives a compound of formula 5B. Reductive amination of a compound of formula 5B with compound 5A gives a compound of formula 7B. Removal of the N-Boc protecting group from a 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 a compound of formula 10A in the presence of a suitable hydroxide source gives compounds of formula 11A.

[00256] The reaction conditions for the transformations of General Scheme B are given in the General Procedures that follow, in particular General Procedures B, D, F, G, H, and P.

[00257] General Scheme B may be modified to prepare variants of compounds of formula 11A, starting with variants of 1B having 5 and 6 carbon ligands between the nitrogen atom bearing the R2 group and the tetrahydronaphthyridine group. These variants of compounds of formula 11A may be synthesized using the route described in General Scheme B by substituting 1B with ethyl 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentanoate or ethyl 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexanoate. Ethyl 6-oxoheptanoate and ethyl 7-oxoctanoate 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 an appropriate catalyst followed by hydrogenation of the resulting naphthyridine ring to the 5,6,7,8-tetrahydronaphthyridine ring using procedures known in the chemical literature.

[00258] Compounds of formula 10C may be prepared according to General Scheme C, wherein R is C1-C5 alkyl optionally substituted by R2a, and R1 and R2a are as defined for formula (I), or any applicable variations detailed herein. GENERAL SCHEME C

[00259] Coupling of 1C with a compound of formula 4C in the presence of a suitable coupling agent produces a compound of formula 2C, which is reduced to produce a compound of formula 3C. Reductive amination of a compound of formula 3C with compound 5A gives a compound of formula 5C. Global removal of the N-Boc protecting groups with a compound of formula 5C by exposure to an appropriate acid gives a compound of formula 6C, which can be coupled with a compound of formula 8A to give a compound of formula 9C. Hydrolysis of a compound of formula 9C in the presence of a suitable hydroxide source gives compounds of formula 10C.

[00260] The reaction conditions for the transformations of General Scheme C are given in the General Procedures that follow, in particular General Procedures B, D, F, G, H, and P.

[00261] General Scheme C can be modified to prepare variants of compounds of formula 10C, starting with variants of 1C having 5 and 6 carbon ligands between the nitrogen atom bearing the -CH2R group and the tetrahydronaphthyridine group. These variants of compounds of formula 10C can be synthesized using the pathway described in General Scheme C 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. 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 an appropriate 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 a primary amine by a two-step procedure that includes coupling the carboxylic acid with an appropriate ammonia source in the presence of suitable coupling reagents followed by reduction.

[00262] Compounds of formula 10C may alternatively be prepared according to General Scheme D, wherein R is C1-C5 alkyl optionally substituted by R2a and R1 and R2a are as defined for formula (I), or any applicable variations detailed herein. GENERAL SCHEME D

[00263] Alkylation of 1C with a compound of formula 2D in the presence of a suitable alkyl halide yields 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 with a compound of formula 5C by exposure to an appropriate 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 compounds of formula 10C.

[00264] The reaction conditions for the transformations of General Scheme D are given in the General Procedures that follow, in particular General Procedures C, F, G, H, and P.

[00265] General Scheme D can be modified to prepare variants of compounds of formula 10C, starting with variants of 1C having 5 and 6 carbon ligands between the nitrogen atom bearing the -CH2R group and the tetrahydronaphthyridine group. These variants of compounds of formula 10C can be synthesized using the pathway described in General Scheme D 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. 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 an appropriate 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 a primary amine by a two-step procedure that includes coupling the carboxylic acid with an appropriate ammonia source in the presence of suitable coupling reagents followed by reduction.

[00266] Compounds of formula 1f may be prepared according to General Scheme E. It should be understood that the ring containing the description Het may be any heteroaromatic ring. GENERAL SCHEME E

[00267] Hydrolysis of a compound of formula 1a gives a compound of formula 1b which can be alkylated with a suitable electrophile to give a compound of formula 1c. Deprotection under reductive conditions of a compound of formula 1c gives a compound of formula 1d. Metal-catalyzed cross-coupling of a halogenated arene with a compound of formula 1d gives a compound of formula 1e, which can be hydrolyzed under acidic conditions to give compound of formula 1f.

[00268] The reaction conditions for the transformations of General Scheme E are given in the General Procedures that follow, in particular General Procedures Q, R, S, T, and U.

[00269] It is understood that the above schemes may be modified to arrive at various compounds of the invention by selection of appropriate reagents and starting materials. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4th edition, Wiley-Interscience, New York, 2006.

[00270] Additional methods of preparing compounds according to Formula (I), and salts thereof, are provided in the Examples. As one skilled in the art would recognize, the methods of preparation taught herein may be adapted to provide additional compounds within the scope of Formula (I), for example, by selecting starting materials that would provide a desired compound.

[00271] PHARMACEUTICAL COMPOSITIONS AND FORMULATIONS

[00272] Pharmaceutical compositions of any of the compounds detailed herein, including compounds of formula (I), (I-A), (I-B), (IC), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), or a salt thereof, or any of the compounds of Figure 1, or a salt thereof, or mixtures thereof, are encompassed by this invention. Pharmaceutical compositions of any of the compounds detailed herein, including compounds of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), or a salt thereof, or any of the compounds of Figure 1, or a salt thereof, or mixtures thereof, are encompassed by this invention. Pharmaceutical compositions of compounds of formula (A), or a salt thereof, or mixtures thereof, are encompassed by this invention. Thus, the invention includes pharmaceutical compositions comprising a compound of the 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. The pharmaceutical compositions according to the invention may be in a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or in a form suitable for administration by inhalation. In one embodiment, the pharmaceutical composition is a composition for controlled release of any of the compounds detailed herein.

[00273] A compound as detailed herein may, in one aspect, be in a purified form, and compositions comprising a compound in purified forms are detailed herein. In one embodiment, the compositions may have no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof, for example, a composition of a compound selected from a compound of Figure 1 may contain no more than 35% impurity, wherein the impurity denotes a compound other than the compound of Figure 1 or a salt thereof. In one embodiment, the compositions may have no more than 35% impurity, wherein impurity denotes a compound other than the compound comprising the majority of the composition, or a salt thereof, for example, a composition of a compound selected from a compound of Figure 1 may contain no more than 35% impurity, wherein impurity denotes a compound other than the compound of Figure 1, or a salt thereof. In one embodiment, the compositions may contain no more than 25% impurity. In one embodiment, the compositions may contain no more than 20% impurity. In still other embodiments, compositions comprising a compound as detailed herein or a salt thereof are provided as compositions of substantially pure compounds. “Substantially pure” compositions comprise no more than 10% impurity, such as a composition comprising less than 9%, 7%, 5%, 3%, 1%, or 0.5% impurity. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. In yet another variation, a substantially pure compound composition or a salt thereof is provided wherein the composition contains or contains no more than 10% impurity. In another variation, a substantially pure compound composition or a salt thereof is provided wherein the composition contains or contains no more than 9% impurity. In another variation, a substantially pure compound composition or a salt thereof is provided wherein the composition contains or contains no more than 7% impurity. In another variation, a substantially pure compound composition or a salt thereof is provided wherein the composition contains or contains no more than 5% impurity. In another variation, a substantially pure compound composition or a salt thereof is provided wherein the composition contains or contains no more than 3% impurity. In yet another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or contains not more than 1% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or contains not more than 0.5% impurity. In still other variations, a composition of substantially pure compound means that the composition contains not more than 10% or preferably not more than 5% or more preferably not more than 3% or even more preferably not more than 1% impurity or most preferably not more than 0.5% impurity, which impurity may be the compound in a different stereochemical form. For example, a composition of substantially pure compound (S) means that the composition contains not more than 10% or not more than 5% or not more than 3% or not more than 1% or not more than 0.5% of the (R) form of the compound.

[00274] In one variation, the compounds herein are synthetic compounds prepared for administration to a subject, such as a human. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the invention encompasses pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier or excipient. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for any compound or form detailed herein.

[00275] A compound detailed herein or salt thereof may be formulated for any available route of delivery, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery. Format. A compound or salt thereof may be formulated with suitable vehicles to provide delivery forms including, but not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), wafers, troches, lozenges, gums, dispersions, suppositories, ointments, poultices (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil emulsions), solutions, and elixirs.

[00276] One or more compounds described herein or a salt thereof may be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may take various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, colorants, adjusters and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants. Formulations comprising the compound may also contain other substances that have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations may be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st ed. (2005), which is incorporated herein by reference.

[00277] The compounds described herein may be administered to individuals (e.g., a human) in a form of generally accepted oral compositions, such as tablets, coated tablets and gel capsules in a hard or soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for soft shell gel capsules are, for example, vegetable oils, wax, fats, semi-solid and liquid polyols, and so on. In addition, the pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, colorants, adjusters and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.

[00278] Any of the compounds described herein may be formulated into a tablet in any dosage form described, for example, a compound as described herein or a pharmaceutically acceptable salt thereof may be formulated as a 10 mg tablet.

[00279] Compositions comprising a compound provided herein are also described. In one variation, the composition comprises a compound and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided. In some embodiments, the composition is for use as a human or veterinary medicament. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in treating a disease or disorder described herein.

METHODS OF USE

[00280] The compounds and compositions of the invention, such as a pharmaceutical composition containing a compound of any 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 of administering a compound or composition to cells for screening purposes and/or for performing quality control assays.

[00281] In one aspect, a method of treating a fibrotic disease in a subject in need thereof is provided which comprises administering to the subject a therapeutically effective amount of a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compounds Nos. 1-66 in Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, a method of treating a fibrotic disease in a subject in need thereof is provided which comprises administering to the subject a therapeutically effective amount of a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (IID), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compounds Nos. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, a method of treating a fibrotic disease in a subject in need thereof is provided which comprises administering to the subject a therapeutically effective amount of a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compounds Nos. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, a method of treating a fibrotic disease in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compounds Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, a method of treating a fibrotic disease in a subject in need thereof is provided comprising administering to the subject a therapeutically effective amount of a compound of formula (A), or any variation thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, the subject is a human. The subject, as a human, may be in need of treatment, such as a human who has or is suspected of having a fibrotic disease.

[00282] In another aspect, a method is provided for delaying the onset and/or development of a fibrotic disease in an individual (such as a human) who is at risk of developing a fibrotic disease. It is recognized that delaying development may include prevention in the event that the individual does not develop the fibrotic disease. An individual at risk of developing a fibrotic disease in one aspect has or is suspected of having one or more risk factors for developing a fibrotic disease. Risk factors for fibrotic disease may include an individual's age (e.g., middle-aged or older adults), the presence of inflammation, having one or more genetic components associated with the development of a fibrotic disease, medical history such as treatment with a drug or procedure believed to be associated with an increased susceptibility to fibrosis (e.g., radiology) or a medical condition believed to be associated with fibrosis, a history of smoking, the presence of occupational and/or environmental factors such as exposure to pollutants associated with the development of a fibrotic disease. In some embodiments, the individual at risk for developing a fibrotic disease is an individual who has or is suspected of having NAFLD, NASH, CKD, scleroderma, Crohn's disease, NSIP, PSC, PBC, or is an individual who has had or is suspected of having had a myocardial infarction.

[00283] In some embodiments, the fibrotic disease is fibrosis of a tissue, such as the lung (pulmonary fibrosis), liver, skin, heart (cardiac fibrosis), kidney (renal fibrosis), or gastrointestinal tract (gastrointestinal fibrosis).

[00284] In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skin fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis (such as PBC).

[00285] In some embodiments, the fibrotic disease is a pulmonary fibrosis, e.g., idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis is, e.g., interstitial lung disease, radiation-induced pulmonary fibrosis, or interstitial lung disease associated with systemic sclerosis.

[00286] 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.

[00287] In some embodiments, the fibrotic disease is non-specific fibrotic interstitial pneumonia (NSIP).

[00288] In some embodiments, the fibrotic disease is a liver fibrosis, e.g., infectious liver fibrosis (from pathogens such as HCV, HBV, or parasites such as schistosomiasis), NASH, alcoholic steatosis-induced liver fibrosis, and cirrhosis. In some embodiments, the liver fibrosis is non-alcoholic fatty liver disease (NAFLD). In some embodiments, the liver fibrosis is NASH.

[00289] In some embodiments, the fibrotic disease is fibrosis of the biliary tract.

[00290] In some embodiments, the fibrotic disease is renal fibrosis, e.g., diabetic nephrosclerosis, hypertensive nephrosclerosis, focal segmental glomerulosclerosis ("FSGS"), and contrast-induced nephropathy acute kidney injury. In various embodiments, the fibrotic disease is diabetic nephropathy, diabetic kidney disease, or chronic kidney disease.

[00291] 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.

[00292] In some embodiments, the fibrotic disease is systemic and local sclerosis or scleroderma, keloids and hypertrophic scars, or post-surgical adhesions. In some embodiments, the fibrotic disease is systemic scleroderma or sclerosis.

[00293] In some embodiments, the fibrotic disease is atherosclerosis or restenosis.

[00294] In some embodiments, the fibrotic disease is a gastrointestinal fibrosis, e.g., Crohn's disease.

[00295] In some embodiments, the fibrotic disease is cardiac fibrosis, e.g., fibrosis induced after myocardial infarction and hereditary cardiomyopathy.

[00296] In some embodiments, the methods 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 αVβ6. The method can include modulating the activity of αVβ1. The method can include modulating the activity of both αVβ1 and αVβ6. Modulating the activity of at least one integrin can include, for example, inhibiting the at least one integrin. The method can 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 in the subject, for example, at least one of αVβ1 and αVβ6. The subject in need of modulating 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 may include idiopathic pulmonary fibrosis, interstitial lung disease, radiation-induced pulmonary fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic-induced liver fibrosis, Alport syndrome, primary sclerosing cholangitis, primary biliary cholangitis (also known as primary biliary cirrhosis), biliary atresia, systemic sclerosis-associated 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 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 in the subject, e.g., at least one of αVβ1 and αVβ6, the subject in need of treatment for NASH. 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 in the subject, e.g., at least one of αVβ1 and αVβ6, in the subject in need of treatment for IPF.

[00297] The fibrotic disease may be mediated primarily by αVβ6, e.g., the fibrotic disease may include idiopathic pulmonary fibrosis or renal fibrosis. Accordingly, the method may include modulating the activity of αVβ6 to treat conditions mediated primarily by αVβ6, such as IPF. The fibrotic disease may be mediated primarily by αVβ1, e.g., the fibrotic disease may include NASH. Accordingly, the method may include modulating the activity of αVβ1 to treat conditions mediated primarily by αVβ1, e.g., NASH. The fibrotic disease may be mediated by both αVβ1 and αVβ6, e.g., the fibrotic disease may include PSC or biliary atresia. Accordingly, the method may include modulating the activity of αVβ1 and αVβ6 to treat conditions mediated by αVβ1 and αVβ6.

[00298] The compound may be a modulator, e.g., an inhibitor, of αVβ1. The compound may be a modulator, e.g., an inhibitor, of αVβ6. The compound may be a dual modulator, such as a dual inhibitor, e.g., a dual selective inhibitor, of αVβ1 and αVβ6. For example, Table B-3 demonstrates that some exemplary compounds primarily inhibit αVβ1 over αVβ6; some exemplary compounds primarily inhibit αVβ6 over αVβ1; and some exemplary compounds inhibit αVβ1 and αVβ6 comparably, and may be considered, e.g., “dual αVβ1/αVβ6 inhibitors.”

[00299] Modulating or inhibiting the activity of either or both integrin αVβ1 and integrin αVβ6, thereby treating an individual with a fibrotic disease, indicates that integrin αVβ1, integrin αVβ6, or integrin αVβ1 and integrin αVβ6 are modulated or inhibited to a degree sufficient to treat the fibrotic disease in the individual.

[00300] In one aspect, there is provided a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compounds Nos. 1-66 in Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating a fibrotic disease.

[00301] In one aspect, there is provided a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compounds Nos. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating a fibrotic disease.

[00302] In one aspect, there is provided a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compounds Nos. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating a fibrotic disease.

[00303] In one aspect, there is provided a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compounds Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating a fibrotic disease.

[00304] Also provided is the use of a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compounds Nos. 1-66 in Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.

[00305] Also provided is the use of a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compounds Nos. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.

[00306] Also provided is the use of a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compounds Nos. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.

[00307] Also provided is the use of a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.

[00308] In another aspect, a method is provided for inhibiting αvβ6 integrin in a subject comprising administering a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a stereoisomer thereof, or a compound selected from Compounds Nos. 1-66 in Figure 1, or a pharmaceutically acceptable salt thereof.

[00309] In another aspect, a method is provided for inhibiting αvβ6 integrin in a subject comprising administering a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a stereoisomer thereof, or a compound selected from Compounds Nos. 1-147, or a pharmaceutically acceptable salt thereof.

[00310] In another aspect, a method is provided for inhibiting αvβ6 integrin in a subject comprising administering a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a stereoisomer thereof, or a compound selected from Compound Nos. 1-665, or a pharmaceutically acceptable salt thereof.

[00311] In another aspect, a method is provided for inhibiting αvβ6 integrin in a subject comprising administering a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a stereoisomer thereof, or a compound selected from Compound Nos. 1-780, or a pharmaceutically acceptable salt thereof.

[00312] Also provided is a method of inhibiting TGFβ activation in a cell comprising administering to the cell a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compounds Nos. 1-66 in Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[00313] Also provided is a method of inhibiting TGFβ activation in a cell comprising administering to the cell a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compounds Nos. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[00314] Also provided is a method of inhibiting TGFβ activation in a cell comprising administering to the cell a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compounds Nos. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[00315] Also provided is a method of inhibiting TGFβ activation in a cell comprising administering to the cell a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compounds Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[00316] Also provided is a method of inhibiting αvβ6 integrin in a subject in need thereof comprising administering to the subject a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (ID), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compounds Nos. 1 and 166 in Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Also provided is a method of inhibiting αvβ6 integrin in a subject in need thereof comprising administering to the subject a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compounds Nos. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Also provided is a method of inhibiting αvβ6 integrin in a subject in need thereof comprising administering to the subject a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compounds Nos. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Also provided is a method of inhibiting αvβ6 integrin in a subject in need thereof comprising administering to the subject a compound of formula (I), or any variation thereof, e.g., a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In such a method, the compound is a selective inhibitor of αvβ6 integrin. In another such method, the compound does not substantially inhibit α4β1, αvβ8, and/or α2β3 integrin. In yet another such method, the compound inhibits αvβ6 integrin, but does not substantially inhibit α4β1 integrin. In yet another method, the compound inhibits αvβ6 integrin, but does not substantially inhibit αvβ8 integrin. In another 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 in a subject in need thereof. In another embodiment, a method of inhibiting integrin αvβ6 and integrin αvβ1 is provided. In another embodiment, a method of inhibiting integrin αvβ6, integrin αvβ3, and integrin αvβ5 is provided. In another embodiment, a method of inhibiting integrin αvβ6 and integrin α2β1 is provided. In another embodiment, a method of inhibiting integrin αvβ6, integrin α2β1, and integrin α3β1 is provided. In another embodiment, a method of inhibiting integrin αvβ6 and integrin α6β1 is provided. In another embodiment, a method is provided for inhibiting integrin αvβ6 and integrin α7β1. In another embodiment, a method is provided for inhibiting integrin αvβ6 and integrin α11β1. In all such embodiments, in one aspect, the method of inhibiting is for a subject in need thereof, such as a subject who has or is suspected of having a fibrotic disease, and wherein the method comprises administering to the subject a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compounds Nos. 1-66 in Figure 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In all such embodiments, in one aspect, the method of inhibition is for a subject in need thereof, such as a subject who has or is suspected of having a fibrotic disease, and wherein the method comprises administering to the subject a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compounds Nos. 1-147, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In all such embodiments, in one aspect, the method of inhibition is for a subject in need thereof, such as a subject who has or is suspected of having a fibrotic disease, and wherein the method comprises administering to the subject a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (IID), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compounds Nos. 1-665, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In all such embodiments, in one aspect, the method of inhibition is for a subject in need thereof, such as a subject who has or is suspected of having a fibrotic disease, and wherein the method comprises administering to the subject a compound of formula (I), or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), a compound selected from Compound Nos. 1-780, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[00317] Compounds of formula (A) may be used in any of the compositions, methods and uses recited herein for formula (I) and variations of formula (I).

[00318] In any of the methods described, in one aspect, the subject is a human being, such as a human being in need of the method. The subject may be a human being who has been diagnosed with or is suspected of having a fibrotic disease. The subject may be a human being with no detectable disease but with one or more risk factors for developing a fibrotic disease.

KITS

[00319] The invention further provides kits for carrying out the methods of the invention, comprising one or more compounds described herein, or a salt thereof, or a pharmacological composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a pharmaceutically acceptable salt thereof. The kits may be used for any one or more of the uses described herein and accordingly may contain instructions for use in the treatment of a fibrotic disease.

[00320] Kits generally include suitable packaging. Kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) may be packaged in separate containers or some components may be combined in one container where cross-reactivity and shelf life permit. One or more components of a kit may be sterile and/or may be contained in sterile packaging.

[00321] Kits may be in unit dosage forms, bulk packaging (e.g., multi-dose packaging), or sub-unit doses. For example, kits may be provided that contain sufficient dosages 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 provide effective treatment of an individual for an extended period, such as any of 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. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[00322] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of the component(s) of the methods of the present invention. The instructions included in the kit generally include information about the components and administration thereof to a subject.

GENERAL PROCEDURES

[00323] The compounds provided herein may be prepared according to the General Schemes as exemplified by the General Procedures and Examples. Minor variations in temperatures, concentrations, reaction times, and other parameters may be made in following the General Procedures which do not substantially affect the results of the procedures.

[00324] When a specific stereoisomer, or an unspecified stereoisomer, or a mixture of stereoisomers is shown in the following general procedures, it is understood that similar chemical transformations can be carried out on other specific stereoisomers, or an unspecified stereoisomer, or mixtures thereof. For example, a hydrolysis reaction of a methyl (S)-4-amino-butanoate to a (S)-4-amino-butanoic acid can also be carried out on a methyl (R)-4-amino-butanoate to prepare a (R)-4-amino-butanoic acid, or on a mixture of a methyl (S)-4-amino-butanoate and a methyl (R)-4-amino-butanoate to prepare a mixture of a (S)-4-amino-butanoic acid and a (R)-4-amino-butanoic acid.

[00325] Some of the following general procedures use specific compounds to illustrate a general reaction (e.g., deprotection of a compound having a Boc-protected amine to a compound having a deprotected amine using acid). The general reaction may be performed on other specific compounds having the same functional group (e.g., a different compound having a protected amine in which the Boc-protecting group can be removed using acid in the same manner), provided that such other specific compounds do not contain additional functional groups affected by 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 such additional functional groups is desired (e.g., such other specific compounds have another group that is affected by acid, and the effect of the acid on that other group is a desirable reaction).

[00326] Where specific reagents or solvents are specified for reactions in the general procedures, one of skill in the art will recognize that other reagents or solvents may be substituted as desired. For example, when hydrochloric acid is used to remove a Boc group, trifluoroacetic acid may 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-yl-oxytripyrrolidinophosphonium hexafluorophosphate) may be used instead. GENERAL PROCEDURE A

[00327] 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 CH2Cl2 (80 mL) at room temperature was added DIPEA (13.57 mL, 77.9 mmol). To this was then added HATU (8.1 g, 21.42 mmol) and the resulting mixture was stirred at room temperature for 2 h. 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. GENERAL PROCEDURE B

[00328] 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 allowed to stir at room temperature for 1 h. The reaction mixture was concentrated in vacuo and purified by normal phase chromatography on silica gel to give N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide. GENERAL PROCEDURE C

[00329] 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. °C for 18 h. The reaction mixture was allowed to cool to room temperature and 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. GENERAL PROCEDURE D

[00330] 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 borane tetrahydrofuran complex solution (1.0 M in THF, 4.0 mL, 4.0 mmol) dropwise. The resulting mixture was then heated at 60 °C for 2 h 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 chromatography on silica gel to give N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. GENERAL PROCEDURE AND

[00331] 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 LiAlH4 (1.0 M in THF, 123 mL, 2.2 equiv) and the resulting mixture was heated at reflux for 20 h and then cooled to 0 °C. To this solution was added H2O (4.7 ml), followed by 1 M NaOH (4.7 ml), then H2O (4.7 ml) and warmed to room temperature and stirred for 30 min, at which time solid MgSO4 was added and stirred for an additional 30 min. 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.

GENERAL PROCEDURE F

[00332] 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 methyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (217 mg, 0.94 mmol). The resulting mixture was allowed to stir at room temperature for 15 min, at which time, sodium cyanoborohydride (80 mg, 1.28 mmol) was added to the reaction mixture and stirred for 30 min and then concentrated in vacuo. The crude residue was purified by normal phase chromatography on silica gel to afford methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. GENERAL PROCEDURE G

[00333] 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 CH2Cl2 (2 mL) at room temperature was added 4 N HCl in 1,4-dioxane (1 mL, 4 mmol) and the resulting mixture was allowed to stir for 2 h. 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. GENERAL PROCEDURE H

[00334] A solution of methyl (S)-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 chromatography on silica gel 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. GENERAL PROCEDURE P

[00335] (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 4:1:1 THF/MeOH/H2O was added lithium hydroxide at room temperature (about four equivalents) and the resulting mixture was stirred for 30 min. The reaction mixture was concentrated in vacuo and the resulting crude residue purified by reversed-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. GENERAL PROCEDURE Q

[00336] S)-2-(((benzyloxy)carbonyl)amino acid)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8 -naphthyridin-2-yl)butyl)amino)butanoic acid. A mixture of (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 H2O (3 ml) and THF (3 ml) and MeOH (3 ml) was added LiOH • H2O (159.36 mg, 3.80 mmol) and then the mixture was stirred at room temperature for 1 h and the resulting mixture was concentrated in vacuo. The mixture was adjusted to pH = 6 by AcOH (2 ml) and the residue was concentrated in vacuo to give a residue to yield the compound (S)-2-(((benzyloxy)carbonyl)amino)-4-yl acid. -(((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)+.1H 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, 6.06 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). GENERAL PROCEDURE R

[00337] 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 umol, HOAc salt) in DMA (4 mL) was added N-benzyl-N,N-diethylethanaminium chloride (119.32 mg, 523.84 umol), K2CO3 (1.88 g, 13.62 mmol), 2-bromo-2-methylpropane (3.45 g, 25.14 mmol). The mixture was stirred for 18 h at 55 °C 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 Na 2 SO 4 , filtered, and concentrated in vacuo. The crude residue was purified by prep-TLC to afford 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. (ESI+): m/z = 569.3 (M+H)+. GENERAL PROCEDURE

[00338] 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 umol) in i-PrOH (2 mL) was added Pd(OH)2 (26 mg) under a N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (1.034 bar (15 psi)) at room temperature for 15 h. The mixture was filtered and concentrated in vacuo to afford 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)+. 1H 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 = 6.11 Hz, 3 H). GENERAL PROCEDURE T

[00339] (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- tert-butyl 2-((5-methylpyrimidin-2-yl)amino)butanoate. To a solution of 2-amino-4-(((R)-2-methoxypropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl))butyl)amino )(S)-tert-butyl butanoate and (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) tert-butyl butanoate (100 mg, 230.09 umol) and 2-chloro-5-methyl-pyrimidine (24.65 mg, 191.74 umol) in 2-Methyl-2-butanol (2 ml) was added t-BuONa (2 M in THF, 191.74 µl) and [2- (2-aminophenyl)phenyl]-methylsulfonyloxypalladium; ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (15.23 mg, 19.17 umol), and the resulting mixture was stirred at 100 °C for 14 h. The mixture was concentrated in vacuo to give 4-(((S)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin (S)-tert-Butyl (2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate. LCMS (ESI+): m/z = 527.3 (M+H )+. GENERAL PROCEDURE U

[00340] (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid) -2-((5-methylpyrimidin-2-yl)amino)butanoic acid. To a solution of (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) tert-Butyl -2-((5-methylpyrimidin-2-yl)amino)butanoate (80 mg, 151.89 umol) in DCM (2 ml) TFA was added (254.14 mg, 2.23 mmol) at 0°C. The mixture was stirred at room temperature for 6 h. The mixture was concentrated in vacuo and the resulting crude residue was purified by preparative HPLC to furnish 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)+. 1H 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, 3 H) 1.76 - 1.99 (m, 6 H) 1.22 (d, J = 5.95 Hz, 3 H).

LISTED MODALITIES

[00341] The following enumerated embodiments are representative of some aspects of the invention.

[00342] A compound of formula (I) or a salt thereof, wherein: R1is C6-C14 aryl or 5- to 10-membered heteroaryl wherein the C6-C14 aryl and the 5- to 10-membered heteroaryl are optionally substituted by R1a; R2is C1-C6 alkyl optionally substituted by R2a; C3-C6 cycloalkyl optionally substituted by R2b; 3- to 12-membered heterocyclyl optionally substituted by R2c; or -S(O)2R2d; each R1a is 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-C14 aryl, deuterium, halogen, -CN, -OR3, -SR3, -NR4R5, -NO2, -C=NH(OR3), -C(O)R3, - OC(O)R3, -C(O)OR3, -C(O)NR4R5, -NR3C(O)R4, -NR3C(O)OR4, - NR3C(O)NR4R5, -S(O)R3, -S(O)2R3, -NR3S(O)R4, -NR3S(O)2R4, - S(O)NR4R5, -S(O)2NR4R5 or -P(O)(OR4)(OR5), wherein each R1a is, whenever possible, independently optionally substituted by deuterium, halogen, oxo, -OR6, -NR6R7, -C(O)R6, -CN, -S(O)R6, -S(O)2R6, -P(O)(OR6)(OR7), C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-C14 aryl or C1-C6 alkyl optionally substituted by deuterium, oxo, -OH or halogen; each R2a, R2b, R2c, R2e and R2f is independently oxo or R1a; R2d is C1-C6 alkyl optionally substituted by R2e or C3-C5 cycloalkyl optionally substituted by R2f; R3is independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl of R3 are independently optionally substituted by halogen, deuterium, oxo, -CN, -OR8, -NR8R9, -P(O)(OR8)(OR9) or C1-C6 alkyl optionally substituted by deuterium, halogen, OH, or oxo; R4 and R5 are each, independently, hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl of R4 and R5 are, independently, optionally substituted by deuterium, halogen, oxo, -CN, -OR8, -NR8R9 or C1-C6 alkyl optionally substituted by deuterium, halogen, -OH, or oxo; or R4 and R5 are taken together with the atom to which they are attached to form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, -OR8, -NR8R9 or C1-C6 alkyl optionally substituted by deuterium, halogen, oxo or -OH; R6 and R7 are each, independently, hydrogen, deuterium, C1-C6 alkyl optionally substituted by deuterium, halogen or oxo, C2-C6 alkenyl optionally substituted by deuterium, halogen or oxo, or C2-C6 alkynyl optionally substituted by deuterium, halogen or oxo; or R6 and R7 are taken together with the atom to which they are attached to form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo or C1-C6 alkyl optionally substituted by deuterium, halogen or oxo; R8 and R9 are each independently hydrogen, deuterium, C1-C6 alkyl optionally substituted by deuterium, halogen or oxo, C2-C6 alkenyl optionally substituted by deuterium, halogen or oxo, or C2-C6 alkynyl optionally substituted by deuterium, halogen or oxo; or R8 and R9 are taken together with the atom to which they are attached to 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 R10, R11, R12 and R13 are independently hydrogen or deuterium; R14 is deuterium; q is 0, 1, 2, 3, 4, 5, 6, 7 or 8 and p is 3, 4, 5, 6, 7, 8 or 9.

[00343] Embodiment 2. The compound of embodiment 1, or a salt thereof, wherein at least one of R1a, R2a, R2b, R2c, R2e, R2f, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, or R14 is deuterium.

[00344] Embodiment 3. The compound of embodiment 1 or a salt thereof, wherein R10, R11, R12, R13, and R14are hydrogen; p is 3; and is represented by the compound of formula (II): Embodiment 4. The compound of embodiment 1, 2 or 3, or a salt thereof, wherein R1 is a 5- to 10-membered heteroaryl optionally substituted by R1a.

[00345] Embodiment 5. The compound of embodiment 1, 2 or 3, or a salt thereof, wherein R1 is pyrimidin-4-yl optionally substituted by R1a.

[00346] Embodiment 6. The compound of embodiment 1, 2 or 3, or a salt thereof, wherein R1 is pyrimidin-4-yl optionally substituted by R1a, wherein R1a is 5- to 10-membered heteroaryl or C1-C6 alkyl optionally substituted by halogen.

[00347] Embodiment 7. The compound of embodiment 1, 2 or 3, or a salt thereof, wherein R1 is pyrimidin-4-yl optionally substituted by pyrazolyl, methyl, difluoromethyl or trifluoromethyl.

[00348] Embodiment 8. The compound of embodiment 1, 2 or 3, or a salt thereof, wherein R1 is pyrimidin-4-yl substituted by methyl and trifluoromethyl.

[00349] Embodiment 9. The compound of embodiment 1, 2 or 3, or a salt thereof, wherein R1 is quinazolin-4-yl optionally substituted by R1a.

[00350] Embodiment 10. The compound of embodiment 1, 2 or 3, or a salt thereof, wherein R1 is quinazolin-4-yl optionally substituted by halogen, C1-C6 alkyl optionally substituted by halogen, or C1-C6 alkoxy.

[00351] Embodiment 11. The compound of embodiment 1, 2 or 3, or a salt thereof, wherein R1 is quinazolin-4-yl optionally substituted by fluorine, chlorine, methyl, trifluoromethyl or methoxy.

[00352] Embodiment 12. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl optionally substituted by R2a.

[00353] Embodiment 13. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl optionally substituted by R2a, wherein R2a is: halogen; C3-C8 cycloalkyl optionally substituted by halogen; 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl; -NR4R5; -NR3C(O)R4; -S(O)2R3; or oxo.

[00354] Embodiment 14. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl optionally substituted by R2a, wherein R2a is: fluorine; fluorine-substituted cyclobutyl; methyl-substituted pyrazolyl; or -S(O)2CH3.

[00355] Embodiment 15. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl optionally substituted by -OR3.

[00356] Embodiment 16. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl optionally substituted by -OR3, and R3 is: hydrogen; C1-C6 alkyl optionally substituted by halogen; C3-C6 cycloalkyl optionally substituted by halogen; C6-C14 aryl optionally substituted by halogen; or 5- to 6-membered heteroaryl optionally substituted by halogen or C1-C6 alkyl.

[00357] Embodiment 17. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl optionally substituted by -OR3, and R3 is: hydrogen; methyl; ethyl; difluoromethyl; -CH2CHF2; -CH2CF3; fluorosubstituted cyclopropyl; phenyl optionally substituted by fluorine; or pyridinyl optionally substituted by fluorine or methyl.

[00358] Embodiment 18. The compound of any one of embodiments 1 through 11, wherein R2 is -CH2CH2OCH3.

[00359] Embodiment 19. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl substituted by halogen and OR3, wherein R3 is C1-C6 alkyl.

[00360] Embodiment 20. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C3-C6 cycloalkyl optionally substituted by R2b.

[00361] Embodiment 21. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is cyclopropyl.

[00362] Embodiment 22. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R1is , where m is 0, 1, 2 or 3 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are, independently, optionally substituted by deuterium.

[00363] Embodiment 23. The compound of embodiment 22, or a salt thereof, wherein R1is pending, deuterium, alkyl, haloalkyl or heteroaryl.

[00364] Embodiment 24. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R1 is or -L , where m is 0, 1, 2 or 3 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are, independently, optionally substituted by deuterium.

[00365] Embodiment 25. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R1 is where m is 0, 1, 2, 3, 4 or 5 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are, independently, optionally substituted by deuterium.

[00366] Embodiment 26. The compound of embodiment 25, or a salt thereof, wherein R1 where each R1a is independently deuterium, halogen, alkyl, haloalkyl, or alkoxy.

[00367] Embodiment 27. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R1 is J , or JL , where m is 0, 1, 2, 3, 4 or 5 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are, independently, optionally substituted by deuterium.

[00368] Embodiment 28. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R1 is , where m is 0, 1, 2, 3 or 4, and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are, independently, optionally substituted by deuterium.

[00369] Embodiment 29. The compound of embodiment 28, or a salt thereof, wherein R1 is selected from the group consisting of

[00370] Embodiment 30. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R1 is m where m is 0, 1, 2, 3 or 4, and each R1ais, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1aare, independently, optionally substituted by deuterium.

[00371] Embodiment 31. The compound of embodiment 30, or a salt thereof, wherein R1 is selected from the group consisting of

[00372] Embodiment 32. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R1 is where m is 0, 1, 2, 3 or 4, and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are, independently, optionally substituted by deuterium.

[00373] Embodiment 33. The compound of embodiment 32, or a salt thereof, wherein R1 is selected from the group consisting of

[00374] Embodiment 34. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R1 is , where m is 0, 1, 2, 3, 4, 5 or 6 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are, independently, optionally substituted by deuterium.

[00375] Embodiment 35. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R1is , where m is 0, 1, 2, 3, 4, 5 or 6 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are, independently, optionally substituted by deuterium.

[00376] Embodiment 36. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R1 is , where m is 0, 1 or 2 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are, independently, optionally substituted by deuterium.

[00377] Embodiment 37. The compound of embodiment 1, 2 or 3, or a salt thereof, wherein R1 is selected from the group consisting of , and any of the preceding groups in which any one or more hydrogen atoms are replaced by an atom (or atoms) of deuterium.

[00378] Embodiment 38. The compound of embodiment 1, 2 or 3, or a salt thereof, wherein R1 is selected from the group consisting of -L-, and any of the preceding groups in which any one or more hydrogen atoms are replaced by an atom (or atoms) of deuterium.

[00379] Embodiment 39. The compound of embodiment 1, 2 or 3, or a salt thereof, wherein R1 is selected from the group consisting of and any of the preceding groups in which any one or more hydrogen atoms are replaced by an atom (or atoms) of deuterium.

[00380] Embodiment 40. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 wherein n is 1, 2, 3, 4, 5 or 6, and R3 is C1-C2 alkyl optionally substituted by fluorine; phenyl optionally substituted by fluorine; pyridinyl optionally substituted by fluorine or methyl; or cyclopropyl optionally substituted by fluorine.

[00381] Embodiment 41. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R2 is selected from the group consisting of and any of the preceding groups in which any one or more hydrogen atoms are replaced by an atom (or atoms) of deuterium.

[00382] Embodiment 42. A compound, or a salt thereof, selected from Compounds Nos. 1-66 in Figure 1.

[00383] Embodiment 43. A compound, or a salt thereof, selected from Compound Nos. 1-147.

[00384] Embodiment 44. A compound, or a salt thereof, selected from Compound Nos. 1-665.

[00385] 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.

[00386] Embodiment 46. A method of treating a fibrotic disease in a subject in need thereof comprising administering a compound of any one of embodiments 1 to 44, or a pharmaceutically acceptable salt thereof.

[00387] Embodiment 47. The method of embodiment 46, wherein the fibrotic disease is pulmonary fibrosis, hepatic fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis.

[00388] Embodiment 48. A kit comprising a compound of any one of embodiments 1 to 44, or a pharmaceutically acceptable salt thereof.

[00389] Embodiment 49. The kit of embodiment 48, further comprising instructions for treating a fibrotic disease.

[00390] Embodiment 50. A method of inhibiting αvβ6 integrin in a subject comprising administering a compound of any one of embodiments 1 to 44, or a pharmaceutically acceptable salt thereof.

[00391] Embodiment 51. A method of 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.

[00392] 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 the treatment of a fibrotic disease.

[00393] Embodiment 53. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C3-C5 alkyl substituted by fluorine and -OCH3.

[00394] Embodiment 54. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl optionally substituted by -OR3 and R3 is phenyl optionally substituted by fluorine.

[00395] Embodiment 55. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl optionally substituted by -OR3 and R3 is pyridinyl optionally substituted by fluorine or methyl.

[00396] Embodiment 56. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl substituted by R2a, wherein R2a is halogen.

[00397] Embodiment 57. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl substituted by R2a, wherein R2a is deuterium.

[00398] Embodiment 58. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl substituted by R2a, wherein R2a is a 3- to 12-membered heterocyclyl optionally substituted by oxo.

[00399] Embodiment 59. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl substituted by R2a, wherein R2a is a 4- to 5-membered heterocyclyl optionally substituted by oxo.

[00400] Embodiment 60. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl substituted by R2a, wherein R2a is C6-C14 aryl optionally substituted by halogen or -OR6.

[00401] Embodiment 61. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl substituted by R2a, wherein R2a is phenyl optionally substituted by halogen or -OR6.

[00402] Embodiment 62. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl substituted by R2a, wherein R2a is a 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl.

[00403] Embodiment 63. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl substituted by R2a, wherein R2a is pyrazolyl optionally substituted by methyl.

[00404] Embodiment 64. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl substituted by R2a, wherein R2a is C3-C8 cycloalkyl optionally substituted by -CN, halogen, or -OR6.

[00405] Embodiment 65. The compound of any one of embodiments 1 to 11, or a salt thereof, wherein R2 is C1-C6 alkyl substituted by R2a, wherein R2a is -S(O)2R3.

[00406] Embodiment 66. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R1 is pyridyl optionally substituted by R1a.

[00407] Embodiment 67. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R1 is indazolyl optionally substituted by R1a.

[00408] Embodiment 68. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R1 is 1H-pyrrolopyridyl optionally substituted by R1a.

[00409] Embodiment 69. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R1 is quinolinyl optionally substituted by R1a.

[00410] Embodiment 70. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R1 is phenyl optionally substituted by R1a.

[00411] Embodiment 71. The compound of embodiment 1, 2, or 3, or a salt thereof, wherein R1 is indanyl optionally substituted by R1a.

SYNTHETIC EXAMPLES

[00412] The chemical reactions in the Synthetic Examples described can be readily adapted to prepare a number of other compounds of the invention, and alternative methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully accomplished by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art in addition to those described, or by making routine modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability to preparing other compounds of the invention.

[00413] For the examples described herein, reference to a General Procedure indicates that the reaction was prepared using reaction conditions and parameters similar to those in the General Procedures stated above.

PROCEDURES

[00414] The compounds provided herein may be prepared according to the Schemes as exemplified by the Procedures and Examples. Minor variations in temperatures, concentrations, reaction times, and other parameters may be made in following the procedures which do not substantially affect the results of the procedures. PROCEDURE A

[00415] 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 CH2Cl2 (80 mL) at room temperature was added DIPEA (13.57 mL, 77.9 mmol). To this was then added HATU (8.1 g, 21.42 mmol) and the resulting mixture was stirred at room temperature for 2 h. 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. PROCEDURE B

[00416] 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 4:1 THF/DMF (5 mL) was added HATU (844 mg, 2.22 mmol) followed by DIPEA (0.89 mL, 5.13 mmol) and the reaction was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated in vacuo and purified by normal phase chromatography on silica gel to give N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide. PROCEDURE C

[00417] 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. °C for 18 h. The reaction mixture was allowed to cool to room temperature and 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. PROCEDURE D

[00418] 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 borane tetrahydrofuran complex solution (1.0 M in THF, 4.0 mL, 4.0 mmol) dropwise. The resulting mixture was then heated at 60 °C for 2 h 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 chromatography on silica gel to give N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. PROCEDURE AND

[00419] 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 Li-AlH4 (1.0 M in THF, 123 mL, 2.2 equiv) and the resulting mixture was heated at reflux for 20 h and then cooled to 0 °C. To this solution was added H2O (4.7 ml), followed by 1 M NaOH (4.7 ml), then H2O (4.7 ml) and warmed to room temperature and stirred for 30 min, at which time solid MgSO4 was added and stirred for an additional 30 min. 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. PROCEDURE F

[00420] 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 methyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (217 mg, 0.94 mmol). The resulting mixture was allowed to stir at room temperature for 15 min, at which time, sodium cyanoborohydride (80 mg, 1.28 mmol) was added to the reaction mixture and stirred for 30 min and then concentrated in vacuo. The crude residue was purified by normal phase chromatography on silica gel to afford methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. PROCEDURE G

[00421] 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 CH2Cl2 (2 mL) at room temperature was added 4 N HCl in 1,4-dioxane (1 mL, 4 mmol) and the resulting mixture was allowed to stir for 2 h. 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. PROCEDURE H

[00422] A solution of methyl (S)-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 chromatography on silica gel 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. PROCEDURE P

[00423] (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 4:1:1 THF/MeOH/H2O was added lithium hydroxide at room temperature (about four equivalents) and the resulting mixture was stirred for 30 min. The reaction mixture was concentrated in vacuo and the resulting crude residue purified by reversed-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. PROCEDURE Q

[00424] (S)-2-(((benzyloxy)carbonyl)amino acid)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1, 8-naphthyridin-2-yl)butyl)amino)butanoic acid. A mixture of (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 H2O (3 ml) and THF (3 ml) and MeOH (3 ml) was added LiOH • H2O (159.36 mg, 3.80 mmol) and then the mixture was stirred at room temperature for 1 h and the resulting mixture was concentrated in vacuo. The mixture was adjusted to pH = 6 by AcOH (2 ml) and the residue was concentrated in vacuo to give a residue to yield the compound (S)-2-(((benzyloxy)carbonyl)amino)-4-ylamino acid. -(((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)+.1H 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, 6.06 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). PROCEDURE R

[00425] 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: 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 for 18 h at 55 °C 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 prep-TLC to afford 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)+. PROCEDURE S

[00426] 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)2 (26 mg) under a N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (1.034 bar (15 psi)) at room temperature for 15 h. The mixture was filtered and concentrated in vacuo to afford 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)+. 1H 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 = 6.11 Hz, 3 H). PROCEDURE T

[00427] (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- tert-butyl 2-((5-methylpyrimidin-2-yl)amino)butanoate. To a solution of 2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl))butyl)amino )(S)-tert-butyl butanoate and (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) tert-butyl 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]-methylsulfonyloxypalladium; ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (15.23 mg, 19.17 μmol), and the resulting mixture was stirred at 100 °C for 14 h. The mixture was concentrated in vacuo to give 4-(((S)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin (S)-tert-Butyl (2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate. LCMS (ESI+): m/z = 527.3 (M+H )+. PROCEDURE U

[00428] (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 h. The mixture was concentrated in vacuo and the resulting crude residue was purified by preparative HPLC to furnish 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)+. 1H 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, 3 H) 1.76 - 1.99 (m, 6 H) 1.22 (d, J = 5.95 Hz, 3 H).

SYNTHETIC EXAMPLES

[00429] The chemical reactions in the Synthetic Examples described may be readily adapted to prepare a number of other compounds of the invention, and alternative methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully accomplished by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art than those described, or by making routine modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability to preparing other compounds of the invention.

[00430] For the examples described herein, reference to a Procedure indicates that the reaction was prepared using reaction conditions and parameters similar to the Procedures stated above. EXAMPLE A1 Synthesis of (s)-2-fluoro-3-methoxypropan-1-amine

[00431] Methyl dibenzyl-D-serinate. To a mixture of methyl D-serinate hydrochloride (100 g, 642.76 mmol) and 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 lx 3). The organic layer was washed with brine (1 L), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by normal phase chromatography on silica gel to give methyl dibenzyl-D-serinate.

[00432] 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 for 14 h at rt. The reaction mixture was quenched with saturated aqueous NaHCO3 solution (1 L) at 0 °C and extracted with EtOAc (500 ml x 3). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by normal phase chromatography on silica gel to afford methyl (S)-3-(dibenzylamino)-2-fluoropropanoate.

[00433] (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 LiBH4 (14.89 g, 683.58 mmol) at 0 °C. The mixture was stirred at 40 °C for 12 h. The mixture was poured into aqueous NH4Cl solution (500 mL) at 0 °C. The aqueous phase was extracted with ethyl acetate (300 mL x 3). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford (S)-3-(dibenzylamino)-2-fluoropropan-1-ol which was used without further purification.

[00434] (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) was added NaH (60% dispersion in mineral oil, 11.19 g, 279.87 mmol)) at 0 °C and the resulting mixture was stirred at 0 °C for 30 min. To this was then added iodomethane (18.58 mL, 298.52 mmol) and the mixture was stirred at room temperature for 12 h. The mixture was quenched with aqueous NH4Cl solution (500 mL) at 0 °C. The aqueous phase was extracted with EtOAc (500 mL x 3). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude residue was purified by normal phase chromatography on silica gel to afford (S)-N,N-dibenzyl-2-fluoro-3-methoxypropan-1-amine.

[00435] (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 (3.44 bar (50 psi)) at 50 °C for 12 h. The reaction mixture was filtered through a pad of Celite 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. EXAMPLE A2 Synthesis of tert-butyl 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

[00436] 7-(4-ethoxy-4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-tert-butyl carboxylate. For 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 (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 h, the reaction was diluted with EtOAc (50 ml) and quenched with saturated NH4Cl solution (50 ml). After 30 min of stirring, the layers were separated and the organic layer was washed with brine (20 ml), dried over Na2SO4, and concentrated -se in vacuo. The resulting crude residue was purified by normal phase chromatography on silica gel to provide 7-(4-ethoxy-4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-tert-butyl carboxylate.

[00437] 7-(4-hydroxybutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- tert-butyl carboxylate. To a solution of 7-(4-ethoxy-4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- tert-butyl carboxylate (6.81 g, 19.5 mmol) in THF (50 mL) was added LiBH4 (1.0 M in THF, 19.5 mL, 19.5 mmol) at room temperature. The mixture was stirred overnight and then quenched with saturated NH4Cl solution and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by normal phase chromatography on silica gel to give tert-butyl 7-(4-hydroxybutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate.

[00438] 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 CH2Cl2 (69 mL) was cooled to -78 °C for 5 min, at which time dimethyl sulfoxide (4.2 mL, 58.6 mmol) was added and the mixture was stirred for 30 min. A solution of tert-butyl 7-(4-hydroxybutyl)-3,4-dihydro- 2H-1,8-naphthyridine-1-carboxylate (6.9 g, 22.6 mmol) in CH2Cl2 (10.5 mL) was added and stirred at -78 °C for 1 h. Triethylamine (10.5 mL, 75.1 mmol) was then added to the reaction mixture and stirred for 30 min. The reaction was quenched with water and extracted with CH2Cl2. The organic layer was collected and dried over sodium sulfate. The organic layer was concentrated to give tert-butyl 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate which was used without further purification. EXAMPLE A3 Synthesis of methyl (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinolin-4-ylamino)butanoate

[00439] 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 Procedure A with 2-methoxyethylamine, then Procedure E, Procedure F, and Procedure G to afford methyl (S)-2-amino-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate.

[00440] (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinolin Methyl -4-ylamino)butanoate. A microwave vial containing (S)-2-amino-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Methyl)butyl)amino)butanoate (125 mg, 0.3 mmol) was charged with 4-bromoquinoline (65 mg, 0.3 mmol), Pd(OAc)2 (6.3 mg, 0.03 mmol), rac -BINAP (35 mg, 0.6 mmol) and K3PO4 (210 mg, 1.0 mmol) and then diluted with dioxane (2 mL). The mixture was degassed and then sealed and heated at 100 °C for 1 h. The The reaction mixture was allowed to cool to room temperature and then filtered and concentrated in vacuo. The crude residue was purified by normal phase chromatography on silica gel to give (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin- Methyl (2-yl)butyl)amino)-2-(quinolin-4-ylamino)butanoate. EXAMPLE A4 Synthesis of (S)-2-(isoquinolin-1-ylamino)-4-((2-methoxyethyl)(4 -methyl(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate

[00441] (S)-2-(isoquinolin-1-ylamino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl methyl)butyl)amino)butanoate. A microwave vial containing (S)-2-amino-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Methyl)butyl)amino)butanoate (125 mg, 0.3 mmol) was charged with 1-bromoisoquinoline (65 mg, 0.3 mmol), Pd(OAc)2 (6.3 mg, 0.03 mmol), rac -BINAP (35 mg, 0.6 mmol) and K3PO4 (210 mg, 1.0 mmol) and then diluted with dioxane (2 mL). The mixture was degassed and then sealed and heated at 100 °C for 1 h. The The reaction mixture was allowed to cool to room temperature and then filtered and concentrated in vacuo. The crude residue was purified by normal phase chromatography on silica gel to give (S)-2-(isoquinolin-1-ylamino)-4-((2-methoxyethyl)(4-(5,6,7,8- methyl tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate.

[00442] In the following examples, compounds without specific synthetic descriptions can be synthesized by procedures described herein, e.g., analogous to compound 2, Scheme 1; compound 81, Scheme 5; and compound 213, Scheme 24.

[00443] 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 slight modification of the procedures of Scheme 1. In step 1, 2-(3,5-difluorophenoxy)ethan-1-amine can be replaced by cyclopropylamine which can provide the analogous amine product. The amine product can then undergo a Boc deprotection as in step 2 followed by a reductive amination as in step 3 to provide an analogous tertiary amine product. This tertiary amine can then undergo base-mediated hydrolysis as in step 4 followed by deprotection of the benzyl carbamate under reductive conditions as in step 5 to provide an analogous amino acid product. This amino acid can then be reacted with a suitably activated heterocycle in an SNAr reaction, such as 3-chloropyrazine-2-carbonitrile to provide the described compound. Likewise, the analogous free amino acid product from step 5 can be reacted with an analogous activated heterocycle as depicted in step 6 and then subjected to reducing conditions as shown in step 7 of Scheme 1 or cross-coupling conditions as shown in step 2 of Scheme 5 to provide further described prophetic compounds.

[00444] The tertiary amine products arising from step 3 in Scheme 1, if alternative amines have been substituted for cyclopropylamine, may alternatively be hydrolyzed as depicted in step 1 of Scheme 24 followed by t-butylation of the acid product with t-butyl bromide under basic conditions as shown in step 2 of Scheme 24. The resulting t-butyl ester product may be deprotected under reductive conditions as in step 3 of Scheme 24 to afford an amino ester product, which may then undergo palladium-catalyzed cross-coupling with an appropriate aryl or heteroaryl halide as in step 4 of Scheme 24 to afford an ester product that may be exposed to acid to generate a final compound as in step 5 of Scheme 24.

[00445] 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 slight modification of the procedures of Scheme 1. In step 1, 2-(3,5-difluorophenoxy)ethan-1-amine can be replaced by cyclopropylamine, which would provide the analogous amine product. This amine product can then undergo a Boc deprotection as in step 2 followed by a reductive amination as in step 3 to provide an analogous tertiary amine product. The tertiary amine product can be hydrolyzed as depicted in step 1 of Scheme 24 followed by t-butylation of the acid product 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 afford an amino ester product, which can then undergo palladium-catalyzed cross-coupling by substituting 3-bromo-1-methyl-1H-indazole for 6-chloro-N,N-dimethylpyrimidin-4-amine in step 4 of Scheme 24 to afford an ester product that can be exposed to acid to afford the described compound.

[00446] 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]+, found 475.2.

[00447] 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]+, found 475.2. SCHEME 1, COMPOUND 2:

[00448] 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 NaBH3CN (4.13 g, 65.7 mmol) in MeOH (100 mL) at 0 °C was added a solution of 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-tert-butyl carboxylate (10.0 g, 32.9 mmol) in MeOH (100 mL) and the resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated NaHCO3 solution and stirred until gas evolution ceased and 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. Theoretical LCMS m/z = 346.3. [M+H]+, found 346.5.

[00449] 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-naphthyridin-1(2H)-carboxylate (2.5 g, 7.24 mmol) in EtOAc (10 mL) was added 4 M HCl in EtOAc (1.8 mL) and the resulting mixture was stirred at room temperature for 12 h and then concentrated in vacuo. The crude residue was used without further purification. LCMS theoretical m/z = 246.2. [M+H]+, found 246.0.

[00450] Step 3: (S)-2-(((benzyloxy)carbonyl)amino)-4- (cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- methyl yl)butyl)amino)butanoate. To a mixture of methyl (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 (2.5 g, 8.9 mmol) in DCE (40 mL) was added AcOH (761 μL, 13.3 mmol) to 0 °C, NaBH(OAc)3 (2.82 g, 13.3 mmol) was added and the resulting mixture was stirred for 1 h at room temperature. The mixture was diluted with aqueous NaHCO3 solution and stirred until the evolution of gas and then extracted with CH2Cl2. The combined organic extracts were washed with brine and then dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by normal phase chromatography on silica gel to furnish the title compound. LCMS theoretical m/z = 495.3 . [M+H]+, found 495.4.

[00451] 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 1:1:1 THF/MeOH/H2O (36 mL) was added LiOH • H2O (664 mg, 15.8 mmol) at 0 °C and the resulting mixture was stirred at room temperature for 1 h. The mixture was then adjusted to pH = 6 by careful addition of 1 N HCl and then concentrated in vacuo to furnish the title compound. LCMS theoretical m/z = 480.3 [M]+, found 480.1.

[00452] Step 5: (S)-2-amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. A vial 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 charged with 20 wt % Pd(OH)2/C (4.5 g) and then diluted with i-PrOH (300 mL) and stirred under a H2 atmosphere at 3.44 bar (50 psi) for 48 h at rt. The reaction mixture was filtered through a pad of CELITE® and rinsed with MeOH and then concentrated in vacuo. The crude residue was purified by preparative reversed-phase HPLC to afford the title compound. LCMS theoretical m/z = 347.2. [M+H]+, found 347.2.

[00453] Step 6: (S)-2-((5-bromopyrimidin-4-yl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-) acid 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 4:1 THF/H2O (3 ml) was added 5-bromo-4-chloro-pyrimidine (69 mg, 0.4 mmol) and NaHCO3 (137 mg, 1.63 mmol ) and then stirred at 70 °C for 2 h and then cooled to room temperature and concentrated in vacuo. The crude residue was used without further purification.

[00454] Step 7: (S)-4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid. A vial 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 charged with 20 wt % Pd/C (200 mg) and then diluted with MeOH (20 mL) and the resulting mixture was stirred at room temperature under an atmosphere of H2 for 4 h and then filtered and concentrated in vacuo. The crude residue was purified by preparative reversed-phase HPLC to furnish 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 (t br, 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]+, found 425.2.

[00455] Compound 3: (S)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(( 1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid. For 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 4:1 THF/H2O (2.5 ml) was added 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (75 mg, 0.4 mmol) and NaHCO3 (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 HPLC reverse phase to furnish the title compound as the trifluoroacetate 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]+, found 479.2.

[00456] 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.

[00457] 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.

[00458] 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.

[00459] 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.

[00460] Compound 8: (S)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazoline-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.

[00461] Compound 9: (S)-4-((3,3-Difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazoline-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.

[00462] 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.

[00463] 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.

[00464] 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.

[00465] 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.

[00466] 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]+, found 561.3.

[00467] 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.

[00468] 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.

[00469] 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-methoxyethan-1-amine, Procedure H with 4-chloropyrido[3,4-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 494.3. [M+H]+, found 494.3.

[00470] Compound 18: (S)-2-((5-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-5-fluoroquinazoline, and Procedure P. LCMS theoretical m/z = 511.3. [M+H]+, found 511.3.

[00471] Compound 19: (S)-2-((6-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-6-fluoroquinazoline, and Procedure P. LCMS theoretical m/z = 511.3. [M+H]+, found 511.3.

[00472] Compound 20: (S)-2-((8-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-8-fluoroquinazoline, and Procedure P. LCMS theoretical m/z = 511.3. [M+H]+, found 511.3.

[00473] Compound 21: (S)-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. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 4-chloro-6,7-difluoroquinazoline, and Procedure P. LCMS theoretical m/z = 529.3. [M+H]+, found 529.3.

[00474] Compound 22: (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)butanoic acid. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 4-chloro-2-methyl-6-(trifluoromethyl)pyrimidine, and Procedure P. LCMS theoretical m/z = 525.3. [M+H]+, found 525.3.

[00475] Compound 23: (S)-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. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 4-chloro-6-(difluoromethyl)pyrimidine, and Procedure P. LCMS theoretical m/z = 493.3. [M+H]+, found 493.3.

[00476] Compound 24: (S)-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. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 4-chloro-2-(trifluoromethyl)pyrimidine, and Procedure P. LCMS theoretical m/z = 511.3. [M+H]+, found 511.3.

[00477] Compound 25: (S)-4-(((S)-2-methoxypropyl)(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-(S)-2-methoxypropan-1-amine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 507.3. [M+H]+, found 507.4.

[00478] Compound 26: (S)-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. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 4-chloro-6-methyl-2-(trifluoromethyl)pyrimidine, and Procedure P. LCMS theoretical m/z = 525.3. [M+H]+, found 525.3.

[00479] Compound 27: (S)-4-((2-(methylsulfonyl)ethyl)(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-(methylsulfonyl)ethan-1-amine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 541.3. [M+H]+, found 541.3.

[00480] Compound 28: (S)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme D using Procedure C with (2-bromoethoxy)benzene, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 555.3. [M+H]+, found 555.3.

[00481] Compound 29: (S)-4-((3,3-difluoropropyl)(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-difluoropropan-1-amine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 513.3. [M+H]+, found 513.4.

[00482] Compound 30: (S)-4-((3-fluoropropyl)(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 2-3-fluoropropan-1-amine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 495.3. [M+H]+, found 495.3.

[00483] Compound 31: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(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 (S)-2-fluoro-3-methoxypropan-1-amine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 525.3. [M+H]+, found 525.3.

[00484] Compound 32: (S)-2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with (S)-2-fluoro-3-methoxypropan-1-amine, Procedure H with 4-chloro-7-fluoro-2-methylquinazoline, and Procedure P. LCMS theoretical m/z = 557.3. [M+H]+, found 557.4.

[00485] Compound 33: (S)-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. Prepared according to Scheme D using Procedure C with 3-(bromomethyl)-1,1-difluorocyclobutane, Procedure H with 4-chloro-7-fluoro-2-methylquinazoline, and Procedure P. LCMS theoretical m/z = 571.3. [M+H]+, found 571.3. SCHEME 2, COMPOUND 34:

[00486] Step 1: N-(2-Methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide. To a solution of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanoic acid hydrochloride (2.6 g, 10.29 mmol) in CH2Cl2 (26 mL) was added 2-methoxyethan-1-amine (1.3 mL, 15.44 mmol), DIPEA (5.4 mL, 30.87 mmol), then HATU (5.67 g, 14.92 mmol) and the resulting mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The resulting crude residue was purified using normal phase chromatography on silica gel to furnish the title compound.

[00487] Step 2: N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. To a solution of N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide (1.1 g, 4.0 mmol) in 1,4-dioxane (11 mL) was added 2.0 M LiAlH4 in THF (4 mL, 8.0 mmol) and the resulting mixture was refluxed overnight and then allowed to cool to room temperature. The solution was carefully neutralized by cautious addition of H2O (310 μl), followed by 1 N NaOH (310 μl), then additional H2O (310 μl) and the mixture was stirred at room temperature for 30 min and then dried over MgSO4, filtered and concentrated in vacuo. The resulting crude residue was used without further purification.

[00488] Step 3: (S)-2-((tert-butoxycarbonyl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin Methyl -2- yl)butyl)amino)butanoate. To a solution of N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (927 mg, 3.52 mmol ) and methyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (895 mg, 3.87 mmol) in MeOH (10 ml) at room temperature was added AcOH (222 μl, 3.87 mmol), then NaCNBHβ (243 mg, 3.87 mmol) and the resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The resulting crude residue was purified by normal phase chromatography on silica gel to provide the title compound.

[00489] Step 4: Methyl (S)-2-amino-4-((2-methoxyethyl)(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-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (700 mg, 1.46 mmol) in CH2Cl2 (3 mL) was added 4 N HCl in dioxane (5 mL) and the resulting mixture was stirred at room temperature for 2 h and concentrated in vacuo. The resulting crude residue was used without further purification.

[00490] Step 5: (S)-2-(isoquinolin-1-ylamino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin- Methyl 2-yl)butyl)amino)butanoate. A microwave vial containing (S)-2-amino-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Methyl)butyl)amino)butanoate (125 mg, 0.3 mmol) was charged with 1-bromoisoquinoline (65 mg, 0.3 mmol), Pd(OAc)2 (6.3 mg, 0.03 mmol), rac -BINAP (35 mg, 0.6 mmol) and K3PO4 (210 mg, 1.0 mmol) and then diluted with dioxane (2 mL). The mixture was degassed and then sealed and heated at 100 °C for 1 h. The The reaction mixture was allowed to cool to room temperature and then filtered and concentrated in vacuo. The crude residue was purified by normal phase chromatography on silica gel to furnish the title compound.

[00491] Step 6: (S)-2-(isoquinolin-1-ylamino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a solution of methyl (S)-2-(isoquinolin-1-ylamino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (20 mg, 0.04 mmol) in 4:1:1 THF/MeOH/H2O (1.5 mL) was added LiOH (5 mg, 0.20 mmol) and the resulting mixture was stirred at room temperature for 1 h and then neutralized with AcOH and concentrated in vacuo. The crude residue was purified by preparative reversed-phase HPLC to furnish the title compound. LCMS theoretical m/z = 492.3. [M+H]+, found 492.4.

[00492] Compound 35: (S)-4-((2-(difluoromethoxy)ethyl)(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-(difluoromethoxy)ethan-1-amine, Procedure D, Procedure F, Procedure G, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 529.3. [M+H]+, found 529.3. SCHEME 3, COMPOUND 36:

[00493] Step 1: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2 -(methylquinolin-4-ylamino)butanoate. A microwave vial containing (S)-2-amino-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Methyl (butyl)amino)butanoate (125 mg, 0.3 mmol) was loaded with 4-bromoquinoline (65 mg, 0.3 mmol), Pd(OAc)2 (6 mg, 0.03 mmol), rac-BINAP (35 mg, 0.6 mmol) and K3PO4 (210 mg, 1.0 mmol) and then diluted with dioxane (2 mL). The mixture was degassed and then sealed and heated at 100 °C for 1 h. The mixture of reaction was cooled to room temperature and then filtered and concentrated in vacuo. The crude residue was purified by normal phase chromatography on silica gel to give (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin- Methyl 2-(2-yl)butyl)amino)-2-(quinolin-4-ylamino)butanoate.

[00494] Step 2: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinolin-4-ylamino)butanoic acid. To a solution of methyl (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinolin-4-ylamino)butanoate (54 mg, 0.11 mmol) in 4:1:1 THF/MeOH/H2O (3 mL) was added Li-OH (25.5 mg, 1.1 mmol) and the resulting mixture was stirred at room temperature for 1 h and then neutralized with AcOH and concentrated in vacuo. The resulting crude residue was purified by preparative reversed-phase HPLC to furnish the title compound. LCMS theoretical m/z = 492.3. [M+H]+, found 492.3.

[00495] Compound 37: (S)-2-((7-chloroquinazolin-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-methoxyethane-1-amine, Procedure H with 4,7-dichloroquinazoline, and Procedure P. Theoretical LCMS m/z = 527.3. [M+H]+, found 527.3.

[00496] Compound 38: (S)-2-((8-chloroquinazolin-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-methoxyethane-1-amine, Procedure H with 4,8-dichloroquinazoline, and Procedure P. Theoretical LCMS m/z = 527.3. [M+H]+, found 527.3.

[00497] Compound 39: (S)-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. Prepared according to Scheme A using Procedure A with 2-(2,2,2-trifluoroethoxy)ethan-1-amine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 561.3. [M+H]+, found 561.3.

[00498] Compound 40: (S)-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. Prepared according to Scheme D using Procedure C with 1-(2-bromoethoxy)-4-fluorobenzene, Procedure H with 4-chloro-7-fluoro-2-methylquinazoline, and Procedure P. LCMS theoretical m/z = 605.3. [M+H]+, found 605.3.

[00499] Compound 41: (S)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-methoxyquinazolin-4-yl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with 3-fluoropropan-1-amine, Procedure H with 4-chloro-7-methoxyquinazoline, and Procedure P. LCMS theoretical m/z = 525.3. [M+H]+, found 525.3.

[00500] Compound 42: (2S)-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. Prepared according to Scheme D using Procedure C with 2-(2-bromoethoxy)-1,1-difluorocyclopropane, Procedure H with 4-chloro-7-fluoro-2-methylquinazoline, and Procedure P. LCMS theoretical m/z = 587.3. [M+H]+, found 587.3.

[00501] Compound 43: (S)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((8-methoxyquinazolin-4-yl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with 3-fluoropropan-1-amine, Procedure H with 4-chloro-8-methoxyquinazoline, and Procedure P. LCMS theoretical m/z = 525.3. [M+H]+, found 525.3.

[00502] Compound 44: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-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-6-(1H-pyrazol-1-yl)pyrimidine, and Procedure P. Theoretical LCMS m/z = 509.3. [M+H]+, found 509.3.

[00503] Compound 45: (S)-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. Prepared according to Scheme D using Procedure C with 1-(2-bromoethyl)-3,5-dimethyl-1H-pyrazole, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 557.3. [M+H]+, found 557.3.

[00504] Compound 46: (S)-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. Prepared according to Scheme A using Procedure A with (S)-2-fluoro-3-methoxypropan-1-amine, Procedure H with 4-chloro-2-methylquinazoline, and Procedure P. LCMS theoretical m/z = 539.3. [M+H]+, found 539.3.

[00505] Compound 47: (S)-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. Prepared according to Scheme C using Procedure B with 2-(3,5-difluorophenoxy)acetic acid, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 591.3. [M+H]+, found 591.3.

[00506] Compound 48: (S)-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. Prepared according to Scheme C using Procedure B with 2-(pyridin-2-yloxy)acetic acid, Procedure H with 4,8-dichloroquinazoline, and Procedure P. LCMS theoretical m/z = 590.3. [M+H]+, found 590.3.

[00507] Compound 49: (S)-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. Prepared according to Scheme C using Procedure B with 2-(pyridin-2-yloxy)acetic acid, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 556.3. [M+H]+, found 556.3.

[00508] Compound 50: (S)-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. Prepared according to Scheme C using Procedure B with 2-(2,2-difluoroethoxy)acetic acid, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 543.3. [M+H]+, found 543.3.

[00509] Compound 51: (S)-2-(Pyrid[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. Prepared according to Scheme A using Procedure A with 2-(2,2,2-trifluoroethoxy)ethan-1-amine, Procedure G, Procedure H with 4-chloropyrido[3,2-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 562.3. [M+H]+, found 562.3.

[00510] Compound 52: (S)-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. Prepared according to Scheme C using Procedure B with 2-((2-methylpyridin-3-yl)oxy)acetic acid, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 570.3. [M+H]+, found 570.3.

[00511] Compound 53: (S)-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. Prepared according to Scheme C using Procedure B with 2-((2-methylpyridin-3-yl)oxy)acetic acid, Procedure H with 4-chloro-7-fluoro-2-methylquinazoline, and Procedure P. LCMS theoretical m/z = 602.3. [M+H]+, found 602.3.

[00512] Compound 54: (S)-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. Prepared according to Scheme C using Procedure B with 2-((2-methylpyridin-3-yl)oxy)acetic acid, Procedure H with 4-chloropyrido[3,2-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 571.3. [M+H]+, found 571.3.

[00513] Compound 55: (S)-4-((2-ethoxyethyl)(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-ethoxyethan-1-amine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 507.3. [M+H]+, found 507.3.

[00514] Compound 56: (S)-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. Prepared according to Scheme C using Procedure B with 2-((6-methylpyridin-3-yl)oxy)acetic acid, Procedure H with 4-chloro-7-fluoro-2-methylquinazoline, and Procedure P. LCMS theoretical m/z = 602.3. [M+H]+, found 602.3.

[00515] Compound 57: (S)-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. Prepared according to Scheme C using Procedure B with 2-((6-methylpyridin-3-yl)oxy)acetic acid, Procedure H with 4-chloropyrido[3,2-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 571.3. [M+H]+, found 571.3.

[00516] Compound 58: (S)-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. Prepared according to Scheme C using Procedure B with 2-((5-fluoropyridin-3-yl)oxy)acetic acid, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 574.3. [M+H]+ , 574.3.

[00517] Compound 59: (S)-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. Prepared according to Scheme C using Procedure B with 2-((6-methylpyridin-3-yl)oxy)acetic acid, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 570.3. [M+H]+, found 570.3.

[00518] Compound 60: (S)-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. Prepared according to Scheme C using Procedure B with 2-((5-fluoropyridin-3-yl)oxy)acetic acid, Procedure H with 4-chloropyrido[3,2-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 575.3. [M+H]+, found 575.3.

[00519] Compound 61: (S)-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. Prepared according to Scheme C using Procedure B with 2-((5-fluoropyridin-3-yl)oxy)acetic acid, Procedure H with 4-chloro-7-fluoro-2-methylquinazoline, and Procedure P. LCMS theoretical m/z = 606.3. [M+H]+, found 606.3.

[00520] Compound 62: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme C using Procedure B with (R)-2-methoxypropanoic acid, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 507.3. [M+H]+, found 507.3.

[00521] Compound 63: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with N-(2-aminoethyl)acetamide, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 520.3. [M+H]+, found 520.3.

[00522] Compound 64: (S)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with 2-amino-N,N-dimethylacetamide, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 520.3. [M+H]+, found 520.3.

[00523] Compound 65: (S)-2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. Prepared according to Scheme C using Procedure B with (R)-2-methoxypropanoic acid, Procedure H with 4-chloro-7-fluoro-2-methylquinazoline, and Procedure P. LCMS theoretical m/z = 539.3. [M+H]+, found 539.3.

[00524] Compound 66: (S)-4-(((R)-2-methoxypropyl)(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 C using Procedure B with (R)-2-methoxypropanoic acid, Procedure H with 4-chloro-2-methylquinazoline, and Procedure P. LCMS theoretical m/z = 521.3. [M+H]+, found 521.3.

[00525] Compound 67: (S)-2-((3-cyanopyrazin-2-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 3-chloropyrazine-2-carbonitrile, and Procedure P. LCMS theoretical m/z = 468.3. [M+H]+, found 468.3. SCHEME 4, COMPOUND 68:

[00526] Step 1: (R)-N-(2-methoxypropyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide. To a solution of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanoic acid hydrochloride (2.6 g, 10.29 mmol) in CH2Cl2 (26 mL) was added (R)-2-methoxypropan-1-amine (1.38 g, 15.44 mmol), DIPEA (5.4 mL, 30.87 mmol), then HATU (5.67 g, 14.92 mmol) and the resulting mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The resulting crude residue was purified using normal phase chromatography on silica gel to furnish the title compound.

[00527] Step 2: (R)-N-(2-methoxypropyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. To a solution of (R)-N-(2-methoxypropyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide (1.2 g, 4.0 mmol) in 1,4-dioxane (11 mL) was added 2.0 M LiAlH4 in THF (4 mL, 8.0 mmol) and the resulting mixture was refluxed overnight and then allowed to cool to room temperature. The solution was carefully neutralized by cautious addition of H2O (310 μl), followed by 1 N NaOH (310 μl), then additional H2O (310 μl) and the mixture was stirred at room temperature for 30 min and then dried over MgSO4, filtered and concentrated in vacuo. The resulting crude residue was used without further purification.

[00528] Step 3: (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro- Methyl 1,8-naphthyridin-2-yl)butyl)amino)butanoate: For a mixture of (R)-N-(2- methoxypropyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (10 g, 36.05 mmol) and (S)-2-( Methyl ((benzyloxy)carbonyl)amino)-4-oxobutanoate (10.52 g, 39.65 mmol) in 1,2-DCE (100 ml) at 0 °C AcOH (3.09 ml, 54.07 mmol) was added, then NaBH(OAc)3 (11.46 g, 54.07 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with MeOH and then concentrated in vacuo. The residue was taken up in CH2Cl2 and saturated aqueous NaHCO3 solution and then the layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude residue was purified by multiphase chromatography on silica gel to give the title compound. LCMS (ESI+): m/z = 527.5 (M+H)+.

[00529] Step 4: (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 (6 g, 11.39 mmol) in 1:1:1 THF/MeOH/H2O (60 mL) was added LiOH.H2O (956 mg, 22.78 mmol) and the resulting mixture was stirred at room temperature for 1 h. The mixture was then adjusted to pH = 6 by the addition of AcOH and then concentrated in vacuo to furnish the title compound as the acetate salt which was used without further purification. LCMS (ESI+): m/z = 513.2 (M+H)+.

[00530] Step 5: (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: 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 acetate (8 g, 13.97 mmol) in i-PrOH (50 mL) was added 20 wt % Pd(OH) 2 /C (1.96 g), and the resulting suspension was evacuated and filled with H 2 several times. The resulting mixture was stirred under an atmosphere of H2 at room temperature for 2 h, and then the mixture was filtered and concentrated under reduced pressure to furnish the title compound as the acetate salt, which was used without further purification. LCMS (ESI+): m/z = 379.2 (M+H)+.

[00531] Step 6: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a solution of (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid acetate (100 mg, 228 μmol) in 4:1 THF/H2O (2.5 mL) was added solid NaHCO3 (57 mg, 684 μmol) followed by 2-chloropyrimidine-5-carbonitrile (33 mg, 239 μmol). The resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature. The mixture was adjusted to pH = 6 by the addition of 1 M aqueous HCl solution and then concentrated in vacuo. The resulting crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 482.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.48 - 8.64 (m, 2 H) 7.21 (d, J = 7.28 Hz, 1 H) 6.42 (d, J = 7.28 Hz, 1 H) 4.41 (dd, J = 6.62, 4.85 Hz, 1 H) 3.71 (ddd, J = 9.26, 6.06, 3.20 Hz, 1 H) 3.36 - 3.41 (m, 2 H) 3.32 - 3.34 (m, 1 H) 3.33 (s, 2 H) 3.26 (br dd, J = 13.78, 6.73 Hz, 1 H) 3.02 - 3.12 (m, 2 H) 2.87 - 3.01 (m, 3 H) 2.71 (t, J = 6.06 Hz, 2 H) 2.59 (br t, J = 7.06 Hz, 2 H) 2.22 - 2.32 (m, 1 H) 2.06 - 2.16 (m, 1 H) 1.88 (dt, J = 11.52, 6.04 Hz, 2 H) 1.72 (br s, 4 H) 1.17 (d, J = 6.17 Hz, 3 H).

[00532] Compound 69: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid. (S)-2-Amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid acetate )amino)butanoic acid (100 mg, 228 μmol) in 4:1 THF/H2O (2.5 ml) was added solid NaHCO3 (38 mg, 456 μmol) followed by 2-chloro-5-(trifluoromethyl)pyrimidine (44 mg , 239.42 μmol). The resulting mixture was stirred at 70 °C for 1 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M HCl and then concentrated in vacuo. The resulting crude residue was purified by Reverse-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 525.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.72 - 10.42 (m, 1 H) 8.65 (s, 2 H) 8.05 - 8.33 (m, 2 H) 7, 59 (d, J = 7.34 Hz, 1 H) 6.62 (d, J = 7.34 Hz, 1 H) 4.57 (br s, 1 H) 3.88 (ddd, J = 8.99, 6.11, 3.12 Hz, 1 H) 3.45 (t, J = 5.56 Hz, 2 H) 3.24 - 3.38 (m, 4 H) 3.06 - 3.23 (m, 5 H) 2.69 - 2.80 (m, 4H) 2.23 - 2.43 (m, 3 H) 1.81 - 1.90 (m, 2 H) 1.70 - 1.80 (m, 4 H) 1.14 (d, J = 6.24 Hz, 3H).

[00533] Compound 70: (S)-2-((5-bromopyrimidin-2-yl)amino acid)-4- (((R)-2-methoxypropyl)(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. (S)-2-Amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid acetate )amino)butanoic acid (100 mg, 228 μmol) in 4:1 THF/H2O (2.5 ml) was added solid NaHCO3 (57 mg, 684 μmol) followed by 5-bromo-2-chloro-pyrimidine (46 mg, 239 μmol). The resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature. The mixture was adjusted to pH = 6 by the addition of 1 M aqueous HCl solution and then concentrated in vacuo. The crude residue resulting was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 535.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.47 - 8.55 (m, 2 H) 7.59 (d, J = 7.28 Hz, 1 H) 6.65 (d, J = 7.50 Hz, 1 H) 4.70 (dt, J = 8.49, 4.35 Hz, 1 H) 3.82 (br s, 1 H) 3.49 - 3.53 (m, 2 H) 3.37 (d, J = 12.13 Hz, 4 H) 3.13 - 3.29 (m, 4 H) 2.76 - 2.85 (m, 4 H) 2.41 - 2.51 (m, 2 H) 2.30 (br d, J = 10.80 Hz, 1 H) 1.90 - 2.00 (m, 2 H) 1.79 (br s, 4 H) 1.21 (t, J = 5.29 Hz, 3 H).

[00534] Compound 71: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-(((R)-2-methoxypropyl)(4-( 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. (S)-2-Amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid acetate )amino)butanoic acid (150 mg, 342 μmol) in 4:1 THF/H2O (2.5 ml) was added NaHCO3 (86 mg, 1.03 mmol) followed by 4-chloro-1H-pyrazolo[3,4- d]pyrimidine (56 mg, 359 μmol). The resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature. The mixture was adjusted to pH = 6 by the addition of 1 M aqueous HCl solution and then concentrated in vacuo. The resulting crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 497.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 14.34 (br s, 1 H) 9.83 - 10.11 (m, 1 H) 8.93 (br s, 1 H) 8.54 ( br s, 1 H) 8.11 (br s, 1 H) 7.60 (d, J = 7.28 Hz, 1 H) 6.63 (d, J = 7.50 Hz, 1 H) 4.93 (br s, 1 H) 3.88 (br s, 1 H) 3.42 (br s, 2 H ) 3.26 - 3.39 (m, 2 H) 3.24 (s, 3 H) 3.17 (br s, 4 H) 2.72 (br d, J = 5.95 Hz, 4 H) 2.42 (br s, 2 H) 1.64 - 1.86 (m, 6 H) 1.11 (d, J = 5.95 Hz, 3 H).

[00535] Compound 72: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid. (S)-2-Amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid acetate )amino)butanoic acid (100 mg, 228 μmol) in 4:1 THF/H2O (2.5 ml) was added NaHCO3 (57 mg, 684 μmol) followed by 4-chloro-2-(trifluoromethyl)pyrimidine (44 mg, 239 μmol). The resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature. The mixture was adjusted to pH = 6 by the addition of 1 M aqueous HCl solution and then concentrated in vacuo. The The resulting crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 525.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.27 (br d, J = 5.51 Hz, 1 H) 7.60 (d, J = 7.28 Hz, 1 H) 6.96 ( d, J = 6.39 Hz, 1 H) 6.65 (d, J = 7.28 Hz, 1 H) 4.86 (br s, 1 H) 3.82 (br d, J = 5.95 Hz, 1 H) 3.42 - 3.55 (m, 3 H) 3.37 (d, J = 8, 38 Hz, 4 H) 3.12 - 3.30 (m, 4 H) 2.72 - 2.86 (m, 4 H) 2.48 (dt, J = 11.85, 5.87 Hz, 1 H) 2.26 - 2.39 (m, 1 H) 1.95 (q, J = 5.90 Hz, 2 H) 1.73 - 1.90 (m , 4 H) 1.22 (dd, J = 6.06, 1.87 Hz, 3 H).

[00536] Compound 73: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((2-phenylpyrimidin-4-yl)amino)butanoic acid. (S)-2-Amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid acetate )amino)butanoic acid (150 mg, 342 μmol), 4-chloro-2-phenylpyrimidine (65 mg, 342 μmol) in DMA (2 ml) was added DIPEA (179 μl, 1.03 mmol) and the resulting mixture was shaken at 100 °C for 2 h. The mixture was cooled to room temperature and then adjusted to pH = 6 by 1 M aqueous HCl solution and then concentrated in vacuo. The resulting crude residue was purified by reversed-phase prep. HPLC to to provide the title compound. LCMS (ESI+): m/z = 533.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.24 (br d, J = 5.95 Hz, 2 H) 8.11 (br s, 1 H) 7.37 - 7.48 (m, 3 H) 7.16 (br d, J = 5.51 Hz, 1 H) 6.49 (br s, 1 H) 6.38 (d, J = 7.50 Hz, 1 H) 4.65 (br s, 1 H) 3.68 (br d, J = 5.95 Hz, 1 H) 3.36 (br s, 1 H) 3.23 - 3.30 (m, 5 H) 2.82 - 3.18 (m, 5 H) 2.52 - 2.69 (m, 4 H) 2.35 (br s, 1 H) 2.13 - 2.21 (m, 1 H) 1.62 - 1.86 (m, 6 H) 1.14 (d, J = 6.17 Hz , 3 H).

[00537] Compound 74: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid. (S)-2-Amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid acetate )amino)butanoic acid (100 mg, 228 μmol) in 4:1 THF/H2O (2.5 ml) was added NaHCO3 (57 mg, 684 μmol) followed by 4-chloro-1-methyl-pyrazolo[3,4- d]pyrimidine (40 mg, 239 μmol) and the resulting mixture was stirred at 70 °C for 1 h. The mixture was cooled to room temperature and then adjusted to pH = 6 by 1 M aqueous HCl solution and then concentrated in vacuo. The resulting crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 511.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.60 (br d, J = 16.54 Hz, 1 H) 8.50 (s, 1 H) 7.59 (d, J = 7.50 Hz, 1 H) 6.66 (d, J = 7.28 Hz, 1 H) 5.07 (br dd, J = 8.05, 5.62 Hz, 1 H) 4.09 (s, 3 H) 3.87 (br s, 1 H) 3.59 (br d, J = 16.76 Hz, 1 H) 3, 43 - 3.53 (m, 4 H) 3.39 (s, 3 H) 3.33 - 3.36 (m, 1 H) 3.15 - 3.29 (m, 2 H) 2.77 - 2.85 (m, 4 H) 2.51 - 2.68 (m, 2 H) 1.78 - 1.98 (m, 6 H) 1, 23 (d, J = 5.95 Hz, 3 H).

[00538] Compound 75: (S)-4-((2-hydroxyethyl)(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-aminoethan-1-ol, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 479.3. [M+H]+, found 479.3.

[00539] Compound 76: (S)-2-((3-cyanopyrazin-2-yl)amino acid)-4- (((R)-2-methoxypropyl)(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. (S)-2-Amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid acetate )amino)butanoic acid (100 mg, 228 μmol) in i-PrOH (2 ml) was added DPIEA (199 μl, 1.14 mmol) and 3-chloropyrazine-2-carbonitrile (35 mg, 250.82 μmol) and the resulting mixture was stirred at 70 °C for 12 h. The mixture was cooled to room temperature and then adjusted to pH = 6 by 1 M aqueous HCl solution and then concentrated in vacuo. The resulting crude residue was purified by prep HPLC . reverse phase to provide the title compound. LCMS (ESI+): m/z = 482.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.23 (d, J = 2.32 Hz, 1 H) 7.87 (d, J = 2.32 Hz, 1 H) 7.15 (d , J = 7.34 Hz, 1 H) 6.38 (d, J = 7.34 Hz, 1 H) 4.40 (t, J = 5.50 Hz, 1 H) 3.63 - 3.73 (m, 1 H) 3.35 - 3.39 (m, 2 H) 3.31 - 3.32 (m, 3 H) 3.12 - 3.22 (m, 1 H) 2.81 - 3.03 (m, 5 H) 2.69 (t, J = 6.17 Hz, 2 H) 2.51 - 2.60 (m, 2 H) 2.26 (dq, J = 14.35, 6.99 Hz, 1 H) 2.06 - 2.16 (m, 1 H ) 1.86 (q, J = 5.90 Hz, 2 H) 1.67 (br s, 4 H) 1.15 (d, J = 5.99 Hz, 3 H).

[00540] Compound 77: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-(((R)-2-methoxypropyl)(4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. (S)-2-Amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid acetate )amino)butanoic acid (100 mg, 228 μmol) in DMA (2 ml) was added DIPEA (119 μl, 684 μmol) followed by 4-chloro-6-pyrazol-1-yl-pyrimidine (45 mg, 251 μmol) and the resulting mixture was stirred at 100 °C for 2 h. The mixture was cooled to room temperature and then adjusted to pH = 6 by 1 M HCl and then concentrated in vacuo. The resulting crude residue was purified by prep HPLC. reverse phase to provide the title compound. LCMS (ESI+): m/z = 523.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.51 (d, J = 2.21 Hz, 1 H) 8.33 (s, 1 H) 7.75 (s, 1 H) 7.16 (d, J = 7.28 Hz, 1 H) 7.00 (br s, 1 H) 6.52 (d, J = 1.76 Hz, 1 H) 6.39 (d, J = 7.28 Hz, 1 H) 4.49 (br s, 1 H) 3.75 (br s, 1 H) 3.33 - 3, 42 (m, 6 H) 3.00 - 3.15 (m, 3 H) 2.86 - 2.98 (m, 2 H) 2.67 (br t, J = 6.17 Hz, 2 H) 2.56 - 2.62 (m, 2 H) 2.23 - 2.35 (m, 1 H) 2.11 (br dd, J = 14.44, 5 .40 Hz, 1 H) 1.85 (q, J = 5.95 Hz, 2 H) 1.72 (br d, J = 3.75 Hz, 4 H) 1.18 (d, J = 5.95 Hz, 3 H).

[00541] Compound 78: (S)-2-((5-fluoropyrimidin-2-yl)amino acid)-4- (((R)-2-methoxypropyl)(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. (S)-2-Amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid acetate )amino)butanoic acid (150 mg, 342 μmol), 2-chloro-5-fluoropyrimidine (50 mg, 376 μmol) in DMA (2 ml) was added DIPEA (179 μl, 1.03 mmol) and the resulting mixture was shaken at 100 °C for 2 h. The mixture was cooled to room temperature and then adjusted to pH = 6 by 1 M aqueous HCl solution and then concentrated in vacuo. The resulting crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 475.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.33 (s, 2 H) 7.60 (d, J = 7.28 Hz, 1 H) 6.61 - 6.67 (m, 1 H ) 4.57 - 4.66 (m, 1 H)) 3.74 - 3.87 (m, 1 H) 3.48 - 3.53 (m, 2 H) 3.39 - 3.48 (m, 1 H) 3.32 - 3.39 (m, 4 H) 3.12 - 3.29 (m, 4 H) 2.80 (dt, J = 17.81, 6.64 Hz, 4 H) 2.37 - 2.50 (m, 1 H) 2.25 (br dd, J = 9.04, 3.53 Hz, 1 H) 1.95 (dt, J = 11.91, 5.95 Hz, 2 H) 1.79 (br d, J = 5.73 Hz, 4 H) 1.21 (t, J = 6.28 Hz, 3 H).

[00542] Compound 79: (S)-2-((1H-pyrazolo[4,3-d]pyrimidin-7-yl)amino acid)-4-(((R)-2-methoxypropyl)(4-( 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: acetate (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) butanoic acid (100 mg, 241 μmol) in 4:1 THF/H2O (2.5 ml) was added NaHCO3 (57 mg, 684 μmol) followed by 7-chloro-1H- pyrazolo[4,3-d]pyrimidine (45 mg, 289 μmol) and the resulting mixture was stirred at 70 °C for 12 h. The mixture was cooled to room temperature and then adjusted to pH = 6 by 1 M and then concentrated in vacuo. The resulting crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 497.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.18 - 8.48 (m, 2 H) 7.60 (d, J = 7.21 Hz, 1 H) 6.59 (d, J = 7.21 Hz, 1 H) 4.87 (br s, 1 H) 3.73 (br s, 1 H) 3.41 (br s, 2 H) 3.25 - 3.37 (m, 1 H) 3.19 - 3.24 (m, 3 H) 3.02 - 3.19 (m, 5 H) 2 .63 - 2.77 (m, 4 H) 2.33 (br s, 1 H) 2.20 (br d, J = 10.15 Hz, 1H) 1.59 - 1.87 (m, 6 H) 1.10 (br d, J = 5.87 Hz, 3 H).

[00543] Compound 80: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid: To a solution of (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (100 mg, 241 μmol) and 4-chloro-6-phenyl-pyrimidine (51 mg, 265 μmol) in 4:1 THF/H2O (2.5 ml) was added NaHCO3 (61 mg, 723 ol) and the resulting mixture was stirred at 70 °C for 12 h. The mixture was cooled to room temperature and then adjusted to pH = 6 by 1 M aqueous HCl solution and then concentrated in vacuo. The resulting crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 533.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.47 (s, 1H) 7.81 - 7.92 (m, 2 H) 7.44 - 7.53 (m, 3 H) 7.15 (d, J = 7.50 Hz, 1 H) 6.93 - 7.05 (m, 1 H) 6.39 (d, J = 7.50 Hz, 1 H) 4.47 (br s, 1 H) 3.75 (br s, 1 H) 3.32 - 3.39 (m, 6 H) 2.84 - 3.21 (m, 5 H) 2.66 (t, J = 6.17 Hz, 2 H) 2.56 - 2.62 (m, 2H) 2.24 - 2.35 (m, 1 H) 2.05 - 2.17 (m, 1 H) 1.84 (q, J = 5.90 Hz, 2 H) 1.72 (br s, 4 H) 1.18 (d, J = 6.17 Hz, 3 H). SCHEME 5, COMPOUND 81:

[00544] Step 1: (S)-2-((5-bromopyrimidin-4-yl)amino acid)-4-(((R)- 2-methoxypropyl)(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)butyl)amino)butanoic acid: A solution of (S)-2- acid hydrochloride amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 241 μmol) and 5-bromo-4-chloropyrimidine (51 mg, 265 μmol) in 4:1 THF/H2O (2.5 ml) NaHCO3 was added (101 mg, 1.20 mmol) and the resulting mixture was stirred at 70 °C for 2 h. The mixture was cooled to room temperature and then adjusted to pH = 6 by 1 M aqueous HCl solution and then concentrated in vacuo to give the title compound which was used without further purification. LCMS (ESI+): m/z = 535.3 (M+H)+.

[00545] Step 2: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((5-phenylpyrimidin-4- yl)amino)butanoic acid: a mixture of (S)-2-((5-bromopyrimidin-4- yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (30 mg, 56 μmol), phenylboronic acid (8 mg, 67 μmol), Pd(dppf)Cl2 (4 mg, 6 μmol), and K2CO3 (15 mg, 112 μmol) were diluted in 4:1 dioxane/H2O (1.25 ml) and the resulting mixture was stirred at 100 °C for 2 h. The mixture was cooled to room temperature and then filtered and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 533.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.86 (s, 1 H) 8.22 (s, 1 H) 7.53 - 7.66 (m, 6 H) 6.66 (br d , J = 6.84 Hz, 1 H) 5.11 (br s, 1 H) 3.84 (br s, 1 H) 3.48 - 3.54 (m, 2 H) 3.46 (br s, 1 H) 3.34 - 3.39 (m, 3 H) 3.08 - 3.29 (m, 4 H) 2 .74 - 2.86 (m, 5 H) 2.56 (br s, 1 H) 2.37 (br s, 1 H) 1.76 - 2.00 (m, 6 H) 1.21 (br d, J = 5.29 Hz, 3 H). SCHEME 6, COMPOUND 82:

[00546] Step 1: N-(2-phenoxyethyl)-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 (5 g, 15.89 mmol) in DCM (70 mL) was added CDI (2.83 g, 17.48 mmol) at 0 °C and the resulting mixture was stirred at room temperature for 1 h at which time, 2-phenoxyethanamine (2.40 g, 17.48 mmol) was added and stirred for an additional 1 h at room temperature. The mixture was diluted with H2O and the layers were separated. The aqueous layer was extracted with DCM and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 339.9 (M+H)+.

[00547] Step 2: N-(2-phenoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine: To a mixture of LiAlH4 (1.21 g, 31.79 mmol) in 1,4-dioxane (50 mL) at room temperature was added N-(2-phenoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide (5 g, 14.45 mmol) and the resulting mixture was heated at reflux for 30 min and then allowed to cool to room temperature. The mixture was carefully neutralized by dropwise addition of H2O (1.2 ml), then 1 M aqueous NaOH solution (1.2 ml), and then H2O (3.6 ml) again, followed by drying over MgSO4. The mixture was filtered and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 326.1 (M+H)+.

[00548] Step 3: Methyl (S)-2-(((benzyloxy)carbonyl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: To a mixture of N-(2-phenoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (5 g, 12.84 mmol) and (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (3.75 g, 14.12 mmol) in DCE (75 mL) at 0°C were added AcOH (1.10 mL, 19.26 mmol) and NaBH(OAc)3 (4.08 g, 19.26 mmol) and the resulting mixture was stirred for 3 h at room temperature. The mixture was diluted with MeOH (50 mL) and the mixture was concentrated in vacuo. The crude product was taken up in DCM and saturated aqueous NaHCO3 solution was added. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by normal phase chromatography on silica gel to furnish the title compound. LCMS (ESI+): m/z = 575.1 (M+H)+.

[00549] Step 4: (S)-2-(((benzyloxy)carbonyl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (1 g, 1.74 mmol) in 1:1:1 THF/MeOH/H2O (9 mL) was added LiOH • H2O (146 mg, 3.48 mmol) at 0 °C and the resulting mixture was stirred at room temperature for 40 min. The mixture was adjusted to pH = 6 by addition of AcOH and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 561.1 (M+H)+.

[00550] Step 5: (S)-2-amino-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (3.78 g, 6.74 mmol) in MeOH (300 mL) was added 20 wt % Pd(OH)2/C (2.9 g) and the resulting mixture was stirred under an atmosphere of H2 for 2 h at rt. The mixture was filtered and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 427.2 (M+H)+.

[00551] Step 6: (S)-2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-phenoxyethyl)(4-( 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A solution of 4-chloro-1-methyl-1H- pyrazol[3,4-d]pyrimidine (43 mg, 258 umol) in 4:1 THF/H2O (2 ml) was added (S)-2-amino-4-((2-phenoxyethyl)(4-() acid 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 234 μmol) and NaHCOβ (59 mg, 703 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 559.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 14.37 (br s, 1 H) 10.79 - 11.21 (m, 1 H) 9.88 - 10.34 (m, 1 H) 8 .64 (s, 1 H) 8.40 (s, 1 H) 8.14 (br s, 1 H) 7.58 (d, J = 7.45 Hz, 1 H) 7.20 - 7.32 (m, 2 H) 6.87 - 7.03 (m, 3 H) 6.62 (d, J = 7.45 Hz, 1 H) 5.01 (br s, 1 H) 4.37 - 4.51 (m, 2 H) 3.96 (s, 3H) 3.34 - 3.72 (m, 5 H) 3.26 (br s, 2 H) 2.71 (br t, J = 6.14 Hz, 4 H) 2.50 (br s, 3 H) 1.64 - 1.94 (m, 5 H).

[00552] Compound 83: (S)-2-((5-Bromopyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 234 μmol) in 4:1 THF/H2O (2 ml) was added 5-bromo-2-fluoropyrimidine (46 mg, 258 μmol) and NaHCOβ (59 mg, 703 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 583.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.16 (s, 2 H) 7.29 (d, J = 7.45 Hz, 1 H) 7.16 - 7.25 (m, 2 H) 6.90 (t, J = 7.24 Hz, 1 H) 6.84 (d, J = 7.89 Hz, 2 H) 6.46 (d, J = 7.45 Hz, 1 H) 4.32 (t, J = 6.14 Hz, 1 H) 4.18 (t, J = 5.26 Hz, 2 H) 3.33 - 3.43 (m, 2 H) 3.05 - 3.27 (m, 4 H) 2.94 (br s, 2 H) 2.59 - 2.75 (m, 4 H) 2.05 - 2.27 (m, 2 H) 1.69 - 1.93 (m, 6 H). SCHEME 7, COMPOUND 84:

[00553] Step 1: 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- tert-butyl carboxylate: To a mixture of oxalyl chloride (16.00 g, 126.04 mmol) in DCM (200 mL) was added DMSO (15.15 g, 193.91 mmol) at -78 °C, and the resulting mixture was stirred at -78 °C for 30 min, at which time, a solution of 7-(4-hydroxybutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- tert-butyl carboxylate (29.71 g, 96.95 mmol) in DCM (100 mL) was added. The reaction mixture was stirred at -78 °C for 1 h and then triethylamine (67.5 mL, 484.77 mmol) was added and the mixture was stirred at -78 °C for an additional 30 min and then slowly warmed to -40 °C and then diluted with H2O and allowed to warm to room temperature. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound which was used without further purification.

[00554] Step 2: (S)-7-(4-((2-fluoro-3-methoxypropyl)amino)butyl)-tert-butyl 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate: To a solution of tert-butyl 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (15 g, 49.28 mmol) in MeOH (50 mL) was added (S)-2-fluoro-3-methoxypropan-1-amine hydrochloride (10.61 g, 73.92 mmol), AcOH (2.82 mL, 49.28 mmol), and NaBH3CN (6.19 g, 98.56 mmol) at 0 °C and stirred at room temperature for 12 h. The resulting mixture was concentrated in vacuo and then diluted with sat. aq. NaHCO3 solution and 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 normal phase chromatography on silica gel to furnish the title compound. LCMS (ESI+): m/z = 396.2 (M+H)+.

[00555] Step 3: 7-(4-(((S)-3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)((S)-2-fluoro-3-methoxypropyl) amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-tert-butyl carboxylate: A mixture of (S)-7-(4-((2-fluoro-3-methoxypropyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-tert-butyl carboxylate (2 .00 g, 6.77 mmol) and methyl (S)-2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (1.98 g, 7.45 mmol) in DCE (20 ml) was added AcOH (581 μL, 10.16 mmol) and NaBH(OAc)3 (2.15 g, 10.16 mmol) were added at 0 °C and the resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with MeOH and then concentrated in vacuo. The crude residue was diluted with DCM and sat. aq. NaHCO3 solution and the layers were separated. The aqueous layer was extracted with DCM and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo . The crude residue was purified by normal phase chromatography on silica gel to furnish the title compound. LCMS (ESI+): m/z = 645.5 (M+H)+.

[00556] Step 4: Methyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: tert-butyl 7-(4-(((S)-3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)((S)-2-fluoro-3-methoxypropyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (1.8 g, 2.79 mmol) was taken up in 4 M HCl in EtO-Ac (20 mL) and the mixture was stirred at room temperature for 15 h and then concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 545.4 (M+H)+.

[00557] Step 5: (S)-2-(((benzyloxy)carbonyl)amino acid)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8 -tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic: A mixture of (S)-2- (((benzyloxy)carbonyl)amino)-4-(((S)-2-fluoro-3-methoxypropyl hydrochloride)(4-(5,6,7,8-tetrahydro-1,8- methyl naphthyridin-2-yl)butyl)amino)butanoate (500 mg, 860 μmol), in 1:1:1 THF/H2O/MeOH (3 ml) was added LiOH • H2O (72 mg, 1.72 mmol) and the resulting mixture was stirred at room temperature for 1 h and then diluted with MeOH and adjusted to pH = 6 by the addition of AcOH and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m /z = 531.4 (M+H)+.

[00558] Step 6: (S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid acetate (1 g, 1.69 mmol) in i-PrOH (10 mL) was added 20 wt % Pd(OH) 2 /C (238 mg) and the resulting mixture was stirred under an atmosphere of H 2 for 2 h. The mixture was filtered and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 397.2 (M+H)+.

[00559] Step 7: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (120 mg, 277 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (70 mg, 831 μmol) and then 2-chloropyrimidine-5-carbonitrile (43 mg, 305 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature. The mixture was adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 500.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.56 (br s, 1 H) 8.45 (br s, 1 H) 7.42 (br d, J = 7.28 Hz, 1 H) 6.52 (d, J = 7.50 Hz, 1 H) 4.75 (br d, J = 3.31 Hz, 1 H) 4.51 (t, J = 5.84 Hz, 1 H) 3.57 (d, J = 3.97 Hz, 1 H) 3.49 - 3.53 (m, 1 H)) 3.37 - 3.46 (m, 2 H) 3.33 - 3.37 (m, 3 H) 2.84 - 2.96 (m, 2 H) 2.65 - 2.83 (m, 8 H) 2.15 - 2.24 (m, 1H) 2.04 - 2.14 (m, 1 H) 1.87 - 1.94 (m, 2 H) 1.81 (br dd, J = 13.78, 6.73 Hz, 2 H) 1.58 - 1.69 (m, 2 H).

[00560] Compound 85: (S)-4-(((S)-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: To a solution of (S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 252 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (64 mg, 757 μmol) and then 2-chloro-5-(trifluoromethyl)pyrimidine (51 mg, 277 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then cooled to room temperature. The mixture was adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 543.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.64 (s, 2 H) 7.59 (d, J = 7.46 Hz, 1 H) 6.65 (d, J = 7.34 Hz, 1 H) 5.10 - 5.28 (m, 1 H) 4.79 (br s, 1 H) 3.54 - 3.74 (m, 4 H) 3.42 - 3.54 (m, 4 H) 3.40 (s, 3 H) 3.33 - 3.39 (m, 2 H) 2.75 - 2.86 (m, 4 H) 2.43 - 2.57 (m, 1 H) 2.35 (br s, 1 H) 1.74 - 2.00 (m, 6 H).

[00561] Compound 86: (S)-2-((5-bromopyrimidin-2-yl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6, 7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino)butanoic acid (100 mg, 231 μmol) in THF (1 ml) and H2O (0.25 ml) was added NaHCO3 (58 mg, 693 μmol) and 5-bromo-2-fluoropyrimidine (49 mg, 277 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature. The mixture was adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The Crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 553.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.24 (s, 2 H) 7.40 (d, J = 7.50 Hz, 1 H) 6.52 (d, J = 7.28 Hz , 1 H) 4.77 (br d, J = 3.53 Hz, 1 H) 4.36 (t, J = 6.17 Hz, 1 H) 3.58 (d, J = 4.41 Hz, 1 H) 3.52 (d, J = 4.19 Hz, 1 H) 3.35 - 3.44 (m, 2 H) 3.33 (s, 3 H) 2.83 - 2.95 (m, 4 H) 2.66 - 2.76 (m, 6 H) 2.05 - 2.18 (m, 2 H) 1.84 - 1.91 (m, 3 H) 1.75 - 1.83 (m, 1 H) 1.61 - 1.71 (m, 2 H).

[00562] Compound 87: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2) acid -yl)butyl)amino)-2-((2- (trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid: (S)-2- hydrochloride amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid ( 100 mg, 231 ol) in THF (2 ml) and H2O (0.5 ml) were added NaHCO3 (58 mg, 693 μmol) and 4-chloro-2- (trifluoromethyl)pyrimidine (46 mg, 254 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then cooled to room temperature. The mixture was adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo . The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 543.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.06 (br d, J = 5.26 Hz, 1 H) 7.42 (d, J = 7.34 Hz, 1 H) 6, 66 (br d, J = 5.62 Hz, 1 H) 6.51 (d, J = 7.34 Hz, 1 H) 4.71 - 4.78 (m, 1 H) 4.68 (br s, 1 H) 3.46 - 3.61 (m, 2 H) 3.36 - 3.44 (m, 2 H) 3 .31 (s, 3 H) 2.95 (br d, J = 4.89 Hz, 2 H) 2.54 - 2.85 (m, 8 H) 2.23 (br s, 1 H) 2.06 (br d, J = 4.52 Hz, 1 H) 1.73 - 1.94 (m, 4 H) 1.51 - 1.73 (m, 2 H) . SCHEME 8, COMPOUND 88:

[00563] Step 1: 7-(4-((2,2-difluoroethyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl: To a mixture of 2,2-difluoroethanamine (3.99 g, 49.28 mmol, 1.5 eq) in MeOH (80 mL) was added AcOH (1.88 mL, 32.85 mmol), NaBH3CN (4.13 g, 65.71 mmol), and then a solution of 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl (10 g, 32.85 mmol) in MeOH (30 mL) at 0°C. The resulting mixture was stirred at room temperature for 3 h and then diluted with aq. NaHCO3 solution and concentrated in vacuo to remove volatiles. The remaining aqueous phase was extracted with EtOAc and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reversed-phase HPLC to give the title compound. LCMS (ESI+): m/z = 370.2.

[00564] Step 2: (S)-tert-butyl 7-(4-((3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)(2,2-difluoroethyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate: To a mixture of 7-(4-((2,2-difluoroethyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-tert-butyl carboxylate (5.7 g, 15.43 mmol) and (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (4.50 g, 16.97 mmol) in DCE (60 mL) was added AcOH (1.32 mL, English: 23.14 mmol), NaBH(OAc)3 (4.90 g, 23.14 mmol) at 0 °C and the resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with aqueous NaHCO3 solution and DCM and the layers were separated. The aqueous layer was extracted with DCM and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by normal phase chromatography on silica gel to furnish the title compound. LCMS (ESI+): m/z = 619.2.

[00565] Step 3: (S)-Methyl 2-(((benzyloxy)carbonyl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: (S)-tert-butyl 7-(4-((3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)(2,2-difluoroethyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (3 g, 4.85 mmol) was diluted in 4 M HCl in EtOAc (5 mL) and stirred at room temperature for 16 h and then concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 519.2.

[00566] Step 4: (S)-2-(((benzyloxy)carbonyl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate hydrochloride (2.7 g, 4.86 mmol) in 1:1:1 THF/H2O/MeOH (25 mL) was added LiOH.H2O (408 mg, 9.73 mmol) at 0 °C and the resulting mixture was stirred at room temperature for 1 h. The mixture was adjusted to pH = 6 by addition of 1 M aq. HCl solution and concentrated in vacuo to furnish the title compound. LCMS (ESI+): m/z = 505.3.

[00567] Step 5: (S)-2-amino-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (2.9 g, 5.75 mmol) in MeOH (20 mL) was added 20 wt % Pd(OH) 2 /C (1.29 g) and the resulting mixture was stirred under an atmosphere of H 2 for 2 h. The mixture was filtered and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 371.4.

[00568] Step 6: (S)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid )-2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid: A mixture of acid (S)-2-amino-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid ( 110 mg, 297 μmol) and 4-chloro-1-methyl-1H-pyrazol[3,4-d]pyrimidine (55 mg, 327 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (50 mg, 594 µmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 503.3. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.63 (s, 1 H) 8.49 (s, 1 H) 7.59 (br d, J = 6.61 Hz, 1 H) 6, 37 - 6.71 (m, 2 H) 5.10 (br s, 1 H) 4.09 (s, 3 H) 3.86 (br t, J = 14.22 Hz, 2 H) 3.55 - 3.76 (m, 2 H) 3.36 - 3.54 (m, 4 H) 2.82 (br d, J = 5.95 Hz, 4 H) 2.54 - 2.75 (m, 2 H) 1.76 - 2.00 (m, 6 H).

[00569] Compound 89: (S)-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: (S)-2-amino-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 234 μmol) in 4:1 THF/H2O (2 ml) was added 2-chloro-5-(trifluoromethyl)pyrimidine (47 mg, 258 μmol) and NaHCO3 (59 mg, 703 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 573.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.57 (s, 2 H) 7.58 (d, J = 7.34 Hz, 1 H) 7.30 (br t, J = 7.15 Hz, 2 H) 6.93 - 7.05 (m, 3 H) 6.63 (d, J = 7.21 Hz, 1 H) 4.79 (dd, J = 8.38, 5.07 Hz, 1 H) 4.38 (br s, 2 H) 3.63 - 3.78 (m, 2 H) 3.46 (br s, 3 H) 3.42 - 3.60 (m, 1 H) 3.37 (br d, J = 8.80 Hz, 2 H) 2.74 - 2.85 (m, 4 H) 2.51 - 2.62 (m, 1 H) 2.37 (br s, 1 H) 1.75 - 1.99 (m, 6 H).

[00570] Compound 90: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-phenoxyethyl)(4-(5,6, 7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2-amino-4-((2- phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 234 μmol) in 4:1 THF/H2O (2 ml ) 4-chloro-1H-pyrazol[3,4-d]pyrimidine (40 mg, 258 μmol) and NaHCOβ (59 mg, 703 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+) : m/z = 545.0 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.78 (br d, J = 19.07 Hz, 1 H) 8.59 (s, 1 H) 7.58 (d, J = 7.46 Hz, 1 H) 7.25 (br t, J = 7.89 Hz, 2 H) 6.90 - 7.02 (m, 3 H) 6.64 (d, J = 7.34 Hz, 1 H) 5.29 (br s, 1 H) 4.40 (br d, J = 5.01 Hz, 2 H) 3 .73 (br s, 2 H) 3.48 - 3.68 (m, 4 H) 3.42 (br t, J = 7.76 Hz, 2H) 2.75 - 2.85 (m, 4 H) 2.71 (br s, 1 H) 2.54 (br s, 1 H) 1.88 - 2.03 (m, 4 H) 1.71 - 1.87 (m, 2H).

[00571] Compound 91: (S)-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: To a solution of (S)-2-amino-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (100 mg, 216 μmol) in DMA (2 ml) was added DIPEA (188 μl, 1.08 mmol) and then 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (43 mg, 238 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 571.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.46 (d, J = 2.44 Hz, 1 H) 8.23 (br s, 1 H) 7.72 (d, J = 0.98 Hz, 1 H) 7.24 (br s, 1 H) 7.12 (dd, J = 8.56, 7.46 Hz, 2 H) 6.78 - 6.89 (m, 4 H) 6.51 (dd, J = 2.57, 1.71 Hz, 1 H) 6.46 (d, J = 7.34 Hz, 1 H) 4.56 (br s, 1 H) 4.12 - 4.22 (m, 2 H) 3.08 - 3.29 (m, 7 H) 2.54 - 2.74 (m, 5 H) 2.20 - 2.35 (m, 1 H) 2.04 - 2.16 (m, 1 H) 1.73 - 1.88 (m, 6 H).

[00572] Compound 92: (S)-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: To a mixture of (S)-2-amino-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 234 μmol) in 4:1 THF/H2O (2 ml) was added 4-chloro-2-(trifluoromethyl)pyrimidine (47 mg, 258 μmol) and NaHCO3 (59 mg, 703 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 573.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.21 (br d, J = 5.75 Hz, 1 H) 7.57 (d, J = 7.34 Hz, 1 H) 7.30 (t, J = 7.89 Hz, 2 H) 6.92 - 7.07 (m, 3 H) 6.81 (d, J = 6.11 Hz, 1 H) 6.63 (d, J = 7.21 Hz, 1 H) 4.81 - 4.85 (m, 1 H) 4.38 (br t, J = 4.22 Hz, 2 H) 3.70 (br d, J = 3.91 Hz, 2 H) 3.34 - 3.60 (m, 6 H) 2.72 - 2.87 (m, 4 H) 2.49 - 2.63 (m, 1 H) 2.28 - 2.44 (m, 1 H) 1.72 - 2.03 (m, 6 H).

[00573] Compound 93: (S)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 234 μmol) in 4:1 THF/H2O (2 ml) was added 4-chloro-6-phenylpyrimidine (49 mg, 258 μmol) and NaHCOβ (59 mg, 703 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 581.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.74 (s, 1 H) 7.83 (br d, J = 7.21 Hz, 2 H) 7.62 - 7.74 (m, 3 H) 7.57 (d, J = 7.34 Hz, 1 H) 7.18 - 7.31 (m, 3 H) 6.93 - 7.03 (m, 3 H) 6.64 (d, J = 7.34 Hz, 1 H) 5.09 (br s, 1 H) 4.40 (br s, 2 H) 3.47 - 3.73 (m, 4 H)) 3.38 - 3.46 (m, 2 H) 2.80 (q, J = 5.87Hz, 4 H) 2.65 (br s, 1 H) 2.45 (br s, 1 H) 1.87 - 2.00 (m, 4 H).

[00574] Compound 94: (S)-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: To a solution of (S)-2-amino-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (100 mg, 216 μmol) in DMA (2 ml) was added DIPEA (188 μl, 1.08 mmol) followed by 4-chloro-2-(pyridin-3-yl)quinazoline (57 mg, 238 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 632.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 9.52 (d, J = 1.35 Hz, 1 H) 8.78 (dt, J = 7.98, 1.88 Hz, 1 H) 8.58 (dd, J = 4.89, 1.71 Hz, 1 H) 8.03 (d, J = 8.44 Hz, 1 H) 7.77 - 7.84 (m, 1 H) 7.68 - 7.76 (m, 1 H) 7.46 (dd, J = 7.58, 4.52 Hz, 1 H) 7.35 (t, J = 8.13 Hz, 1 H) 7.19 (d, J = 6.97 Hz, 1 H) 7.01 - 7.09 (m, 2 H) 6.79 (t, J = 7.34 Hz, 1 H) 6.71 (d, J = 7.82 Hz, 2 H) 6.36 (d, J = 7.21 Hz, 1 H) 5.00 (t, J = 5.93 Hz, 1 H) 4.10 - 4.21 (m, 2 H) 2.81 - 3.27 (m, 8 H) 2.60 (br d, J = 6.72 Hz, 4 H) 2.46 (br s, 1 H) 2.29 (br dd, J = 15.04, 4.89 Hz, 1 H) 1.70 - 1.90 (m, 6 H).

[00575] Compound 95: (S)-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: To a mixture of (S)-2-amino-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (160 mg, 432 μmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (87 mg, 475 μmol) in H2O (0.5 ml) and THF (2 ml) was added NaHCO3 (73 mg, 864 μmol) and The resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 517.2. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.62 (s, 2 H) 7.60 (d, J = 7.50 Hz, 1 H) 6.65 (d, J = 7.28 Hz, 1 H) 6.33 - 6.64 (m, 1 H) 4.78 (dd, J = 8.49, 5.18 Hz, 1 H) 3.83 (td, J = 15.05, 3.42 Hz, 2 H) 3.35 - 3.62 (m, 6 H) 2.76 - 2.88 (m, 4 H) 2.46 - 2.59 (m, 1 H) 2.30 - 2.43 (m, 1 H) 1.74 - 2.02 (m, 6 H).

[00576] Compound 96: (S)-2-((5-bromopyrimidin-2-yl)amino acid)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetra- hydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a mixture of (S)-2-amino-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)butanoic acid (160 mg, 432 μmol) and 5-bromo-2-chloropyrimidine (84 mg, 475 μmol) in THF (2 ml), H2O (0.5 ml) and NaHCO3 (73 mg, 864 μmol) were added and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m /z = 527.1. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.55 (s, 2 H) 7.59 (d, J = 7.28 Hz, 1 H) 6.32 - 6.71 (m, 2 H ) 4.73 (dd, J = 8.38, 5.07 Hz, 1 H) 3.82 (td, J = 14.88, 3.31 Hz, 2 H) 3.35 - 3.60 (m, 6 H) 2.75 - 2.85 (m, 4 H) 2.46 - 2.60 (m, 1 H ) 2.29 - 2.43 (m, 1 H) 1.74 - 2.00 (m, 6 H).

[00577] Compound 97: (S)-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: To a mixture of (S)-2-amino-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (160 mg, 432 μmol) and 4-chloro-2-(trifluoromethyl)pyrimidine (87 mg, 475 μmol) in THF (2 ml), H2O (0.5 ml) was added NaHCO3 (73 mg, 864 μmol) and the The resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 517.2. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.29 (br d, J = 6.39 Hz, 1 H) 7.60 (d, J = 7.50 Hz, 1 H) 6.98 - 7.09 (m, 1 H) 6.31 - 6.70 (m, 2 H) 4.85 - 4.91 (m, 1 H) 3.83 (td, J = 14.94, 3.20 Hz, 2 H) 3.36 - 3.64 (m, 6 H) 2.76 - 2.85 (m, 4 H) 2.49 - 2.62 (m, 1 H) 2.33 - 2.46 (m, 1 H) 1.75 - 1.99 (m, 6H).

[00578] Compound 98: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((2,2-difluoroethyl)(4-(5) ,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of acid (S)-2-amino-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid ( 100 mg, 270 μmol) and 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (54 mg, 297 μmol) in DMA (2 ml) was added DIPEA (235 μl, 1.35 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 515.2. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.61 (br s, 2 H) 7.93 (s, 1 H) 7.59 (d, J = 7.28 Hz, 1 H) 7, 31 (br s, 1 H) 6.35 - 6.74 (m, 3 H) 4.98 (br s, 1 H) 3.85 (td, J = 14.99, 3.31 Hz, 2 H) 3.39 - 3.66 (m, 6 H) 2.75 - 2.87 (m, 4 H) 2, 36 - 2.70 (m, 2 H) 1.75 - 2.01 (m, 6 H).

[00579] Compound 99: (S)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid )-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid: A mixture of (S)-2-amino-4-((2,2- difluoroethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 270 μmol) and 4-chloro-2-(pyridin- 3-yl)quinazoline (72 mg, 297 μmol) in DMA (2 ml) was added DPIEA (235 μl, 1.35 mmol) and The resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m /z = 576.3. 1H NMR (400 MHz, Methanol-d4) δ ppm 9.88 (d, J = 1.76 Hz, 1 H) 9.52 (d, J = 8.38 Hz, 1 H) 9.16 (d , J = 5.51 Hz, 1 H) 8.73 (d, J = 8.38 Hz, 1 H) 8.35 (dd, J = 8.27, 5.84 Hz, 1 H) 8.12 - 8.21 (m, 2 H) 7.88 - 7.96 (m, 1 H) 7.59 (d, J = 7.28 Hz, 1 H) 6.36 - 6.69 (m, 2 H) 5.54 (dd, J = 8.60, 5.51Hz, 1 H) 3.59 - 3.93 (m, 4 H) 3.40 - 3.54 (m, 4 H) 2.65 - 2.88 (m, 6 H) 1.75 - 2.01 ( m, 6 H).

[00580] Compound 100: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid: A mixture of acid (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) butanoic acid (100 mg, 264 μmol) in DMA (2 ml) DIPEA (171 mg, 1.32 mmol) was added and 4-chloro-2-(pyridin-3-yl)quinazoline (70 mg, 291 μmol) and the resulting mixture was heated at 100 °C for 2 h and then allowed to cool to room temperature and concentrated in vacuo. The resulting crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m /z = 584.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 9.57 (s, 1 H) 8.85 (br d, J = 7.95 Hz, 1 H) 8.63 (d, J = 4.40 Hz, 1 H) 8.16 (d, J = 8.19 Hz, 1 H) 7.77 - 7.90 (m, 2 H) 7.51 - 7.59 (m, 2 H) 7.12 (br d, J = 7.34 Hz, 1 H) 6.32 (d, J = 7.21 Hz, 1 H) 3 .75 (br s, 1 H) 3.37 - 3.49 (m, 1 H) 3.27 (s, 5 H) 2.88 - 3.25 (m, 6 H) 2.64 (br t, J = 5.93 Hz, 2 H) 2.45 - 2.57 (m, 3 H) 2.32 (br dd, J = 14.79, 5 .14 Hz, 1 H) 1.77 - 1.86 (m, 2 H) 1.71 (br s, 4 H) 1.10 - 1.20 (m, 3 H). SCHEME 9, COMPOUND 101:

[00581] Step 1: N-(2-(methylsulfonyl)ethyl)-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 (20 g, 63.56 mmol) in DCM (400 mL) was added CDI (11.34 g, 69.92 mmol) at 0 °C and the resulting mixture was stirred at room temperature for 1 h at which time, 2-(methylsulfonyl)ethanamine hydrochloride (11.16 g, 69.92 mmol) was added and stirred at room temperature for an additional 2 h. The mixture was diluted with H2O and the layers were separated. The aqueous layer was extracted with DCM, and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was redissolved in EtOAc (80 mL) and then heated to reflux, at which time hexanes (20 mL) were added and the mixture was cooled to room temperature causing a precipitate to form. The solid was filtered, and the filtrate was concentrated in vacuo to afford the title compound. LCMS (ESI+): m/z = 325.9 (M+H)+.

[00582] Step 2: N-(2-(methylsulfonyl)ethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine: To a solution of LiAlH4 (1.28 g, 33.80 mmol) in THF (20 mL) at 0 °C was added N-(2-(methylsulfonyl)ethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide (5 g, 15.36 mmol) and the resulting mixture was heated at reflux for 12 h and then cooled to room temperature. The mixture was carefully neutralized by the addition of H2O (1.3 mL), 1 M aq. NaOH (1.3 ml), then with H2O (1.3 ml) again, followed by drying over MgSO4. The mixture was filtered and concentrated under reduced pressure to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 311.9 (M+H)+.

[00583] Step 3: (S)-Methyl 2-(((benzyloxy)carbonyl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: To a mixture of N-(2-(methylsulfonyl)ethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butane-1-amine (3 g, 9.63 mmol) and (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (2.56 g, 9.63 mmol) in DCE (30 mL) at 0 °C was added AcOH (862 μL, 14.45 mmol) and then NaBH(OAc)3 (3.06 g, 14.45 mmol) and the resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with MeOH and then concentrated under reduced pressure. The crude residue was taken up in DCM and aq. NaHCO3 solution and the layers were separated. The aqueous layer was extracted with DCM and the combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography on silica gel to furnish the title compound. LCMS (ESI+): m/z = 561.4 (M+H)+.

[00584] Step 4: (S)-2-(((benzyloxy)carbonyl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (1 g, 1.78 mmol) in 1:1:1 THF/MeOH/H2O (9 mL) was added LiOH.H2O (150 mg, 3.57 mmol) and the resulting mixture was stirred at room temperature for 1 h. The mixture was adjusted to pH = 6 by addition of 1 M aq. HCl solution and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 547.2 (M+H)+.

[00585] Step 5: (S)-2-Amino-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (1 g, 1.71 mmol) in i-PrOH (20 mL) was added 20 wt % Pd(OH) 2 /C (241 mg) and the resulting mixture was stirred under an atmosphere of H 2 for 12 h. The mixture was filtered and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 413.1 (M+H)+.

[00586] Step 6: (S)-2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-(methylsulfonyl)ethyl)( 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of acid (S)-2-amino-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 242) in THF (2 ml) and H2O (0.5 ml) NaHCO3 (61 mg, 727) was added followed by 4-chloro-1-methyl-1H-pyrazol[3,4-d]pyrimidine (49 mg, 291 μmol) and the resulting mixture was stirred at 70 °C for 18 h and then allowed to cool to room temperature and then adjusted to pH = 6 by adding 1 M aq. of HCl and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 545.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.61 (s, 1H) 8.50 (s, 1H) 7.59 (d, J = 7.28 Hz, 1 H) 6.67 (d , J = 7.50 Hz, 1 H) 5.10 (br dd, J = 8.05, 5.18 Hz, 1 H) 4.10 (s, 3 H) 3.70 - 3.90 (m, 4 H) 3.53 - 3.68 (m, 2 H) 3.49 - 3.53 (m, 2 H)) 3.35 - 3.43 (m, 2 H) 3.13 (s, 3 H) 2.77 - 2.86 (m, 4H) 2.53 - 2.77 (m, 2 H) 1.77 - 2.00 (m, 6 H).

[00587] Compound 102: (S)-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: To a solution of (S)-2-amino-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 242 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (61 mg, 727 μmol) followed by 2-chloro-5-(trifluoromethyl)pyrimidine (53 mg, 291 μmol) and the resulting mixture was stirred at 70 °C for 18 h and then allowed to cool to room temperature and then adjusted to pH = 6 by the addition of 1 M aq. HCl and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 559.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.60 (s, 2 H) 7.59 (br d, J = 7.21 Hz, 1 H) 6.65 (d, J = 7.34 Hz, 1 H) 4.77 (br dd, J = 8.01, 4.95 Hz, 1 H) 3.67 - 3.82 (m, 4 H) 3.49 - 3.54 (m, 2 H) 3.32 - 3.49 (m, 4 H) 3.13 (s, 3 H) 2.75 - 2.86 (m, 4 H) 2.46 - 2.58 (m, 1 H) 2.36 (br s, 1 H) 1.92 - 1.99 (m, 2 H) 1.84 (br s, 4 H).

[00588] Compound 103: (S)-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: To a mixture of (S)-2-amino-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 242 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (61 mg, 727 μmol), followed by 5-bromo-2-chloropyrimidine (51 mg, 291 μmol) and the resulting mixture was stirred at 70 °C for 18 h and then allowed to cool to room temperature and then adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 569.0 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.44 - 8.56 (m, 2 H) 7.59 (d, J = 7.28 Hz, 1 H) 6.66 (d, J = 7.28 Hz, 1 H) 4.68 - 4.77 (m, 1 H) 3.68 - 3.82 (m, 4 H) 3.49 - 3.55 (m, 2 H) 3.32 - 3.49 (m, 4 H) 3.13 (s, 3 H) 2.76 - 2.87 (m, 4 H) 2.46 - 2.58 (m, 1 H) 2.28 - 2.43 (m, 1 H) 1.96 (q, J = 5.90 Hz, 2 H) 1.83 (br s, 4 H).

[00589] Compound 104: (S)-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: To a mixture of (S)-2-amino-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 242 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (61 mg, 727 μmol) followed by 4-chloro-2-(trifluoromethyl)pyrimidine (53 mg, 291 μmol) and the resulting mixture was stirred at 70 °C for 18 h and then allowed to cool to room temperature and then adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 559.1 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.26 (br d, J = 5.95 Hz, 1 H) 7.59 (d, J = 7.28 Hz, 1 H) 6.92 (d, J = 6.39 Hz, 1 H) 6.65 (d, J = 7.50 Hz, 1 H) 4.83 - 4.87 (m, 1 H) 3.69 - 3.80 (m, 4 H) 3.49 - 3.53 (m, 2 H) 3.32 - 3.49 (m, 4 H) 3.12 (s, 3 H) 2.81 (dt, J = 12.29, 6.31 Hz, 4 H) 2.48 - 2.59 (m, 1 H) 2.30 - 2.42 (m, 1 H) 1.92 - 2.00 (m, 2 H) 1.83 (br s, 4 H).

[00590] Compound 105: (S)-4-(((S)-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: To a solution of (S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (100 mg, 231 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (58 mg, 693 μmol), and then 4-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (43 mg, 254 μmol) was added and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature. The mixture was adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 529.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.63 (s, 1 H) 8.50 (s, 1 H) 7.59 (d, J = 7.28 Hz, 1 H) 6.67 (d, J = 7.50 Hz, 1 H) 5.15 - 5.34 (m, 1 H) 5.08 (br dd, J = 8.49, 5.40 Hz, 1 H) 4.10 (s, 3 H) 3.63 - 3.74 (m, 4 H) 3.49 - 3.63 (m, 4 H) 3.41 (s, 5 H) 2.76 - 2.88 (m, 4 H) 2.55 - 2.73 (m, 2 H) 1.75 - 2.02 (m, 6 H). SCHEME 10, COMPOUND 106:

[00591] Step 1: (S)-2-((5-bromopyrimidin-4-yl)amino acid)-4-(((R)- 2-methoxypropyl)(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)butyl)amino)butanoic acid: A solution of (S)-2- acid hydrochloride amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (200 mg, 482 μmol) and 5-bromo-4-chloropyrimidine (102 mg, 530 μmol) in THF (4 ml) and H2O (1 ml) NaHCO3 was added (202 mg, 2.4 mmol) and the The resulting mixture was stirred at 70 °C for 2 h and then cooled to room temperature and concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 535.3 (M +H)+.

[00592] Step 2: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid: To a solution of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 280 μmol) in MeOH (2 mL) was added 10 wt % Pd/C (297 mg) and the resulting mixture was stirred under an atmosphere of H 2 for 15 h. The mixture was filtered and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 457.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.41 (s, 1 H) 8.03 (br d, J = 6.11 Hz, 1 H) 7.21 (d, J = 7.34 Hz, 1 H) 6.63 (br d, J = 5.99 Hz, 1 H) 6.43 (d, J = 7.34 Hz, 1 H) 4.43 (br s, 1 H) 3.76 (br s, 1 H) 3.37 - 3.42 (m, 3 H) 3.35 (s, 3 H) 2.91 - 3.18 (m, 5 H) 2.72 (t, J = 6.11 Hz, 2 H) 2.60 (br s, 2 H) 2.21 - 2.34 (m, 1 H) 2.03 - 2.15 (m, 1 H) 1.89 (dt, J = 11.74, 5.99 Hz, 2 H) 1.73 (br s, 4 H) 1.20 (d, J = 6.11 Hz, 3 H).

[00593] Compound 107: (S)-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: To a solution of (S)-2-amino-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 242 μmol) in DMA (2 ml) was added DIPEA (210 μl, 1.21 mmol) and 4-chloro-2-(pyridin-3-yl)quinazoline (59 mg, 242 μmol and the resulting mixture was stirred at 100 °C for 2 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound.). LCMS (ESI+): m/z = 618.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 9.57 (d, J = 1.47 Hz, 1 H) 8.84 (dt, J = 8.04, 1.85 Hz, 1 H) 8.61 (dd, J = 4.89, 1.71 Hz, 1 H) 8.12 (d, J = 7.70 Hz, 1 H) 7.83 - 7.88 (m, 1 H) 7.76 - 7.82 (m, 1 H) 7.48 - 7.55 (m, 2 H) 7.34 (d, J = 7.34 Hz, 1 H) 6.45 (d, J = 7.34 Hz, 1 H) 5.05 (t, J = 6.05 Hz, 1 H) 3.26 - 3.31 (m, 2 H) 3.24 (t, J = 5.56 Hz, 2 H) 3.01 - 3.17 (m, 2 H) 2.84 - 2.93 (m, 4 H) 2.61 - 2.77 (m, 7 H) 2.36 - 2.46 (m, 1 H) 2.22 - 2.32 (m, 1 H) 1.76 - 1.91 (m, 4 H) 1.57 - 1.72 (m, 2 H).

[00594] Compound 108: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-(((S)-2-fluoro-3-methoxypropyl )(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (50 mg, 277 μmol) in DMA (2 ml) and DIPEA (201 μl, 1.15 mmol) was added then acid hydrochloride (S) -2- amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 231 μmol) and the resulting mixture was stirred at 70 °C for 18 h and then allowed to cool to room temperature and then adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 541.3 (M+H)+.1H NMR (400 MHz, Methanol-d4) δ ppm 8.49 (br s, 1 H) 8.28 (br s, 1 H) 7.72 (s, 1 H) 7.26 (br s, 1 H) 6.87 (s, 1 H) 6.42 - 6.53 (m, 2 H) 4.76 (br s, 1 H) 4.66 (br s, 1 H) 3.46 - 3.59 (m, 2 H) 3.32 - 3.32 (m, 3 H) 2.90 (br s, 2 H ) 2.65 (br d, J = 6.60 Hz, 10 H) 2.19 (br s, 1 H) 2.09 (br d, J = 5.01 Hz, 1 H) 1.82 (br s, 4 H) 1.62 (br d, J = 6.72 Hz, 2 H).

[00595] Compound 109: (S)-4-(((S)-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: To a mixture of 4-chloro-2-(pyridin-3-yl)quinazoline (67 mg, 277 μmol) in DMA (2 ml) and DIPEA (201 μl, 1.15 mmol) was added, then (S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- (100 mg, 231 μmol) was added and the resulting mixture was stirred at 70 °C for 18 h and then allowed to cool to rt and then adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 602.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 9.56 (d, J = 1.47 Hz, 1 H) 8.83 (dt, J = 8.04, 1.85 Hz, 1 H) 8.60 (dd, J = 4.89, 1.59 Hz, 1 H) 8.07 (d, J = 8.19 Hz, 1 H) 7.81 - 7.85 (m, 1 H) 7.73 - 7.79 (m, 1 H) 7.44 - 7.52 (m, 2 H) 7.25 (d, J = 7.21 Hz, 1 H) 6.39 (d, J = 7.34 Hz, 1 H) 5.09 (br t, J = 5.69 Hz, 1 H) 4.79 (br s, 1 H) 3.40 - 3.59 (m, 2 H) 3.22 (s, 3 H) 3.10 - 3.16 (m, 2 H) 3.03 (dt, J = 14.03, 9.00 Hz, 2 H) 2.80 - 2.89 (m, 1 H) 2.67 - 2.76 (m, 2 H) 2.58 - 2.66 (m, 5 H) 2.37 - 2.45 (m, 1 H) 2.21 - 2.29 (m, 1 H) 1.79 - 1.92 (m, 2 H) 1.74 (br dd, J = 12.53, 5.81 Hz, 3 H) 1.59 - 1.66 (m, 1 H).

[00596] Compound 110: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2) acid -yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid: To a solution of acid (S)-2-((5-bromopyrimidin-4-yl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro -1,8- naphthyridin-2-yl)butyl)amino)butanoic acid (200 mg, 361 μmol) and phenylboronic acid (53 mg, 434 μmol) in 1,4-dioxane (2 ml) and H2O (1 ml) Pd(dppf)Cl2 (26 mg, 36 μmol) and K2CO3 (50 mg, 361 μmol) were added and the resulting mixture was stirred at 100 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo . The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 551.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.84 (s, 1 H) 8.21 (s, 1 H) 7.56 - 7.63 (m, 6 H) 6.65 (d, J = 7.34 Hz, 1 H) 5.09 - 5.28 (m, 2 H) 3.70 (br d, J = 3.42 Hz, 1 H) 3.54 - 3.68 (m, 3 H) 3.48 - 3.53 (m, 3 H) 3.39 (s, 3 H) 3.34 (br s, 3 H) 2.80 (dt, J = 12.81, 6.37 Hz, 4 H) 2.58 (br t, J = 11.98Hz, 1 H) 2.39 (br d, J = 6.24 Hz, 1 H) 1.94 (q, J = 5.90 Hz, 2 H) 1.80 (br s, 4 H).

[00597] Compound 111: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 234 μmol) in 4:1 THF/H2O (2 ml) was added 2-chloropyrimidine-5-carbonitrile (36 mg, 258 μmol) and NaHCO3 (59 mg, 703 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then adjusted to pH = 6 by addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 530.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.43 (br s, 1 H) 8.35 (br s, 1 H) 7.33 (d, J = 7.34 Hz, 1 H) 7.16 - 7.24 (m, 2 H)) 6.87 - 6.97 (m, 1 H) 6.78 - 6.85 (m, 2 H) 6.48 (d, J = 7.34 Hz, 1 H) 4.47 (t, J = 6.17 Hz, 1 H) 4.15 (t, J = 5.26 Hz, 2 H) 3.35 - 3.43 (m, 2 H) 2.99 - 3.24 (m, 4 H) 2.97 - 2.99 (m, 1 H) 2.92 (br d, J = 5.75 Hz, 2 H) 2.63 - 2.76 (m, 4 H) 2.20 - 2.33 (m, 1 H) 2.04 - 2.15 (m, 1 H) 1.70 - 1.91 (m, 6 H).

[00598] Compound 112: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2,2-difluoroethyl)(4-(5, 6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of acid (S)-2-amino-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid ( 100 mg, 270 μmol) and 4-chloro-1H-pyrazol[3,4- d]pyrimidine (46 mg, 2,975 μmol) in H2O (0.5 ml) and THF (2 ml) was added NaHCO3 (45 mg, 540 μmol) and the resulting mixture was stirred at 70 °C for 15 h and then allowed to cool to room temperature and then adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 489.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.18 (s, 1 H) 8.01 (s, 1 H) 7.42 (br d, J = 7.50 Hz, 1 H) 6, 50 (d, J = 7.28 Hz, 1 H) 5.68 - 6.13 (m, 1 H) 4.89 - 4.98 (m, 1 H) 3.38 (br d, J = 5.51 Hz, 2 H) 2.82 - 2.95 (m, 2 H) 2.56 - 2.77 (m, 8 H) 2.24 (br s, 1 H) 2.13 (br d, J = 6.17 Hz, 1 H) 1.78 - 1.97 (m, 4 H) 1.49 - 1.75 (m, 2 H).

[00599] Compound 113: (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, 444 μmol) in 4:1 THF/H2O (2.5 ml) was added 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (75 mg, 444 μmol) and NaHCO3 (112 mg, 1.33 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound as the hydrochloride salt. LCMS (ESI+): m/z = 479.2 (M+H)+. 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).

[00600] Compound 114: (S)-4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-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, 444 μmol) in 4:1 THF/H2O (2 ml) was added 2-chloro-5-(trifluoromethyl)pyrimidine (89 mg, 488 μmol) and NaHCO3 (112 mg, 1.33 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 493.2 (M+H)+. 1H NMR (400 MHz, D2O): δ ppm 8.61 (br s, 2 H) 7.49 (d, J = 7.34 Hz, 1 H) 6.53 (d, J = 7.21 Hz, 1 H) 4.56 - 4.68 (m, 1 H) 3.24 - 3.58 (m, 6 H) 2.61 - 2.93 (m, 5 H) 2.50 (br s, 1 H) 2.35 (br s, 1 H) 1.63 - 1.95 (m, 6 H) 0.96 (br dd, J = 12.59, 7.58 Hz, 4 H).

[00601] Compound 115: (S)-4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)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, 444 μmol) in 4:1 THF/H2O (2 ml) was added 4-chloro-2-(trifluoromethyl)pyrimidine (89 mg, 488 μmol) and NaHCO3 (112 mg, 1.33 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 493.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4): δ ppm 8.09 (br s, 1 H) 7.34 (br d, J = 7.28 Hz, 1 H) 6.71 (br s, 1 H) 6.48 (br d, J = 6.84 Hz, 1 H) 6.41 - 6.41 (m, 1 H) 4.56 (br s, 1 H) 3.39 (br s, 2 H) 2.82 - 3.16 (m, 4 H) 2.58 - 2.73 (m, 4 H) 2.25 (br d, J = 5.95 Hz, 1 H) 2.09 (br d, J = 11.47 Hz, 2 H) 1.65 - 1.89 (m, 6 H) 0.44 - 0.76 (m, 4 H).

[00602] Compound 116: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-(cyclopropyl(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2- acid hydrochloride amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (170 mg, 491 μmol) in 4:1 THF/ H2O (2 ml) was added 4-chloro-1H-pyrazol[3,4-d]pyrimidine (83 mg, 540 μmol) and NaHCO3 (124 mg, 1.47 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 465.2 (M+H)+. 1H NMR (400 MHz, D2O): δ ppm 8.65 (s, 1 H) 8.56 (s, 1 H) 7.52 (br d, J = 7.34 Hz, 1 H) 6.56 (br d, J = 7.34 Hz, 1 H) 5.02 (br s, 1 H) 3.30 - 3.60 (m, 6 H) 2.37 - 2.88 (m, 7 H) 1.68 - 1.94 (m, 6 H) 0.91 - 1.07 (m, 4 H).

[00603] Compound 117: (S)-2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 234 μmol) in 4:1 THF/H2O (2 ml) was added 5-cyclopropyl-2-fluoropyrimidine (36 mg, 258 μmol) and NaHCO3 (59 mg, 703 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 545.3 (M+H)+. 1H NMR (400 MHz, deuterium oxide) δ ppm 8.27 (br s, 2 H) 7.48 (br d, J = 7.21 Hz, 1 H) 7.28 - 7.39 (m, 2 H) 7.02 - 7.12 (m, 1 H)) 6.91 (br d, J = 7.95 Hz, 2 H) 6.52 (d, J = 7.34 Hz, 1 H) 4.63 - 4.72 (m, 1 H) 4.33 (br s, 2 H) 3.65 (br s, 2 H) 3.28 - 3.54 (m, 6 H) 2.65 - 2.80 (m, 4 H) 2.53 (br s, 1H) 2.31 (br d, J = 7.70 Hz, 1 H) 1.70 - 1.94 (m, 7 H) 0.98 - 1.09 (m, 2 H) 0.67 (q, J = 5.09 Hz, 2 H).

[00604] Compound 118: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetra-) hydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2-amino-4-((2,2- difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)butyl)amino)butanoic acid (100 mg, 270 μmol, 1 eq) and 2-chloropyrimidine-5- carbonitrile (41 mg, 297 μmol) in H2O (0.5 ml) and THF (2 ml) was added NaHCO3 (45 mg, 540 μmol) and the resulting mixture was stirred at 50 °C for 1 h and then allowed to cool to room temperature and then adjusted to pH = 6 by the addition of 1 M aq. HCl solution and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 474.3. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.64 (br, s, 2 H) 7.60 (d, J = 7.34 Hz, 1 H) 6.25 - 6.74 (m, 2 H) 4.78 (dd, J = 8.56, 5.26 Hz, 1 H) 3.82 (td, J = 15.07, 3.36 Hz, 2 H) 3.35 - 3.62 (m, 6 H) 2.73 - 2.89 (m, 4 H) 2.45 - 2.59 (m, 1 H) 2.26 - 2.41 (m, 1 H) 1.72 - 2.02 (m, 6 H). SCHEME 11, COMPOUND 119:

[00605] Step 1: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-amino-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 405 μmol) and 5-bromo-4-chloropyrimidine (94 mg, 486 μmol) in THF (1.2 ml) and H2O (0.3 ml) was added NaHCO3 (170 mg, 2.02 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then adjusted to pH = 6 by addition of 1 M aq. HCl solution and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 527.2 (M+H)+.

[00606] Step 2: (S)-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: To a solution of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (213 mg, 404 μmol) and phenylboronic acid (59 mg, 485 μmol) in 1,4-dioxane (1 ml) H2O (0.25 ml) was added Pd(dppf)Cl2 (30 mg, 40 μmol) and K2CO3 (112 mg, 808 μmol) were added and the resulting mixture was stirred at 100 °C for 2 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 525.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.85 (s, 1 H) 8.22 (s, 1 H) 7.61 (s, 3 H) 7.60 - 7.68 (m, 1 H) 7.59 (br s, 2 H) 6.63 - 6.69 (m, 1 H) 6.30 - 6.62 (m, 1 H) 5.13 (br t, J = 6.05 Hz, 1 H) 3.78 (br t, J = 13.75 Hz, 2 H) 3.47 - 3.60 (m, 3 H) 3.35 - 3.44 (m, 3 H) 2.71 - 2.92 (m, 4 H) 2.53 - 2.68 (m, 1 H) 2.40 (br s, 1 H) 1.92 - 2.06 (m, 1 H) 1.92 - 2.01 (m, 1 H) 1.67 - 1.92 (m, 4 H). SCHEME 12, COMPOUND 120:

[00607] Step 1: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-amino-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 405 μmol) and 5-bromo-4-chloropyrimidine (94 mg, 486 μmol) in THF (1.2 ml) and H2O (0.3 ml) was added NaHCO3 (170 mg, 2.02 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then adjusted to pH = 6 by addition of 1 M aq. HCl solution and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 527.2 (M+H)+.

[00608] Step 2: (S)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid: To a solution of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (213 mg, 404 μmol) in MeOH (3 mL) was added 10 wt % Pd/C (60 mg) and the resulting mixture was stirred under an atmosphere of H 2 for 5 h and then filtered and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 449.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.78 (s, 1 H) 8.21 (dd, J = 7.34, 1.35 Hz, 1 H) 7.60 (d, J = 7.34 Hz, 1 H) 7.00 - 7.08 (m, 1 H) 6.28 - 6.73 (m, 2 H) 4.99 - 5.09 (m, 1 H) 3.83 (td, J = 15.07, 3.36 Hz, 2 H) 3.36 - 3.65 (m, 6 H) 2.75 - 2.89 (m, 4 H) 2.51 - 2.64 (m, 1 H) 2.34 - 2.48 (m, 1 H) 1.73 - 2.05 (m, 6 H).

[00609] Compound 121: (S)-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: To a solution of (S)-2-amino-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (200 mg, 540 μmol) and 2-chloro-5-fluoropyrimidine (74 μl, 594 μmol) in DMA (3 ml) was added DIPEA (470 μl, 2.70 mmol) and the resulting mixture was stirred at 70 °C for 15 h and then allowed to cool to room temperature and then adjusted to pH = 6 by addition of 1 M aq. HCl solution and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 467.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.16 (s, 2 H) 7.46 (d, J = 7.34 Hz, 1 H) 6.54 (d, J = 7.34 Hz, 1 H) 5.68 - 6.08 (m, 1 H) 4.34 - 4.49 (m, 1 H) 3.36 - 3.50 (m, 2 H) 2.65 - 2.82 (m, 9 H) 2.51 - 2.60 (m, 1 H) 1.98 - 2.17 (m, 2 H) 1.76 - 1.96 (m, 4 H) 1.58 (q, J = 6.60 Hz, 2 H).

[00610] Compound 122: (S)-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: To a solution of (S)-2-amino-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 405 μmol) and 4-chloro-6-methyl-2-(pyridin-4-yl)pyrimidine (92 mg, 445 μmol) in DMA (2 ml) was added DIPEA (71 μl, 405 μmol) and the resulting mixture was stirred at 70 °C for 12 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 540.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.54 (br d, J = 4.85 Hz, 2 H) 8.23 (br s, 2 H) 7.43 (br s, 1 H) 6.44 - 6.65 (m, 1 H) 6.24 (s, 1 H) 5.63 - 6.12 (m, 1 H) 4.61 - 4.83 (m, 1 H) 4.73 (br s, 1 H) 2.92 - 3.26 (m, 2 H) 2.51 - 2.67 (m, 3 H) 2.51 - 2.91 (m, 7 H) 2.24 - 2.50 (m, 3 H) 2.17 (br s, 1 H) 2.06 (br s, 1 H) 1.92 (br d, J = 5.95 Hz, 2 H) 1.60 - 1.79 (m, 3 H). SCHEME 13, COMPOUND 123:

[00611] Step 1: N-(2-(4-fluorophenoxy)ethyl)-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 (5 g, 15.89 mmol) in DCM (75 mL) was added CDI (2.83 g, 17.48 mmol) at 0 °C and the mixture was stirred for 1 h. To this was then added 2-(4-fluorophenoxy)ethanamine hydrochloride (11.4 mL, 17.48 mmol) and the resulting mixture was stirred at room temperature for 2 h and then diluted with H2O. The layers were separated and the aqueous layers were extracted with DCM and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was redissolved in EtOAc (40 mL) and then heated to reflux. Hexanes (15 mL) were then added and the solution was cooled to room temperature causing a precipitate to form. The solid was filtered and the filtrate was concentrated in vacuo to give the title compound. LCMS (ESI+): m/z = 358.0 (M+H)+.

[00612] Step 2: N-(2-(4-fluorophenoxy)ethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine: To a mixture of LiAlH4 (590 mg, 15.56 mmol) in 1,4-dioxane (30 mL) was added N-(2-(4-fluorophenoxy)ethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide (2.78 g, 7.78 mmol) and the resulting mixture was heated at reflux for 30 min and then allowed to cool to room temperature. The mixture was cooled to 10 °C and then neutralized by careful addition of H2O (0.6 mL), 1 M NaOH (0.6 mL), then with H2O (0.6 mL), followed by drying over MgSO4. The mixture was filtered and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 344.2 (M+H)+.

[00613] Step 3: (S)-Methyl 2-(((benzyloxy)carbonyl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: To a mixture of N-(2-(4-fluorophenoxy)ethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (2.67 g, 7.77 mmol) and methyl (2S)-2-(benzyloxycarbonylamino)-4-oxo-butanoate (2.17 g, 8.16 mmol) in DCE (50 mL) at 0 °C was added AcOH (667 μL, 11.66 mmol) and then NaBH(OAc)3, (2.47 g, 11.66 mmol) the resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with aqueous NaHCO3 solution and then extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by normal phase chromatography on silica gel to furnish the title compound. LCMS (ESI+): m/z = 593.4 (M+H)+.

[00614] Step 4: (S)-2-(((benzyloxy)carbonyl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (4 g, 6.75 mmol) in 1:1:1 THF/MeOH/H2O (37.5 mL) was added LiOH.H2O (566 mg, 13.50 mmol) and the resulting mixture was stirred at room temperature for 1 h. The mixture was adjusted to pH = 6 by the addition of 1 M aq. HCl solution and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 579.5 (M+H)+.

[00615] Step 5: (S)-2-amino-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (4 g, 6.91 mmol) in i-PrOH (30 mL) was added 10 wt % Pd(OH) 2 /C (1.9 g) and the resulting mixture was stirred under an atmosphere of H 2 for 48 h. The mixture was filtered and then concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 445.4 (M+H)+.

[00616] Step 6: (S)-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: To a solution of (S)-2-amino-4-((2-(4-fluorophenoxy))ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (80 mg, 180 μmol) and 4-chloro-1-methyl-pyrazolo[3,4- d ]pyrimidine (33 mg, 198 μmol) in H2O (0.5 ml) and THF (2 ml) NaHCO3 (76 mg, 900 μmol) was added and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 577.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.15 (s, 1 H) 7.97 (s, 1 H) 7.21 - 7.46 (m, 1 H) 6.76 - 6.90 (m, 2 H) 6.71 (br s, 2 H) 6.46 (br d, J = 7.02 Hz, 1 H) 4.61 - 4.82 (m, 1 H) 4.09 (br s, 2 H) 3.92 (s, 3 H) 3.38 (br s, 2 H) 3.21 - 3.30 (m, 4 H) 2.90 - 3.11 (m, 3 H) 2.86 (br s, 1 H) 2.63 - 2.75 (m, 4 H) 2.36 (br s, 1 H) 2.07 - 2.18 (m, 1 H) 1.68 - 1.90 (m, 6 H). SCHEME 14, COMPOUND 124:

[00617] Step 1: 5-Cyclopropyl-2-fluoropyrimidine: To a solution of 5-bromo-2-fluoro-pyrimidine (5 g, 28.25 mmol) and cyclopropylboronic acid (2.91 g, 33.90 mmol) in toluene (100 mL) was added K3PO4 (17.99 g, 84.76 mmol), PCy3 (916 μL, 2.83 mmol), and Pd(OAc)2 (317 mg, 1.41 mmol) and the resulting mixture was stirred at 100 °C for 10 h and then cooled to rt. The mixture was poured into H2O and the resulting mixture 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 normal phase chromatography on silica gel to furnish the title compound.

[00618] Step 2: (S)-2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (100 mg, 241 μmol) and 5-cyclopropyl-2-fluoropyrimidine (36.62 mg, 265.08 μmol, 1.1 eq) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (101 mg, 1.20 mmol) and the resulting mixture was stirred at 70 °C for 12 h and then allowed to cool to room temperature and then adjusted to pH = 6 by the addition of 1 M aq. HCl solution and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 497.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.56 (br s, 2 H) 7.60 (br d, J = 6.85 Hz, 1 H) 6.67 (br d, J = 7.09 Hz, 1 H) 4.86 - 4.92 (m, 1 H) 3.87 (br s, 1 H) 3.50 - 3.54 (m, 2 H) 3.39 (s, 4 H) 3.08 - 3.31 (m, 5 H) 2.77 - 2.85 (m, 4 H) 2.54 (br s, 1 H) 2.42 (br s, 1 H) 2.20 - 2.25 (m, 1 H) 1.92 - 2.00 (m, 3 H) 1.81 (br s, 3 H) 1.22 (br d, J = 5.50 Hz, 3 H) 1.05 - 1.11 (m, 2 H) 0.82 (br d, J = 4.77 Hz, 2 H).

[00619] Compound 125: (S)-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: To a mixture of (S)-2-amino-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 242 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (61 mg, 727 μmol) followed by 4-chloro-1H- Pyrazol[3,4-d]pyrimidine (45 mg, 291 μmol) and the resulting mixture was stirred at 70 °C for 18 h and then allowed to cool to rt and then adjusted to pH = 6 by the addition of 1 M aq. HCl solution and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 531.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.84 (s, 1 H) 8.61 (s, 1 H) 7.58 (d, J = 7.34 Hz, 1 H) 6.66 (d, J = 7.34 Hz, 1 H) 5.27 (br dd, J = 8.31, 5.01 Hz, 1 H) 3.81 (br d, J = 6.85 Hz, 2 H) 3.69 - 3.77 (m, 2 H) 3.53 - 3.58 (m, 1 H) 3.45 - 3.53 (m, 3 H) 3.37 (br t, J = 7.40 Hz, 2 H) 3.12 (s, 3 H) 2.77 - 2.84 (m, 4 H) 2.61 - 2.71 (m, 1 H) 2.47 - 2.59 (m, 1 H) 1.95 (q, J = 5.90 Hz, 2 H) 1.85 (td, J = 13.11, 6.17 Hz, 4 H).

[00620] Compound 126: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((2-(methylsulfonyl)ethyl)(4-( 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of acid (S)-2-amino-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 242 μmol) in DMA (2 ml) DIPEA (211 μl, 1.21 mmol) was added followed by 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (48 mg, 267 μmol) and the resulting mixture was stirred at 100 °C for 2 h and then allowed to cool to room temperature and then adjusted to pH = 6 by the addition of 1 M aq. HCl solution and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 557.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.51 - 8.64 (m, 2 H) 7.89 (s, 1 H) 7.58 (d, J = 7.06 Hz, 1 H ) 7.25 (br s, 1 H) 6.65 (br d, J = 7.06 Hz, 2 H) 4.95 (br s, 1 H) 3.77 (br dd, J = 19.96, 5.62 Hz, 4 H) 3.47 - 3.55 (m, 3 H) 3.45 (br s , 1 H) 3.35 (br d, J = 7.50 Hz, 2 H) 3.13 (s, 3 H) 2.76 - 2.85 (m, 4 H) 2.58 (br s, 1 H) 2.41 (br s, 1 H) 1.77 - 2.00 (m, 6 H). SCHEME 15, COMPOUND 127:

[00621] Step 1: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (250 mg, 577 μmol) and 5-bromo-4-chloropyrimidine (134 mg, 693 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (243 mg, 2.89 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then adjusted to pH = 6 by the addition of 1 M aq. HCl solution and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 554.2 (M+H)+.

[00622] Step 2: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid: To a solution of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (200 mg, 361 μmol) in MeOH (5 mL) was added 20 wt % Pd/C (38 mg) and the resulting mixture was stirred under an atmosphere of H 2 for 5 h and then filtered and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 475.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.33 (s, 1 H) 7.94 (br s, 1 H) 7.40 (d, J = 7.28 Hz, 1 H) 6.44 - 6.55 (m, 2 H) 4.80 - 4.83 (m, 1 H) 4.55 - 4.79 (m, 1 H) 3.53 - 3.58 (m, 1 H) 3.50 (dd, J = 6.95, 4.52 Hz, 1 H) 3.39 (q, J = 5.59 Hz, 2 H) 3.33 (s, 3 H) 2.93 (br s, 2 H) 2.63 - 2.76 (m, 8H) 2.14 - 2.24 (m, 1 H) 2.02 - 2.11 (m, 1 H) 1.76 - 1.92 (m, 4 H) 1.57 - 1.69 (m, 2 H). SCHEME 16, COMPOUND 128:

[00623] Step 1: (S)-2-((6-chloropyrimidin-4-yl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6, 7,8-tetrahydro-1,8-naphthyridin-2- yl)butyl)amino)butanoic acid: A solution of (S)-2- acid hydrochloride amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid ( 100 mg, 231 μmol) and 4,6-dichloropyrimidine (41 mg, 277 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (97 mg, 1.15 mmol) and the resulting mixture was stirred at 70 °C for 18 h and then allowed to cool to room temperature and then adjusted to pH = 6 by the addition of 1 M aq. HCl solution and concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 510.3 (M+H)+.

[00624] Step 2: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2) acid -yl)butyl)amino)-2-((6-phenylpyrimidin-4- yl)amino)butanoic acid: To a solution of (S)-2-((6-chloropyrimidin-4- yl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino )butanoic acid (100 mg, 196 μmol) and phenylboronic acid (29 mg, 236 μmol) in 1,4-dioxane (2 ml) and H2O (1 ml) were Pd(dppf)Cl2 (14 mg, 20 μmol) and K2CO3 (81 mg, 589 μmol) were added and the resulting mixture was stirred at 100 °C for 2 h and then cooled to room temperature. The mixture was filtered and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 551.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.81 (s, 1H) 7.88 (br d, J = 7.46 Hz, 2 H) 7.63 - 7.74 (m, 3 H ) 7.59 (br d, J = 6.97 Hz, 1 H) 7.30 (br s, 1 H) 6.67 (br d, J = 7.21 Hz, 1 H) 5.14 - 5.34 (m, 1 H) 5.10 (br s, 1 H) 3.63 - 3.77 (m, 4 H) 3.57 (br d, J = 8.68 Hz, 2 H) 3.48 - 3.53 (m, 3 H) 3.41 (s, 4H) 2.81 (br d, J = 4.89 Hz, 4 H) 2.40 - 2.64 (m, 2 H) 1.79 - 1.97 (m, 6 H).

[00625] Compound 129: (2S)-4-((oxetan-2-ylmethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with oxetan-2-ylmethanamine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 505.3. [M+H]+, found 505.3.

[00626] Compound 130: (S)-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. Prepared according to Scheme B using Procedure F with 2-(aminomethyl)propane-1,3-diol, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 523.3; [M+H]+ found 523.3. SCHEME 17, COMPOUND 131:

[00627] Step 1: tert-butyl 7-(4-((3,3-difluoropropyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate: To a solution of 3,3-difluoropropan-1-amine hydrochloride (12.04 g, 82.39 mmol) in MeOH (200 mL) at 0 °C was added AcOH (3.2 mL, 56.18 mmol), NaBH3CN (4.71 g, 74.90 mmol), then a solution of tert-butyl 7-(4-oxobutyl)-3,4-dihydro-2H-1,8-naphthyridine-1-carboxylate (12 g, 37.45 mmol) in MeOH (100 mL) and the resulting mixture was stirred for 2 h at rt. The mixture was diluted with aqueous NaHCO3 solution and then extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 384.1 (M+H)+

[00628] Step 2: (S)-tert-butyl 7-(4-((3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)(3,3-difluoropropyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate: To a solution of 7-(4-((3,3-difluoropropyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-tert-butyl carboxylate (19 g, 44.59 mmol) and (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (13.70 g, 49.05 mmol) in DCE (200 mL) at 0 °C was added AcOH (3.8 mL, 66.89 mmol) was added then NaBH(OAc)3 (14.18 g, 66.89 mmol) and the resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with aqueous NaHCO3 solution and the layers were separated. The aqueous layer was extracted with DCM and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on alumina to furnish the title compound. LCMS (ESI+): m/z = 633.3 (M+H)+

[00629] Step 3: (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: A mixture of (S)-tert-butyl 7-(4-((3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)(3,3-difluoropropyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (26 g, 36.98 mmol) in 4 M HCl in EtOAc (300 mL) was stirred for 16 h at room temperature and then concentrated in vacuo. The crude residue was taken up in water and then washed with MTBE. The aqueous layer was adjusted to pH = 8 by the addition of 1 M NaOH and then extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to furnish the title compound. LCMS (ESI+): m/z = 533.3 (M+H)+;

[00630] Step 4: (S)-2-(((benzyloxy)carbonyl)amino)-4-((4-(8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(3,3-difluoropropyl)amino)butanoic acid: To a solution of (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (5 g, 8.45 mmol) in 4:1:1 THF/MeOH/H2O (60 mL) was added LiOH.H2O (709 mg, 16.90 mmol) and the resulting mixture was stirred for 16 h at room temperature. The mixture was adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 519.4 (M+H)+;

[00631] Step 5: (S)-2-amino-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-((4-(8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(3,3-difluoropropyl)amino)butanoic acid (4 g, 7.33 mmol) in i-PrOH (200 mL) was added 10 wt % Pd(OH) 2 /C (6.0 g) and the resulting mixture was stirred under an atmosphere of H 2 (3.44 bar (50 psi) for 2 h and then evaporated to room temperature. filtered and concentrated in vacuo to give the title compound which was used without further purification. LCMS (ESI+): m/z = 385.2 (M+H)+

[00632] Step 6: (S)-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: To a solution of (S)-2-amino-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 327.73 mol) in THF (4 ml) and H2O (1 ml) was added 5-bromo-2-chloropyrimidine (70 mg, 361 μmol) and NaHCO3 (138 mg, 1.64 mmol) and the resulting mixture was stirred at 70 °C for 5 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 541.1 (M+H)+. 1H NMR (400 MHz, D2O) δ ppm 8.42 (s, 2 H) 7.51 (d, J = 7.46 Hz, 1 H) 6.53 (br d, J = 7.21 Hz, 1 H) 5.91 - 6.26 (m, 1 H) 4.56 (dd, J = 5.01, 8.68 Hz, 1 H) 3.30 - 3.48 (m, 6 H) 3.22 (br d, J = 7.83 Hz, 2 H) 2.74 (t, J = 6.11 Hz, 2 H) 2.67 (br s, 2 H) 2.21 - 2.49 (m, 4 H) 1.88 (q, J = 5.93Hz, 2H) 1.70 (br s, 4 H).

[00633] Compound 132: (S)-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: To a solution of (S)-2-amino-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 328 μmol) in THF (4 ml) and H2O (1 ml) was added 2-chloro-5-(trifluoromethyl)pyrimidine (66 mg, 361 μmol) and NaHCO3 (138 mg, 1.64 mmol) and the mixture The resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 531.2 (M+H)+. 1H NMR (400 MHz, D2O) δ ppm 8.66 (s, 2 H) 7.54 (br d, J = 7.21 Hz, 1 H) 6.57 (br d, J = 7.34 Hz, 1 H) 5.94 - 6.28 (m, 1 H) 4.6 2- 4.69 (m, 1 H) 3.34 - 3.52 (m, 6 H) 3.26 (br s, 2 H) 2.66 - 2.82 (m, 4 H) 2.28 - 2.53 (m, 4 H) 1.85 - 1.96 (m, 2 H) 1.74 (br s, 4 H).

[00634] Compound 133: (S)-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: To a solution of (S)-2-amino-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 328 μmol) in THF (4 mL) and H2O (1 mL) was added 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (55 mg, 328 μmol) and NaHCO3 (138 mg, 1.64 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 517.2 (M+H)+. 1H NMR (400 MHz, Deuterium Oxide) δ ppm 8.30 - 8.48 (m, 2 H) 7.52 (br d, J = 6.97 Hz, 1 H) 6.55 (br d, J = 6.85 Hz, 1 H) 5.95 - 6.28 (m, 1 H) 4.86 (br s, 1 H) 4.04 (s, 3 H) 3.38 - 3.56 (m, 6 H) 3.29 (br s, 2 H) 2.66 - 2.80 (m, 4 H) 2.30 - 2.63 (m, 4 H) 1.86 - 1.96 (m, 2 H) 1.75 (br s, 4 H).

[00635] Compound 134: (S)-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: To a solution of (S)-2-amino-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 328 μmol) in THF (4 mL) and H2O (1 mL) was added 4-chloro-2-(trifluoromethyl)pyrimidine (66 mg, 361 μmol) and NaHCO3 (138 mg, 1.64 mmol) and the resulting mixture was stirred at 70 °C for 18 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 531.2 (M+H)+. 1H NMR (400 MHz, D2O) δ ppm 8.22 (br d, J = 5.75 Hz, 1 H) 7.49 (br d, J = 7.09 Hz, 1 H) 6.84 (d, J = 6.24 Hz, 1 H) 6.52 (br d, J = 7.34 Hz, 1 H) 5.91 - 6.26 (m, 1 H) 4.72 (br s, 1 H) 3.14 - 3.50 (m, 8 H) 2.61 - 2.78 (m, 4 H) 2.21 - 2.52 (m, 4 H) 1.82 - 1.94 (m, 2 H) 1.69 (br s, 4 H).

[00636] Compound 135: (S)-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: To a solution of (S)-2-amino-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 327.73 mol) in THF (4 ml) and H2O (1 ml) was added 1-cyclopropyl-4-fluorobenzene (50 mg, 361 μmol) and NaHCO3 (138 mg, 1.64 mmol) and the resulting mixture was stirred at 70 °C for 5 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 503.2 (M+H)+. 1H NMR (400 MHz, D2O) δ ppm 8.40 (br s, 2 H) 7.52 (d, J = 7.46 Hz, 1 H) 6.56 (d, J = 7.34 Hz, 1 H) 5.91 - 6.25 (m, 1 H) 4.67 - 4.71 (m, 1 H) 3.21 - 3.49 (m, 8 H) 2.67 - 2.79 (m, 4 H) 2.24 - 2.52 (m, 4 H) 1.85 - 1.93 (m, 3 H) 1.73 (br d, J = 3.67 Hz, 4 H) 0.96 - 1.08 (m, 2 H) 0.65 - 0.73 (m, 2 H). SCHEME 18, COMPOUND 136:

[00637] Step 1: 7-(4-((3-fluoropropyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl: To a solution of 3-fluoropropan-1-amine hydrochloride (6.72 g, 56.18 mmol) and NaBH3CN (3.92 g, 62.42 mmol) in MeOH (100 mL) was added a solution of 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl (10 g, 31.21 mmol) in MeOH (80 mL) and the resulting mixture was stirred at room temperature for 2 h. The resulting solution was poured into water and then extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 366.0 (M+H)+

[00638] Step 2: (S)-tert-butyl 7-(4-((3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)(3-fluoropropyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate: To a solution of 7-(4-((3-fluoropropyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-tert-butyl carboxylate (12 g, 30.53 mmol) and (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (11.08 g, 39.70 mmol) in DCE (150 mL) at 0 °C was added AcOH (2.62 ml, 45.80 mmol), then NaBH(OAc)3 (9.71 g, 45.80 mmol) and the resulting mixture was stirred at room temperature for 1 h and then diluted with sat. aq. NaHCO3 solution. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on alumina to furnish the title compound. LCMS (ESI+): m/z = 615.5 (M+H)+

[00639] Step 3: (S)-Methyl 2-(((benzyloxy)carbonyl)amino)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: (S)-tert-butyl 7-(4-((3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)(3-fluoropropyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (14 g, 21.41 mmol) was taken up in 4 M HCl in EtOAc (150 mL) and then stirred at room temperature for 16 h and concentrated in vacuo. The crude residue was taken up in water and then washed with MTBE and then adjusted to pH = 8 by the addition of 1 M NaOH and then extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 515.2 (M+H)+

[00640] Step 4: (S)-2-(((benzyloxy)carbonyl)amino)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (4 g, 7.00 mmol) in 4:1:1 THF/MeOH/H2O (600 mL) was added LiOH.H2O (881 mg, 20.99 mmol) and the resulting mixture was stirred at room temperature for 1 h and then adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 501.2 (M+H)+

[00641] Step 5: (S)-2-amino-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (4.8 g, 9.01 mmol) in i-PrOH (200 mL) was added 10 wt % Pd(OH) 2 /C (7.41 g) and the resulting mixture was stirred under an atmosphere of H 2 (3.44 bar (50 psi)) for 38 h and then filtered and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 367.3 (M+H)+

[00642] Step 6: (S)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- acid 2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid: A solution of (S)-2-amino-4-((3- fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 368 μmol) in THF (4 ml) and H2O (1 ml) 4-chloro-1H-pyrazol[3,4-d]pyrimidine (68 mg, 405 μmol) and NaHCO3 (155 mg, 1.84 mmol) and the resulting mixture was stirred at 70 °C for 1 h and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 499.3 (M+H)+. 1H NMR (400 MHz, D2O) δ ppm 8.42 (s, 1 H) 8.35 (s, 1 H) 7.49 (br d, J = 6.97 Hz, 1 H) 6.53 ( br s, 1 H) 4.81 - 4.96 (m, 1 H) 4.63 (t, J = 5.20 Hz, 1 H) 4.51 (t, J = 5.26 Hz, 1 H) 4.02 (s, 3 H) 3.18 - 3.49 (m, 8 H) 2.62 - 2.80 (m, 4 H) 2.33 - 2.60 (m, 2 H) 2.05 - 2.22 (m, 2 H) 1.83 - 1.93 (m, 2 H) 1.73 (br s, 4 H).

[00643] Compound 137: (S)-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: To a solution of (S)-2-amino-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 368 μmol) in THF (4 ml) and H2O (1 ml) was added 2-chloro-5-(trifluoromethyl)pyrimidine (74 mg, 405 μmol) and NaHCO3 (155 mg, 1.84 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 513.2 (M+H)+. 1H NMR (400 MHz, D2O) δ ppm 8.57 (s, 2 H) 7.44 (br d, J = 7.34 Hz, 1 H) 6.48 (dd, J = 3.85, 7.27 Hz, 1 H) 4.52 - 4.62 (m, 2 H) 4.44 (br t, J = 4.34 Hz, 1 H) 3.11 - 3.42 (m, 8 H) 2.57 - 2.72 (m, 4 H) 2.16 - 2.46 (m, 2 H) 1.94 - 2.12 (m, 2 H) 1.81 (q, J = 5.90 Hz, 2 H) 1.65 (br d, J = 2.69Hz, 4H).

[00644] Compound 138: (S)-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: To a solution of (S)-2-amino-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (120 mg, 270 μmol) and 2-chloropyrimidine-5-carbonitrile (41 mg, 297 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (113 mg, 1.35 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 548.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.27 - 8.63 (m, 2 H) 7.31 (br d, J = 7.21 Hz, 1 H) 6.90 - 7.00 (m, 2 H) 6.78 - 6.88 (m, 2 H) 6.47 (d, J = 7.21 Hz, 1 H) 4.45 - 4.48 (m, 1 H) 4.12 (t, J = 5.20 Hz, 2 H) 3.33 - 3.43 (m, 2 H) 3.03 - 3.22 (m, 4 H) 2.81 - 2.92 (m, 2 H) 2.72 (br t, J = 6.24 Hz, 2H) 2.65 (br t, J = 7.76 Hz, 2 H) 2.19 - 2.31 (m, 1 H) 2.03 - 2.17 (m, 1 H) 1.67 - 1.91 (m, 6 H).

[00645] Compound 139: (S)-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: To a solution of (S)-2-amino-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (120 mg, 270 μmol) and 2-chloropyrimidine-5-carbonitrile (120 mg, 270 μmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (54 mg, 297 μmol) In THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (113 mg, 1.35 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 591.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.25 - 8.61 (m, 2 H) 7.34 (d, J = 7.45 Hz, 1 H) 6.89 - 6.97 (m, 2 H) 6.80 - 6.88 (m, 2 H) 6.46 - 6.52 (m, 1 H) 4.45 (t, J = 6.14 Hz, 1 H) 4.18 (t, J = 5.04 Hz, 2 H) 3.32 - 3.45 (m, 2 H) 3.09 - 3.28 (m, 4 H) 2.91 - 3.08 (m, 2 H) 2.60 - 2.76 (m, 4 H) 2.28 (br d, J = 3.95 Hz, 1 H) 2.15 (br d, J = 4.82 Hz, 1 H) 1.72 - 1.93 (m, 6 H). SCHEME 19, COMPOUND 140:

[00646] Step 1: 7-(4-((2-(dimethylamino)-2-oxoethyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl: To a mixture of 2-amino-N,N-dimethylacetamide (2.01 g, 19.71 mmol) in MeOH (10 mL) at 0 °C was added NaBH3CN (1.24 g, 19.71 mmol), AcOH (1.13 mL, 19.71 mmol), then 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl (3 g, 9.86 mmol) and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was then poured into aq. NaHCO3 solution and then concentrated in vacuo to remove volatiles. The remaining 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 normal phase chromatography on silica gel to afford the title compound. LCMS (ESI+): m/z = 391.0 (M+H)+.

[00647] Step 2: 7-(4-((3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)(2-(dimethylamino)-2-oxoethyl)amino)butyl)-3 (S)-tert-butyl ,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate: A mixture of 7-(4- tert-butyl ((2-(dimethylamino)-2-oxoethyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (1.68 g, 4.10 mmol) and (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (1.14 g, 4.30 mmol) in DCE (15 ml) to 0 °C was added AcOH (352 μL, 6.15 mmol), then NaBH(OAc)3 (1.30 g, 6.15 mmol) and the resulting mixture was stirred at room temperature for 1 h. The mixture The reaction mixture was then poured into aq. NaHCO3 solution and the layers were separated. The aqueous layer was extracted with DCM and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography. normal phase on silica gel to give the title compound. LCMS (ESI+): m/z = 640.5 (M+H)+.

[00648] Step 3: (S)-Methyl 2-(((benzyloxy)carbonyl)amino)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: (S)-tert-butyl 7-(4-((3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)(2-(dimethylamino)-2-oxoethyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (2.5 g, 3.91 mmol) was taken up in 4 M HCl in EtOAc (40 mL) and the resulting solution was stirred at room temperature for 15 h and, then concentrated in vacuo to give the title compound which was used without further purification. LCMS (ESI+): m/z = 540.4 (M+H)+.

[00649] Step 4: (S)-2-(((benzyloxy)carbonyl)amino)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (2.11 g, 3.91 mmol) in 2:2:1 THF/MeOH/H2O (37.5 mL) was added Li-OH.H2O (328 mg, 7.82 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was adjusted to pH = 6 by addition of 1 M aq. HCl solution and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 526.2 (M+H)+.

[00650] Step 5: (S)-2-amino-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-(((benzyloxy)carbonyl)amino)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (2.06 g, 3.82 mmol) in i-PrOH (50 mL) was added 20 wt % Pd(OH) 2 /C (700 mg), and the resulting mixture was stirred overnight under an atmosphere of H 2 , and then the reaction mixture was filtered and concentrated vacuo to give the title compound which was used without further purification. LCMS (ESI+): m/z = 392.4 (M+H)+.

[00651] Step 6: (S)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) acid )butyl)amino)-2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid: A mixture of (S)-2-amino- 4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 383 μmol) and 4-chloro-1-methyl-1H-pyrazol[3,4-d]pyrimidine (71 mg, 421 μmol) in THF (2 ml) and H2O (0.5 mL) was added NaHCO3 (161 mg, 1.92 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 524.5 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.27 (br d, J = 22 Hz, 2 H) 7.29 (br d, J = 6.97 Hz, 1 H) 6.41 (d, J = 7.21 Hz, 1 H) 4.47 - 4.78 (m, 1 H) 3.93 (s, 3 H) 3.58 - 3.69 (m, 1 H) 3.50 (br d, J = 15.04 Hz, 1 H) 3.32 - 3.41 (m, 2 H) 3 .02 (s, 3 H) 2.52 - 2.97 (m, 11 H) 2.13 - 2.32 (m, 2 H) 1.47 - 1.98 (m, 6 H).

[00652] Compound 141: (S)-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: To a mixture of (S)-2-amino-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 383 μmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (70 mg, 383 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (161 mg, 1.92 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 538.2 (M+H)+. 1H NMR (400 MHz, ethanol-d4) δ ppm 8.52 (br s, 2 H) 7.28 (d, J = 7.46 Hz, 1 H) 6.45 (d, J = 7.34 Hz, 1 H) 4.49 (t, J = 5.87 Hz, 1 H) 3.55 - 3.73 (m, 2 H) 3.36 - 3.45 (m, 2 H) 3.06 (s, 3 H) 2.85 - 3.00 (m, 5 H) 2.69 - 2.83 (m, 4 H) 2.52 - 2.67 (m, 2 H) 2.23 (dq, J = 13.68, 6.77 Hz, 1 H) 2.04 - 2.13 (m, 1 H) 1.90 (q, J = 5.93 Hz, 2 H) 1.69 - 1.81 (m, 2 H) 1.59 - 1.66 (m, 2 H).

[00653] Compound 142: (S)-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: To a mixture of (2S)-2-amino-4-[2,2-difluoroethyl-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]amino]butanoic acid (200 mg, 486 μmol) and 4-chloro-6-phenyl-pyrimidine (111 mg, 583 μmol) in THF (2 ml), H2O (0.5 ml) was added NaHCO3 (204 mg, 2.43 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 525.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.41 (br s, 1 H) 7.81 (br s, 2 H) 7.41 - 7.50 (m, 3 H) 7.38 (br d, J = 6.62 Hz, 1 H) 6.78 (s, 1 H) 6.53 (d, J = 7.28 Hz, 1 H) 5.76 - 6.12 (m, 1 H) 4.66 (br s, 1 H) 3.33 - 3.47 (m, 2 H) 2.78 - 2.88 (m, 3 H) 2.56 - 2.78 (m, 7 H) 2.13 - 2.25 (m, 1 H) 2.09 (br s, 1 H) 1.75 - 1.96 (m, 4 H) 1.64 (q, J = 6.39 Hz, 2 H).

[00654] Compound 143: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-(4-fluorophenoxy)ethyl)(4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of acid (S)-2-amino-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino )butanoic acid (120 mg, 270 μmol) and 4-chloro-1H-pyrazol[3,4- d]pyrimidine (50 mg, 324 μmol) in THF (1.2 ml) and H2O (0.3 ml) was added NaHCO3 (113 mg, 1.35 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo . The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 563.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.15 (s, 1 H) 8.03 (s, 1 H) 7.27 (br d, J = 7.28 Hz, 1 H) 6.79 - 6.91 (m, 1 H) 6.73 (br s, 2 H) 6.43 (br d, J = 7.28 Hz, 1 H) 6.38 - 6.47 (m, 1 H) 4.11 (br s, 2 H) 3.36 (br s, 2 H) 3.27 (br s, 2 H ) 2.92 - 3.14 (m, 3 H) 2.92 - 3.14 (m, 1 H) 2.87 (br s, 1H) 2.63 - 2.76 (m, 2 H) 2.54 - 2.76 (m, 1 H) 2.54 - 2.76 (m, 1 H) 2.37 (br d, J = 5, 73 Hz, 1 H) 2.06 - 2.23 (m, 1 H) 1.69 - 1.92 (m, 6 H) 1.63 - 1.88 (m, 1 H).

[00655] Compound 144: (S)-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: To a mixture of (S)-2-amino-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (120 mg, 270 μmol) and 5-bromo-2-chloropyrimidine (63 mg, 324 μmol) in THF (1.2 ml) and H2O (0.3 ml) was added NaHCO3 (113 mg, 1.35 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 601.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.17 (s, 2 H) 7.30 (d, J = 7.50 Hz, 1 H) 6.89 - 6.97 (m, 2 H) 6.79 - 6.87 (m, 2 H)) 6.47 (d, J = 7.28 Hz, 1 H) 4.32 (t, J = 6.06 Hz, 1 H) 4.14 (t, J = 5.18 Hz, 2 H) 3.32 - 3.42 (m, 2 H) 3.00 - 3.25 (m, 4 H) 2.82 - 2.98 (m, 1 H) 2.91 (br s, 1 H) 2.58 - 2.75 (m, 4 H) 2.16 - 2.29 (m, 1 H) 2.00 - 2.15 (m, 1 H) 1.63 - 1.96 (m, 1 H) 1.63 - 1.96 (m, 5 H).

[00656] Compound 145: (S)-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: To a solution of (S)-2-amino-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 383 μmol) and 4-chloro-2-(trifluoromethyl)pyrimidine (84 mg, 460 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (161 mg, 1.92 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 538.2 (M+H)+. 1H NMR (400 MHz, ethanol-d4) δ ppm 8.02 (br d, J = 5.29 Hz, 1 H) 7.37 (br d, J = 7.28 Hz, 1 H) 6.74 (br d, J = 5.73 Hz, 1 H) 6.48 (d, J = 7.28 Hz, 1 H) 4.66 - 4.76 (m, 1 H) 3.67 (br d, J = 15.88 Hz, 1 H) 3.47 (br d, J = 15.21 Hz, 1 H) 3.32 - 3.39 (m, 2 H) 2.93 - 3.05 (m, 4 H) 2.87 (s, 3 H) 2.67 - 2.83 (m, 6 H) 2.56 - 2.67 (m, 1 H) 2.03 - 2.27 (m, 2 H) 1.82 - 1.93 (m, 3 H) 1.50 - 1.82 (m, 2 H) 1.58 (br s, 1 H).

[00657] Compound 146: (S)-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: To a mixture of (S)-2-amino-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (200 mg, 486 μmol) and 5-cyclopropyl-2-fluoropyrimidine (81 mg, 583 μmol) in THF (1.6 ml) and H2O (0.4 ml) was added NaHCO3 (204 mg, 2.43 mmol) and The resulting mixture was stirred at 70 °C for 1 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 489.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.02 (s, 2 H) 7.47 (d, J = 7.50 Hz, 1 H) 6.54 (d, J = 7.28 Hz, 1 H) 5.72 - 6.07 (m, 1 H) 4.44 (t, J = 5.84 Hz, 1 H) 3.35 - 3.44 (m, 2 H) 2.63 - 2.85 (m, 9 H) 2.51 - 2.62 (m, 1 H) 1.98 - 2.18 (m, 2 H) 1.81 - 1.93 (m, 4 H) 1.69 - 1.79 (m, 1 H) 1.58 (q, J = 6.62 Hz, 2 H) 0.86 - 0.97 (m, 2 H) 0.53 - 0.67 (m, 2 H).

[00658] Compound 147: (S)-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. Prepared according to Scheme B using Procedure F with (3-fluorooxetan-3-yl)methanamine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 523.3; [M+H]+ found 523.3.

[00659] Compound 148: (S)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(( 1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid.

[00660] Compound 149: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)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 trifluoroacetate (100 mg, 217 μmol) in 4:1 THF/H2O (2 ml) was added 2-chloropyrimidine-5-carbonitrile (33 mg, 239 μmol) and NaHCO3 (55 mg, 651 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 450.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4): δ ppm 8.58 (br s, 1 H) 8.47 (br s, 1 H) 7.36 (d, J = 7.34 Hz, 1 H) 6.50 (d, J = 7.34 Hz, 1 H) 4.42 (t, J = 6.05 Hz, 1 H) 3.35 - 3.45 (m, 2 H) 2.93 - 3.12 (m, 2 H) 2.80 - 2.92 (m, 2 H) 2.74 (t, J = 6.24 Hz, 2 H) 2.64 (br dd, J = 7.83, 5.75 Hz, 2 H) 2.21 - 2.32 (m, 1 H) 2.00 - 2.18 (m, 2 H) 1.84 - 1.93 (m, 2 H) 1.66 - 1.82 (m, 4 H) 0.56 - 0.70 (m, 4 H).

[00661] Compound 150: 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid)-2-((5-(trifluoromethyl )pyrimidin-2-yl)amino)butanoic acid.

[00662] Compound 151: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-(cyclopropyl(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00663] Compound 152: (S)-2-((5-Bromopyrimidin-2-yl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of 5-bromo-2-fluoro-pyrimidine (42 mg, 239 μmol) in 4:1 THF/H2O (2 ml) was added (S)-2-amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid trifluoroacetate (100 mg, 217 μmol) and NaHCO3 (55 mg, 651 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 503.1 (M+H)+. 1H NMR (400 MHz, D2O): δ ppm 8.39 (s, 2 H) 7.49 (d, J = 7.34 Hz, 1 H) 6.52 (br d, J = 6.24 Hz, 1 H) 4.52 (dd, J = 8.93, 4.89 Hz, 1 H) 3.23 - 3.53 (m, 6 H) 2.58 - 2.90 (m, 5 H) 2.40 - 2.54 (m, 1 H) 2.23 - 2.39 (m, 1 H) 1.57 - 1.96 (m, 6 H) 0.84 - 1.05 (m, 4 H).

[00664] Compound 153: 2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino acid)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00665] Compound 154: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-(cyclopropyl(4-(5,6,7,8) -tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: (S)-2-amino-4- acid trifluoroacetate (cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 217 μmol) was taken up in DMA (2 ml) and the to this was added DIPEA (189 μl, 1.09 mmol) and 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (43 mg, 239 μmol) and the resulting mixture was stirred at 70 °C for 17 h and then allowed to cool to room temperature and then adjusted to pH = 6 by the addition of 1 M aq. HCl and then concentrated in vacuo. The crude residue was purified by prep HPLC . reverse phase to furnish the title compound. LCMS (ESI+): m/z = 491.3 (M+H)+. 1H NMR (400 MHz, D2O): δ ppm 8.34 (br s, 2 H) 7.81 (s, 1 H) 7.35 (br s, 1 H) 6.90 (s, 1 H) 6.56 (br s, 1 H) 6.39 (br s, 1 H) 4.53 - 4.68 (m, 1 H) 3.14 - 3.57 (m, 6 H) 2.20 - 2.85 (m, 7 H) 1.47 - 1.94 (m, 6 H) 0.79 - 1.02 ( m, 4 H).

[00666] Compound 155: (S)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid)-2-(( 2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid.

[00667] Compound 156: (S)-4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-cyclopropylpyrimidin-2-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 trifluoroacetate (100 mg, 217 μmol) in 4:1 THF/H2O (2 ml) was added 5-cyclopropyl-2-fluoro-pyrimidine (33 mg, 239 μmol) and NaHCO3 (55 mg, 651 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 465.3 (M+H)+. 1H NMR (400 MHz, D2O): δ ppm 8.36 (br s, 2 H) 7.50 (d, J = 7.34 Hz, 1 H) 6.54 (d, J = 7.34 Hz, 1 H) 4.63 (br t, J = 6.66 Hz, 1 H) 3.26 - 3.51 (m, 6 H) 2.64 - 2.86 (m, 5 H) 2.48 (br s, 1 H) 2.33 (br s, 1 H) 1.63 - 1.96 (m, 7 H) 0.88 - 1.07 (m, 6 H) 0.62 - 0.75 (m, 2 H).

[00668] Compound 157: 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-2-ylamino acid )butanoic.

[00669] Compound 158 (S)-4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid: (S)-2-Amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid trifluoroacetate (100 mg, 217 μmol) was taken in 4:1 THF/H2O (2 ml) and to this was added 4-chloro-6-phenylpyrimidine (46 mg, 239 μmol) and NaHCO3 (55 mg, 651 μmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 501.3 (M+H)+. 1H NMR (400 MHz, DMSO-d4): δ ppm 8.70 (s, 1 H) 7.76 (br d, J = 7.50 Hz, 2 H) 7.57 - 7.71 (m, 3 H) 7.48 (br d, J = 7.28 Hz, 1 H) 7.12 (s, 1 H) 6.53 (br d, J = 7.28 Hz, 1 H) 4.90 (br s, 1 H) 3.25 - 3.57 (m, 6 H) 2.26 - 2.87 (m, 7 H) 1.63 - 1.98 (m, 6 H) 0.99 (br s, 4 H).

[00670] Compound 159: (S)-4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (163, 324.41 μmol) in 3:1 dioxane/H2O (3 ml) was added K2CO3 (90 mg, 649 μmol), phenylboronic acid (99 mg, 811 μmol), followed by Pd(dppf)Cl2 (24 mg, 32 μmol) and the resulting mixture were heated at 100 °C for 2 h and then cooled to room temperature and concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 501.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4): δ ppm 8.85 (s, 1 H) 8.22 (s, 1 H) 7.55 - 7.71 (m, 6 H) 6.66 (d, J = 7.21 Hz, 1 H) 5.13 (br s, 1 H) 3.46 - 3.60 (m, 3 H) 3.33 - 3.45 (m, 3 H) 2.74 - 3.04 (m, 5 H) 2.66 (br s, 1 H) 2.48 (br s, 1 H) 1.70 - 2.06 (m, 6 H) 0.92 - 1.23 (m, 4 H).

[00671] Compound 160: (S)-2-((1H-pyrazol[4,3-d]pyrimidin-7-yl)amino acid)-4-(cyclopropyl(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00672] Compound 161: (S)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid)-2-(( 2-methoxypyrimidin-4-yl)amino)butanoic acid.

[00673] Compound 162: (S)-4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid: To a solution of (2S)-2-amino-4-[cyclopropyl-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]amino]butanoic acid trifluoroacetate (100 mg, 217 μmol) in DMA (2 ml) was added DIPEA (189 μl, 1.09 mmol), then 4-chloro-2-(pyridin-3-yl)quinazoline (58 mg, 239 μmol), and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then adjusted to pH = 6 by addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 552.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4): δ ppm 9.58 (br s, 1 H) 8.84 (br d, J = 7.70 Hz, 1 H) 8.62 (br s, 1 H) 8.00 (d, J = 8.07 Hz, 1 H) 7.81 - 7.87 (m, 1 H) 7.73 - 7.80 (m, 1 H) 7.54 (br s, 1 H) 7.42 - 7.49 (m, 1 H) 7.21 (d, J = 7.21 Hz, 1 H) 6.36 (br d, J = 7.21 Hz, 1 H) 4.93 (br s, 1 H) 3.12 - 3.29 (m, 3 H) 2.82 - 3.08 (m, 3 H) 2.46 - 2.66 (m, 5 H) 2.24 - 2.36 (m, 1 H) 2.06 (br s, 1 H) 1.75 (br dd, J = 11.37, 5.50 Hz, 6 H) 0.43 - 0.87 (m, 4 H).

[00674] Compound 163: (S)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid)-2-(( 2-methyl-2H-pyrazol[4,3-d]pyrimidin-7-yl)amino)butanoic acid: A mixture of acid trifluoroacetate (S)-2-amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 217 μmol) in 4:1 THF/H2O (2 ml) 7-chloro-2-methyl-2H-pyrazol[4,3-d]pyrimidine (40 mg, 239 μmol) and NaHCO3 (55 mg, 651 μmol) and the resulting mixture was heated at 70 °C for 1 h and then cooled to room temperature and concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m /z = 479.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4): δ ppm 8.59 (s, 1 H) 8.49 (s, 1 H) 7.59 (d, J = 7.21 Hz, 1 H) 6, 67 (d, J = 7.34 Hz, 1 H) 5.07 (br dd, J = 8.25, 5.20 Hz, 1 H) 4.09 (s, 3 H) 3.36 - 3.74 (m, 6 H) 2.48 - 3.05 (m, 7 H) 1.66 - 2.12 (m, 6 H) 0.94 - 1.31 (m, 4 H).

[00675] Compound 164: 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2- ((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid.

[00676] Compound 165: 2-((5-cyanopyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,) acid 8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00677] Compound 166: 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.

[00678] Compound 167: 2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2,2-difluoroethyl)(4-(5,6,7, 8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00679] Compound 168: 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.

[00680] Compound 169: 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((2,2-difluoroethyl)(4-(5,6,7 ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00681] Compound 170: 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.

[00682] Compound 171: 2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,) acid 8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00683] Compound 172: (S)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid )-2-((2-methyl-2H-pyrazol[4,3-d]pyrimidin-7-yl)amino)butanoic acid. To a mixture of (S)-2-amino-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)butanoic acid (150 mg, 405 μmol) and 7-chloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (75 mg, 445 μmol) in THF (2 ml) and H2O (0.5 ml) NaHCO3 (170 mg, 2.02 mmol) was added and the resulting mixture was heated at 70 °C for 1 h and then cooled to room temperature and then concentrated in vacuo. The crude residue was purified by prep HPLC . to furnish the title compound. LCMS (ESI+): m/z = 503.2. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.38 - 8.68 (m, 2 H) 7.59 (d, J = 7.45 Hz, 1 H) 6.24 - 6.72 ( m, 2 H) 5.02 - 5.17 (m, 1 H) 4.08 (s, 3 H) 3.84 (br s, 2 H) 3.56 - 3.73 (m, 2 H) 3.49 - 3.53 (m, 2 H) 3.38 - 3.47 (m, 2 H) 2.78 - 2.87 (m, 4 H) 2.48 - 2.74 (m, 2 H) 1.75 - 2.01 (m, 6 H).

[00684] Compound 173: 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.

[00685] Compound 174: 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2- acid ((6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino)butanoic acid.

[00686] Compound 175: 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.

[00687] Compound 176: 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.

[00688] Compound 177: 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2- ((2-phenylpyrimidin-4-yl)amino)butanoic acid.

[00689] Compound 178: (S)-2-((3-cyanopyrazin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (200 mg, 540 μmol) and 3-chloropyrazine-2-carbonitrile (83 mg, 594 μmol) in i-PrOH (4 ml) was added DIPEA (470 μl, 2.70 mmol) and the resulting mixture was stirred at 70 °C for 12 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 474.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.22 (d, J = 2.20 Hz, 1 H) 7.84 (d, J = 2.21 Hz, 1 H) 7.49 (d, J = 7.28 Hz, 1 H) 6.55 (d, J = 7.28 Hz, 1 H) 5.78 - 6.18 (m, 1 H) 4.62 (t, J = 5.07 Hz, 1 H) 3.34 - 3.47 (m, 2 H) 2.54 - 2.92 (m, 1 H)) 2.54 - 2.92 (m, 9 H) 2.10 - 2.27 (m, 2 H) 1.85 - 1.96 (m, 3 H) 1.79 (td, J = 14.72, 6.50 Hz, 1 H) 1.46 - 1.68 (m, 2 H).

[00690] Compound 179: 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2- (pyrimidin-4-ylamino)butanoic acid.

[00691] Compound 180: 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.

[00692] Compound 181: (S)-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid )-2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid: A mixture of acid (S)-2-amino-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid ( 140 mg, 247 μmol) in THF (4 ml) and H2O (1 ml) 4-chloro-1-methyl-1H-pyrazol[3,4-d]pyrimidine (42 mg, 247 μmol) and NaHCO3 (104 mg, 1.24 mmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound . LCMS (ESI+): m/z = 529.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (d, J = 7.70 Hz, 1 H) 8.22 (d, J = 19.93 Hz, 2 H) 7.01 (d , J = 7.21 Hz, 1 H) 6.48 (br s, 1 H) 6.20 (d, J = 7.21 Hz, 1 H) 4.71 - 4.83 (m, 1 H) 3.90 (s, 3 H) 3.18 - 3.27 (m, 2 H) 2.96 - 3.07 (m, 1 H) 2.55 - 2.67 (m, 5 H) 2.13 - 2.44 (m, 7 H) 1.81 - 2.07 (m, 2 H) 1.74 (q, J = 5.81 Hz, 2 H) 1.51 (q, J = 7.34 Hz, 2 H) 1.28 - 1.42 (m, 2 H ). Note: (S)-2-amino-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)butanoic acid was prepared in a manner analogous to Compound 140.

[00693] Compound 182: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (400 mg, 706 μmol) and 2-chloropyrimidine-5-carbonitrile (99 mg, 706 μmol) in THF (4 ml) and H2O (1 ml) was added NaHCO3 (59 mg, 706 μmol) and the resulting mixture was heated at 50 °C for 1 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 500.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 - 8.78 (m, 2 H) 8.52 (br d, J = 7.46 Hz, 1 H) 7.04 (d, J = 7.34 Hz, 1 H) 6.48 (br s, 1 H) 6.23 (d, J = 7.21 Hz, 1 H) 4.39 - 4.48 (m, 1 H) 3.24 (br s, 2 H) 3.01 (br d, J = 7.09 Hz, 1 H) 2.54 - 2.69 (m, 5 H) 2.14 - 2.44 (m, 7 H) 1.90 - 2.00 (m, 1 H) 1.83 (br d, J = 7.34 Hz, 1 H) 1.75 (q, J = 5.84 Hz, 2 H) 1.51 (q, J = 7.37 Hz, 2 H) 1.34 (br d, J = 4.40 Hz, 2 H).

[00694] Compound 183: (S)-4-((3,3-Difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 247 μmol) in THF (4 ml) and H2O (1 ml) was added 2-chloro-5-(trifluoromethyl)pyrimidine (50 mg, 272 μmol) and NaHCO3 (104 mg, 1.24 mmol) and the The resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 543.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.53 (br s, 2 H) 7.48 (d, J = 7.21 Hz, 1 H) 6.55 (d, J = 7.34 Hz, 1 H) 4.52 (dd, J = 6.60, 5.26 Hz, 1 H) 3.38 - 3.53 (m, 2 H) 3.07 - 3.21 (m, 1 H) 2.41 - 2.80 (m, 12 H) 2.00 - 2.23 (m, 2 H) 1.87 - 1.98 (m, 2 H) 1.70 - 1.85 (m, 2 H) 1.58 (q, J = 7.00 Hz, 2H).

[00695] Compound 184: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((3,3-difluorocyclobutyl)(4-(5, 6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00696] Compound 185: (S)-2-((5-Bromopyrimidin-2-yl)amino)-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 247 μmol) in THF (4 ml) and H2O (1 ml) was added 5-bromo-2-chloropyrimidine (53 mg, 272 μmol) and NaHCO3 (104 mg, 1.24 mmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 553.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (s, 2 H) 7.71 (d, J = 7.70 Hz, 1 H) 7.02 (d, J = 7.21 Hz, 1 H) 6.42 (br s, 1 H) 6.22 (d, J = 7.21 Hz, 1 H) 4.27 - 4.37 (m, 1 H) 3.23 (br t, J = 5.32 Hz, 2 H) 3.01 (br d, J = 6.72 Hz, 1 H) 2.53 - 2.70 (m, 5 H) 2.14 - 2.47 (m, 7 H) 1.67 - 1.98 (m, 4 H) 1.51 (q, J = 7.46 Hz, 2 H) 1.26 - 1.41 (m, 2 H).

[00697] Compound 186: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((3,3-difluorocyclobutyl)(4-(5) ,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of acid (S)-2-amino-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid ( 200 mg, 353 μmol) in DMA (3 ml) was added 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (70 mg, 388 μmol) and DIPEA (308 μl, 1.77 mmol) and the resulting mixture was heated at 70 °C for 2 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 541.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.51 (d, J = 2.32 Hz, 1 H) 8.31 (s, 1 H) 7.76 (d, J = 1.22 Hz , 1 H) 7.43 (d, J = 7.34 Hz, 1 H) 6.99 (br s, 1 H) 6.49 - 6.57 (m, 2 H) 4.64 (br s, 1 H) 3.43 (br s, 2 H) 3.06 - 3.20 (m, 1 H) 2.57 - 2.82 (m, 10 H) 2.47 (br s, 2 H) 1.98 - 2.25 (m, 2 H) 1.72 - 1.94 (m, 4 H) 1.50 - 1.64 (m, 2 H).

[00698] Compound 187: (S)-4-((3,3-Difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 247 μmol) in THF (4 ml) and H2O (1 ml) was added 4-chloro-2-(trifluoromethyl)pyrimidine (50 mg, 272 μmol) and NaHCO3 (104 mg, 1.24 mmol) and the The resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 543.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.11 (br d, J = 6.24 Hz, 1 H) 7.49 (d, J = 7.34 Hz, 1 H) 6.74 (br d, J = 5.50 Hz, 1 H) 6.56 (d, J = 7.34 Hz, 1 H) 4.70 (br s, 1 H) 3.46 (br s, 2 H) 3.06 - 3.19 (m, 1 H) 2.55 - 2.84 (m, 10 H) 2.41 (br s, 2 H) 2.18 (br s, 1 H) 1.65 - 2.05 (m, 5 H) 1.47 - 1.62 (m, 2 H).

[00699] Compound 188: (S)-2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 247 μmol) in THF (4 ml) and H2O (1 ml) was added 1-cyclopropyl-4-fluorobenzene (38 mg, 272 μmol) and NaHCO3 (104 mg, 1.24 mmol) and the resulting mixture was heated at 70 °C for 6 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 515.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.09 (s, 2 H) 7.45 (d, J = 7.46 Hz, 1 H) 6.54 (d, J = 7.34 Hz, 1 H) 4.42 (t, J = 5.75 Hz, 1 H) 3.42 - 3.47 (m, 2 H) 3.09 - 3.19 (m, 1 H) 2.45 - 2.82 (m, 12 H) 2.00 - 2.17 (m, 2 H) 1.86 - 1.96 (m, 2 H) 1.69 - 1.85 (m, 3 H) 1.52 - 1.62 (m, 2 H) 0.88 - 1.00 (m, 2 H) 0.57 - 0.67 (m, 2 H).

[00700] Compound 189: (S)-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid )-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid. SCHEME 20, COMPOUND 190:

[00701] Step 1: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 247 μmol) in THF (4 ml) and H2O (1 ml) was added 5-bromo-4-chloropyrimidine (53 mg, 272 μmol) and NaHCO3 (104 mg, 1.24 mmol) and the resulting mixture was heated to 70 °C for 1 h, cooled to room temperature, and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 553.0 (M+H)+.

[00702] Step 2: (S)-4-((3,3-Difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (136 mg, 246 μmol) in dioxane (4 ml) and H2O (1 ml) was added phenylboronic acid (45 mg, 369 μmol), K2CO3 (68 mg, 491 μmol) and Pd(dppf)Cl2 (18 mg, 25 μmol) and the resulting mixture was heated at 100 °C for 2 h, cooled to rt, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 551.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.46 (s, 1 H) 7.96 (s, 1 H) 7.43 - 7.56 (m, 6 H) 6.53 (d, J = 7.34 Hz, 1 H) 4.64 (br t, J = 4.95 Hz, 1 H) 3.39 - 3.48 (m, 2 H) 3.02 - 3.13 (m, 1 H) 2.47 - 2.81 (m, 10 H) 2.06 - 2.43 (m, 4 H) 1.92 (q, J = 5.90 Hz, 2 H) 1.64 (tq, J = 14.24, 6.89 Hz, 2 H) 1.45 (q, J = 7.12 Hz, 2 H). SCHEME 21, COMPOUND 191:

[00703] Step 1: (S)-2-((6-Chloropyrimidin-4-yl)amino)-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 247 μmol) in THF (4 ml) and H2O (1 ml) was added 4,6-dichloropyrimidine (41 mg, 272 μmol) and NaHCO3 (104 mg, 1.24 mmol) and the resulting mixture was heated to 70 °C for 1 h, cooled to room temperature and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 509.0 (M+H)+.

[00704] Step 2: (S)-4-((3,3-Difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-((6-chloropyrimidin-4-yl)amino)-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (125 mg, 246 μmol) in dioxane (4 ml) and H2O (1 ml) was added phenylboronic acid (45 mg, 368 μmol), K2CO3 (68 mg, 491 μmol) and Pd(dppf)Cl2 (18 mg, 25 μmol) and the resulting mixture were heated at 100 °C for 2 h, cooled to rt, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 551.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.44 (d, J = 0.73 Hz, 1 H) 7.88 (br s, 2 H) 7.42 - 7.52 (m, 4 H) 6.97 (br s, 1 H) 6.52 (d, J = 7.34 Hz, 1 H) 4.45 - 4.72 (m, 1 H) 3.36 - 3.51 (m, 2 H) 3.15 (br dd, J = 3.30, 1.71 Hz, 1 H) 2.58 - 2.84 (m, 10 H) 2.34 - 2.53 (m, 2 H) 2.00 - 2.28 (m, 2 H) 1.72 - 1.94 (m, 4 H) 1.48 - 1.62 (m, 2 H).

[00705] Compound 192: (S)-4-((3,3-Difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-phenylpyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (200 mg, 353 μmol) in DMA (3 ml) was added 4-chloro-2-phenylpyrimidine (82 mg, 388 μmol) and DIPEA (308 μl, 1.77 mmol) and the resulting mixture was heated to 70 °C for 16 h, cooled to room temperature and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 551.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.09 - 8.28 (m, 3 H) 7.36 - 7.47 (m, 4 H) 6.49 (br d, J = 7.21 Hz, 2 H) 4.78 (br s, 1 H) 3.29 (br d, J = 5.26 Hz, 2 H) 3.10 - 3.19 (m, 1 H) 2.57 - 2.84 (m, 10 H) 2.46 (br s, 2 H) 2.23 (br s, 1 H) 2.05 (br d, J = 4.89 Hz, 1 H) 1.71 - 1.90 (m, 4 H) 1.51 - 1.66 (m, 2 H).

[00706] Compound 193: (S)-2-((3-cyanopyrazin-2-yl)amino)-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetra-) hydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2-amino-4-((3,3- difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (200 mg, 353 μmol) in i-PrOH (3 ml) was added -onado 3-chloropyrazine-2-carbonitrile (54 mg, 388 μmol) and DIPEA (308 μl, 1.77 mmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 500.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.26 (d, J = 2.32 Hz, 1 H) 7.88 (d, J = 2.45 Hz, 1 H) 7.48 (d , J = 7.34 Hz, 1 H) 6.56 (d, J = 7.34 Hz, 1 H) 4.58 (t, J = 5.26 Hz, 1 H) 3.38 - 3.49 (m, 2 H) 3.08 - 3.20 (m, 1 H) 2.55 - 2.84 (m, 12 H) 2.08 - 2.27 (m, 2 H) 1.74 - 1.97 (m, 4 H) 1.59 (q, J = 7.31 Hz, 2 H). SCHEME 22, COMPOUND 194:

[00707] Step 1: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (300 mg, 530 μmol) in THF (4 mL) and H2O (1 mL) was added 5-bromo-4-chloropyrimidine (113 mg, 583 μmol) and NaHCO3 (222 mg, 2.65 mmol) and the resulting mixture was heated to 70 °C for 1 h, cooled to room temperature, and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 552.9 (M+H)+.

[00708] Step 2: (S)-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid: To a mixture of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (293 mg, 529 μmol) in MeOH (10 mL) was added 10 wt % Pd/C (200 mg) and the resulting mixture was stirred under an atmosphere of H 2 for 3 h and then filtered and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 475.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (s, 1 H) 8.05 (br d, J = 5.50 Hz, 1 H) 7.61 (br s, 1 H) 7.04 (d, J = 7.34 Hz, 1 H) 6.55 (br d, J = 13.57 Hz, 2 H) 6.24 (d, J = 7.34 Hz, 1 H) 4.48 (br s, 1 H) 3.21 - 3.29 (m, 2 H) 3.01 (br d, J = 6.11 Hz, 1 H) 2.60 (br t, J = 6.05 Hz, 4 H) 2.17 - 2.48 (m, 8 H) 1.93 (br dd, J = 13.27, 4.95 Hz, 1 H) 1.68 - 1.83 (m, 3 H) 1.52 (q, J = 7.37 Hz, 2 H) 1.28 - 1.42 (m, 2 H).

[00709] Compound 195: (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)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (100 mg, 230 μmol) and 2-chloro-5-methyl-pyrimidine (25 mg, 192 μmol) in t-AmOH (2 ml) was added 2.0 M t-BuONa in THF (192 μl, 384 μmol) and tBuXPhos-Pd-G3 (15 mg, 19 μmol) and the resulting mixture was heated at 100 °C for 14 h and then cooled to room temperature and then concentrated in vacuo to afford (S)-tert-butyl 4-(((S)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate intermediate, which was used without further purification, Of the butanoate intermediate, 80 mg, 152 μmol was taken up in DCM (2 ml) to which TFA (165 μl) was added and the resulting mixture was stirred at room temperature for 6 h and concentrated in vacuo. The crude residue was purified by preparative HPLC to give the title compound. LCMS (ESI+): m/z = 471.2 (M+H)+. 1H 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, 3 H) 1.76 - 1.99 (m, 6 H) 1.22 (d, J = 5.95 Hz, 3 H).

[00710] Compound 196: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-(pyridin-3-ylamino)butanoic acid: A mixture of (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) tert-butyl butanoate (100 mg, 230.09 μmol) and 3-bromopyridine (30 mg, 192 μmol) in t-AmOH (2 ml) was added t- 2.0 M BuONa in THF (192 μl, 384 μmol) and tBuXPhos-Pd-G3 (15 mg, 19 μmol) and tBuXPhos-Pd-G3 (15 mg, 19 μmol) and the resulting mixture was heated at 100 °C for 14 h and then cooled to room temperature and then concentrated in vacuo to provide a 4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2 -(S)-tert-butyl (pyridin-3-ylamino)butanoate intermediate, LCMS (ESI+): m/z = 512.3 (M+H)+, which was used without further purification. Of the butanoate intermediate, 80 mg, 156 μmol, was taken up in DCM (2 ml) and TFA (200 μl) and the resulting mixture was stirred at room temperature for 6 h and concentrated in vacuo. The crude residue was purified by prep HPLC. to furnish the title compound. LCMS (ESI+): m/z = 456.4 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 7.93 (dd, J = 11.03, 2.65 Hz, 1 H) 7.79 (d, J = 4.63 Hz, 1 H) 7 .13 - 7.24 (m, 2 H) 7.03 (td, J = 8.99, 1.43 Hz, 1 H) 6.42 (dd, J = 7.39, 1.87 Hz, 1 H) 3.90 (t, J = 5.84 Hz, 1 H) 3.66 - 3.76 (m , 1 H) 3.36 (br dd, J = 11.03, 5.95 Hz, 3 H) 3.27 - 3.31 (m, 3H) 3.08 - 3.25 (m, 2 H) 2.94 - 3.06 (m, 3 H) 2.69 (q, J = 6.10 Hz, 2 H) 2.60 (br s, 2 H) 2.05 - 2.23 (m, 2 H) 1.81 - 1.90 (m, 2 H) 1.67 - 1.79 (m, 4 H) 1.16 (dd, J = 9.92, 5.95 Hz, 3 H).

[00711] Compound 197: 4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid.

[00712] Compound 198: 2-((5-cyanopyrimidin-2-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00713] Compound 199: 4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid. SCHEME 23, COMPOUND 200:

[00714] Step 1: (S)-2-((4-Bromopyridin-2-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (300 mg, 723 μmol) and 4-bromo-2-fluoropyridine (140 mg, 795 μmol) in DMSO (4 ml) was added K2CO3 (500 mg, 3.61 mmol) and the resulting mixture was stirred at 130 °C for 3 h and then allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 534.3 (M+H)+.

[00715] Step 2: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-(pyridin-2-ylamino)butanoic acid: A mixture of acid (S)-2-((4-bromopyridin-2-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8 -naphthyridin-2-yl)butyl)amino)butanoic acid (200 mg, 374 μmol) in MeOH (5 ml) was added 10% by weight of Pd/C (39 mg) and the resulting mixture was stirred under an H2 atmosphere for 12 h. The mixture was filtered and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 456.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 7.92 (d, J = 5.07 Hz, 1 H) 7.43 - 7.49 (m, 1 H) 7.15 (d, J = 7.28 Hz, 1 H) 6.58 - 6.67 (m, 2 H) 6.37 (d, J = 7.28 Hz, 1 H) 4.19 (t, J = 6.28 Hz, 1 H) 3.79 (ddd, J = 9.65, 6.23, 3.09 Hz, 1 H) 3, 35 - 3.40 (m, 2 H) 3.34 (s, 3 H) 3.28 (br d, J = 5.29 Hz, 1 H) 3.08 - 3.23 (m, 3 H) 2.97 - 3.06 (m, 2 H) 2.70 (t, J = 6.17 Hz, 2 H) 2.55 (br t, J = 6, 84 Hz, 2 H) 2.28 - 2.39 (m, 1 H) 1.93 - 2.04 (m, 1 H) 1.87 (q, J = 5.95 Hz, 2 H) 1.63 - 1.74 (m, 4 H) 1.21 (d, J = 6.17 Hz, 3 H).

[00716] Compound 201: 2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-(((R)-2-methoxypropyl)(4-(5,6, 7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00717] Compound 202: 2-((5-bromopyrimidin-2-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00718] Compound 203: 2-((1H-pyrazol[4,3-d]pyrimidin-7-yl)amino acid)-4-(((R)-2-methoxypropyl)(4-(5,6, 7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00719] Compound 204: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((2-methoxypyrimidin-4-yl)amino)butanoic acid: A mixture of (S)-2-amino-4-(((R)-2- methoxypropyl)(tert-butyl4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (101 mg, 232 μmol) and 4-chloro-2 - methoxypyrimidine (28 mg, 194 μmol) in t-AmOH (2 ml) was added t-BuONa 2.0 M in THF (194 μl, 388 μL) and tBuXPhos-Pd-G3 (15 mg, 19 μmol) and the resulting mixture was heated at 100 °C for 15 h, cooled to room temperature, and then concentrated in vacuo to furnish a 4-(((R )-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methoxypyrimidin-4-yl)amino )((S)-tert-butyl butanoate intermediate, LCMS (ESI+): m/z = 543.4 (M+H)+, which was used without further purification. Of the butanoate intermediate, 100 mg, 184 μmol, was taken up in DCM (2 ml) TFA (333 μl) was added and the resulting mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 487.3 (M+H )+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.81 (br s, 1 H) 7.47 - 7.62 (m, 1 H) 7.01 (br d, J = 7.21 Hz, 1 H) 6.35 (br d, J = 13.57 Hz, 1 H) 6.18 - 6.28 (m, 2 H) 4.31 (br s, 1 H) 3.73 (s, 3 H) 3.23 (br s, 2 H) 3.19 (s, 4 H) 2.67 (br s, 1 H ) 2.59 (br t, J = 6.11 Hz, 4 H) 2.31 - 2.43 (m, 5 H) 1.86 - 1.97 (m, 1 H) 1.71 - 1.78 (m, 3 H) 1.54 (br dd, J = 14.73, 7.40 Hz, 2 H) 1.41 (br d, J = 7.21 Hz , 2 H) 1.03 (t, J = 5.50 Hz, 3 H).

[00720] Compound 205: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((6-methylpyrazin-2-yl)amino)butanoic acid: A mixture of (S)-2-amino-4-(((R)-2- methoxypropyl)(tert-butyl4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (203 mg, 467 μmol), 2-chloro-6 - methyl-pyrazine (50 mg, 389 μmol) in t-AmOH (3 ml) was added 2.0 M NaO-tBu (389 μl, 778 μmol), then tBuXPhos-Pd-G3 (31 mg, 39 μmol) and the resulting mixture was heated at 100 °C for 15 h and then cooled to room temperature and then concentrated in vacuo to furnish a 4 -(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methylpyrazin- (S)-tert-Butyl 2-yl)amino)butanoate intermediate, LCMS (ESI+): m/z = 527.3 (M+H)+, which was used without further purification. Of the intermediate butanoate, 260 mg, 494 μmol, was taken up in DCM (2 ml) and TFA (1.5 ml) and the resulting mixture was stirred at room temperature for 6 h and concentrated in vacuo. The crude residue was purified by prep HPLC . to furnish the title compound. LCMS (ESI+): m/z = 471.1 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.11 (d, J = 2.43 Hz, 1 H) 7.85 (s, 1 H) 7.60 (d, J = 7.28 Hz , 1 H) 6.67 (d, J = 7.28 Hz, 1 H) 4.80 - 4.87 (m, 1 H) 3.85 (br d, J = 2.87 Hz, 1 H) 3.41 - 3.56 (m, 4 H) 3.39 (dd, J = 2.65, 1.76 Hz, 3 H) 3.32 - 3.38 (m, 1 H) 3.13 - 3.30 (m, 3 H) 2.77 - 2.85 (m, 4 H) 2.54 - 2.58 (m, 3 H) 2.44 - 2.54 (m, 1 H) 2.29 - 2.42 (m, 1 H) 1.95 (q, J = 5 .84 Hz, 2 H) 1.81 (br d, J = 4.63 Hz, 4 H) 1.23 (d, J = 5.95 Hz, 3H).

[00721] Compound 206: 2-((3-cyanopyrazin-2-yl)amino)-4-(((R)- 2-methoxypropyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00722] Compound 207: 4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- acid 2-(pyrimidin-4-ylamino)butanoic acid.

[00723] Compound 208: 2-((5-fluoropyrimidin-2-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00724] Compound 209: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)butanoic acid: A mixture of (S)-2-amino-4-(((R)- 2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) tert-butyl butanoate (149 mg, 344 μmol) and 4-chloro-7-methyl-7H-pyrrol[2,3-d]pyrimidine (48 mg, 286.40 μmol) in t-AmOH (3 ml) was added 2.0 M t-BuONa in THF (286 μl, 572 μmol) and tBuXPhos-Pd-G3 (23 mg, 29 μmol) and the resulting mixture was heated at 100 °C for 15 h. reaction mixture was cooled to room temperature and then concentrated in vacuo to provide a 4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8 (S)-tert-butyl (naphthyridin-2-yl)butyl)amino)-2-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)butanoate intermediate, LCMS (ESI+): m/z = 566.5 (M+H)+, which was used without further purification. Of the intermediate butanoate, 80 mg, 141 μmol, was taken up in DCM (1 ml) and TFA (400 μl) and the resulting mixture was stirred at room temperature for 6 h and then concentrated in vacuo. The crude residue was purified by chiral SFC to give a first fraction containing the title compound. LCMS (ESI+): m/z = 510.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.18 (s, 1 H) 7.19 (d, J = 7.28 Hz, 1 H) 7.08 (d, J = 3.53 Hz , 1 H) 6.59 (d, J = 3.53 Hz, 1 H) 6.40 (d, J = 7.28 Hz, 1 H) 4.61 (t, J = 6.17 Hz, 1 H) 3.76 (s, 4 H) 3.34 - 3.40 (m, 3 H) 3.33 (s, 3 H) 3.22 - 3.29 (m, 1 H) 2.99 - 3.19 (m, 4 H) 2.69 (t, J = 6.17 Hz, 2 H) 2.58 (br s, 2 H) 2.32 - 2.43 (m, 1 H) 2.11 - 2.21 (m, 1 H) 1.86 (dt, J = 11 .52, 6.04 Hz, 2 H) 1.74 (br s, 4 H) 1.16 (d, J = 5.95 Hz, 3H).

[00725] Compound 210: (R)-2-((6-(tert-butyl)pyrimidin-4-yl)amino acid)-4-(((R)-2-methoxypropyl)(4-(5.6 ,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) tert-butyl butanoate (153 mg, 352 μmol) and 4-tert-butyl-6-chloro-pyrimidine (50 mg, 293 μmol) in t-AmOH (3 ml) 2.0 M t-BuONa was added in THF (293 μL, 586 mmol) was added, then tBuX-Phos-Pd-G3 (23 mg, 29 μmol) and the resulting mixture was heated at 100 °C for 15 h. The reaction mixture was cooled to room temperature and, then concentrated in vacuo to provide a 2-((6-(tert-butyl)pyrimidin-4-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7 (S)-tert-Butyl ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate intermediate, LCMS (ESI+): m/z = 569.6 (M+H)+ , which was used without further purification. Of the intermediate butanoate, 75 mg, 132 μmol, was taken up in DCM (1 ml) and TFA (400 μl) and the resulting mixture was stirred at room temperature for 6 h and then concentrated in vacuo. The crude residue was purified by SFC chiral to give the title compound. LCMS (ESI+): m/z = 513.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.35 (s, 1 H) 7.20 (d, J = 7.28 Hz, 1 H) 6.60 (s, 1 H) 6.41 (d, J = 7.28 Hz, 1 H) 4.42 (br s, 1 H) 3.70 (br s, 1 H) 3.35 - 3.40 (m, 2 H) 3.33 (s, 3 H) 3.25 (br s, 1 H) 3.11 - 3.20 (m, 1 H) 2, 92 - 3.10 (m, 4 H) 2.70 (t, J = 6.17 Hz, 2 H) 2.59 (br t, J = 6.95Hz, 2 H) 2.24 (dq, J = 14.22, 7.09 Hz, 1 H) 2.06 (br dd, J = 14.22, 5.62 Hz, 1 H) 1.83 - 1, 91 (m, 2 H) 1.73 (br s, 4 H) 1.26 (s, 9 H) 1.16 (d, J = 6.17 Hz, 3 H).

[00726] Compound 211: 2-((5-cyclopropylpyrimidin-2-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00727] Compound 212: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((6-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid. SCHEME 24, COMPOUND 213:

[00728] Step 1: (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 1:1:1 H2O/THF/MeOH (9 mL) was added LiOH.H2O (159 mg, 3.80 mmol) and the resulting mixture was stirred at room temperature for 1 h and then adjusted to pH = 6 by addition of AcOH and concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 513.5 (M+H)+.

[00729] Step 2: (S)-tert-Butyl 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 acetate (300 mg, 524 μmol) in DMA (4 ml) was added benzyltriethylammonium chloride (119 mg, 524 μmol), K2CO3 (1.88 g, 13.62 mmol), 2-Bromo-2-methylpropane (2.92 mL, 25.14 mmol) was added and the resulting mixture was stirred at 55 °C for 18 h and then allowed to cool to room temperature. The reaction mixture was diluted with H2O and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by normal phase chromatography on silica gel to afford the title compound. LCMS (ESI+): m/z = 569.3 (M+H)+.

[00730] Step 3: 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 μmol) in i-PrOH (2 mL) was added 20 wt % Pd(OH)2/C (26 mg), and the resulting mixture was stirred under an atmosphere of H2 at room temperature for 15 h. The mixture was filtered and concentrated under reduced pressure to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 435.5 (M+H)+.

[00731] Step 4: 2-((6-(dimethylamino)pyrimidin-4-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetra- (S)-tert-butylhydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: A mixture of (S)-2- tert-butyl amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate ( 152 mg, 349 μmol) and 6-chloro-N,N-dimethyl-pyrimidin-4-amine (46 mg, 291 μmol) in t-AmOH (3 ml) t-BuONa was added 2.0 M in THF (291 μL, 582 μmol) was added, then tBuXPhos-Pd-G3 (23 mg, 29 μmol) and the resulting mixture was heated at 100 °C for 2 h. The reaction mixture was cooled to room temperature and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 556.6 (M+H)+.

[00732] Step 5: (S)-2-((6-(dimethylamino)pyrimidin-4-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: (S)-tert-Butyl 2-((6-(dimethylamino)pyrimidin-4-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (80 mg, 144 μmol) was taken up in DCM (1 ml) and TFA (200 μl) and the resulting mixture was stirred for 6 h at room temperature and then concentrated in vacuo. The crude residue was purified by chiral SFC to give the title compound. LCMS (ESI+): m/z = 500.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.00 (s, 1 H) 7.21 (d, J = 7.28 Hz, 1 H) 6.42 (d, J = 7.28 Hz, 1 H) 5.58 (s, 1 H) 4.22 (br t, J = 5.18 Hz, 1 H) 3.74 (ddd, J = 9.37, 6.17, 3.42 Hz, 1 H) 3.36 - 3.40 (m, 2 H) 3.35 (s, 3 H) 3.16 - 3.29 (m, 2 H) 3.04 - 3.14 (m, 3 H) 3.02 (s, 6 H) 2.96 - 3.01 (m, 1 H) 2.70 (t, J = 6.17 Hz, 2 H) 2.60 (br t, J = 6.73 Hz, 2 H) 2.19 - 2.30 (m, 1 H) 2.03 (br dd, J = 14.66, 5.84 Hz, 1 H) 1.87 (q, J = 5.95 Hz, 2 H) 1.73 (br s, 4 H) 1.17 (d, J = 5.95 Hz, 3 H).

[00733] Compound 214: 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-(((R)-2-methoxypropyl)(4-(5.6 ,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00734] Compound 215: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-(quinoxalin-2-ylamino)butanoic acid: A mixture of (S)-2-amino-4-(((R)-2- methoxypropyl)(tert-butyl4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (203 mg, 467 μmol), 2-chloroquinoxaline (64 mg, 389 μmol) in t-AmOH (3 ml) was added t-BuONa 2.0 M in THF (389 μl, 778 μmol), in then tBuXPhos-Pd-G3 (31 mg, 39 μmol) was added, the resulting mixture was stirred for 15 h at 100 °C and then cooled to room temperature and concentrated in vacuo to afford 4-(((R)-2-methoxypropyl) (S)-isopropyl (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinoxalin-2-ylamino)butanoate intermediate, LCMS (ESI+): m/z = 563.3 (M+H)+, which was used without further purification. Of the intermediate butanoate, 300 mg, 533 μmol) in DCM (2 ml) and TFA (1.60 ml) and The resulting mixture was stirred at room temperature for 6 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 507.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.33 (d, J = 9.70 Hz, 1 H) 7.78 (d, J = 8.16 Hz, 1 H) 7.59 - 7 .64 (m, 1H) 7.52 - 7.59 (m, 1H) 7.33 - 7.40 (m, 1 H) 7.15 (d, J = 7.50 Hz, 1 H) 6.36 (t, J = 6.84 Hz, 1 H) 4.56 (t, J = 5.73 Hz , 1 H) 3.69 - 3.84 (m, 1 H) 3.35 - 3.45 (m, 1 H) 3.32 - 3.35 (m, 3 H) 3.02 - 3.30 (m, 5 H) 2.93 - 3.02 (m, 2 H) 2.65 (q, J = 6.25 Hz, 2 H) 2.55 (br d , J = 5.29 Hz, 2 H) 2.27 - 2.44 (m, 1 H) 2.18 (td, J = 9.76, 5.18 Hz, 1 H) 1.76 - 1.87 (m, 2 H) 1.71 (br d, J = 5.73 Hz, 4 H) 1.16 (dd, J = 15.10, 6.06 Hz, 3 H).

[00735] Compound 216: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((5-methoxypyrazin-2-yl)amino)butanoic acid.

[00736] Compound 217: 4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((6-phenylpyrimidin-4-yl)amino)butanoic acid.

[00737] Compound 218: 4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((2-phenylpyrimidin-4-yl)amino)butanoic acid.

[00738] Compound 219: 4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((5-phenylpyrimidin-4-yl)amino)butanoic acid.

[00739] Compound 220: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino)butanoic acid: A mixture of (S)-2-amino-4-(((R)- 2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) tert-butyl butanoate (203 mg, 467 μmol), 4-chloro-6-methyl-2-(4-pyridyl)pyrimidine (80 mg, 389 μmol) in t-AmOH (3 ml) was added 2.0 M NaO-tBu (389 μl, 778 μmol) and then [2-(2-aminophenyl)phenyl]-methylsulfonyloxypalladium; ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (31 mg, 39 μmol) and the resulting mixture was heated at 100 °C for 15 h and then cooled to room temperature and in then concentrated in vacuo to provide a 4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) (S)-tert-Butyl -2-((6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino)butanoate intermediate, LCMS (ESI+): m/z = 604.3 ( M+H)+, which was used without further purification. Of the butanoate intermediate, 270 mg, 447 μmol, was taken up in DCM (2 ml) and TFA (1.4) and the resulting mixture was stirred at room temperature for 6 h and concentrated in vacuo. The crude residue was purified by prep HPLC. to furnish the title compound. LCMS (ESI+): m/z = 548.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.61 (br s, 2 H) 8.27 (d, J = 5.73 Hz, 2 H) 7.52 (d, J = 7.28 Hz, 1 H) 6.59 (d, J = 7.28 Hz, 1 H) 6.55 (s, 1 H) 4.64 (br s, 1 H) 3.88 (br s, 1 H) 3.71 (br t, J = 10.03 Hz, 1 H) 3.60 (br s, 1 H) 3.37 - 3.51 (m, 4 H) 3.35 (s, 3 H) 3.14 - 3.28 (m, 2 H) 2.72 - 2.83 (m, 4 H) 2.61 (br s, 1 H) 2.41 (s, 3 H) 2.21 (br d, J = 11.69 Hz, 1 H) 1.75 - 2.07 ( m, 6 H) 1.24 (d, J = 5.95 Hz, 3 H).

[00740] Compound 221: 4-(((R)-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.

[00741] Compound 222: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((6-(pyridin-4-yl)pyrazin-2-yl)amino)butanoic acid: A mixture of (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) tert-butyl butanoate (199 mg, 457 μmol) and 2-chloro-6-(4-pyridyl)pyrazine (73 mg, 381 μmol) in t-AmOH (3 ml) was added t-BuONa 2.0 M in THF (381 μL, 762 μmol) and then tBuXPhos-Pd-G3 (30 mg, 38 μmol) and the resulting mixture was heated to 100 °C for 15 h and then cooled to room temperature and concentrated in vacuo to furnish a 4-( ((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-(pyridin-4 (S)-tert-Butyl (-yl)pyrazin-2-yl)amino)butanoate intermediate, LCMS (ESI+): m/z = 590.5 (M+H)+, which was used without further purification. Of the intermediate butanoate, 270 mg, 458 μmol, was taken up in DCM (2 ml) and TFA (1.4 ml) and the resulting mixture was stirred at room temperature for 6 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 534.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.96 (d, J = 5.87 Hz, 2 H) 8.70 - 8.82 (m, 3 H) 8.33 - 8.37 ( m, 1 H) 7.60 (d, J = 6.72 Hz, 1 H) 6.66 (d, J = 7.34 Hz, 1 H) 4.80 - 4.86 (m, 1 H) 3.85 (br d, J = 2.45 Hz, 1 H) 3.44 - 3.58 (m, 4 H ) 3.32 - 3.44 (m, 5 H) 3.27 (br d, J = 7.46 Hz, 1 H) 3.14 - 3.24 (m, 1 H) 2.75 - 2.86 (m, 4 H) 2.47 - 2.62 (m, 1 H) 2.31 - 2.46 (m, 1 H) 1.95 (dt, J = 11.68, 6.02 Hz, 2 H) 1.74 - 1.90 (m, 4 H) 1.21 (d, J = 5.99Hz, 3H).

[00742] Compound 223: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((5-phenylpyrazin-2-yl)amino)butanoic acid.

[00743] Compound 224: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((6-phenylpyrazin-2-yl)amino)butanoic acid: A mixture of (S)-2-amino-4-(((R)-2- methoxypropyl)(tert-butyl4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (200 mg, 460 μmol) and 2-chloro-6 - phenyl-pyrazine (73 mg, 383 μmol) in t-AmOH (3 ml) was added 2.0 M NaO-tBu (382 μl, 764 μmol), then tBuXPhos-Pd-G3 (30 mg, 38 μmol) and the resulting mixture was heated at 100 °C for 15 h and then cooled to room temperature and then concentrated in vacuo to afford a 4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrazin (S)-tert-Butyl (2-yl)amino)butanoate intermediate, LCMS (ESI+): m/z = 589.5 (M+H)+, which was used without further purification. Of the butanoate intermediate, 280 mg, 476 μmol was taken up in DCM (2 ml) and TFA (1.1 ml) and the resulting mixture was stirred at room temperature for 6 h and concentrated in vacuo. The crude residue was purified by prep HPLC. to furnish the title compound. LCMS (ESI+): m/z = 533.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.21 (s, 1H) 7.97 - 8.04 (m, 2H) 7.90 (s, 1H) 7.38 - 7.47 (m, 3 H) 7.23 (d, J = 7.28 Hz, 1 H) 6.43 (d, J = 7.28 Hz, 1 H) 4.54 (dd, J = 7.17, 4.74 Hz, 1 H) 3.69 - 3.79 (m, 1 H) 3.32 - 3.48 (m , 2 H) 3.30 (s, 3 H) 3.23 - 3.29 (m, 2 H) 2.98 - 3.15 (m, 4H) 2.56 - 2.70 (m, 4 H) 2.30 - 2.42 (m, 1 H) 2.13 - 2.25 (m, 1 H) 1.70 - 1.86 (m, 6 H) 1.13 (d, J = 6.17 Hz, 3 H).

[00744] Compounds 225: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((1-methyl-1H-pyrazol-5-yl)amino)butanoic acid.

[00745] Compound 226: (S)-2-(benzo[d]oxazol-2-ylamino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetra) acid -hydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00746] Compound 227: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)butanoic acid.

[00747] Compound 228: (S)-2-(benzo[d]thiazol-2-ylamino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetra) acid -hydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2-amino-4-(((R)-2- methoxypropyl)(tert-butyl4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (150 mg, 345 μmol) and 2-chlorobenzo[d ]thiazole (49 mg, 288 μmol) in t-AmOH (3 ml) was added 2.0 M t-BuONa in THF (288 μl, 576 μmol), then, tBuXPhos-Pd-G3 (23 mg, 29 μmol) and the resulting mixture was stirred at 100 °C for 14 h and then cooled to room temperature and concentrated in vacuo to furnish a 2-(benzo[d]thiazole -2-ylamino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (S)-tert-butyl intermediate, LCMS (ESI+): m/z = 568.5 (M+H)+, which was used without further purification. Of the intermediate butanoate, 100 mg, 176 μmol, was taken up in DCM (2 ml) and TFA (200 μl) and the resulting mixture was stirred at room temperature for 6 h and concentrated in vacuo. The crude residue was purified by prep. HPLC from reverse phase to furnish the title compound. LCMS (ESI+): m/z = 512.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 7.86 (d, J = 7.95 Hz, 1 H) 7.62 - 7.66 (m, 1 H) 7.59 (br d, J = 7.34 Hz, 1 H) 7.52 - 7.57 (m, 1 H) 7.39 - 7.45 (m, 1 H) 6.66 (d, J = 7.21 Hz, 1 H) 4.86 - 4.88 (m, 1 H) 3.83 - 3.94 (m, 1 H) 3, 60 (br d, J = 17.12 Hz, 1 H) 3.49 - 3.52 (m, 2 H) 3.48 (br s, 1H) 3.40 (s, 3 H) 3.35 (br s, 2 H) 3.23 (br d, J = 6.97 Hz, 2 H) 2.77 - 2.85 (m, 4 H) 2 .55 - 2.67 (m, 1 H) 2.48 (br s, 1 H) 1.76 - 1.98 (m, 6 H) 1.23 (d, J = 5.87 Hz, 3 H)

[00748] Compound 229: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((2-methyl-2H-pyrazol[4,3-d]pyrimidin-7-yl)amino)butanoic acid. For a mixture of (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) acid hydrochloride -yl)butyl)amino)butanoic acid (100 mg, 264 μmol) and 7-chloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (49 mg, 291 μmol) in THF (2 ml) were added NaHCO3 (111 mg, 1.32 mmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 511.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.60 (br d, J = 11.49 Hz, 1 H) 8.48 (s, 1 H) 7.54 (d, J = 7.34 Hz, 1 H) 6.66 (d, J = 7.21 Hz, 1 H) 5.03 - 5.13 (m, 1 H) 4.08 (s, 3 H) 3.81 - 3.95 (m, 1 H) 3.57 (br s, 1 H) 3.49 - 3.53 (m, 2 H ) 3.41 - 3.49 (m, 1 H) 3.39 (s, 3 H) 3.32 - 3.38 (m, 2 H) 3.15 - 3.30 (m, 2 H) 2.73 - 2.87 (m, 4 H) 2.47 - 2.72 (m, 2 H) 1.76 - 1.99 (m, 6 H) 1, 23 (d, J = 5.75 Hz, 3 H).

[00749] Compound 230: (S)-2-((9H-purin-6-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2-amino-4-(((R)-2- methoxypropyl)(tert-butyl4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (199 mg, 458 μmol) and 6-chloro-9H - purine (59 mg, 382 μmol) in t-AmOH (3 ml) was added 2.0 M t-BuONa in THF (382 μl, 764 μmol), then tBuXPhos-Pd-G3 (30 mg, 38 μmol) and the resulting mixture was stirred for 15 h at 100 °C and then cooled to room temperature and concentrated in vacuo to furnish a 2-( (9H-purin-6-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) (S)-tert-Butyl)amino)butanoate intermediate, LCMS (ESI+): m/z = 553.5 (M+H)+, which was used without further purification. Of the butanoate intermediate, 270 mg, 489 μmol, was taken up in DCM (2 ml) and TFA (512 μl) and the resulting mixture was stirred at room temperature for 6 h and then concentrated in vacuo. The resulting crude residue was purified by HPLC reversed phase prep. to furnish the title compound. LCMS (ESI+): m/z = 497.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.26 (d, J = 2.08 Hz, 1 H) 8.09 (d, J = 3.06 Hz, 1 H) 7.14 - 7 .21 (m, 1H) 6.39 (d, J = 7.21 Hz, 1 H) 4.63 (br s, 1 H) 3.67 - 3.87 (m, 1 H) 3.35 - 3.39 (m, 2 H) 3.33 (s, 3 H) 3.18 - 3.29 (m, 2 H)) 2.99 - 3.18 (m, 4 H) 2.69 (q, J = 5.62 Hz, 2 H) 2.57 (br s, 2 H) 2.28 - 2.49 (m, 1 H) 2.14 - 2.26 (m, 1 H) 1.80 - 1.91 (m, 2 H) 1.73 (br s, 4 H ) 1.18 (dd, J = 15.47, 6.05 Hz, 3 H). SCHEME 25, COMPOUND 231:

[00750] Step 1: (S)-2-((5-bromopyridin-2-yl)amino acid)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2- acid hydrochloride amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (300 mg, 723 μmol) and 5-bromo-2-fluoropyridine (140 mg, 795 μmol) in DMSO (4 ml) K2CO3 (500 mg, 3.61 mmol) and the resulting mixture was stirred at 130 °C for 3 h, cooled to room temperature and then concentrated in vacuo. The crude residue was purified by preparative reversed-phase HPLC to furnish the title compound. LCMS (ESI+): m/z = 534. 3 (M+H)+.

[00751] Step 2: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((5-phenylpyridin-2-yl)amino)butanoic acid. For a mixture of (S)-2-((5-bromopyridin-2-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetra- hydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 187 μmol) and phenylboronic acid (46 mg, 374 μmol) in dioxane (1 ml) and H2O (0.25 ml) was added K2CO3 (129 mg, 936 μmol) and Pd(dppf)Ch.CH2Ch (15 mg, 19 μmol) and the resulting mixture was stirred at 100 °C for 2 h, cooled to room temperature, and then concentrated in vacuo.The crude residue was purified by preparative reversed-phase HPLC to furnish the title compound. LCMS (ESI+): m/z = 532.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.37 (dd, J = 9.37, 2.09 Hz, 1 H) 8.18 (s, 1 H) 7.65 (d, J = 7.28 Hz, 2 H) 7.59 (d, J = 7.28 Hz, 1 H) 7.48 - 7.54 (m, 2 H) 7.42 - 7.47 (m, 1 H) 7.40 (br d, J = 9.26 Hz, 1 H) 6.67 (d, J = 7.28 Hz, 1 H) 4.80 - 4.85 (m, 1 H) 3.89 (br s, 1 H) 3.58 (br s, 1 H) 3.43 - 3.54 (m, 3 H) 3.41 (s, 3 H) 3.35 (br s, 2 H) 3.17 - 3.30 (m, 2 H) 2.82 (br d, J = 5.73 Hz, 4 H) 2.53 - 2.66 (m, 1 H) 2.37 - 2.50 (m, 1 H) 1.78 - 1.98 (m, 6 H) 1.24 (d, J = 6.17 Hz, 3 H).

[00752] Compound 232: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((4-phenylpyridin-2-yl)amino)butanoic acid.

[00753] Compound 233: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((1-methyl-1H-indazol-3-yl)amino)butanoic acid: A mixture of (S)-2-amino-4-(((R)-2- methoxypropyl)(tert-butyl4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (104 mg, 240 μmol) and 3-bromo-1 - methyl-1H-indazole (42 mg, 200 μmol) in THF (2 ml) was added t-BuONa 2.0 M in THF (200 μl, 400 μmol), then tBuXPhos-Pd-G3 (16 mg, 20 μmol) and the resulting mixture was heated at 100 °C for 15 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 509.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.73 (d, J = 8.07 Hz, 1 H) 7.24 - 7.34 (m, 2 H) 6.99 (d, J = 7.21 Hz, 1 H) 6.91 (td, J = 7.21, 1.10 Hz, 1 H) 6.30 (br d, J = 11.62 Hz, 1 H) 6.20 (dd, J = 7.27, 5.32 Hz, 1 H) 4.13 (q, J = 6.28 Hz, 1 H) 3.71 (s, 3 H) 3.43 (br d, J = 6.11 Hz, 1 H) 3.20 - 3.23 (m, 2 H) 3.17 (d, J = 9.78 Hz, 3 H) 2.73 - 2.87 (m, 1 H) 2.53 - 2.73 (m, 5 H) 2.31 - 2.46 ( m, 4 H) 1.83 - 2.02 (m, 2 H) 1.68 - 1.78 (m, 2 H) 1.36 - 1.62 (m, 4 H) 1.03 (t, J = 6.60 Hz, 3 H).

[00754] Compound 234: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((1-methyl-1H-indol-3-yl)amino)butanoic acid.

[00755] Compound 235: 2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-(methylsulfonyl)ethyl)(4-(5 ,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00756] Compound 236: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (100 mg, 223 µmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (94 mg, 1.11 mmol) then 2-chloropyrimidine-5-carbonitrile (37 mg, 267 μmol) and the resulting mixture was heated at 70 °C for 1 h and then cooled to room temperature and adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 516.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.63 (s, 2 H) 7.59 (d, J = 7.28 Hz, 1 H) 6.66 (d, J = 7.28 Hz, 1 H) 4.75 - 4.82 (m, 1 H) 3.66 - 3.84 (m, 4 H) 3.32 - 3.55 (m, 6 H) 3.13 (s, 3 H) 2.75 - 2.85 (m, 4 H) 2.30 - 2.55 (m, 2 H) 1.96 (q, J = 5.84 Hz, 2 H) 1.83 (br s, 4 H).

[00757] Compound 237: 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.

[00758] Compound 238: 2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7 ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00759] Compound 239: 2-((5-bromopyrimidin-2-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1) acid ,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00760] Compound 240: 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((2-(methylsulfonyl)ethyl)(4-(5,6, 7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00761] Compound 241: 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.

[00762] Compound 242: (S)-2-((5-cyclopropylpyrimidin-2-yl)amino acid)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetra -hydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00763] Compound 243: (S)-2-((3-cyanopyrazin-2-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetra) -hydro-1,8-naphthyridin-2- yl)butyl)amino)butanoic acid: A mixture of (S)-2- acid hydrochloride amino-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 223 μmol ) in i-PrOH (2 ml) DIPEA (194 μl, 1.11 mmol) was added, then 3-chloropyrazine-2- carbonitrile (35 mg, 251 μmol) and the resulting mixture was heated at 70 °C for 1 h and then cooled to room temperature and adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by HPLC reverse phase prep. to furnish the title compound. LCMS (ESI+): m/z = 516.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.30 (d, J = 2.20 Hz, 1 H) 8.00 (d, J = 2.43 Hz, 1 H) 7.59 (d , J = 7.50 Hz, 1 H) 6.65 (d, J = 7.50 Hz, 1 H) 4.81 - 4.85 (m, 1 H) 3.65 - 3.83 (m, 4 H) 3.32 - 3.54 (m, 6 H) 3.12 (s, 3 H) 2.76 - 2 .86 (m, 4 H) 2.51 - 2.61 (m, 1 H) 2.34 - 2.44 (m, 1 H) 1.92 - 2.00 (m, 2 H) 1.82 (br d, J = 6.17 Hz, 4 H).

[00764] Compound 244: 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.

[00765] Compound 245: 4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2- ((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid.

[00766] Compound 246: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (130 mg, 321 μmol) in THF (4 ml) and H2O (1 ml) was added 2-chloropyrimidine-5-carbonitrile (49 mg, 353 μmol) and NaHCO3 (135 mg, 1.61 mmol) and the resulting mixture was stirred at 50 °C for 1 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 488.2 (M+H)+. 1H NMR (400 MHz, D2O) δ ppm 8.59 (s, 2 H) 7.47 (d, J = 7.34 Hz, 1 H) 6.50 (d, J = 7.46 Hz, 1 H) 5.86 - 6.21 (m, 1 H) 4.58 (dd, J = 5.38, 8.07 Hz, 1 H) 3.13 - 3.46 (m, 8 H) 2.56 - 2.80 (m, 4 H) 2.18 - 2.44 (m, 4 H) 1.78 - 1.88 (m, 2 H) 1.57 - 1.75 (m, 4 H).

[00767] Compound 247: 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.

[00768] Compound 248: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((3,3-difluoropropyl)(4-(5, 6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of acid (S)-2-amino-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid ( 130 mg, 321 ol) in THF (4 ml) and H2O (1 ml) 4-chloro-1H-pyrazol[3,4-d]pyrimidine (55 mg, 353 μmol) and NaHCO3 (135 mg, 1.61 mmol) and the resulting mixture was heated at 70 °C for 1 h and then cooled to room temperature and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound . LCMS (ESI+): m/z = 503.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.21 (s, 1 H) 8.14 (s, 1 H) 7.37 (br d, J = 7.09 Hz, 1 H) 6, 50 (d, J = 7.34 Hz, 1 H) 5.78 - 6.17 (m, 1 H) 4.86 (br s, 1 H) 3.42 (br s, 2 H) 2.63 - 3.09 (m, 10 H) 2.26 - 2.42 (m, 1 H) 1.97 - 2.20 (m, 3 H) 1.57 - 1.96 (m, 6 H).

[00769] Compound 249: 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.

[00770] Compound 250: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((3,3-difluoropropyl)(4-(5) ,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of acid (S)-2-amino-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid ( 130 mg, 321 μmol) in DMA (3 ml) was added 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (64 mg, 353 μmol) and DIPEA (280 μl, 1.61 mmol) and the resulting mixture was stirred at 70 °C for 16 h and then allowed to cool to room temperature and then adjusted to pH = 6 by the addition of 1 M aq. HCl solution and concentrated in vacuo. The residue The crude was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 529.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.52 (d, J = 2.57 Hz, 1 H) 8.30 (br s, 1 H) 7.77 (d, J = 1.10 Hz, 1 H) 7.32 (br d, J = 6.60 Hz, 1 H) 6.96 (br s, 1 H) 6.47 - 6.58 (m, 2 H) 5.83 - 6.16 (m, 1 H) 4.39 - 4.62 (m, 1 H) 3.36 - 3.45 (m , 2 H) 2.65 - 2.96 (m, 10 H) 2.03 - 2.26 (m, 4 H) 1.84 (br d, J = 17.12 Hz, 4 H) 1.63 - 1.74 (m, 2 H).

[00771] Compound 251: 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.

[00772] Compound 252: 2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,) acid 8-naphthyridin-2-yl)butyl)amino)butanoic acid. SCHEME 26, COMPOUND 253:

[00773] Step 1 (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-amino-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 344 μmol) in THF (4 ml) and H2O (1 ml) was added 5-bromo-4-chloropyrimidine (73 mg, 378 μmol) and NaHCO3 (144 mg, 1.72 mmol) and the resulting mixture was heated at 60 °C for 17 h and then cooled to room temperature and then concentrated in vacuo. The crude residue was used without further purification. LCMS (ESI+): m/z = 540.9 (M+H)+.

[00774] Step 2: (S)-4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid: To a mixture of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (186 mg, 344 μmol) in MeOH (10 mL) was added 10 wt % Pd/C (100 mg) and the resulting mixture was stirred under an atmosphere of H 2 for 16 h. The mixture was filtered and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 463.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.35 (s, 1 H) 8.00 (br s, 1H) 7.35 (d, J = 7.34 Hz, 1 H) 6.57 (br d, J = 4.52 Hz, 1 H) 6.49 (d, J = 7.34 Hz, 1 H) 5.80 - 6.13 (m, 1 H) 4.54 (br s, 1 H) 3.37 - 3.47 (m, 2 H) 2.58 - 3.01 (m, 10 H) 1.61 - 2.26 (m, 10 H).

[00775] Compound 254: (S)-2-((3-cyanopyrazin-2-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetra-) hydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2-amino-4-((3,3- difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (130 mg, 321 μmol) in i-PrOH (3 ml) was added -onated 3-chloropyrazine-2-carbonitrile (49 mg, 353 μmol) and DIPEA (280 μl, 1.61 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 488.1 (M+ H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.25 (d, J = 2.45 Hz, 1 H) 7.88 (d, J = 2.45 Hz, 1 H) 7.39 (d , J = 7.34 Hz, 1 H) 6.52 (d, J = 7.34 Hz, 1 H) 5.8 1- 6.16 (m, 1 H) 4.57 (t, J = 5.38 Hz, 1 H) 3.39 - 3.47 (m, 1 H) 3.39 - 3.47 (m, 1 H) 2.90 - 3.02 (m, 2 H) 2.64 - 2.82 (m, 8 H) 2.08 - 2.30 (m, 4 H) 1.74 - 1.94 (m, 4 H) 1.59 - 1.69 (m, 2 H).

[00776] Compound 255: (S)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid )-2-((2-methyl-2H-pyrazol[4,3- d]pyrimidin-7-yl)amino)butanoic acid: A mixture of (S)-2-amino- 4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (130 mg, 321 ol) in THF (4 ml) and H2O (1 ml) 7-chloro-2-methyl-2H-pyrazol[4,3-d]pyrimidine (66 mg, 353 μmol) and NaHCO3 (134.93 mg, 1.61 mmol) and the resulting mixture was heated at 70 °C for 1 h and then cooled to room temperature and then concentrated in vacuo. The crude residue was purified by prep. HPLC to to provide the title compound. LCMS (ESI+): m/z = 517.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.21 (s, 1 H) 8.04 (s, 1 H) 7.38 (d, J = 7.34 Hz, 1 H) 6.50 (d, J = 7.21 Hz, 1 H) 5.73 - 6.17 (m, 1 H) 4.76 - 4.87 (m, 1 H) 3.94 (s, 3 H) 3.43 (br t, J = 5.07 Hz, 2 H) 2.59 - 3.07 (m, 10 H) 2, 26 -2.45 (m, 1 H) 1.61 - 2.19 (m, 9 H).

[00777] Compound 256: (S)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid )-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid: A mixture of acid (S)-2-amino-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid ( 130 mg, 321 μmol) in DMA (3 ml) was added 4-chloro-2-(pyridin-3-yl)quinazoline (95 mg, 353 μmol) and DIPEA (280 μl, 1.61 mmol) and the resulting mixture was stirred at 70 °C for 16 h and then allowed to cool to room temperature and then adjusted to pH = 6 by the addition of 1 M aq. HCl solution and concentrated in vacuo. The crude residue was purified by HPLC reverse phase prep. to furnish the title compound. LCMS (ESI+): m/z = 590.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 9.55 (dd, J = 0.67, 2.02 Hz, 1 H) 8.81 (td, J = 1.91, 8.04 Hz, 1 H) 8.61 (dd, J = 1.71, 4.89 Hz, 1 H) 8.12 (d, J = 7.58 Hz, 1 H) 7.76 - 7.92 (m, 2 H) 7.44 - 7.57 (m, 2 H) 7.27 (d, J = 7.34 Hz, 1 H) 6.42 (d, J = 7.34 Hz, 1 H) 5.77 - 6.14 (m, 1 H) 5.00 (t, J = 6.11 Hz, 1 H) 3.24 (t, J = 5.62 Hz, 2 H) 2.60 - 3.09 (m, 10 H) 2.23 - 2.51 (m, 2 H) 2.00 - 2.17 (m, 2 H) 1.74 - 1.90 (m, 4 H) 1.55 - 1.72 (m, 2 H). SCHEME 27, COMPOUND 257:

[00778] Step 1: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 344 μmol) in THF (4 ml) and H2O (1 ml) was added 5-bromo-4-chloropyrimidine (73 mg, 378 μmol) and NaHCO3 (144 mg, 1.72 mmol) and the resulting mixture was stirred for 17 h at 60 °C and then cooled to room temperature and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 541.0 (M+H)+.

[00779] Step 2: (S)-4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (186 mg, 344 μmol) in dioxane (4 ml) and H2O (1 ml) was added phenylboronic acid (63 mg, 515 μmol), K2CO3 (95 mg, 687 μmol) and Pd(dppf)Cl2 (25 mg, 34 μmol), the mixture was stirred for 2 h at 100 °C and then cooled to rt and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 539.9 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.45 (s, 1 H) 7.95 (s, 1 H) 7.32 - 7.57 (m, 6 H) 6.48 (d, J = 7.34 Hz, 1 H) 5.79 - 6.12 (m, 1 H) 4.61 (t, J = 5.26 Hz, 1 H) 3.36 - 3.45 (m, 2 H) 2.53 - 2.98 (m, 10 H) 1.85 - 2.25 (m, 6 H) 1.45 - 1.71 (m, 4 H).

[00780] Compound 258: (S)-4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (130 mg, 321 μmol) in THF (4 ml) and H2O (1 ml) was added 4-chloro-6-phenylpyrimidine (67 mg, 353 μmol) and NaHCO3 (135 mg, 1.61 mmol) and the resulting mixture was stirred for 17 h at 70 °C and then cooled to room temperature and concentrated in vacuo. The crude residue was purified by chiral SFC to furnish the title compound. LCMS (ESI+): m/z = 539.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.45 (s, 1 H) 7.95 (s, 1H) 7.32 - 7.57 (m, 6 H) 6.48 (d, J = 7.34 Hz, 1 H) 5.79 - 6.12 (m, 1 H) 4.61 (t, J = 5.26 Hz, 1 H) 3.36 - 3.45 (m, 2 H) 2.53 - 2.98 (m, 10 H) 1.85 - 2.25 (m, 6 H) 1.45 - 1.71 (m, 4 H).

[00781] Compound 259: (S)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid )-2-((2-phenylpyrimidin-4-yl)amino)butanoic acid.

[00782] Compound 260: 4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(( 1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid.

[00783] Compound 261: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 344 μmol) in THF (1 ml) and H2O (0.25 ml) was added 2-chloropyrimidine-5-carbonitrile (53 mg, 378 μmol) and NaHCO3 (144 mg, 1.72 mmol) and the resulting mixture was stirred at 50 °C for 1 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 470.1 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.50 - 8.65 (m, 2 H) 7.28 (d, J = 7.21 Hz, 1 H) 6.47 (d, J = 7.34 Hz, 1 H) 4.58 (t, J = 5.62 Hz, 1 H) 4.37 - 4.49 (m, 2 H) 3.38 - 3.45 (m, 2 H) 2.90 - 3.23 (m, 6 H) 2.73 (t, J = 6.24 Hz, 2 H) 2.58 - 2.67 (m, 2 H) 1.98 - 2.31 (m, 4 H) 1.88 - 1.94 (m, 2H) 1.66 - 1.83 (m, 4 H).

[00784] Compound 262: 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.

[00785] Compound 263: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((3-fluoropropyl)(4-(5,6, 7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2-amino-4-((3- fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 259 ol) in THF (1 ml) and H2O (0 .25 ml) 4-chloro-1H-pyrazol[3,4-d]pyrimidine (44 mg, 285 μmol) and NaHCO3 were added (109mg, 1.30 mmol) and the resulting mixture was heated at 70 °C for 1 h and then cooled to room temperature and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 485.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.25 (br s, 1 H) 8.17 (s, 1 H) 7.23 (br d, J = 7.09 Hz, 1 H) 6 .43 (d, J = 7.34 Hz, 1 H) 4.78 (br s, 1 H) 4.40 - 4.64 (m, 2 H) 3.39 (br s, 2 H) 2.88 - 3.29 (m, 6 H) 2.61 - 2.75 (m, 4 H) 2.29 - 2 .43 (m, 1 H) 2.18 (td, J = 5.00, 14.95 Hz, 1 H) 1.95 - 2.11 (m, 2 H) 1.68 - 1.92 (m, 6 H).

[00786] Compound 264: (S)-2-((5-Bromopyrimidin-2-yl)amino)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-amino-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 344 μmol) in THF (2 ml) and H2O (0.5 ml) was added 5-bromo-2-chloro-pyrimidine (73 mg, 378 μmol) and NaHCO3 (144 mg, 1.72 mmol) and the resulting mixture was stirred at 70 °C for 6 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound LCMS (ESI+): m/z = 523.1 (M+H)+. 1H NMR (400 MHz, D2O) δ ppm 8.38 (d, J = 2.20 Hz, 2 H) 7.45 (d, J = 7.34 Hz, 1 H) 6.48 (dd, J = 4.59, 7.27 Hz, 1 H) 4.42 - 4.63 (m, 3 H) 3.26 - 3.40 (m, 6 H) 3.16 (br d, J = 7.58 Hz, 2 H) 2.69 (br t, J = 6.11 Hz, 2 H) 2.62 (br d, J = 4.28 Hz, 2 H) 2.38 (qd, J = 5.43, 18.94 Hz, 1 H) 2.17 - 2.28 (m, 1 H) 1.98 - 2.13 (m, 2 H) 1.82 (q, J = 5.93 Hz, 2 H) 1.65 (br d, J = 3.30 Hz, 4 H).

[00787] Compound 265: 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((3-fluoropropyl)(4-(5,6,7,8 -tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00788] Compound 266: (S)-4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid: To a solution of (S)-2-amino-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 368 μmol) in THF (4 ml) and H2O (1 ml) was added 4-chloro-2-(trifluoromethyl)pyrimidine (74 mg, 405 μmol) and NaHCO3 (155 mg, 1.84 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 513.1 (M+H)+. 1H NMR (400 MHz, D2O) δ ppm 8.22 (br d, J = 5.75 Hz, 1 H) 7.49 (br d, J = 7.09 Hz, 1 H) 6.84 (d, J = 6.24 Hz, 1 H) 6.52 (br d, J = 7.34 Hz, 1 H) 5.91 - 6.26 (m, 1 H) 4.72 (br s, 1 H) 3.14 - 3.50 (m, 8 H) 2.61 - 2.78 (m, 4 H) 2.21 - 2.52 (m, 4 H) 1.82 - 1.94 (m, 2 H) 1.69 (br s, 4 H).

[00789] Compound 267: (S)-2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 368 μmol) in THF (4 ml) and H2O (1 ml) was added 1-cyclopropyl-4-fluorobenzene (56 mg, 405 μmol) and NaHCO3 (155 mg, 1.84 mmol) and the resulting mixture was stirred at 70 °C for 6 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 485.2 (M+H)+. 1H NMR (400 MHz, D2O) δ ppm 8.32 (s, 2 H) 7.45 (d, J = 7.34 Hz, 1 H) 6.49 (d, J = 7.34 Hz, 1 H) 4.54 - 4.64 (m, 2 H) 4.45 (t, J = 5.44 Hz, 1 H) 3.13 - 3.40 (m, 8 H) 2.60 - 2.72 (m, 4 H) 1.97 - 2.44 (m, 4 H) 1.78 - 1.86 (m, 3 H) 1.66 (br d, J = 3.67 Hz, 4 H) 0.90 - 1.00 (m, 2 H) 0.57 - 0.68 (m, 2 H). SCHEME 28, COMPOUND 268:

[00790] Step 1: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-amino-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 344 μmol) in THF (4 ml) and H2O (1 ml) was added 5-bromo-4-chloropyrimidine (73 mg, 378 μmol) and NaHCO3 (144 mg, 1.72 mmol) and the resulting mixture was stirred for 17 h at 60°C and then cooled to room temperature and concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 523.2 (M+H)+.

[00791] Step 2: (S)-4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid: To a mixture of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (170 mg, 325 μmol) in MeOH (10 mL) was added 10 wt % Pd/C (200 mg), and the resulting mixture was stirred under an atmosphere of H 2 for 16 h and then filtered and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 445.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.40 (s, 1 H) 8.02 (br d, J = 5.26 Hz, 1 H) 7.24 (d, J = 7.21 Hz, 1 H) 6.61 (br d, J = 5.87 Hz, 1 H) 6.45 (d, J = 7.34 Hz, 1 H) 4.54-4.63 (m, 1 H) 4.33 - 4.51 (m, 2 H) 3.36 - 3.43 (m, 2 H) 2.89 - 3.27 (m, 6 H) 2.72 (t, J = 6.30 Hz, 2 H) 2.57 - 2.66 (m, 2H) 1.96 - 2.29 (m, 4 H) 1.85 - 1.94 (m, 2 H) 1.68 - 1.81 (m, 4 H).

[00792] Compound 269: (S)-2-((3-cyanopyrazin-2-yl)amino)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2-amino-4-((3- fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 344 μmol) in i-PrOH (3 ml) was added -onada 3-chloropyrazine-2-carbonitrile (53 mg, 378 μmol) and DIPEA (299 μl, 1.72 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 470.1 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.26 (d, J = 2.45 Hz, 1 H) 7.90 (d, J = 2.45 Hz, 1 H) 7.25 (d , J = 7.34 Hz, 1 H) 6.45 (d, J = 7.34 Hz, 1 H) 4.59 (t, J = 5.69 Hz, 1 H) 4.44 - 4.49 (m, 2 H) 3.37 - 3.42 (m, 2 H) 2.83 - 3.23 (m, 6 H) 2.72 (t, J = 6.17 Hz, 2 H) 2.59 - 2.66 (m, 2 H) 1.98 - 2.31 (m, 4 H) 1.86 - 1.93 (m, 2 H) 1.65 - 1.82 (m, 4 H).

[00793] Compound 270: (S)-4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methyl-2H-pyrazolo[4,3- d ]pyrimidin-7-yl)amino)butanoic acid: To a solution of (S)-2-amino-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 259 μmol) in THF (1 ml) and H2O (0.25 ml) was added 7-chloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (53 mg, 285 μmol) and NaHCO3 (109 mg, 1.30 mmol) and the resulting mixture was heated at 70 °C for 1 h and then cooled to room temperature and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 499.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.27 (s, 1 H) 8.07 - 8.16 (m, 1 H) 7.24 (br d, J = 7.21 Hz, 1 H) 6.44 (d, J = 7.34 Hz, 1 H) 4.78 (br s, 1 H) 4.41 - 4.62 (m, 2 H) 3.97 (s, 3 H) 3.39 (br s, 2 H) 2.84 - 3.29 (m, 6 H) 2.58 - 2.78 (m, 4 H) 2.26 - 2.44 (m, 1 H) 1.95 - 2.22 (m, 3 H) 1.65 - 1.93 (m, 6 H).

[00794] Compound 271: 4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(( 2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid. SCHEME 29, COMPOUND 272:

[00795] Step 1: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 344 μmol) in THF (4 ml) and H2O (1 ml) was added 5-bromo-4-chloropyrimidine (73 mg, 378 μmol) and NaHCO3 (144 mg, 1.72 mmol) and the resulting mixture was stirred for 17 h at 60°C and then cooled to room temperature and concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 523.2 (M+H)+.

[00796] Step 2 (S)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (170 mg, 325 μmol) in dioxane (4 ml) and H2O (1 ml) was added phenylboronic acid (59 mg, 487 μmol), K2CO3 (90 mg, 650 μmol), and Pd(dppf)Ch (24 mg, 32 μmol) and the resulting mixture was stirred for 2 h at 100 °C and then cooled to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 521.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.47 (s, 1H) 7.99 (s, 1H) 7.51 - 7.58 (m, 2 H) 7.41 - 7.49 (m, 3 H) 7.19 - 7.24 (m, 1 H) 6.42 (d, J = 7.34 Hz, 1 H) 4.56 (t, J = 5.62 Hz, 1 H) 4.42 - 4.49 (m, 2 H) 3.37 (dd, J = 4.83, 6.42 Hz, 2 H) 2.84 - 3.25 (m, 6 H) 2.70 (t, J = 6.24 Hz, 2 H) 2.57 (br t, J = 6.72 Hz, 2 H) 2.19 (q, J = 5.75 Hz, 2 H) 1.83 - 2.09 (m, 4 H) 1.58 - 1.77 (m, 4 H). SCHEME 30, COMPOUND 273:

[00797] (S)-2-((6-Chloropyrimidin-4-yl)amino)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-amino-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 344 μmol) in THF (4 ml) and H2O (1 ml) was added 4,6-dichloropyrimidine (56 mg, 378 μmol) and NaHCO3 (144 mg, 1.72 mmol) and the resulting mixture was stirred at 60 °C for 17 h and then allowed to cool to room temperature and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 479.3 (M+H)+.

[00798] (S)-4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-((6-chloropyrimidin-4-yl)amino)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (164 mg, 342 μmol) in dioxane (4 ml) and H2O (1 ml) and phenylboronic acid was added (63 mg, 514 μmol), K2CO3 (95 mg, 685 μmol), and Pd(dppf)Ch (25 mg, 34 μmol) and the resulting mixture was stirred for 2 h at 100 °C and then cooled to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 539.9 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.45 (s, 1 H) 7.95 (s, 1 H) 7.32 - 7.57 (m, 6 H) 6.48 (d, J = 7.34 Hz, 1 H) 5.79 - 6.12 (m, 1 H) 4.61 (t, J = 5.26 Hz, 1 H) 3.36 - 3.45 (m, 2 H) 2.53 - 2.98 (m, 10 H) 1.85 - 2.25 (m, 6 H) 1.45 - 1.71 (m, 4 H).

[00799] Compound 274: 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid.

[00800] Compound 275: 2-((5-cyanopyrimidin-2-yl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00801] Compound 276: 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid.

[00802] Compound 277: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2) acid -yl)butyl)amino)-2-(pyridin-2-ylamino)butanoic acid.

[00803] Compound 278: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-(((S)-2-fluoro-3-methoxypropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of acid hydrochloride (S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino)butanoic acid (200 mg, 462 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (116 mg, 1.39 mmol) and then 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (79 mg, 508 μmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 515.2 (M+H)+.1H NMR (400 MHz, Methanol-d4) δ ppm 8.93 (br s, 1 H) 8.65 (s, 1 H) 7.59 (d, J = 7.28 Hz, 1 H) 6, 67 (d, J = 7.28 Hz, 1 H) 5.15 - 5.33 (m, 2 H) 3.72 (d, J = 3.53 Hz, 1 H) 3.64 - 3.70 (m, 2 H) 3.55 - 3.63 (m, 2 H) 3.48 - 3.54 (m, 3 H) 3.40 (s, 5 H) 2.77 - 2.84 (m, 4 H) 2.49 - 2.69 (m, 2 H) 1.79 - 1.98 (m, 6 H).

[00804] Compound 279: 2-((5-bromopyrimidin-2-yl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00805] Compound 280: 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-(((S)-2-fluoro-3-methoxypropyl)(4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00806] Compound 281: 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid.

[00807] Compound 282: (S)-2-((5-cyclopropylpyrimidin-2-yl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (100 mg, 252 µmol) in THF (1 ml) and H2O (0.25 ml) was added NaHCO3 (106 mg, 1.26 mmol) then 5-cyclopropyl-2-fluoropyrimidine (38 mg, 277 μmol) and the resulting mixture was heated at 70 °C for 1 h and then cooled to room temperature and adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 515.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.03 (s, 2 H) 7.35 (d, J = 7.28 Hz, 1 H) 6.48 (d, J = 7.50 Hz, 1 H) 4.75 - 4.81 (m, 1 H) 4.35 (t, J = 5.95 Hz, 1 H) 3.57 (d, J = 4.19 Hz, 1 H) 3.49 - 3.53 (m, 1 H) 3.37 (dt, J = 8.65, 5.82 Hz, 2 H) 3.32 (s, 3 H) 2.81 - 2.95 (m, 4 H) 2.76 - 2.80 (m, 1H) 2.72 (br t, J = 6.28 Hz, 3 H) 2.66 (t, J = 7.83 Hz, 2 H) 2.02 - 2.20 (m, 2 H) 1.80 - 1.91 (m, 3 H) 1.69 - 1.79 (m, 2 H) 1.57 - 1.68 (m, 2 H) 0.91 (br dd, J = 8.38, 1.54 Hz, 2 H) 0.55 - 0.62 (m, 2 H).

[00808] Compound 283: 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-(pyrimidin-4-ylamino)butanoic acid.

[00809] Compound 284: (S)-2-((3-cyanopyrazin-2-yl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6, 7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2- acid hydrochloride amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid ( 200 mg, 462 μmol) in i-PrOH (2 ml) DIPEA (402 μl, 2.31 mmol) was added, then 3- chloropyrazine-2-carbonitrile (71 mg, 508 μmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by Prep. HPLC to give the title compound LCMS (ESI+): m/z = 500.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.30 (d, J = 2.43 Hz, 1 H) 8.00 (d, J = 2.43 Hz, 1 H) 7.59 (d , J = 7.50 Hz, 1 H) 6.64 (d, J = 7.28 Hz, 1 H) 5.09 - 5.28 (m, 1 H) 4.81 (dd, J = 8.82, 5.29 Hz, 1 H) 3.62 - 3.73 (m, 3 H) 3.54 - 3.62 (m, 1 H) 3.42 - 3.54 (m, 4 H) 3.40 (s, 3 H) 3.32 - 3.39 (m, 2 H) 2.76 - 2.85 (m, 4 H) 2.49 - 2.60 (m, 1 H) 2.33 - 2.45 (m, 1 H) 1.96 (dt, J = 11 .74, 5.93 Hz, 2 H) 1.74 - 1.92 (m, 4 H).

[00810] Compound 285: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2) acid -yl)butyl)amino)-2-((3-methyl-1H-pyrazol[4,3-d]pyrimidin-7-yl)amino)butanoic acid.

[00811] Compound 286: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2) acid -yl)butyl)amino)-2-((5-phenylpyridin-2-yl)amino)butanoic acid. SCHEME 31, COMPOUND 287:

[00812] Step 1: 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl) (S)-tert-butyl amino)-2-((4-phenylpyridin-2-yl)amino)butanoate: A mixture of 2-amino-4- (((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (S)- tert-butyl (150 mg, 331 μmol) and 2-chloro-4-phenylpyridine (52 mg, 276 μmol) in t-AmOH (3 ml) were added t-BuONa 2.0 M in THF (276 μL, 552 μmol) and t-BuXPhosPd G3 (22 mg, 28 μmol) and the resulting mixture was heated at 100 °C for 5 h, cooled to room temperature, and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 606.3 (M+H)+. Note: The t-butyl ester was prepared analogously to Compound 213.

[00813] Step 2: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((4-phenylpyridin-2-yl)amino)butanoic acid: (S)-tert-Butyl 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((4-phenylpyridin-2-yl)amino)butanoate (167 mg, 276 μmol) was taken up in 3:1 DCM/TFA (4 mL) and the resulting mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 550.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.06 (br d, J = 6.48 Hz, 1 H) 7.82 (br d, J = 3.55 Hz, 2 H) 7.54 - 7.62 (m, 4 H) 7.45 (br s, 1 H) 7.29 (br d, J = 6.36 Hz, 1 H) 6.62 (d, J = 7.34 Hz, 1 H) 5.17 - 5.40 (m, 1 H) 4.81 (br s, 1 H) 3.32 - 3.55 (m, 8 H) 3.30 (s, 3 H) 3.23 (br s, 2 H) 2.70 (br d, J = 6.24 Hz, 4 H) 2.44 (br s, 1 H) 2.27 (br d, J = 8.93 Hz, 1 H) 1.59 - 1.85 (m, 6 H). SCHEME 32, COMPOUND 288:

[00814] Step 1: 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl) (S)-tert-butyl amino)-2-((6-phenylpyrazin-2- yl)amino)butanoate: A mixture of 2-amino-4- (((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (S)- tert-butyl (150 mg, 331 μmol) and 2-chloro-6-phenylpyrazine (53 mg, 276 μmol) in t-AmOH (3 ml) were added t-BuONa 2.0 M in THF (276 μL, 552 μmol) was added, followed by t-BuXPhosPdG3 (22 mg, 28 μmol), and the resulting mixture was heated at 100 °C for 5 h, cooled to room temperature, and then concentrated in vacuo to provide the title compound which was used without further purification. LCMS (ESI+): m/z = 607.2 (M+H)+.

[00815] Step 2: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrazin-2-yl)amino)butanoic acid: (S)-tert-Butyl 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrazin-2-yl)amino)butanoate (200 mg, 330 μmol) was taken up in 3:1 DCM/TFA (2 mL) and the resulting mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 551.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (s, 1 H) 7.90 - 8.02 (m, 3 H) 7.37 - 7.46 (m, 3 H) 6.99 (d, J = 7.06 Hz, 1 H) 6.18 (dd, J = 7.28, 2.43 Hz, 1 H) 4.55 - 4.80 (m, 1 H) 4.43 (br d, J = 5.73 Hz, 1 H) 3.36 - 3.50 (m, 2 H) 3.09 - 3.24 (m, 5 H) 2.52 - 2.77 (m, 7 H) 2.29 - 2.47 (m, 3 H) 2.00 (br dd, J = 13.34, 6.50 Hz, 1 H) 1.77 - 1.88 (m, 1 H) 1.64 - 1.74 (m, 2 H) 1.45 - 1.56 (m, 2 H) 1.31 - 1.41 (m, 2 H).

[00816] Compound 289: 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid.

[00817] Compound 290: 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid.

[00818] Compound 291: 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid.

[00819] Compound 292: 2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-phenoxyethyl)(4-(5,6, 7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00820] Compound 293: 2-((5-cyanopyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-) naphthyridin-2-yl)butyl)amino)butanoic acid.

[00821] Compound 294: 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.

[00822] Compound 295: 2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-phenoxyethyl)(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00823] Compound 296: 2-((5-bromopyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-) naphthyridin-2-yl)butyl)amino)butanoic acid.

[00824] Compound 297: 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((2-phenoxyethyl)(4-(5,6,7,8 -tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00825] Compound 298: 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.

[00826] Compound 299: 2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-) acid naphthyridin-2-yl)butyl)amino)butanoic acid.

[00827] Compound 300: (S)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- acid 2-(pyrimidin-4-ylamino)butanoic acid.

[00828] Compound 301: 4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(( 6-phenylpyrimidin-4-yl)amino)butanoic acid.

[00829] Compound 302: (S)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid: To (S)-2-amino-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 324 μmol) in 4:1 THF/H2O (2 ml) was added 5-bromo-4-chloropyrimidine (69 mg, 356 μmol) and NaHCOβ (136, 1.62 mmol) and the resulting mixture was stirred at 70 °C. °C for 2 h. The reaction mixture was cooled to room temperature and then concentrated in vacuo to afford an intermediate (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid, which was used without further purification. The intermediate butanoic acid, 189 mg, 324 μmol, was mixed with phenylboronic acid (43 mg, 356 μmol) in 3:1 dioxane/H2O (3 mL), to which was added K2CO3 (90 mg, 649 μmol) then Pd(dppf)Cl2 (24 mg, 32 μmol), and the resulting mixture was heated at 100 °C for 2 h. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to afford the title compound. LCMS (ESI+): m/z = 581.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.42 (s, 1H) 7.94 (s, 1H) 7.45 - 7.51 (m, 2 H) 7.38 - 7.45 (m, 3 H) 7.20 - 7.30 (m, 3 H) 6.83 - 7.00 (m, 3 H) 6.42 (d, J = 7.34 Hz, 1 H) 4.52 (dd, J = 6.79, 4.22 Hz, 1 H) 4.19 (t, J = 5.14 Hz, 2 H) 3.33 - 3.41 (m, 3 H) 3.20 - 3.30 (m, 2 H) 2.88 - 3.11 (m, 3 H) 2.70 (t, J = 6.17 Hz, 2 H) 2.57 (br t, J = 6.97 Hz, 2 H) 2.22 - 2.32 (m, 1 H) 2.12 - 2.20 (m, 1 H) 1.86 (q, J = 5.90 Hz, 2 H) 1.55 - 1.72 (m, 4H).

[00830] Compound 303: 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.

[00831] Compound 304: 4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid) -2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid.

[00832] Compound 305: 2-((5-cyanopyrimidin-2-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro) acid -1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00833] Compound 306: 4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid) -2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid.

[00834] Compound 307: 2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6 ,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00835] Compound 308: 2-((5-bromopyrimidin-2-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro) acid -1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00836] Compound 309: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((2-(4-fluorophenoxy)ethyl)(4 -(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00837] Compound 310: (S)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (120 mg, 270 μmol) and 4-chloro-2-(trifluoromethyl)pyrimidine (59 mg, 324 μmol) in THF (2 ml), H2O (0.5 ml) was added NaHCO3 (113 mg, 1.35 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 591.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.01 (br s, 1 H) 7.32 (br d, J = 6.84 Hz, 1 H) 6.91 (br d, J = 7.94 Hz, 2 H) 6.81 (br s, 2 H) 6.60 (br s, 1 H) 6.47 (br d, J = 7.50 Hz, 1 H) 4.61 (br s, 1 H) 4.10 (br d, J = 3.97 Hz, 2 H) 3.38 (br s, 2 H) 3.25 (br s, 2 H) 3.11 (br s, 1 H) 3.00 (br d, J = 5.95 Hz, 2 H) 2.88 (br s, 1 H) 2.59 - 2.80 (m, 4 H) 2.28 (br s, 1 H) 2.06 (br s, 2 H) 1.67 - 1.90 (m, 5 H).

[00838] Compound 311: (S)-2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 337 μmol) in 4:1 THF/H2O (2 ml) was added 5-cyclopropyl-2-fluoropyrimidine (51 mg, 371 μmol) and NaHCO3 (85 mg, 1.01 mmol) and the resulting mixture was heated at 70 °C for 1 h and then cooled to room temperature and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 563.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.29 (s, 2 H) 7.58 (d, J = 7.34 Hz, 1 H) 6.94 - 7.09 (m, 4 H) 6.64 (d, J = 7.34 Hz, 1 H) 4.76 (dd, J = 8.38, 5.20 Hz, 1 H) 4.35 (br t, J = 4.52 Hz, 2 H) 3.33 - 3.78 (m, 8 H) 2.73 - 2.86 (m, 4 H) 2.52 - 2.65 (m, 1 H) 2.30 - 2.43 (m, 1 H) 1.70 - 2.01 (m, 7H) 0.93 - 1.11 (m, 2 H) 0.61 - 0.76 (m, 2 H).

[00839] Compound 312: (S)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (120 mg, 270 μmol) and 4-chloro-6-phenyl-pyrimidine (62 mg, 324 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (113 mg, 1.35 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 599.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.29 - 8.45 (m, 1 H) 7.70 (br s, 1 H) 7.60 - 7.80 (m, 1 H) 7.40 - 7.47 (m, 3 H) 7.19 - 7.29 (m, 1 H) 6.78 - 6.85 (m, 4 H) 6.69 (s, 1 H) 6.47 (d, J = 7.50 Hz, 1 H) 4.57 (br s, 1 H) 4.10 - 4.17 (m, 2 H) 3.34 - 3.48 (m, 2 H) 3.13 (br s, 2 H) 3.08 (br s, 1H) 3.00 (br s, 1 H) 2.93 - 2.94 (m, 1 H) 2.80 - 2.93 (m, 1 H) 2.50 - 2.75 (m, 4 H) 2.27 (br s, 1 H) 2.14 (br d, J = 5.29 Hz, 1 H) 1.86 (br dd, J = 13.89, 6.84 Hz, 2 H) 1.93 (br s, 1 H) 1.78 (br s, 3 H).

[00840] Compound 313: (S)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (202 mg, 336 μmol) in 3:1 dioxane/H2O (2 mL) was added K2CO3 (93 mg, 672 μmol), phenylboronic acid (102 mg, 840 μmol), then Pd(dppf)Ch (25 mg, 34 μmol) and the resulting mixture was heated at 100 °C for 2 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 599.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.43 (br s, 1 H) 7.95 (br s, 1 H) 7.38 - 7.55 (m, 5 H) 7.26 (d, J = 7.28 Hz, 1 H) 6.95 - 7.04 (m, 2 H) 6.83 - 6.93 (m, 2 H) 6.42 (d, J = 7.28 Hz, 1 H) 4.49 - 4.58 (m, 1 H) 4.16 (t, J = 5.18 Hz, 2 H) 3.34 - 3.40 (m, 2 H) 3.16 - 3.30 (m, 3 H) 2.84 - 3.11 (m, 3 H) 2.71 (t, J = 6.17 Hz, 2 H) 2.49 - 2.61 (m, 2 H) 2.10 - 2.34 (m, 2 H) 1.82 - 1.94 (m, 2 H) 1.49 - 1.75 (m, 4 H).

[00841] Compound 314: (S)-4-((2-(4-fluorophenoxy)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: To a mixture of (S)-2-amino-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 312 μmol) in DMA (2 ml) was added DIPEA (272 μl, 1.56 mmol) and then 4-chloro-2- (pyridin-3-yl)quinazoline (83 mg, 343 μmol) was prepared and the resulting mixture was heated at 70 °C for 1 h and then cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 650.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 9.51 (d, J = 1.59 Hz, 1 H) 8.77 (dt, J = 8.01, 1.86 Hz, 1 H) 8.58 (dd, J = 4.89, 1.59 Hz, 1 H) 8.03 (d, J = 7.70 Hz, 1 H) 7.78 - 7.85 (m, 1 H) 7.68 - 7.75 (m, 1 H) 7.46 (dd, J = 7.95, 4.89 Hz, 1 H) 7.31 - 7.38 (m, 1 H) 7.20 (d, J = 7.21 Hz, 1 H) 6.70 - 6.78 (m, 2 H) 6.62 - 6.70 (m, 2 H) 6.37 (d, J = 7.34 Hz, 1 H) 5.01 (t, J = 5.93 Hz, 1 H) 4.04 - 4.18 (m, 2 H) 3.12 - 3.29 (m, 4 H) 3.09 - 3.11 (m, 1 H) 2.93 - 3.09 (m, 3 H) 2.77 - 2.87 (m, 1 H) 2.57 - 2.68 (m, 4 H) 2.46 (ddt, J = 14.72, 9.77, 5.00, 5.00 Hz, 1 H) 2.22 - 2.33 (m, 1 H) 1.65 - 1.86 (m, 6 H)

[00842] Compound 315: (S)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(4-fluorophenoxy))ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 337 μmol) in 4:1 THF/H2O (2 ml) was added 7-chloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (63 mg, 371 μmol) and NaHCO3 (85 mg, 1.01 mmol) were added and the resulting mixture was heated at 70 °C for 1 h and then cooled to room temperature and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 577.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.46 (d, J = 19.81 Hz, 2 H) 7.58 (d, J = 7.34 Hz, 1 H) 6.93 - 7.03 (m, 4 H) 6.65 (d, J = 7.34 Hz, 1 H) 5.11 (dd, J = 8.62, 5.07 Hz, 1 H) 4.32 - 4.45 (m, 2 H) 4.06 (s, 3 H) 3.48 - 3.77 (m, 5 H) 3.42 (br t, J = 7.95 Hz, 2 H) 2.66 - 2.86 (m, 5 H) 2.49 - 2.62 (m, 1 H) 1.77 - 2.01 (m, 1 H) 1.68 - 2.03 (m, 6 H).

[00843] Compound 316: (S)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((1-methyl-1H-pyrazol[3,4- d]pyrimidin-4-yl)amino)butanoic acid: A mixture of (S)-2-amino- 4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 396 μmol) and 4-chloro -1-methyl-1H- pyrazol[3,4-d]pyrimidine (73 mg, 436 ol) in THF (2 ml) and H2O (0.5 ml) NaHCO3 (166 mg, 1.98 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 511.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.25 (s, 1 H) 8.08 (s, 1 H) 7.18 (d, J = 7.45 Hz, 1 H) 6 .38 (d, J = 7.02 Hz, 1 H) 4.77 (br s, 1 H) 3.95 (s, 3 H) 3.69 (br s, 2 H) 3.48 (q, J = 6.72 Hz, 2 H) 3.35 (br d, J = 5.26 Hz, 3 H) 3.25 ( br d, J = 14.47 Hz, 1 H) 2.92 - 3.18 (m, 4 H) 2.68 (t, J = 6.14Hz, 2 H) 2.57 (br t, J = 7.02 Hz, 2 H) 2.28 - 2.44 (m, 1 H) 2.13 (br dd, J = 14.69, 5.48 Hz, 1 H) 1.85 (q, J = 5.92 Hz, 2 H) 1.72 (br s, 4 H) 1.13 (t, J = 7.02 Hz, 3 H).

[00844] Compound 317: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 361 μmol) in 4:1 THF/H2O (2 ml) was added 2-chloropyrimidine-5-carbonitrile (55 mg, 398 μmol) and NaHCO3 (91 mg, 1.08 mmol) and the resulting mixture was heated to 70 °C for 1 h, cooled to room temperature and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 482.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.48 - 8.63 (m, 2 H) 7.19 (d, J = 7.45 Hz, 1 H) 6.40 (d, J = 7.45 Hz, 1 H) 4.42 (t, J = 5.92 Hz, 1 H) 3.66 (t, J = 5.26 Hz, 2 H) 3.49 (q, J = 7.02 Hz, 2 H) 3.34 - 3.41 (m, 2 H) 2.87 - 3.26 (m, 6 H)) 2.70 (t, J = 6.14 Hz, 2 H) 2.52 - 2.62 (m, 2 H) 2.23 (dq, J = 14.03, 7.02 Hz, 1 H) 2.02 - 2.14 (m, 1 H) 1.82 - 1.93 (m, 2 H) 1.70 (br s, 4 H) 1.11 - 1.20 (m, 1 H) 1.16 (t, J = 7.02 Hz, 2 H). SCHEME 33, COMPOUND 318:

[00845] Step 1: N-(2-Ethoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide: To a solution of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanoic acid (15 g, 47.67 mmol) in DCM (150 mL) at 0 °C was added CDI (8.50 g, 52.44 mmol) followed by 2-ethoxyethanamine (4.67 g, 52.44 mmol) and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H2O and the layers were separated. The aqueous layers were extracted with DCM and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with MTBE and then the solid was removed by filtration and the filtrate was concentrated in vacuo to afford the title compound. LCMS (ESI+): m/z = 291.7 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 7.71 (br s, 1 H) 7.07 (d, J = 7.02 Hz, 1 H) 6.34 (d, J = 7.02 Hz, 1 H) 5.14 (br s, 1 H) 3.52 - 3.60 (m, 4 H) 3.46 - 3.52 (m, 2 H) 3.36 - 3.43 (m, 2 H) 2.70 (t, J = 6.36 Hz, 2 H) 2.60 (t, J = 6.80 Hz, 2 H) 2.17 - 2.25 (m, 2 H) 1.86 - 2.04 (m, 4 H) 1.17 - 1.27 (m, 3 H).

[00846] Step 2: N-(2-ethoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine: To a mixture of LiAlH4 (2.15 g, 56.63 mmol) in dioxane (120 mL) at 10 °C was added N-(2-ethoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide (7.5 g, 25.74 mmol) and the resulting mixture was heated at reflux for 30 min and then cooled to room temperature. The mixture was then carefully neutralized by cautious addition of H2O (2.6 mL), 1 M aq. NaOH (2.6 ml), then with H2O (2.6 ml) again, followed by drying over MgSO4. The mixture was filtered and then concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 277.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 7.05 (d, J = 7.28 Hz, 1 H) 6.34 (d, J = 7.28 Hz, 1 H) 4.78 (br s, 1 H) 3.71 (s, 1 H) 3.45 - 3.56 (m, 4 H) 3.36 - 3.43 (m, 2 H) 2.77 (t, J = 5.18 Hz, 2 H) 2.61 - 2.71 (m, 4 H) 2.55 (t, J = 7.72 Hz, 2 H) 1.84 - 1.95 (m, 2 H) 1.69 (q, J = 7.61 Hz, 2 H) 1.51 - 1.61 (m, 2 H) 1.15 - 1.23 (m, 3 H).

[00847] Step 3: (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: To a solution of N-(2-ethoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (11 g, 39.65 mmol) and (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (11.57 g, 43.62 mmol) in DCE (170 mL) at 0 °C was added AcOH (3.40 mL, 59.48 mmol) then NaBH(OAc)3 (12.61 g, 59.48 mmol) and the resulting mixture was stirred at 10 °C for 1 h. The reaction mixture was diluted with MeOH and then concentrated in vacuo. The crude residue was taken up in DCM and aq. NaHCO3 solution and the layers were separated. The aqueous layer was extracted with DCM and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by normal phase chromatography on silica gel to furnish the title compound. LCMS (ESI+): m/z = 527.4 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 7.24 - 7.39 (m, 5 H) 7.07 - 7.14 (m, 1 H) 6.36 (d, J = 7.50 Hz, 1 H) 4.99 - 5.13 (m, 2 H) 4.29 (dd, J = 8.16, 4.41 Hz, 1 H) 3.71 (s, 1 H) 3.68 - 3.73 (m, 1 H) 3.39 - 3.52 (m, 4 H) 3.35 (dd, J = 6.17, 5.07 Hz, 2 H) 2.39 - 2.75 (m, 10 H) 2.02 - 2.09 (m, 1H) 1.96 - 2.00 (m, 1 H) 1.80 - 1.88 (m, 2 H) 1.78 (br d, J = 7.28 Hz, 1 H) 1.55 - 1.70 (m, 2 H) 1.48 (q, J = 7.50 Hz, 2 H) 1.12 (t, J = 7.06 Hz, 3H).

[00848] Step 4: (S)-2-(((benzyloxy)carbonyl)amino)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (7 g, 13.29 mmol) in 1:1 THF/MeOH (50 mL) was added LiOH.H2O (1.12 g, 26.58 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was adjusted to pH = 6 by addition of 1 M aq. HCl solution and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 513.5 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 7.58 (d, J = 7.50 Hz, 1 H) 7.24 - 7.41 (m, 5 H) 6.60 - 6.68 (m, 1 H) 5.05 - 5.17 (m, 1 H) 5.05 - 5.17 (m, 1 H) 4.22 - 4.36 (m, 1 H) 3.75 (br s, 2 H) 3.48 - 3.59 (m, 4 H) 3.33 - 3.45 (m, 3 H) 3.27 (br d, J = 7.28 Hz, 2 H) 2.68 - 2.89 (m, 4 H) 2.26 - 2.45 (m, 1 H) 2.05 - 2.23 (m, 1 H) 1.89 - 2.03 (m, 3 H) 1.79 (br s, 4 H) 1.12 - 1.26 (m, 3 H).

[00849] Step 5: (S)-2-amino-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (4 g, 7.80 mmol) in i-PrOH (40 mL) was added 10 wt % Pd(OH) 2 /C (2 g) and the resulting mixture was stirred under an atmosphere of H 2 for 12 h. The reaction mixture was filtered and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 379.4 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 7.52 - 7.64 (m, 1 H) 6.64 (d, J = 7.28 Hz, 1 H) 4.05 (br d, J = 7.28 Hz, 1 H) 3.80 (br s, 2 H) 3.63 (br s, 1 H) 3.41 - 3.60 (m, 8 H) 2.69 - 2.86 (m, 4 H) 2.38 - 2.58 (m, 1 H) 2.18 - 2.35 (m, 1 H) 1.86 - 2.02 (m, 5 H) 1.74 - 1.86 (m, 2 H) 1.12 - 1.21 (m, 3 H).

[00850] Step 6: (S)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid: To a solution of (S)-2-amino-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 396 μmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (80 mg, 436 μmol) in 4:1 THF/H2O (2 ml) was added NaHCOβ (166 mg, 1.98 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 525.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.53 (br s, 2 H) 7.20 (d, J = 7.28 Hz, 1 H) 6.42 (d, J = 7.28 Hz, 1 H) 4.42 (dd, J = 6.84, 4.85 Hz, 1 H) 3.69 (t, J = 5.18 Hz, 2 H) 3.50 (q, J = 6.76 Hz, 2 H) 3.37 (td, J = 5.46, 2.32 Hz, 2 H) 2.96 - 3.28 (m, 6 H) 2.66 - 2.76 (m, 1 H) 2.70 (t, J = 6.28Hz, 1H) 2.55 - 2.64 (m, 2 H) 2.26 (dq, J = 14.19, 7.18 Hz, 1 H) 2.06 - 2.17 (m, 1 H) 1.86 (q, J = 5.95 Hz, 2 H) 1.73 (br s, 4 H) 1.16 (t, J = 7.06 Hz, 3H).

[00851] Compound 319: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-ethoxyethyl)(4-(5,6, 7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2-amino-4-((2- ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 396 μmol) and 4-chloro-1H-pyrazol[3 ,4-d]pyrimidine (67 mg, 436 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCOβ (166 mg, 1.98 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 497.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.24 (s, 1 H) 8.13 - 8.17 (m, 1 H) 7.12 - 7.21 (m, 1 H) 6, 39 (d, J = 7.50 Hz, 1 H) 4.75 (br s, 1 H) 3.62 - 3.77 (m, 1 H) 3.69 (br s, 1 H) 3.48 (q, J = 6.84 Hz, 2 H) 3.35 (br d, J = 5.51 Hz, 3 H) 3.24 (br s, 1 H) 3.13 (br s, 3 H) 3.01 (br s, 1 H) 2.68 (t, J = 6.17 Hz, 2 H) 2.53 - 2.62 (m, 2 H) 2.28 - 2.44 (m, 1 H) 2.14 (br dd, J = 14.66, 5.40 Hz, 1 H) 1.85 (q, J = 5.84 Hz, 2 H) 1.73 (br s, 4 H) 1.12 (t, J = 7.06 Hz, 3 H).

[00852] Compound 320: (S)-2-((5-Bromopyrimidin-2-yl)amino)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 396 μmol) and 5-bromo-2-chloropyrimidine (84 mg, 436 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (166 mg, 1.98 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 535.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.31 (s, 2 H) 7.15 - 7.23 (m, 1 H) 6.40 (d, J = 7.28 Hz, 1 H) 4.28 (t, J = 5.84 Hz, 1 H) 3.67 (t, J = 5.18 Hz, 2 H) 3.46 - 3.54 (m, 2 H) 3.33 - 3.39 (m, 2 H) 2.92 - 3.29 (m, 6 H) 2.70 (t, J = 6.28 Hz, 2 H) 2.50 - 2.63 (m, 2 H) 2.15 - 2.27 (m, 1 H) 2.02 - 2.13 (m, 1 H) 1.81 - 1.94 (m, 2 H) 1.62 - 1.80 (m, 4 H) 1.16 (t, J = 7.06 Hz, 3 H).

[00853] Compound 321: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 361 μmol) in DMA (2 ml) was added DIPEA (315 μl, 1.81 mmol) and then 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (72 mg, 398 μmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 523.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.51 (d, J = 2.63 Hz, 1 H) 8.33 (s, 1 H) 7.75 (d, J = 1.32 Hz, 1 H) 7.16 (d, J = 7.02 Hz, 1 H) 6.99 (br s, 1 H) 6.52 (dd, J = 2.63, 1.75 Hz, 1 H) 6.40 (d, J = 7.45 Hz, 1 H) 4.51 (br s, 1 H) 3.69 (t, J = 5.26 Hz, 2 H) 3.51 (q, J = 6.72 Hz, 2 H) 3.33 - 3.42 (m, 2 H) 2.92 - 3.30 (m, 6 H) 2.54 - 2.77 (m, 4 H) 2.22 - 2.34 (m, 1 H) 1.99 - 2.16 (m, 1 H) 1.67 - 1.90 (m, 6 H) 1.15 (t, J = 7.02 Hz, 3 H).

[00854] Compound 322: (S)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 361 μmol) in 4:1 THF/H2O (2 ml) was added 4-chloro-2-(trifluoromethyl)pyrimidine (73 mg, 398 μmol) and NaHCO3 (91 mg, 1.08 mmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, and then concentrated in vacuo. LCMS (ESI+): m/z = 525.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.12 (br s, 1 H) 7.21 (br d, J = 7.45 Hz, 1 H) 6.74 (br s, 1 H) 6.42 (d, J = 7.45 Hz, 1 H) 4.54 (br s, 1 H) 3.68 (br s, 2 H) 3.44 - 3.54 (m, 2 H) 3.33 - 3.42 (m, 3 H) 2.90 - 3.28 (m, 5 H) 2.70 (t, J = 6.36 Hz, 2 H) 2.60 (br t, J = 7.24 Hz, 2 H) 2.24 (br s, 1H) 2.02 - 2.12 (m, 1 H) 1.83 - 1.90 (m, 2 H) 1.73 (br s, 4 H) 1.15 (t, J = 7.02 Hz, 3 H).

[00855] Compound 323: (S)-2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 361 μmol) of 4:1 in THF/H2O (2 ml) was added 5-cyclopropyl-2-fluoropyrimidine (55 mg, 398 μmol) and NaHCO3 (91 mg, 1.08 mmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 497.2 (M+H) +. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.32 - 8.44 (m, 2 H) 7.60 (d, J = 7.45 Hz, 1 H) 6.65 (d, J = 7.45 Hz, 1 H) 4.78 (dd, J = 8.11, 5.04 Hz, 1 H) 3.78 (t, J = 4.60 Hz, 2 H) 3.37 - 3.64 (m, 8 H) 3.30 (br s, 1 H) 3.28 (br s, 2 H) 2.73 - 2.87 (m, 4 H) 2.47 - 2.60 (m, 1 H) 2.28 - 2.41 (m, 1 H) 1.71 - 2.01 (m, 6 H) 1.19 (t, J = 7.02 Hz, 3 H) 1.00 - 1.08 (m, 2 H) 0.70 - 0.78 (m, 2 H). SCHEME 34, COMPOUND 324:

[00856] Step 1: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 361 μmol) in 4:1 THF/H2O (3 mL) was added 5-bromo-4-chloropyrimidine (77 mg, 398 μmol) and NaHCOβ (152 mg, 1.81 mmol) and the resulting mixture was heated to 70 °C for 1 h, cooled to room temperature, and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 535.0 (M+H)+.

[00857] Step 2: (S)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid: To a mixture of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (387 mg, 723 μmol) in MeOH (20 mL) was added 20 wt % Pd/C (200 mg), and the resulting mixture was stirred under an H 2 atmosphere for 3 h and then filtered and concentrated in vacuo. The crude residue was purified by prep. HPLC. reverse phase to furnish the title compound. LCMS (ESI+): m/z = 457.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.78 (s, 1 H) 8.20 (d, J = 6.17 Hz, 1 H) 7.59 (d, J = 7.28 Hz, 1 H) 7.04 (d, J = 7.28 Hz, 1 H) 6.66 (d, J = 7.28 Hz, 1 H) 5.01 (br s, 1 H) 3.78 (br d, J = 4.19 Hz, 2 H) 3.32 - 3.63 (m, 10 H) 2.75 - 2.87 (m, 4 H) 2.47 - 2.61 (m, 1 H) 2.37 (br s, 1 H) 1.74 - 2.00 (m, 6 H) 1.17 (t, J = 7.06 Hz, 3 H).

[00858] Compound 325: (S)-2-((3-cyanopyrazin-2-yl)amino)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 361 μmol) in i-PrOH (3 mL) was added 3-chloropyrazine-2-carbonitrile (55 mg, 398 μmol) and DIPEA (315 μl, 1.81 mmol) and the resulting mixture was heated to 70 °C for 1 h, cooled to room temperature and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 482.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.25 (d, J = 2.63 Hz, 1 H) 7.89 (d, J = 2.19 Hz, 1 H) 7.21 (d, J = 7.02 Hz, 1 H) 6.42 (d, J = 7.45 Hz, 1 H) 4.45 (dd, J = 7.02, 4.38 Hz, 1 H) 3.71 (t, J = 5.26 Hz, 2 H) 3.51 (q, J = 7.02 Hz, 2 H) 3.33 - 3.40 (m, 3 H) 2.90 - 3.29 (m, 5 H) 2.71 (t, J = 6.14 Hz, 2 H) 2.60 (br d, J = 2.63 Hz, 2 H) 2.22 - 2.36 (m, 1 H) 2.09 - 2.19 (m, 1 H) 1.83 - 1.93 (m, 2 H) 1.68 - 1.79 (m, 4 H) 1.16 (t, J = 7.02 Hz, 3 H).

[00859] Compound 326: (S)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 361 μmol) in 4:1 THF/H2O (2 ml) was added 4-chloro-6-phenylpyrimidine (76 mg, 398 μmol) and NaHCO3 (91 mg, 1.08 mmol) and the resulting mixture was heated to 70 °C for 1 h, cooled to room temperature and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 533.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.81 (s, 1 H) 7.87 (d, J = 7.09 Hz, 2 H) 7.63 - 7.73 (m, 3 H) 7.59 (d, J = 7.21 Hz, 1 H) 7.29 (s, 1 H) 6.66 (d, J = 7.34 Hz, 1 H) 5.04 - 5.12 (m, 1 H) 3.80 (br s, 2 H) 3.44 - 3.62 (m, 8 H) 3.33 - 3.38 (m, 2 H) 2.77 - 2.86 (m, 4 H) 2.58 (br s, 1 H) 2.42 (br d, J = 6.24 Hz, 1 H) 1.78 - 1.98 (m, 6 H) 1.21 (t, J = 6.91 Hz, 3 H).

[00860] Compound 327: (S)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((2-methyl-2H-pyrazol[4,3- d]pyrimidin-7-yl)amino)butanoic acid: A mixture of acid hydrochloride (S)-2-amino-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg , 361 μmol) in 4:1 THF/H2O (2 ml) 7-chloro-2-methyl-2H-pyrazol[4,3-d]pyrimidine (67 mg, 398 μmol) and NaHCO3 (91 mg, 1.08 mmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound title. LCMS (ESI+): m/z = 511.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.57 (br s, 1 H) 8.49 (s, 1 H) 7.59 (d, J = 7.34 Hz, 1 H) 6, 66 (d, J = 7.46 Hz, 1 H) 5.07 (br s, 1 H) 4.09 (s, 3 H) 3.81 (br s, 2 H) 3.44 - 3.67 (m, 8 H) 3.33 - 3.40 (m, 2 H) 2.76 - 2.86 (m, 4 H) 2.62 - 2.74 (m, 1 H) 2.52 (br d, J = 11.00 Hz, 1 H) 1.72 - 2.05 (m, 6 H) 1.19 (t, J = 6.97 Hz, 3 H).

[00861] Compound 328: (S)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 362 μmol) in DMA (2 ml) was added DIPEA (315 μl, 1.81 mmol) and then 4-chloro-2-(pyridin-3-yl)quinazoline (96 mg, 398 μmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 584.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 9.56 (d, J = 1.32 Hz, 1 H) 8.83 (dt, J = 8.11, 1.86 Hz, 1 H) 8.58 - 8.66 (m, 1 H) 8.13 (d, J = 7.89 Hz, 1 H) 7.72 - 7.89 (m, 2 H) 7.45 - 7.60 (m, 2 H) 7.12 (d, J = 7.45 Hz, 1 H) 6.33 (d, J = 7.45 Hz, 1 H) 4.92 (br s, 1 H) 3.70 (t, J = 5.04 Hz, 2 H) 3.44 (q, J = 7.02 Hz, 3 H) 3.09 - 3.29 (m, 5 H) 2.94 - 3.02 (m, 1 H) 2.61 (t, J = 6.14 Hz, 2 H) 2.41 - 2.57 (m, 3 H) 2.26 - 2.36 (m, 1 H) 1.66 - 1.83 (m, 6 H) 1.03 - 1.08 (m, 1 H) 1.06 (t, J = 7.02 Hz, 2 H) 1.02 - 1.10 (m, 1 H).

[00862] Compound 329: (S)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (387 mg, 723 μmol) in 3:1 dioxane/H2O (2 ml) was added K2CO3 (300 mg, 2.17 mmol), phenylboronic acid (220 mg, 1.81 mmol), then Pd(dppf)Ch (53 mg, 72 μmol) and the resulting mixture were heated at 100 °C for 2 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 533.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.46 (br s, 1 H) 7.98 (br s, 1 H) 7.42 - 7.57 (m, 5 H) 7.10 - 7.20 (m, 1 H) 6.34 - 6.41 (m, 1 H) 4.41 - 4.48 (m, 1 H) 3.66 (t, J = 5.18 Hz, 2 H) 3.47 - 3.52 (m, 3 H) 3.30 (br s, 2 H) 2.88 - 3.29 (m, 5 H) 2.68 (t, J = 6.06 Hz, 2 H) 2.52 - 2.60 (m, 2 H) 2.08 - 2.29 (m, 2 H) 1.82 - 1.90 (m, 2 H) 1.54 - 1.79 (m, 4 H) 1.13 - 1.19 (m, J = 7.02 Hz, 3 H). SCHEME 35, COMPOUND 330:

[00863] Step 1: (S)-tert-Butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate: To a mixture of (S)-tert-butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoate (150 mg, 335 μmol) and 2-chloro-5-methyl-pyrimidine (36 mg, 279 μmol) in t-AmOH (2 ml) was added 2.0 M t-BuONa in THF (279 μl, 558 English: μmol), then t-BuXPhos-Pd-G3 (22 mg, 28 μmol) and the resulting mixture was heated at 100 °C for 14 h, cooled to room temperature, and then concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 540.1 (M+H)+. Note: The t-butyl ester starting material was prepared in a manner analogous to Example 213.

[00864] Step 2: (S)-4-(((S)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid: (S)-tert-Butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate (200 mg, 371 μmol) was taken up in 5:1 DCM/TFA (2 ml) and the resulting mixture was stirred at room temperature for 5 h and then concentrated in vacuo. The crude residue was purified by prep. HPLC. reverse phase to furnish the title compound. LCMS (ESI+): m/z = 484.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (s, 2 H) 7.87 (br s, 1 H) 7.14 (br d, J = 6.62 Hz, 1 H) 7.01 (br d, J = 6.39 Hz, 1 H) 6.63 (br s, 1 H) 6.34 (br d, J = 7.28 Hz, 1 H) 4.31 (br s, 1 H) 3.33 (br s, 2 H) 3.22 (br s, 2 H) 2.70 (br s, 4 H) 2.60 (br s, 6 H) 2.15 (br s, 3 H) 1.99 (br d, J = 5.95 Hz, 2H) 1.79 - 1.91 (m, 5 H) 1.63 (br s, 2 H) 1.48 (br s, 2 H).

[00865] Compound 331: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-(pyridin-3-ylamino)butanoic acid.

[00866] Compound 332: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((1-methyl-1H-pyrazol[3,4- d]pyrimidin-4-yl)amino)butanoic acid: A mixture of (S)-4-((2- acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoic acid (150 mg, 383 μmol) and 4-chloro-1- methyl-1H-pyrazol[3,4-d]pyrimidine (71 mg, 421 μmol) in THF (2 ml) and H2O (0.5 ml) was NaHCO3 (161 mg, 1.92 mmol) was added and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by prep HPLC . reverse phase to furnish the title compound. LCMS (ESI+): m/z = 524.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.24 (br s, 1 H) 7.99 - 8.13 (m, 1 H) 7.27 (br d, J = 7.21 Hz, 1 H) 6.43 (br d, J = 7.34 Hz, 1 H) 4.56 (br s, 1 H) 3.95 (s, 3 H) 3.37 (br d, J = 6.60 Hz, 4 H) 2.94 - 3.06 (m, 1 H) 2.65 - 2.94 (m, 7 H) 2.61 (br t, J = 7.52 Hz, 2 H) 2.24 - 2.38 (m, 1 H) 2.07 - 2.22 (m, 1 H) 1.55 - 2.03 (m, 9 H).

[00867] Compound 333: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((5-cyanopyrimidin-2-yl)amino)butanoic acid.

[00868] Compound 334: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid: To a mixture of (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoic acid (150 mg, 383 μmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (77 mg, 421 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (161 mg, 1.98 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 538.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.52 (br s, 2 H) 7.34 (d, J = 7.45 Hz, 1 H) 6.49 (d, J = 7.02 Hz, 1 H) 4.45 (t, J = 5.48 Hz, 1 H) 3.32 - 3.50 (m, 4 H) 2.87 (t, J = 5.92 Hz, 2 H) 2.60 - 2.82 (m, 8 H) 2.10 - 2.25 (m, 2 H) 1.93 (s, 3 H) 1.83 - 1.90 (m, 2 H) 1.69 - 1.82 (m, 2 H) 1.56 - 1.67 (m, 2 H).

[00869] Compound 335: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-acetamidoethyl)(4-(5,6, 7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-4-((2- acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoic acid (150 mg, 383 μmol) and 4-chloro-1H- pyrazol[3,4-d]pyrimidine (65 mg, 421 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (161 mg, 1.92 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m /z = 510.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.06 - 8.29 (m, 2 H) 7.23 - 7.39 (m, 1 H) 6.40 - 6.54 (m, 1 H) 4.76 - 4.83 (m, 1 H) 3.33 - 3.42 (m, 4 H) 3.03 (br s, 1 H) 2.78 - 2.97 (m, 4 H) 2.58 - 2.74 (m, 5 H) 2.31 (br d, J = 5.70 Hz, 1 H) 2.11 - 2.22 (m, 1 H) 1.82 - 1.95 (m, 5 H) 1.76 (br s, 2H) 1.65 (br d, J = 4.82 Hz, 2 H). SCHEME 36, COMPOUND 336:

[00870] Step 1: 7-(4-((2-acetamidoethyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl: To a mixture of N-(2-aminoethyl)acetamide (18.8 ml, 197.12 mmol) and NaBH3CN (8.26 g, 131.41 mmol) in MeOH (300 ml) at 0°C was added AcOH (37.6 ml, 657.07 mmol) then a solution of 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl (20 g, 65.71 mmol) in MeOH (100 ml) and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was poured into aq. NaHCO3 solution and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 391.4 (M+H)+.

[00871] Step 2: (S)-tert-Butyl 7-(4-((2-acetamidoethyl)(3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate: To a mixture of 7-(4-((2-acetamidoethyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-tert-butyl carboxylate (18 g, 46.09 mmol) and methyl (2S)-2-(benzyloxycarbonylamino)-4-oxo-butanoate (13.45 g, 50.70 mmol) in DCE (200 ml) at 0 °C was added AcOH (4.0 ml, English: 69.14 mmol), then NaBH(OAc)3 (14.65 g, 69.14 mmol) was added portionwise and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was poured into aq. NaHCO3 solution (200 mL) and then 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 normal phase chromatography on silica gel to furnish the title compound. LCMS (ESI+): m/z = 640.5 (M+H)+.

[00872] Step 3: (S)-methyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(((benzyloxy)carbonyl)amino)butanoate: (S)-tert-butyl 7-(4-((2-acetamidoethyl)(3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)amino)butyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (3.47 g, 5.42 mmol) was taken up in 4 M HCl in EtOAc (30 mL) and the resulting mixture was stirred at room temperature for 1.5 h and then concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 540.4 (M+H)+.

[00873] Step 4: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(((benzyloxy)carbonyl)amino)butanoic acid: To a mixture of (S)-methyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(((benzyloxy)carbonyl)amino)butanoate (3.5 g, 6.49 mmol) in 2:2:1 THF/MeOH/H2O (50 mL) was added LiOH.H2O (1.09 g, 25.94 mmol) and the resulting mixture was stirred at room temperature for 1 h and then adjusted to pH = 4 by addition of 1 M aq. HCl solution and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 526.4 (M+H)+.

[00874] Step 5: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoic acid: To a mixture of (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(((benzyloxy))carbonyl)amino)butanoic acid (2 g, 3.80 mmol) in i-PrOH (30 mL) was added 10 wt % Pd(OH)2/C (2 g) and the resulting mixture was stirred under an atmosphere of H2 for 16 h. The reaction mixture was filtered and then concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 392.2 (M+H)+.

[00875] Step 6: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-bromopyrimidin-2-yl)amino)butanoic acid: To a solution of (2S)-4-[2-acetamidoethyl-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]amino]-2-amino-butanoic acid (150 mg, 383 μmol) and 5-bromo-2-chloro-pyrimidine (89 mg, 460 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (161 mg, 1.92 mmol) and the resulting mixture was stirred at 70 °C for 1 h, cooled to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 548.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.28 (s, 2 H) 7.34 (d, J = 7.28 Hz, 1 H) 6.49 (d, J = 7.50 Hz, 1 H) 4.32 (t, J = 5.73 Hz, 1 H) 3.48 (br s, 1 H) 3.32 - 3.51 (m, 3 H) 2.76 - 2.91 (m, 3 H) 2.73 (br t, J = 6.17 Hz, 3 H) 2.65 (br t, J = 7.39 Hz, 2 H) 2.60 - 2.68 (m, 1 H) 2.60 - 2.92 (m, 1 H) 2.15 (br d, J = 3.09 Hz, 2 H) 1.92 (s, 3 H) 1.87 (q, J = 5.79 Hz, 2 H) 1.69 - 1.84 (m, 2 H) 1.58 - 1.69 (m, 1 H) 1.58 - 1.69 (m, 1 H).

[00876] Compound 337: (S)-2-((7H-pyrrol[2,3-d]pyrimidin-4-yl)amino acid)-4-((2-acetamidoethyl)(4-(5,6, 7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00877] Compound 338: (S)-2-((1H-pyrazol[4,3-d]pyrimidin-7-yl)amino acid)-4-((2-acetamidoethyl)(4-(5,6, 7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00878] Compound 339: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((2-methoxypyrimidin-4-yl)amino)butanoic acid. SCHEME 37, COMPOUND 340:

[00879] Step 1: 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-acetamidoethyl)(4-(5,6,7,8- (S)-tert-butyl tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: A mixture of 4-((2- acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2- (S)-tert-butyl aminobutanoate (150 mg, 335 μmol ) and 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (50 mg, 279 μmol) in t-AmOH (3 ml) has been added t-BuONa (279 μL, 558 μmol) was added, followed by t-BuXPhos-Pd-G3 (22 mg, 28 μmol), and the resulting mixture was heated at 100 °C for 5 h, cooled to room temperature, and then , concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 592.5 (M+H)+.

[00880] Step 2: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((2-acetamidoethyl)(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-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1, (S)-tert-butyl 8-naphthyridin-2-yl)butyl)amino)butanoate (148 mg, 249 μmol) was taken up in 3:1 DCM/TFA (2 ml) and the resulting mixture was stirred at room temperature for 1.5 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 536.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 14.23 (br s, 1 H) 10.63 (br s, 1 H) 8.55 (d, J = 2.44 Hz, 1 H) 8 .41 (d, J = 0.73 Hz, 1 H) 8.31 (br s, 2 H) 8.07 (br s, 1 H) 7.86 (d, J = 0.98 Hz, 1 H) 7.59 (d, J = 7.34 Hz, 1 H) 7.08 - 7.13 (m, 1 H) 6.63 (d, J = 7.34 Hz, 1 H) 6.57 (dd, J = 2.57, 1.71 Hz, 1H) 4.63 (br s, 1 H) 3.43 (br d, J = 4.77 Hz, 4 H) 3.31 (br s, 1 H) 3.16 (br s, 5 H) 2.63 - 2.78 (m, 4 H) 2.32 (br t, J = 12.29 Hz, 1 H) 2.18 (br s, 1 H) 1.78 - 1.86 (m, 5 H) 1.66 - 1.76 (m, 4 H).

[00881] Compound 341: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((6-(dimethylamino)pyrimidin-4-yl)amino)butanoic acid: A mixture of (S)-tert-butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoate (100 mg, 223 μmol) and 6-chloro-N,N-dimethylpyrimidin-4-amine (29 mg, 186 μmol) in t-AmOH (2 ml) 2.0 M t-BuONa in THF (186 μl, 372 μl), then tBuXPhos-Pd-G3 (15 mg, 19 μmol) and the resulting mixture was heated at 100 °C for 14 h, cooled to room temperature, and then concentrated in vacuo to furnish a 4 -((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-(dimethylamino)pyrimidin-4 (S)-tert-Butyl (-yl)amino)butanoate intermediate, LCMS (ESI+): m/z = 569.6 (M+H)+, which was used without further purification. Of the intermediate butanoate, 130 mg, 229 μmol, was taken up in DCM (2 ml) and TFA (400 μl) was added and the resulting mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The crude residue was purified by prep HPLC . reverse phase to furnish the title compound. LCMS (ESI+): m/z = 513.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (s, 1 H) 7.76 (br s, 1 H) 6.93 - 7.12 (m, 1 H) 6.71 (br s, 1 H) 6.55 (br s, 1 H) 6.25 (d, J = 7.21 Hz, 1 H) 5.55 (br s, 1 H) 4.26 (br s, 1 H) 3.22 (br d, J = 5.38 Hz, 2 H) 3.10 - 3.14 (m, 2 H) 2.93 (s, 6 H) 2.54 - 2.68 (m, 5 H) 2.33 - 2.45 (m, 3 H) 1.67 - 1.96 (m, 7 H) 1.48 - 1.60 (m, 2 H) 1.31 - 1.47 (m, 2 H).

[00882] Compound 342: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoic acid (150 mg, 383 μmol) and 4-fluoro-2-(trifluoromethyl)pyrimidine (76 mg, 460 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (161 mg, 1.92 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 538.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.09 (br s, 1 H) 7.24 - 7.34 (m, 1 H) 6.71 (br s, 1 H) 6.45 (d, J = 7.28 Hz, 1 H) 4.58 (br s, 1 H) 3.32 - 3.43 (m, 3 H) 3.32 - 3.44 (m, 1 H) 2.84 (br s, 1 H) 2.73 (br d, J = 5.51 Hz, 6 H) 2.47 - 2.66 (m, 1 H) 2.62 (br t, J = 7.50 Hz, 2 H) 2.19 (br s, 1 H) 2.02 - 2.14 (m, 1 H) 1.81 - 1.94 (m, 5 H) 1.71 (br s, 2 H) 1.52 - 1.65 (m, 2 H).

[00883] Compound 343: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-cyclopropylpyrimidin-2-yl)amino)butanoic acid: To a mixture of (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl))butyl)amino)-2-aminobutanoic acid (150 mg, 383 μmol) and 5-cyclopropyl-2-fluoropyrimidine (64 mg, 460 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (161 mg, 1.92 mmol) and the resulting mixture was stirred at 70 °C for 1 h, cooled to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 510.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.06 (s, 2 H) 7.27 (d, J = 7.28 Hz, 1 H) 6.44 (d, J = 7.28 Hz, 1 H) 4.32 (t, J = 5.73 Hz, 1 H) 3.34 - 3.44 (m, 3 H) 3.22 - 3.30 (m, 1 H) 2.78 - 2.86 (m, 1 H) 2.78 - 2.89 (m, 1 H) 2.66 - 2.77 (m, 5 H) 2.56 - 2.65 (m, 3 H) 2.05 - 2.25 (m, 2 H) 1.92 (s, 3H) 1.81 - 1.90 (m, 2 H) 1.66 - 1.79 (m, 3 H) 1.52 - 1.64 (m, 2 H) 0.85 - 0.97 (m, 2 H) 0.53 - 0.64 (m, 2 H).

[00884] Compound 344: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-(tert-butyl)pyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-tert-butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoate (100 mg, 223 μmol) and 4-(tert-butyl)-6-chloropyrimidine (32 mg, 186 μmol) in t-AmOH (2 ml) was added 2.0 M t-BuONa in THF (186 English: μl, 372 μmol) and tBuXPhos-Pd-G3 (15 mg, 19 μmol) and the resulting mixture was heated at 100 °C for 14 h, cooled to room temperature, and then concentrated in vacuo to furnish an intermediate (S)-tert-butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-(tert-butyl)pyrimidin-4-yl)amino)butanoate, LCMS (ESI+): m/z = 582.5 (M+H)+, which was used without further purification. Of the butanoate intermediate, 130 mg, 223 μmol, was taken up in DCM (2 ml), TFA (400 μl) was added, and the resulting mixture was stirred at room temperature for 5 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 526.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.35 (s, 1 H) 7.72 (br t, J = 5.18 Hz, 1 H) 7.36 (br s, 1 H) 7.04 (d, J = 7.28 Hz, 1 H) 6.57 (br d, J = 11.69 Hz, 2 H) 6.24 (d, J = 7.28 Hz, 1 H) 4.38 (br s, 1 H) 3.23 (br d, J = 5.07 Hz, 3 H) 3.05 - 3.18 (m, 2 H) 2.52 - 2.72 (m, 6 H) 2.32 - 2.49 (m, 4 H) 1.67 - 1.99 (m, 7 H) 1.49 - 1.64 (m, 2 H) 1.39 (dt, J = 13.89, 6.73 Hz, 2 H) 1.20 (s, 9 H).

[00885] Compound 345: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((7-methyl-7H-pyrrol[2,3- d]pyrimidin-4-yl)amino)butanoic acid: A mixture of 4-((2- acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2- (S)-tert-butyl aminobutanoate (100 mg, 223 μmol ) and 4-chloro-7-methyl-7H-pyrrol[2,3-d]pyrimidine (31 mg, 186 μmol) in t-AmOH (2 ml) was added t-BuONa 2.0 M in THF (186 μL, 372 μmol) was added to tBuXPhos-Pd-G3 (15 mg, 19 μmol) and the resulting mixture was heated at 100 °C for 14 h, cooled to room temperature, and then concentrated in vacuo to provide 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-( (S)-tert-Butyl (7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)butanoate intermediate, LCMS (ESI+): m/z = 579.5 (M+H )+, which was used without further purification. Of the intermediate butanoate, 130 mg, 225 μmol, was taken up in DCM (2 ml) and TFA (500 μl) and the resulting mixture was stirred at room temperature for 5 h and then concentrated in vacuo. The crude residue was purified by Prep. reversed-phase HPLC to furnish the title compound. LCMS (ESI+): m/z = 523.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 13.95 - 14.35 (m, 1H) 10.36 - 10.81 (m, 1H) 8.22 - 8.45 (m, 2 H) 8.04 (br s, 1H) 7.60 (d, J = 7.28 Hz, 1 H) 7.40 (br s, 1 H) 7.00 - 7.13 (m, 1 H) 6.63 (d, J = 7.28 Hz, 1 H) 4.94 (br s, 1 H) 3.80 (s, 3 H) 3.40 - 3.47 (m, 6 H) 3.10 - 3.27 (m, 4 H) 2.64 - 2.81 (m, 4 H) 2.27 - 2.46 (m, 2 H) 1.63 - 1.88 (m, 9 H). SCHEME 38, COMPOUND 346:

[00886] Step 1: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-bromopyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl))butyl)amino)-2-aminobutanoic acid (200 mg, 511 μmol) and 5-bromo-4-chloropyrimidine (109 mg, 562 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (215 mg, 2.55 mmol) and the resulting mixture was heated to 70 °C for 1 h and then cooled to room temperature and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 548.3 (M+H)+.

[00887] Step 2: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid: To a mixture of (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-bromopyrimidin-4-yl)amino)butanoic acid (200 mg, 364.65 μmol, 1 eq) in MeOH (20 mL) was added 20 wt % Pd/C (200 mg), and the resulting mixture was stirred under an atmosphere of H 2 for 3 h and then filtered and concentrated vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 470.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.37 (br s, 1 H) 8.04 (br s, 1 H) 7.34 (d, J = 7.34 Hz, 1 H) 6.59 (br s, 1 H) 6.48 (d, J = 7.34 Hz, 1 H) 4.49 (br s, 1 H) 3.34 - 3.48 (m, 4 H) 2.59 - 3.06 (m, 10 H) 2.06 - 2.26 (m, 2 H) 1.83 - 1.98 (m, 5 H) 1.59 - 1.81 (m, 4 H).

[00888] Compound 347: (S)-4-((2-Acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((3-cyanopyrazin-2-yl)amino)butanoic acid: To a mixture of (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl))butyl)amino)-2-aminobutanoic acid hydrochloride (150 mg, 350 μmol) in i-PrOH (3 mL) was added 3-chloropyrazine-2-carbonitrile (54 mg, 386 μmol) and DIPEA (305 μl, 1.75 mmol) and the resulting mixture was heated to 70 °C for 1 h, cooled to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 495.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.25 (d, J = 2.43 Hz, 1 H) 7.87 (d, J = 2.43 Hz, 1 H) 7.37 (d, J = 7.28 Hz, 1 H) 6.50 (d, J = 7.28 Hz, 1 H) 4.49 (t, J = 5.07 Hz, 1 H) 3.33 - 3.49 (m, 4 H) 2.64 - 2.88 (m, 10 H) 2.25 (q, J = 5.44 Hz, 2 H) 1.85 - 1.96 (m, 5 H)) 1.50 - 1.81 (m, 4 H). SCHEME 39, COMPOUND 348:

[00889] Step 1: 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6 (S)-tert-butyl-methylpyrazin-2-yl)amino)butanoate: A mixture of 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoate ((S)-tert- butyl (150 mg, 335 μmol) and 2-chloro-6-methyl-pyrimidine (36 mg, 279 μmol) in t-AmOH (2 ml) were added 2.0 M t-BuONa in THF (279 μl, 558 μmol), then t-BuXphosPd G3 (22 mg, 28 μmol)) and the resulting mixture was heated at 100 °C for 15 h, cooled to room temperature, and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 540.1 (M+H)+.

[00890] Step 2: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methylpyrazin-2-yl)amino)butanoic acid: (S)-tert-Butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methylpyrazin-2-yl)amino)butanoate (200 mg, 371 μmol) was taken up in 3:1 DCM/TFA = 3:1 (2 ml) and the resulting mixture was stirred at room temperature for 5 h and then concentrated in vacuo. The crude residue was purified by prep. HPLC. reverse phase to furnish the title compound. LCMS (ESI+): m/z = 484.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.81 (s, 1 H) 7.74 (br t, J = 5.38 Hz, 1 H) 7.56 (s, 1 H) 6.99 - 7.06 (m, 2 H) 6.51 (br s, 1 H) 6.24 (d, J = 7.21 Hz, 1 H) 4.27 (q, J = 6.11 Hz, 1 H) 3.22 - 3.25 (m, 2 H) 3.09 - 3.16 (m, 2 H) 2.51 - 2.84 (m, 7 H) 2.44 - 2.49 (m, 1 H) 2.36 - 2.43 (m, 2 H) 2.20 (s, 3 H) 1.92 (dt, J = 13.33, 6.79 Hz, 1 H) 1.79 - 1.85 (m, 1 H) 1.71 - 1.79 (m, 5 H) 1.53 (q, J = 7.27 Hz, 2 H) 1.35 - 1.45 (m, 2 H). SCHEME 40, COMPOUND 349:

[00891] Step 1: 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinoxalin- (S)-tert-butyl 2-ylamino)butanoate: A mixture of 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoate ((S)-tert- butyl (150 mg, 335 μmol) and 2-chloroquinoxaline (46 mg, 279 μmol) in t-AmOH (2 ml) t-BuONa was added 2.0 M (279 μl, 558 μmol), then t- BuXphos Pd G3 (22 mg, 28 μmol) and the resulting mixture was heated at 100 °C for 15 h, cooled to room temperature, and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+ ): m/z = 576.1 (M+H)+.

[00892] Step 2: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinoxalin-2-ylamino)butanoic acid: ((S)-tert-Butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinoxalin-2-ylamino)butanoate (200 mg, 347 μmol) was taken up in 3:1 DCM/TFA (2 ml) and the resulting mixture was stirred at room temperature for 5 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 520.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1 H) 7.86 (br s, 1 H) 7.74 (d, J = 7.72 Hz, 1 H) 7.66 (br d, J = 7.06 Hz, 1 H) 7.47 - 7.53 (m, 2 H) 7.30 (ddd, J = 8.16, 5.62, 2.54 Hz, 1 H) 6.98 (d, J = 7.28 Hz, 1 H) 6.48 (br s, 1 H) 6.19 (d, J = 7.28 Hz, 1 H) 4.35 - 4.43 (m, 1 H) 3.22 (br d, J = 5.07 Hz, 2 H) 3.10 - 3.15 (m, 2 H) 2.52 - 2.71 (m, 7 H)) 2.33 - 2.48 (m, 3 H) 1.86 - 2.05 (m, 2 H) 1.71 - 1.77 (m, 5 H) 1.48 - 1.59 (m, 2 H) 1.34 - 1.46 (m, 2 H). SCHEME 41, COMPOUND 350:

[00893] Step 1: 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2 (S)-tert-butyl-phenylpyrimidin-4-yl)amino)butanoate: A mixture of (S)-tert-butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoate (150 mg, 335 μmol) and 4-chloro-2-phenylpyrimidine (53 mg, 279 μmol) in t-AmOH (3 ml) was added 2.0M t-BuONa in THF (279 μl, 558 μmol), then t-BuXphosPd (22 mg, 28 μmol) and the resulting mixture was heated at 100 °C for 15 h, cooled to room temperature, and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 602.5 (M+H)+.

[00894] Step 2: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-phenylpyrimidin-4-yl)amino)butanoic acid: (S)-tert-Butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-phenylpyrimidin-4-yl)amino)butanoate (150 mg, 249 μmol) was taken up in DCM/TFA (2 ml) and the resulting mixture was stirred at room temperature for 5 h and then concentrated in vacuo. The crude residue was purified by prep. HPLC. reverse phase to furnish the title compound. LCMS (ESI+): m/z = 546.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 - 8.35 (m, 2 H) 8.14 - 8.20 (m, 1 H) 7.73 (br s, 1 H) 7.62 (br s, 1 H) 7.44 (br d, J = 3.55 Hz, 3 H) 6.99 (br d, J = 7.21 Hz, 1 H) 6.39 - 6.61 (m, 2 H) 6.21 (d, J = 7.21 Hz, 1 H) 4.50 (br s, 1 H) 3.01 - 3.25 (m, 4 H) 2.66 (br dd, J = 13.39, 6.66 Hz, 2 H) 2.58 (br t, J = 5.75 Hz, 4 H) 2.31 - 2.43 (m, 2 H) 1.86 - 2.05 (m, 2 H) 1.71 - 1.78 (m, 5 H) 1.33 - 1.62 (m, 6 H).

[00895] Compound 351: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((6-phenylpyrimidin-4-yl)amino)butanoic acid.

[00896] Compound 352: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl))butyl)amino)-2-((5-bromopyrimidin-4-yl)amino)butanoic acid (100 mg, 171 μmol) in 3:1 dioxane/H2O (2 ml) was added K2CO3 (71 mg, 513 μmol) and phenylboronic acid (31 mg, 256 μmol), then Pd(dppf)Cl2 (13 mg, 17 μmol) and the resulting mixture was heated at 100 °C for 2 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 546.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm δ ppm 8.85 (s, 1H) 8.22 (s, 1H) 7.61 (s, 6 H) 6.66 (d, J = 7.34 Hz, 1 H) 5.14 (br t, J = 6.24 Hz, 1 H) 3.33 - 3.60 (m, 10 H) 2.73 - 2.88 (m, 4 H) 2.57 (br s, 1 H) 2.39 (br d, J = 7.09 Hz, 1 H) 1.94 - 2.10 (m, 5 H) 1.83 (br s, 4 H). SCHEME 42, COMPOUND 353:

[00897] Step 1: 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6 (S)-tert-butyl-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino)butanoate: A mixture of 4-((2- acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoate ((S)-tert-butyl (150 mg, 335 μmol) and 4-chloro-6-methyl-2-(pyridin-4-yl)pyrimidine (57 mg, 279 μmol) in t-AmOH (2 ml) was t-BuONa 2.0 M in THF (279 μl, 558 μmol) was added, then t-BuXphosPd G3 (22 mg, 28 μmol) and the resulting mixture was heated at 100 °C for 15 h, cooled to room temperature ambient temperature and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 617.2 (M+H)+.

[00898] Step 2: (S)-4-((2-acetamidoethyl)(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: (S)-tert-Butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino)butanoate (200 mg, 324 μmol) was taken up in DCM/TFA 3:1 (2 mL), and the resulting mixture was stirred at room temperature for 5 h and then evaporated to room temperature. concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 561.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (d, J = 5.87 Hz, 2 H) 8.13 - 8.19 (m, 2 H) 7.73 (br s, 1 H) 7.64 (br s, 1 H) 6.97 - 7.05 (m, 1 H) 6.50 (br s, 2 H) 6.20 (d, J = 7.21 Hz, 1 H) 4.51 (br s, 1 H) 3.20 - 3.24 (m, 2 H) 3.11 - 3.18 (m, 2 H) 2.51 - 2.80 (m, 8 H) 2.39 (t br, J = 7.34 Hz, 2 H) 2.32 (s, 3 H) 1.99 (dq, J = 13.66, 6.73 Hz, 1 H) 1.84 - 1.94 (m, 1 H) 1.68 - 1.79 (m, 5 H) 1.49 - 1.59 (m, 2 H) 1.36 - 1.46 (m, 2 H).

[00899] Compound 354: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((2-methyl-2H-pyrazol[4,3- d]pyrimidin-7-yl)amino)butanoic acid: A mixture of (S)-4-((2- acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoic acid (200 mg, 511 μmol) and 7-chloro-2- methyl-2H-pyrazol[4,3-d]pyrimidine (95 mg, 562 ol) in THF (2 ml), H2O (0.5 ml) was added NaHCO3 (215 mg, 2.55 mmol) and the resulting mixture was heated at 70 °C for 2 h and then cooled to room temperature and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 524.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.62 (br s, 1 H) 8.50 (s, 1 H) 7.60 (d, J = 7.34 Hz, 1 H) 6, 67 (d, J = 7.34 Hz, 1 H) 5.07 (br dd, J = 8.31, 5.26 Hz, 1 H) 4.10 (s, 3 H) 3.60 (br t, J = 5.69 Hz, 3 H) 3.45 - 3.55 (m, 3 H) 3.33 - 3, 44 (m, 4 H) 2.77 - 2.89 (m, 4 H) 2.61 - 2.74 (m, 1 H) 2.56 (br s, 1 H) 1.75 - 2.10 (m, 9 H).

[00900] Compound 355: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((4-phenylpyridin-2-yl)amino)butanoic acid.

[00901] Compound 356: (S)-2-([4,4'-bipyridin]-2-ylamino)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetra-) hydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. SCHEME 43, COMPOUND 357:

[00902] Step 1: (S)-tert-butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino )-2-((6-phenylpyrazin-2-yl)amino)butanoate: A mixture of 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoate ((S)- tert- butyl (150 mg, 335 μmol) and 2-chloro-6-phenylpyrazine (53 mg, 279 μmol) in t-AmOH (3 ml) were added 2.0M t-BuONa (279 μl, 558 μmol), then t-BuXphosPd G3 (22 mg, 28 μmol) and the resulting mixture was heated at 100 °C for 15 h, cooled to room temperature and then concentrated in vacuo to furnish the title compound title that was used without further purification. LCMS (ESI+): m/z = 602.5 (M+H)+.

[00903] Step 2: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrazin-2-yl)amino)butanoic acid: (S)-tert-Butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrazin-2-yl)amino)butanoate (200 mg, 371 μmol) was taken up in 5:1 DCM/TFA (2 ml) and the resulting mixture was stirred at room temperature for 5 h and then concentrated in vacuo. The crude residue was purified by prep. HPLC. reverse phase to furnish the title compound. LCMS (ESI+): m/z = 546.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (s, 1 H) 8.02 (br s, 3 H) 7.74 (br s, 1 H) 7.33 - 7.50 (m, 4 H) 6.99 (br d, J = 7.21 Hz, 1 H) 6.50 (br s, 1 H) 6.20 (br d, J = 7.09 Hz, 1 H) 4.38 (br d, J = 5.99 Hz, 1 H) 3.21 (br s, 2 H) 3.14 (br s, 2 H) 2.52 - 2.80 (m, 8 H) 2.33 - 2.43 (m, 2 H) 1.83 - 2.08 (m, 2 H) 1.68 - 1.81 (m, 5 H) 1.53 (br d, J = 7.09 Hz, 4 H).

[00904] Compound 358: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((5-phenylpyrazin-2-yl)amino)butanoic acid.

[00905] Compound 359: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2 -((6-(pyridin-4-yl)pyrazin-2-yl)amino)butanoic acid.

[00906] Compound 360: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid: A mixture of (S)-4-((2- acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoic acid (150 mg, 383 μmol) in DMA (2 ml) was Add DI PEA (334 uL, 1.92 mmol), then 4-chloro-2-(pyridin-3-yl)quinazoline (102 mg, 421 μmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by HPLC prep. to furnish the title compound. LCMS (ESI+): m/z = 597.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 9.79 (s, 1 H) 9.38 (br d, J = 7.45 Hz, 1 H) 9.07 (d, J = 5.70 Hz, 1 H) 8.64 (t, J = 8.11 Hz, 1 H) 8.21 (dd, J = 8.11, 5.48 Hz, 1 H) 8.06 - 8.15 (m, 2 H) 7.87 (t, J = 6.80 Hz, 1 H) 7.58 (br s, 1 H ) 6.64 (t, J = 7.45 Hz, 1 H) 5.44 (br d, J = 7.89 Hz, 1 H) 3.47 - 3.62 (m, 6 H) 3.33 - 3.40 (m, 4 H) 2.54 - 2.85 (m, 6 H) 1.92 - 1.99 (m, 5 H) 1.74 - 1 .90 (m, 4 H).

[00907] Compound 361: 4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid )-2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid.

[00908] Compound 362: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7, 8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2-amino-4-((2- (dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 383 μmol) and 2-chloropyrimidine -5- carbonitrile (59 mg, 421 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (161 mg, 1.92 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 495.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.33 - 8.76 (m, 2 H) 7.34 (d, J = 7.02 Hz, 1 H) 6.47 (d, J = 7.02 Hz, 1 H) 4.44 - 4.55 (m, 1 H) 3.69 (br d, J = 9.65 Hz, 2 H) 3.37 - 3.46 (m, 2 H) 2.85 - 3.05 (m, 10 H) 2.72 - 2.77 (m, 2 H) 2.60 - 2.67 (m, 2 H) 2.04 - 2.28 (m, 2 H) 1.84 - 1.94 (m, 2H) 1.60 - 1.80 (m, 4 H).

[00909] Compound 363: 4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid )-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid.

[00910] Compound 364: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-(dimethylamino)-2-oxoethyl)(4 -(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2- acid amino-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg , 383 μmol) and 4-chloro-1H-pyrazol[3,4-d]pyrimidine (40 μl, 421 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (161 mg, 1.92 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by Prep. reversed-phase HPLC to furnish the title compound. LCMS (ESI+): m/z = 510.2 (M+H)+. 1H NMR (400 MHz, ethanol-d4) δ ppm 8.35 (s, 1 H) 8.22 (s, 1 H) 7.28 (d, J = 7.45 Hz, 1 H) 6.41 (d, J = 7.45 Hz, 1 H) 4.91 - 4.94 (m, 1 H) 3.60 - 3.71 (m, 1 H) 3.45 - 3.55 (m, 1 H) 3.32 - 3.39 (m, 2 H) 3.01 (s, 3 H) 2.91 - 2, 99 (m, 1 H) 2.88 (s, 3 H) 2.81 (br d, J = 13.59 Hz, 1 H) 2.75 (br t, J = 6.14 Hz, 2 H) 2.56 - 2.71 (m, 4 H) 2.24 (br d, J = 4.82 Hz, 2 H) 1.87 - 2.01 (m, 1 H ) 1.64 - 1.87 (m, 4 H) 1.50 - 1.62 (m, 1 H).

[00911] Compound 365: (S)-2-((5-Bromopyrimidin-2-yl)amino)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-amino-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 383 μmol) and 5-bromo-2-chloropyrimidine (89 mg, 460 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (161 mg, 1.92 mmol) and the resulting mixture was stirred at 70 °C for 1 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 548.2 (M+H)+. 1H NMR (400 MHz, ethanol-d4) δ ppm 8.28 (s, 2 H) 7.30 (d, J = 7.28 Hz, 1 H) 6.45 (d, J = 7.28 Hz, 1 H) 4.36 (t, J = 6.06 Hz, 1 H) 3.66 - 3.79 (m, 2 H) 3.36 - 3.42 (m, 2 H) 3.03 (s, 3 H) 2.98 (br dd, J = 13.78, 7.17 Hz, 2 H) 2.85 - 2.92 (m, 5 H) 2.73 (t, J = 5.95 Hz, 2 H) 2.62 (br t, J = 7.39Hz, 2 H) 2.14 - 2.27 (m, 1 H) 2.01 - 2.12 (m, 1 H) 1.88 (q, J = 5.90 Hz, 2 H) 1.70 - 1.80 (m, 2 H) 1.59 - 1.69 (m, 2 H).

[00912] Compound 366: (S)-2-((1H-pyrazol[4,3-d]pyrimidin-7-yl)amino acid)-4-((2-(dimethylamino)-2-oxoethyl)(4 -(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00913] Compound 367: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((2-(dimethylamino)-2-oxoethyl)( 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00914] Compound 368: 4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino acid )-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid.

[00915] Compound 369: (S)-2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 383 μmol) and 5-cyclopropyl-2-fluoropyrimidine (64 mg, 460 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (161 mg, 1.92 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 510.3 (M+H)+. 1H NMR (400 MHz, ethanol-d4) δ ppm 8.07 (s, 2 H) 7.20 (d, J = 7.28 Hz, 1 H) 6.39 (d, J = 7.28 Hz, 1 H) 4.33 (t, J = 5.73 Hz, 1 H) 3.55 - 3.72 (m, 2 H) 3.35 - 3.40 (m, 2 H) 3.04 (s, 3 H) 2.92 - 3.00 (m, 1 H) 2.82 - 2.92 (m, 4 H) 2.78 (br t, J = 7.17 Hz, 2 H) 2.71 (t, J = 6.17 Hz, 2 H) 2.55 (t, J = 7.50 Hz, 2 H) 2.15 - 2.27 (m, 1 H) 1.94 - 2.06 (m, 1 H) 1.87 (q, J = 5.79 Hz, 2 H) 1.71 - 1.79 (m, 1 H) 1.62 - 1.71 (m, 2 H) 1.52 - 1.62 (m, 2 H) 0.84 - 0.97 (m, 2 H) 0.51 - 0.67 (m, 2 H).

[00916] Compound 370: (S)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) acid )butyl)amino)-2-((5-fluoropyrimidin-2-yl)amino)butanoic acid. SCHEME 44, COMPOUND 371:

[00917] Step 1: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 383 μmol) and 5-bromo-4-chloropyrimidine (89 mg, 460 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (161 mg, 1.92 mmol) and the resulting mixture was stirred at 70 °C for 2 h and then allowed to cool to room temperature and then concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 548.4 (M+H)+.

[00918] Step 2: (S)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid: To a mixture of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (210 mg, 383 μmol) in MeOH (4 mL) was added 10 wt % Pd/C (50 mg), and the resulting mixture was stirred under an atmosphere of H 2 for 5 h. The reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 470.2 (M+H)+. 1H NMR (400 MHz, ethanol-d4) δ ppm 8.34 (s, 1 H) 7.91 (br s, 1 H) 7.26 (br d, J = 7.06 Hz, 1 H) 6.58 (br s, 1 H) 6.42 (d, J = 7.28 Hz, 1 H) 4.54 (br s, 1 H) 3.58 (br d, J = 15.66 Hz, 1 H) 3.34 - 3.46 (m, 3 H) 3.04 (s, 3 H) 2.85 - 2.92 (m, 4 H) 2.51 - 2.79 (m, 7 H) 2.16 (br s, 1 H) 2.05 (br d, J = 5.95 Hz, 1 H) 1.87 (q, J = 5.95 Hz, 2 H) 1.65 - 1.82 (m, 2 H) 1.47 - 1.65 (m, 2 H).

[00919] Compound 372: (S)-2-((3-cyanopyrazin-2-yl)amino)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (200 mg, 511 μmol) and 3-chloropyrazine-2-carbonitrile (86 mg, 613 μmol) in i-PrOH (4 ml) was added DIPEA (445 μl, 2.55 mmol) and the resulting mixture was stirred at 70 °C for 12 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 495.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 9.57 (s, 1H) 8.85 (br d, J = 7.72 Hz, 1 H) 8.56 - 8.65 (m, 1 H) 8.29 (d, J = 7.94 Hz, 1 H) 7.72 - 7.85 (m, 2 H) 7.45 - 7.54 (m, 2 H) 7.18 (d, J = 7.28 Hz, 1 H) 6.33 (d, J = 7.28 Hz, 1 H) 5.04 (t, J = 5.51 Hz, 1 H) 3.68 (br d, J = 15.66 Hz, 1 H) 3.50 (br d, J = 15.21 Hz, 1 H) 3.11 - 3.25 (m, 2 H) 3.05 (br d, J = 4.63 Hz, 1 H) 2.97 (s, 3 H) 2.86 (br dd, J = 11.91, 5.73 Hz, 2 H) 2.78 (s, 3 H) 2.70 - 2.76 (m, 1 H) 2.50 - 2.68 (m, 4 H) 2.40 (br d, J = 6.39 Hz, 1 H) 2.22 - 2.33 (m, 1 H) 1.50 - 1.92 (m, 6 H).

[00920] Compound 373: (S)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) acid )butyl)amino)-2-((2-phenylpyrimidin-4-yl)amino)butanoic acid.

[00921] Compound 374: (S)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) acid )butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid. SCHEME 45, COMPOUND 375:

[00922] Step 1: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 383 μmol) and 5-bromo-4-chloropyrimidine (89 mg, 460 μmol) in THF (1.2 ml) and H2O (0.3 ml) was added NaHCO3 (160.93 mg, 1.92 mmol) and the resulting mixture was stirred at 70 °C for 1 h and then allowed to cool to room temperature and then concentrated in vacuo to give the title compound which was used without further purification. LCMS (ESI+): m/z = 548.4 (M+H)+.

[00923] Step 2: (S)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) acid )butyl)amino)-2-((5-phenylpyrimidin-4- yl)amino)butanoic acid: A mixture of (S)-2-((5-bromopyrimidin-4- yl)amino)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (210 mg, 383 μmol) and phenylboronic acid (56 mg, 459 μmol) in dioxane (2 ml) and H2O (0.5 ml) was added Pd(dppf)Cl2 (28 mg, 38 μmol) and K2CO3 (106 mg, 766 μmol) and the resulting mixture was stirred at 100 °C for 2 h and then cooled to room temperature and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 546.3 (M+H)+. 1H NMR (400 MHz, deuterium oxide) δ ppm 8.70 (s, 1 H) 8.10 (s, 1 H) 7.55 - 7.65 (m, 3 H) 7.49 (br d , J = 7.58 Hz, 3 H) 6.53 (d, J = 7.46 Hz, 1 H) 4.77 - 4.78 (m, 1 H) 4.13 - 4.28 (m, 2 H) 3.35 - 3.45 (m, 3 H) 3.18 - 3.31 (m, 3 H) 2, 84 - 2.99 (m, 6 H) 2.62 - 2.79 (m, 4 H) 2.41 (br s, 1 H) 2.19 (br s, 1 H) 1.85 (q, J = 5.81 Hz, 2 H) 1.70 (br s, 4 H).

[00924] Compound 376: (S)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) acid )butyl)amino)-2-((6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino)butanoic acid.

[00925] Compound 377: (S)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 383 μmol) and 4-chloro-2-(3-pyridyl)quinazoline (102 mg, 421 μmol) in DMA (4 ml) was added DIPEA (334 μL, 1.92 mmol) and the resulting mixture was stirred at 70 °C for 12 h and then allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 597.2 (M+H)+. 1H NMR (400 MHz, ethanol-d4) δ ppm 9.57 (s, 1 H) 8.85 (br d, J = 7.72 Hz, 1 H) 8.56 - 8.65 (m, 1 H) 8.29 (d, J = 7.94 Hz, 1 H) 7.72 - 7.85 (m, 2 H) 7.45 - 7.54 (m, 2 H) 7.18 (d, J = 7.28 Hz, 1 H) 6.33 (d, J = 7.28 Hz, 1 H) 5.04 (t, J = 5.51 Hz, 1 H) 3.68 (br d, J = 15.66 Hz, 1 H) 3.50 (br d, J = 15.21 Hz, 1 H) 3.11 - 3.25 (m, 2 H) 3.05 (br d, J = 4.63 Hz, 1 H) 2.97 (s, 3 H) 2.86 (br dd, J = 11.91, 5.73 Hz, 2 H) 2.78 (s, 3 H) 2.70 - 2.76 (m, 1 H) 2.50 - 2.68 (m, 4 H) 2.40 (br d, J = 6.39 Hz, 1 H) 2.22 - 2.33 (m, 1 H) 1.50 - 1.92 (m, 6 H).

[00926] Compound 378: (S)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) acid )butyl)amino)-2-((4-phenylpyridin-2-yl)amino)butanoic acid. SCHEME 46, COMPOUND 379:

[00927] Step 1: (2-(2,2-difluoroethoxy)ethyl)carbamate: To a solution of tert-butyl (2-hydroxyethyl)carbamate (15 g, 93.05 mmol) in THF (100 mL) was added 60 wt % NaH dispersion in mineral oil (8.19 g, 204.72 mmol) at -10 °C and the resulting mixture was stirred for 30 min at which time a solution of 2,2-difluoroethyl trifluoromethanesulfonate (19.92 g, 93.05 mmol) in THF (10 mL) was added dropwise at -10 °C. The mixture was stirred at 0 °C for 1 h and then diluted with water and then extracted with EtO-Ac. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography on silica gel to furnish the title compound.

[00928] Step 2: 2-(2,2-Difluoroethoxy)ethanamine hydrochloride: tert-butyl (2-(2,2-difluoroethoxy)ethyl)carbamate (20 g, 88.80 mmol) was taken up in 4 M HCl in EtOAc (111 mL) and the resulting mixture was stirred at room temperature for 30 min and then concentrated in vacuo to afford the title compound which was used without further purification.

[00929] Step 3: 7-(4-((2-(2,2-difluoroethoxy)ethyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl: To a solution of 2-(2,2-difluoroethoxy)ethanamine hydrochloride (11.94 g, 73.92 mmol) in MeOH (100 mL) was added HOAc (5.64 mL, 98.56 mmol), NaBH3CN (6.19 g, 98.56 mmol), then a solution of 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl (15 g, 49.28 mmol) in MeOH (50 mL) was added at 0 °C and The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and then diluted with aq. NaHCO3 solution and the resulting mixture was extracted with EtOAc and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 414.4 (M+H)+.

[00930] Step 4: 7-(4-((3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)(2-(2,2-difluoroethoxy)ethyl)amino)butyl)- (S)-tert-butyl 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate: A mixture of 7-(4- tert-butyl ((2-(2,2-difluoroethoxy)ethyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (19 g, 32.16 mmol ) and (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (8.53 g, 32.16 mmol) in DCE (200 ml) was added AcOH (2.76 ml, 48.25 mmol) at 0 °C NaBH(OAc)3 (10.23 g, 48.25 mmol) was added and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with MeOH and then concentrated in vacuo. The crude residue was taken up in a mixture of DCM and sat. aq. NaHCO3 solution and the layers were separated. The aqueous layer was extracted with DCM and the extracts The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by normal-phase silica gel chromatography. LCMS (ESI+): m/z = 663.5 (M+H) +.

[00931] Step 5: (S)-Methyl 2-(((benzyloxy)carbonyl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: (S)-tert-butyl 7-(4-((3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)(2-(2,2-difluoroethoxy)ethyl)amino)butyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (3.5 g, 5.28 mmol) was taken up in 4 M HCl in EtOAc (13.20 mL) and the resulting mixture was stirred at room temperature for 8 h and was then poured into water, adjusted to pH = 8 by the addition of 1 M NaOH and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to furnish the title compound. LCMS (ESI+): m/z = 563.4 (M+H)+.

[00932] Step 6: (S)-2-(((benzyloxy)carbonyl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (2.8 g, 4.98 mmol) in THF (10 mL) and H2O (10 mL) and MeOH (10 mL) was added LiOH.H2O (418 mg, 9.95 mmol) and the resulting mixture was stirred at room temperature for 1 h and then adjusted to pH = 6 by addition of 1 M aq. HCl solution and then concentrated under reduced pressure to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 549.4 (M+H)+.

[00933] Step 7: (S)-2-Amino-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (3 g, 5.13 mmol) in i-PrOH (30 mL) was added 20 wt % Pd(OH) 2 /C (720 mg), and the resulting mixture was stirred under an atmosphere of H 2 for 3 h and then evaporated to room temperature. was filtered and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 415.4 (M+H)+.

[00934] Step 8: (S)-4-((2-(2,2-difluoroethoxy)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: To a mixture of (S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 333 µmol) in THF (1.6 mL) and H2O (0.4 mL) was added NaHCO3 (140 mg, 1.66 mmol) and then 4- English:chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (62 mg, 366 μmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 547.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.56 (s, 1 H) 8.48 (s, 1 H) 7.59 (d, J = 7.34 Hz, 1 H) 6.65 (d, J = 7.46 Hz, 1 H) 5.85 - 6.16 (m, 1 H) 5.07 (br dd, J = 8.01, 5.32 Hz, 1 H) 4.08 (s, 3 H) 3.94 - 4.03 (m, 2 H) 3.78 (td, J = 14.73, 3.67 Hz, 2 H) 3.49 - 3.64 (m, 5 H) 3.32 - 3.40 (m, 3 H) 2.74 - 2.88 (m, 4 H) 2.46 - 2.73 (m, 2 H) 1.75 - 1.99 (m, 6 H).

[00935] Compound 380: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7 ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00936] Compound 381: (S)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 333 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (56 mg, 665 μmol), then 2-chloro-5-(trifluoromethyl)pyrimidine (91 mg, 499 μmol) was prepared and the resulting mixture was heated at 70 °C for 6 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 561.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.62 (s, 2 H) 7.59 (d, J = 7.34 Hz, 1 H) 6.64 (d, J = 7.21 Hz, 1 H) 5.84 - 6.17 (m, 1 H) 4.77 (dd, J = 8.50, 5.07Hz, 1H) 3.96 (br d, J = 4.40Hz, 2H) 3.78 (br t, J = 14.37Hz, 2H) 3.44 - 3.55 (m, 5H) 3.32 - 3.44 (m, 3H) 2.72 - 2.88 (m, 4H) 2.44 - 2.56 (m, 1 H) 2.24 - 2.38 (m, 1 H) 1.73 - 2.00 (m, 6 H).

[00937] Compound 382: (S)-2-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(2,2-difluoroethoxy))ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 333 μmol) in THF (1.6 ml) and H2O (0.4 ml) was added NaHCO3 (140 mg, 1.66 mmol), and in Then 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (57 mg, 366 μmol) was added and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by prep. HPLC to afford the title compound LCMS (ESI+): m/z = 533.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.87 (s, 1H) 8.65 (s, 1H) 7.59 (d, J = 7.34 Hz, 1 H) 6.65 (d, J = 7.34 Hz, 1 H) 5.84 - 6.15 (m, 1 H) 5.26 (dd, J = 8.68, 5.26 Hz, 1 H) 3.97 (br s, 2 H) 3.77 (td, J = 14.79, 3.55 Hz, 2 H) 3.47 - 3.54 (m, 5 H) 3.33 - 3.39 (m, 3 H) 2.76 - 2.85 (m, 4 H) 2.43 - 2.69 (m, 2 H) 1.77 - 1.99 (m, 6 H).

[00938] Compound 383: (S)-2-((5-Bromopyrimidin-2-yl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 333 μmol) in THF (1.6 ml) and H2O (0.4 ml) was added NaHCO3 (140 mg, 1.66 mmol) and then 5- English:bromo-2-fluoropyrimidine (65 mg, 366 μmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 571.1 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.41 (s, 2 H) 7.60 (d, J = 7.34 Hz, 1 H) 6.64 (d, J = 7.46 Hz, 1 H) 5.80 - 6.22 (m, 1 H) 4.64 (dd, J = 8.62, 5.07 Hz, 1 H) 3.95 (br t, J = 4.65 Hz, 2 H) 3.78 (td, J = 14.67, 1.83 Hz, 2 H) 3.47 - 3.55 (m, 4 H) 3.32 - 3.46 (m, 3 H) 3.25 - 3.30 (m, 1 H) 2.75 - 2.86 (m, 4 H) 2.41 - 2.52 (m, 1 H) 2.21 - 2.34 (m, 1 H) 1.96 (dt, J = 11.77, 6.04 Hz, 2 H) 1.80 (br d, J = 2.81 Hz, 4 H).

[00939] Compound 384: (S)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 332 μmol) in THF (1.6 ml) and H2O (0.4 ml) was added NaHCO3 (140 mg, 1.66 mmol) and then 4-chloro-2-(trifluoromethyl)pyrimidine (67 mg, 366 μmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 561.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.25 (br d, J = 6.11 Hz, 1 H) 7.59 (d, J = 7.34 Hz, 1 H) 6.88 (d, J = 6.11 Hz, 1 H) 6.64 (d, J = 7.34 Hz, 1 H) 5.82 - 6.17 (m, 1 H) 4.83 (br s, 1 H) 3.95 (br s, 2 H) 3.77 (td, J = 14.70, 3.61 Hz, 2 H) 3.45 - 3.57 (m, 5 H) 3.32 - 3.45 (m, 3 H) 2.72 - 2.90 (m, 4 H) 2.43 - 2.56 (m, 1 H) 2.25 - 2.40 (m, 1 H) 1.70 - 2.03 (m, 6 H).

[00940] Compound 385: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((5-methylpyrimidin-2 - yl)amino)butanoic acid.

[00941] Compound 386: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-(pyridin-3-ylamino)butanoic acid.

[00942] Compound 387: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid.

[00943] Compound 388: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00944] Compound 389: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid.

[00945] Compound 390: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-(pyridin-2-ylamino)butanoic acid.

[00946] Compound 391: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-methoxyethyl)(4-(5,6, 7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00947] Compound 392: (S)-2-((5-bromopyrimidin-2-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00948] Compound 393: (S)-2-((1H-pyrazol[4,3-d]pyrimidin-7-yl)amino acid)-4-((2-methoxyethyl)(4-(5,6, 7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00949] Compound 394: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((2-methoxypyrimidin-4-yl)amino)butanoic acid.

[00950] Compound 395: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((6-methylpyrazin-2-yl)amino)butanoic acid.

[00951] Compound 396: 2-((3-cyanopyrazin-2-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-) naphthyridin-2-yl)butyl)amino)butanoic acid.

[00952] Compound 397: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- acid 2-(pyrimidin-4-ylamino)butanoic acid.

[00953] Compound 398: (S)-2-((5-fluoropyrimidin-2-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00954] Compound 399: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((7-methyl-7H-pyrrol[2,3-d]pyrimidin-4-yl)amino)butanoic acid.

[00955] Compound 400: (S)-2-((6-(tert-butyl)pyrimidin-4-yl)amino acid)-4-((2-methoxyethyl)(4-(5,6,7,8 -tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00956] Compound 401: (S)-2-((5-cyclopropylpyrimidin-2-yl)amino acid)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00957] Compound 402: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((6-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid.

[00958] Compound 403: (S)-2-((6-(dimethylamino)pyrimidin-4-yl)amino acid)-4-((2-methoxyethyl)(4-(5,6,7,8-tetra -hydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00959] Compound 404: 2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((2-methoxyethyl)(4-(5,6,7,8 -tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00960] Compound 405: 4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinoxalin) -2-ylamino)butanoic acid.

[00961] Compound 406: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((5-methoxypyrazin-2-yl)amino)butanoic acid.

[00962] Compound 407: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((6-phenylpyrimidin-4-yl)amino)butanoic acid.

[00963] Compound 408: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((2-phenylpyrimidin-4-yl)amino)butanoic acid.

[00964] Compound 409: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((5-phenylpyrimidin-4-yl)amino)butanoic acid.

[00965] Compound 410: (S)-4-((2-methoxyethyl)(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.

[00966] Compound 411: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid.

[00967] Compound 412: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((6-(pyridin-4-yl)pyrazin-2-yl)amino)butanoic acid.

[00968] Compound 413: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((5-phenylpyrazin-2-yl)amino)butanoic acid.

[00969] Compound 414: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((6-phenylpyrazin-2-yl)amino)butanoic acid.

[00970] Compound 415: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((1-methyl-1H-pyrazol-5-yl)amino)butanoic acid.

[00971] Compound 416: (S)-2-(benzo[d]oxazol-2-ylamino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1) acid ,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00972] Compound 417: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)butanoic acid.

[00973] Compound 418: (S)-2-(benzo[d]thiazol-2-ylamino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1) acid ,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00974] Compound 419: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((1-methyl-1H-pyrazol[4,3-d]pyrimidin-7-yl)amino)butanoic acid.

[00975] Compound 420: (S)-2-((9H-purin-6-yl)amino acid)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00976] Compound 421: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((5-phenylpyridin-2-yl)amino)butanoic acid.

[00977] Compound 422: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((4-phenylpyridin-2-yl)amino)butanoic acid.

[00978] Compound 423: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((1-methyl-1H-indazol-3-yl)amino)butanoic acid.

[00979] Compound 424: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-((1-methyl-1H-indol-3-yl)amino)butanoic acid.

[00980] Compound 425: (R)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-(quinoxalin-2-ylamino)butanoic acid.

[00981] Compound 426: (S)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid.

[00982] Compound 427: (S)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-(pyridin-3-ylamino)butanoic acid.

[00983] Compound 428: (S)-2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-((2-methylpyridin- 3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00984] Compound 429: (S)-2-((5-cyanopyrimidin-2-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.

[00985] Compound 430: (S)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid.

[00986] Compound 431: (S)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-(pyridin-2-ylamino)butanoic acid.

[00987] Compound 432: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-((2-methylpyridin-3-yl) oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00988] Compound 433: (S)-2-((5-bromopyrimidin-2-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.

[00989] Compound 434: (S)-2-((1H-pyrazol[4,3-d]pyrimidin-7-yl)amino acid)-4-((2-((2-methylpyridin-3-yl) oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00990] Compound 435: (S)-2-((2-methoxypyrimidin-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.

[00991] Compound 436: (S)-2-((6-methylpyrazin-2-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.

[00992] Compound 437: (S)-2-((3-cyanopyrazin-2-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.

[00993] Compound 438: (S)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid.

[00994] Compound 439: (S)-2-((5-fluoropyrimidin-2-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.

[00995] Compound 440: (S)-2-((7-methyl-7H-pyrrol[2,3- d]pyrimidin-4-yl)amino acid)-4-((2-((2-methylpyridin- 3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00996] Compound 441: (S)-2-((6-(tert-butyl)pyrimidin-4-yl)amino)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl acid )(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[00997] Compound 442: (S)-2-((5-cyclopropylpyrimidin-2-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.

[00998] Compound 443: (S)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((6-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid.

[00999] Compound 444: (S)-2-((6-(dimethylamino)pyrimidin-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.

[001000] Compound 445: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((2-((2-methylpyridin-3-yl )oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001001] Compound 446: (S)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-(quinoxalin-2-ylamino)butanoic acid.

[001002] Compound 447: (S)-2-((5-methoxypyrazin-2-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.

[001003] Compound 448: (S)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid.

[001004] Compound 449: (S)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((2-phenylpyrimidin-4-yl)amino)butanoic acid.

[001005] Compound 450: (S)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid.

[001006] Compound 451: (S)-2-((6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino acid)-4-((2-((2-methylpyridin-3 -yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001007] Compound 452: (S)-4-((2-((2-methylpyridin-3-yl)oxy)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.

[001008] Compound 453: (S)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((6-(pyridin-4-yl)pyrazin-2-yl)amino)butanoic acid.

[001009] Compound 454: (S)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrazin-2-yl)amino)butanoic acid.

[001010] Compound 455: (S)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrazin-2-yl)amino)butanoic acid.

[001011] Compound 456: (S)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((4-phenylpyridin-2-yl)amino)butanoic acid.

[001012] Compound 457: (S)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((4-phenylpyridin-2-yl)amino)butanoic acid.

[001013] Compound 458: (S)-2-((9H-purin-6-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.

[001014] Compound 459: (S)-2-((1-methyl-1H-pyrazol[4,3-d]pyrimidin-7-yl)amino acid)-4-((2-((2-methylpyridin- 3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001015] Compound 460: (S)-2-(benzo[d]thiazol-2-ylamino)-4-((2- ((2-methylpyridin-3-yl)oxy)ethyl)(4-(5) ,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001016] Compound 461: (S)-2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino acid)-4-((2-((2-methylpyridin-3-yl) oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001017] Compound 462: (S)-2-(benzo[d]oxazol-2-ylamino)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5) ,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001018] Compound 463: (S)-2-((1-methyl-1H-pyrazol-5-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.

[001019] Compound 464: (S)-2-((1-methyl-1H-indazol-3-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.

[001020] Compound 465: (S)-2-((1-methyl-1H-indol-3-yl)amino)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl) acid (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001021] Compound 466: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid.

[001022] Compound 467: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-(pyridin-3-ylamino)butanoic acid.

[001023] Compound 468: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid.

[001024] Compound 469: (S)-2-((5-cyanopyrimidin-2-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.

[001025] Compound 470: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid.

[001026] Compound 471: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) acid -naphthyridin-2-yl)butyl)amino)-2-(pyridin-2-ylamino)butanoic acid.

[001027] Compound 472: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-((5-fluoropyridin-3-yl) oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001028] Compound 473: (S)-2-((5-bromopyrimidin-2-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.

[001029] Compound 474: (S)-2-((1H-pyrazol[4,3-d]pyrimidin-7-yl)amino acid)-4-((2-((5-fluoropyridin-3-yl) oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001030] Compound 475: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((2-methoxypyrimidin-4-yl)amino)butanoic acid.

[001031] Compound 476: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((2-((5-fluoropyridin-3-yl )oxy)ethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001032] Compound 477: (S)-2-((6-(dimethylamino)pyrimidin-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.

[001033] Compound 478: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) acid -naphthyridin-2-yl)butyl)amino)-2-((6-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid.

[001034] Compound 479: (S)-2-((5-cyclopropylpyrimidin-2-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.

[001035] Compound 480: (S)-2-((6-(tert-butyl)pyrimidin-4-yl)amino)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl acid )(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001036] Compound 481: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) acid -naphthyridin-2-yl)butyl)amino)-2-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)butanoic acid.

[001037] Compound 482: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((5-fluoropyrimidin-2-yl)amino)butanoic acid.

[001038] Compound 483: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) acid -naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid.

[001039] Compound 484: (S)-2-((3-cyanopyrazin-2-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.

[001040] Compound 485: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((6-methylpyrazin-2-yl)amino)butanoic acid.

[001041] Compound 486: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrazin-2-yl)amino)butanoic acid.

[001042] Compound 487: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrazin-2-yl)amino)butanoic acid.

[001043] Compound 488: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((6-(pyridin-4-yl)pyrazin-2-yl)amino)butanoic acid.

[001044] Compound 489: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)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.

[001045] Compound 490: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) acid -naphthyridin-2-yl)butyl)amino)-2-((6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino)butanoic acid.

[001046] Compound 491: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid.

[001047] Compound 492: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) acid -naphthyridin-2-yl)butyl)amino)-2-((2-phenylpyrimidin-4-yl)amino)butanoic acid.

[001048] Compound 493: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid.

[001049] Compound 494: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((5-methoxypyrazin-2-yl)amino)butanoic acid.

[001050] Compound 495: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) acid -naphthyridin-2-yl)butyl)amino)-2-(quinoxalin-2-ylamino)butanoic acid.

[001051] Compound 496: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((4-phenylpyridin-2-yl)amino)butanoic acid.

[001052] Compound 497: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) acid -naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyridin-2-yl)amino)butanoic acid.

[001053] Compound 498: (S)-2-((9H-purin-6-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.

[001054] Compound 499: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) acid -naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazol[4,3-d]pyrimidin-7-yl)amino)butanoic acid.

[001055] Compound 500: (S)-2-(benzo[d]thiazol-2-ylamino)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5) ,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001056] Compound 501: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)butanoic acid.

[001057] Compound 502: (S)-2-(benzo[d]oxazol-2-ylamino)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5) ,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001058] Compound 503: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazol-5-yl)amino)butanoic acid.

[001059] Compound 504: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-indazol-3-yl)amino)butanoic acid.

[001060] Compound 505: (S)-4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-indol-3-yl)amino)butanoic acid.

[001061] Compound 506: (S)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid.

[001062] Compound 507: (S)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-(pyridin-3-ylamino)butanoic acid.

[001063] Compound 508: (S)-2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-((6-methylpyridin- 3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001064] Compound 509: (S)-2-((5-cyanopyrimidin-2-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.

[001065] Compound 510: (S)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid.

[001066] Compound 511: (S)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-(pyridin-2-ylamino)butanoic acid.

[001067] Compound 512: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-((6-methylpyridin-3-yl) oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001068] Compound 513: (S)-2-((5-bromopyrimidin-2-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.

[001069] Compound 514: (S)-2-((1H-pyrazol[4,3-d]pyrimidin-7-yl)amino acid)-4-((2-((6-methylpyridin-3-yl) oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001070] Compound 515: (S)-2-((2-methoxypyrimidin-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.

[001071] Compound 516: (S)-2-((6-methylpyrazin-2-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.

[001072] Compound 517: (S)-2-((3-cyanopyrazin-2-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.

[001073] Compound 518: (S)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid.

[001074] Compound 519: (S)-2-((5-fluoropyrimidin-2-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.

[001075] Compound 520: (S)-2-((7-methyl-7H-pyrrol[2,3-d]pyrimidin-4-yl)amino acid)-4-((2-((6-methylpyridin- 3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001076] Compound 521: (S)-2-((6-(tert-butyl)pyrimidin-4-yl)amino)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl acid )(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001077] Compound 522: (S)-2-((5-cyclopropylpyrimidin-2-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.

[001078] Compound 523: (S)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((6-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid.

[001079] Compound 524: (S)-2-((6-(dimethylamino)pyrimidin-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.

[001080] Compound 525: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((2-((6-methylpyridin-3-yl )oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001081] Compound 526: (S)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-(quinoxalin-2-ylamino)butanoic acid.

[001082] Compound 527: (S)-2-((5-methoxypyrazin-2-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.

[001083] Compound 528: (S)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid.

[001084] Compound 529: (S)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((2-phenylpyrimidin-4-yl)amino)butanoic acid.

[001085] Compound 530: (S)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid.

[001086] Compound 531: (S)-2-((6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino acid)-4-((2-((6-methylpyridin-3 -yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001087] Compound 532: (S)-4-((2-((6-methylpyridin-3-yl)oxy)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.

[001088] Compound 533: (S)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((6-(pyridin-4-yl)pyrazin-2-yl)amino)butanoic acid.

[001089] Compound 534: (S)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrazin-2-yl)amino)butanoic acid.

[001090] Compound 535: (S)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrazin-2-yl)amino)butanoic acid.

[001091] Compound 536: (S)-2-((1-methyl-1H-pyrazol-5-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.

[001092] Compound 537: (S)-2-(benzo[d]oxazol-2-ylamino)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5) ,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001093] Compound 538: (S)-2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino acid)-4-((2-((6-methylpyridin-3-yl) oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001094] Compound 539: (S)-2-(benzo[d]thiazol-2-ylamino)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5) ,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001095] Compound 540: (S)-2-((1-methyl-1H-pyrazol[4,3-d]pyrimidin-7-yl)amino acid)-4-((2-((6-methylpyridin- 3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001096] Compound 541: (S)-2-((9H-purin-6-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.

[001097] Compound 542: (S)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyridin-2-yl)amino)butanoic acid.

[001098] Compound 543: (S)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8) -naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyridin-2-yl)amino)butanoic acid.

[001099] Compound 544: (S)-2-((1-methyl-1H-indazol-3-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.

[001100] Compound 545: (S)-2-((1-methyl-1H-indol-3-yl)amino)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl) acid (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001101] Compound 546: (S)-2-((5-methylpyrimidin-2-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001102] Compound 547: (S)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)butyl)amino)-2-(pyridin-3-ylamino)butanoic acid.

[001103] Compound 548: (S)-2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-(pyridin-2-yloxy )ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001104] Compound 549: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001105] Compound 550: (S)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid.

[001106] Compound 551: (S)-2-(pyridin-2-ylamino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8-tetra-) hydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001107] Compound 552: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-(pyridin-2-yloxy)ethyl)( 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001108] Compound 553: (S)-2-((5-bromopyrimidin-2-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7 ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001109] Compound 554: (S)-2-((1H-pyrazol[4,3-d]pyrimidin-7-yl)amino acid)-4-((2-(pyridin-2-yloxy)ethyl)( 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001110] Compound 555: (S)-2-((2-methoxypyrimidin-4-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7 ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001111] Compound 556: (S)-2-((6-methylpyrazin-2-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001112] Compound 557: (S)-2-((3-cyanopyrazin-2-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001113] Compound 558: (S)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid.

[001114] Compound 559: (S)-2-((5-fluoropyrimidin-2-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001115] Compound 560: (S)-2-((7-methyl-7H-pyrrol[2,3-d]pyrimidin-4-yl)amino acid)-4-((2-(pyridin-2-yloxy )ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001116] Compound 561: (S)-2-((6-(tert-butyl)pyrimidin-4-yl)amino acid)-4-((2-(pyridin-2-yloxy)ethyl)(4-( 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001117] Compound 562: (S)-2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001118] Compound 563: (S)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)butyl)amino)-2-((6-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid.

[001119] Compound 564: (S)-2-((6-(dimethylamino)pyrimidin-4-yl)amino acid)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5, 6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001120] Compound 565: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((2-(pyridin-2-yloxy)ethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001121] Compound 566: (S)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)butyl)amino)-2-(quinoxalin-2-ylamino)butanoic acid.

[001122] Compound 567: (S)-2-((5-methoxypyrazin-2-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001123] Compound 568: (S)-2-((6-phenylpyrimidin-4-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001124] Compound 569: (S)-2-((2-phenylpyrimidin-4-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001125] Compound 570: (S)-2-((5-phenylpyrimidin-4-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001126] Compound 571: (S)-2-((6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino acid)-4-((2-(pyridin-2-yloxy) ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001127] Compound 572: (S)-4-((2-(pyridin-2-yloxy)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.

[001128] Compound 573: (S)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((6-(pyridin-4-yl)pyrazin-2-yl)amino)butanoic acid.

[001129] Compound 574: (S)-2-((5-phenylpyrazin-2-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001130] Compound 575: (S)-2-((6-phenylpyrazin-2-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001131] Compound 576: (S)-2-((1-methyl-1H-pyrazol-5-yl)amino acid)- 4-((2-(pyridin-2-yloxy)ethyl)(4-(5 ,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001132] Compound 577: (S)-2-(benzo[d]oxazol-2-ylamino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7, 8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001133] Compound 578: (S)-2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino acid)-4-((2-(pyridin-2-yloxy)ethyl)( 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001134] Compound 579: (S)-2-(benzo[d]thiazol-2-ylamino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7, 8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001135] Compound 580: (S)-2-((1-methyl-1H-pyrazol[4,3-d]pyrimidin-7-yl)amino acid)-4-((2-(pyridin-2-yloxy )ethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001136] Compound 581: (S)-2-((9H-purin-6-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001137] Compound 582: (S)-2-((5-phenylpyridin-2-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001138] Compound 583: (S)-2-((4-phenylpyridin-2-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001139] Compound 584: (S)-2-((1-methyl-1H-indol-3-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5) ,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001140] Compound 585: (S)-2-((1-methyl-1H-indazol-3-yl)amino acid)- 4-((2-(pyridin-2-yloxy)ethyl)(4-(5 ,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001141] Compound 586: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid.

[001142] Compound 587: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-(pyridin-3-ylamino)butanoic acid.

[001143] Compound 588: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((1-methyl-1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid.

[001144] Compound 589: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7 ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001145] Compound 590: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid.

[001146] Compound 591: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-(pyridin-2-ylamino)butanoic acid.

[001147] Compound 592: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-(3,5-difluorophenoxy)ethyl)( 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001148] Compound 593: (S)-2-((5-bromopyrimidin-2-yl)amino)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001149] Compound 594: (S)-2-((1H-pyrazol[4,3-d]pyrimidin-7-yl)amino acid)-4-((2-(3,5-difluorophenoxy)ethyl)( 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001150] Compound 595: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((2-methoxypyrimidin-4-yl)amino)butanoic acid.

[001151] Compound 596: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((6-methylpyrazin-2-yl)amino)butanoic acid.

[001152] Compound 597: (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.

[001153] Compound 598: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid.

[001154] Compound 599: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((5-fluoropyrimidin-2-yl)amino)butanoic acid.

[001155] Compound 600: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)butanoic acid.

[001156] Compound 601: (S)-2-((6-(tert-butyl)pyrimidin-4-yl)amino acid)-4-((2-(3,5-difluorophenoxy)ethyl)(4-( 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001157] Compound 602: (S)-2-((5-cyclopropylpyrimidin-2-yl)amino acid)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7 ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001158] Compound 603: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((6-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid.

[001159] Compound 604: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((6-(dimethylamino)pyrimidin-4-yl)amino)butanoic acid.

[001160] Compound 605: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((2-(3,5-difluorophenoxy)ethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001161] Compound 606: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-(quinoxalin-2-ylamino)butanoic acid.

[001162] Compound 607: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((5-methoxypyrazin-2-yl)amino)butanoic acid.

[001163] Compound 608: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid.

[001164] Compound 609: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((2-phenylpyrimidin-4-yl)amino)butanoic acid.

[001165] Compound 610: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid.

[001166] Compound 611: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(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.

[001167] Compound 612: (S)-4-((2-(3,5-difluorophenoxy)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.

[001168] Compound 613: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((6-(pyridin-4-yl)pyrazin-2-yl)amino)butanoic acid.

[001169] Compound 614: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((5-phenylpyrazin-2-yl)amino)butanoic acid.

[001170] Compound 615: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((6-phenylpyrazin-2-yl)amino)butanoic acid.

[001171] Compound 616: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((1-methyl-1H-pyrazol-5-yl)amino)butanoic acid.

[001172] Compound 617: (S)-2-(benzo[d]oxazol-2-ylamino)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7, 8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001173] Compound 618: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)butanoic acid.

[001174] Compound 619: (S)-2-(benzo[d]thiazol-2-ylamino)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7, 8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001175] Compound 620: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((1-methyl-1H-pyrazol[4,3-d]pyrimidin-7-yl)amino)butanoic acid.

[001176] Compound 621: (S)-2-((9H-purin-6-yl)amino)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7 ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001177] Compound 622: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((5-phenylpyridin-2-yl)amino)butanoic acid.

[001178] Compound 623: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((4-phenylpyridin-2-yl)amino)butanoic acid.

[001179] Compound 624: (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.

[001180] Compound 625: (S)-4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-) yl)butyl)amino)-2-((1-methyl-1H-indol-3-yl)amino)butanoic acid.

[001181] Compound 626: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid.

[001182] Compound 627: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)-2-(pyridin-3-ylamino)butanoic acid.

[001183] Compound 628: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl))butyl)amino)-2-((1-methyl- 1H-pyrazol[3,4-d]pyrimidin-4-yl)amino)butanoic acid.

[001184] Compound 629: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)() 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001185] Compound 630: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid.

[001186] Compound 631: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)-2-(pyridin-2-ylamino)butanoic acid.

[001187] Compound 632: (S)-2-((1H-pyrazol[3,4-d]pyrimidin-4-yl)amino acid)-4-((2-(3,5-dimethyl-1H-pyrazole -1-yl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001188] Compound 633: (S)-2-((5-bromopyrimidin-2-yl)amino)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)() 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001189] Compound 634: (S)-2-((1H-pyrazol[4,3-d]pyrimidin-7-yl)amino acid)-4-((2-(3,5-dimethyl-1H-pyrazole -1-yl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001190] Compound 635: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methoxypyrimidin-4-yl)amino)butanoic acid.

[001191] Compound 636: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methylpyrazin-2-yl)amino)butanoic acid.

[001192] Compound 637: (S)-2-((3-cyanopyrazin-2-yl)amino)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)() 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001193] Compound 638: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid.

[001194] Compound 639: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)-2-((5-fluoropyrimidin-2-yl)amino)butanoic acid.

[001195] Compound 640: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)-2-((7-methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)butanoic acid.

[001196] Compound 641: (S)-2-((6-(tert-butyl)pyrimidin-4-yl)amino acid)-4-((2-(3,5-dimethyl-1H-pyrazol-1- yl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001197] Compound 642: (S)-2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)( 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001198] Compound 643: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)-2-((6-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid.

[001199] Compound 644: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)-2-((6-(dimethylamino)pyrimidin-4-yl)amino)butanoic acid.

[001200] Compound 645: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((2-(3,5-dimethyl-1H- pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001201] Compound 646: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)-2-(quinoxalin-2-ylamino)butanoic acid.

[001202] Compound 647: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methoxypyrazin-2-yl)amino)butanoic acid.

[001203] Compound 648: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid.

[001204] Compound 649: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)-2-((2-phenylpyrimidin-4-yl)amino)butanoic acid.

[001205] Compound 650: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid.

[001206] Compound 651: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(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.

[001207] Compound 652: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)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.

[001208] Compound 653: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)-2-((6-(pyridin-4-yl)pyrazin-2-yl)amino)butanoic acid.

[001209] Compound 654: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrazin-2-yl)amino)butanoic acid.

[001210] Compound 655: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrazin-2-yl)amino)butanoic acid.

[001211] Compound 656: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazol-5-yl)amino)butanoic acid.

[001212] Compound 657: (S)-2-(benzo[d]oxazol-2-ylamino)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4 -(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001213] Compound 658: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)butanoic acid.

[001214] Compound 659: (S)-2-(benzo[d]thiazol-2-ylamino)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4 -(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001215] Compound 660: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl- 1H-pyrazol[4,3-d]pyrimidin-7-yl)amino)butanoic acid.

[001216] Compound 661: (S)-2-((9H-purin-6-yl)amino)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)( 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid.

[001217] Compound 662: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyridin-2-yl)amino)butanoic acid.

[001218] Compound 663: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)-2-((4-phenylpyridin-2-yl)amino)butanoic acid.

[001219] Compound 664: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-indazol-3-yl)amino)butanoic acid.

[001220] Compound 665: (S)-4-((2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-) 1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-indol-3-yl)amino)butanoic acid.

[001221] Compound 666: (R)-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 F with methyl (R)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 493.3. [M+H]+, found 493.3.

[001222] Compound 667: (S)-4-((2-methoxyethyl)(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)amino)- 2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine and (S)-4-((2-methoxyethyl)(5-(5,6,7,8-tetrahydro-1) acid ,8-naphthyridin-2-yl)pentyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, Procedure H with 4-chloro-2-methylquinazoline and Procedure P. LCMS theoretical m/z = 507.3. [M+H]+, found 507.3.

[001223] Compound 668: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinoxalin-2-ylamino)butanoic acid. Prepared according to Scheme A using Procedure A with 2-methoxyethan-1-amine, Procedure H with 2-chloroquinoxaline, and Procedure P. LCMS theoretical m/z = 493.3. [M+H]+, found 493.3.

[001224] Compound 669: (2S)-2-(quinazolin-4-ylamino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) acid butyl)((tetrahydrofuran-2-yl)methyl)amino)butanoic acid.

[001225] Compound 670: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((3-fluoropropyl)(4-(5,6 ,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: For a mixture of acid (S)-2-amino-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg , 344 μmol) in DMA (3 ml) was added 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (68 mg, 378 μmol) and DIPEA (299 μl, 1.72 mmol) and the resulting mixture was stirred at 70 °C for 16 h and then allowed to cool to room temperature and then adjusted to pH = 6 by the addition of 1 M aq. HCl solution and concentrated in vacuo. The residue The crude was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 511.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.53 (d, J = 2.57 Hz, 1 H) 8.34 (s, 1 H) 7.78 (d, J = 1.10 Hz , 1 H) 7.20 (d, J = 7.34 Hz, 1 H) 7.00 (br s, 1 H) 6.54 (dd, J = 1.71, 2.69 Hz, 1 H) 6.42 (d, J = 7.34 Hz, 1 H) 4.90 (br s, 1 H) 4.58 ( t, J = 5.07 Hz, 1 H) 4.43 - 4.49 (m, 1 H) 3.35 - 3.41 (m, 2 H) 2.80 - 3.19 (m, 6 H) 2.59 - 2.72 (m, 4 H) 1.94 - 2.31 (m, 4 H) 1.86 (q, J = 5.90 Hz, 2H) 1.63 - 1.79 (m, 4H).

[001226] Compound 671: (S)-4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butanoic acid: To a solution of (S)-2-amino-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (140 mg, 344 μmol) in DMA (3 ml) was added 4-chloro-2-(pyridin-3-yl)quinazoline (102 mg, 378 μmol) and DIPEA (299 μl, 1.72 mmol) and The resulting mixture was stirred at 70 °C for 16 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 572.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 9.57 (dd, J = 0.73, 2.08 Hz, 1 H) 8.84 (td, J = 1.86, 8.01 Hz, 1 H) 8.63 (dd, J = 1.59, 4.89 Hz, 1 H) 8.14 (d, J = 7.70 Hz, 1 H) 7.77 - 7.90 (m, 2 H) 7.48 - 7.59 (m, 2 H) 7.16 (d, J = 7.34 Hz, 1 H) 6.36 (d, J = 7.34 Hz, 1 H) 4.90 - 4.93 (m, 1 H) 4.39 - 4.60 (m, 2 H) 3.23 - 3.32 (m, 3 H) 2.89 - 3.19 (m, 5 H) 2.55 - 2.66 (m, 4 H) 2.41 - 2.52 (m, 1 H) 2.27 - 2.39 (m, 1 H) 1.95 - 2.15 (m, 2 H) 1.71 - 1.85 (m, 6 H).

[001227] Compound 672: (R)-2-((6-(dimethylamino)pyrimidin-4-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. From chiral SFC separation of Example 213. LCMS (ESI+): m/z = 500.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 7.98 (s, 1 H) 7.19 (d, J = 7.28 Hz, 1 H) 6.40 (d, J = 7.28 Hz, 1 H) 5.60 (s, 1 H) 4.22 (br s, 1 H) 3.75 (br d, J = 6.62 Hz, 1 H) 3.35 - 3.40 (m, 2 H) 3.33 (s, 3 H) 3.23 - 3.30 (m, 1 H) 3.07 - 3.16 (m, 3 H) 3.03 (s, 6 H) 2.93 - 3.01 (m, 2 H) 2.70 (t, J = 6.17 Hz, 2 H) 2.54 - 2.62 (m, 2 H) 2.22 - 2.34 (m, 1 H) 2.01 (br dd, J = 14.33, 5.07 Hz, 1 H) 1.87 (q, J = 5.84 Hz, 2 H) 1.72 (br s, 4 H) 1.19 (d, J = 5.95 Hz, 3 H).

[001228] Compound 673: (S)-2-((6-(tert-butyl)pyrimidin-4-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. From chiral SFC separation of Example 210. LCMS (ESI+): m/z = 513.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.34 (s, 1 H) 7.21 (d, J = 7.28 Hz, 1 H) 6.61 (s, 1 H) 6.41 (d, J = 7.28 Hz, 1 H) 4.41 (br s, 1 H) 3.75 (br s, 1 H) 3.36 - 3.40 (m, 2 H) 3.33 (s, 3 H) 3.29 - 3.30 (m, 1 H) 2.90 - 3.19 (m, 5 H) 2.70 (t, J = 6.17 Hz, 2 H) 2.55 - 2.63 (m, 2 H) 2.22 - 2.35 (m, 1 H) 2.06 (br dd, J = 14.77, 5.51 Hz, 1 H) 1.87 (q, J = 5.95 Hz, 2 H) 1.73 (br s, 4 H) 1.27 (s, 9 H) 1.19 (d, J = 5.95 Hz, 3 H).

[001229] Compound 674: (R)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-methyl-7H-pyrrolo[2,3- d ]pyrimidin-4-yl)amino)butanoic acid. From chiral SFC separation of Example 209. LCMS (ESI+): m/z = 510.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.19 (s, 1 H) 7.53 (d, J = 7.06 Hz, 1 H) 7.12 (d, J = 3.53 Hz, 1 H) 6.63 (d, J = 3.31 Hz, 1 H) 6.58 (d, J = 7.28 Hz, 1 H) 4.74 (br d, J = 6.39 Hz, 1 H) 3.90 (br s, 1 H) 3.79 (s, 3 H) 3.54 - 3.67 (m, 1 H) 3.47 (t, J = 5.51 Hz, 2 H) 3.38 (br s, 1 H) 3.37 (s, 3H) 3.35 (s, 1 H) 3.27 (br d, J = 10.58 Hz, 1 H) 3.02 - 3.22 (m, 2 H) 2.69 - 2.85 (m, 4 H) 2.54 (br s, 1 H) 2.18 (br d, J = 18.74 Hz, 1 H) 2.04 (s, 1 H) 1.85 - 1.97 (m, 4 H) 1.78 (br s, 1 H) 1.25 (d, J = 5.95 Hz, 3 H). SCHEME 47, COMPOUND 675:

[001230] Step 1: Ethyl 4,4-difluoro-5-hydroxypentanoate. At 0 °C, to a solution of diethyl 2,2-difluoropentanedioate (1 g, 4.46 mmol) in THF/methanol (6/4 mL) was added sodium borohydride (253 mg, 6.7 mmol) in portions. After addition, the mixture was allowed to stir at 0 °C for 30 min; then warmed to room temperature and stirred 1 h. The reaction was quenched by addition of NH4Cl solution; extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine; dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give ethyl 4,4-difluoro-5-hydroxypentanoate (800 mg). LCMS (ESI+): m/z = 182.08; [M+H]+ found 183.4.

[001231] Step 2: Ethyl 5-(benzyloxy)-4,4-difluoropentanoate. At 0 °C, to a THF solution of ethyl 4,4-difluoro-5-hydroxypentanoate (800 mg, 4.4 mmol) was added NaH (60% dispersion in mineral oil, 264 mg, 6.6 mmol) and stirred for 10 min. Benzyl bromide (6.6 mmol, 784 μL) was added; slowly warmed to room temperature and stirred for 1 h. The reaction was quenched by the addition of NH4Cl solution; extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine; dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give ethyl 5-(benzyloxy)-4,4-difluoropentanoate (1.17 g, 97% yield).

[001232] Step 3: 5-(benzyloxy)-4,4-difluoro-N-methoxy-N-methylpentanamide. To a solution of ethyl 5-(benzyloxy)-4,4-difluoropentanoate (1.17 g, 4.3 mmol) in methanol was added NaOH solution (2 M, 4.3 mL) at room temperature. The reaction mixture was stirred for 2 h. It was acidified with 1 N HCl solution and extracted with DCM (20 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was used directly for the next step without further purification.

[001233] To a mixture of 5-(benzyloxy)-4,4-difluoropentanoic acid (720 mg, 2.95 mmol) in THF (10 mL) was added HATU (1.35 g, 3.53 mmol), DIEA (1.29 mL, 7.37 mmol), and N,O-dimethylhydroxylamine hydrochloride (346 mg, 3.53 mmol), the reaction mixture was stirred at RT for 5 h. H2O (10 mL) was added to the mixture; it was extracted with DCM (20 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give 5-(benzyloxy)-4,4-difluoro-N-methoxy-N-methylpentanamide (300 mg). LCMS (ESI+): m/z = 287.13; [M+H]+ found 288.10.

[001234] Step 4: 6-(benzyloxy)-5,5-difluorohexan-2-one. At 0 °C, to a THF solution of 5-(benzyloxy)-4,4-difluoro-N-methoxy-N-methylpentanamide (300 mg, 1.0 mmol) was added methylmagnesium bromide in THF solution (3 M, 0.7 ml, 2 mmol). It was allowed to stir at 0 °C for 30 min. The reaction was quenched by the addition of NH4Cl solution; extracted with ethyl acetate (30 ml x 2). The combined organic phase was washed with brine; dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 6-(benzyloxy)-5,5-difluorohexan-2-one (200 mg).

[001235] Step 5: 2-(4-(benzyloxy)-3,3-difluorobutyl)-1,8-naphthyridine. To a mixture of 6-(benzyloxy)-5,5-difluorohexan-2-one (200 mg, 0.82 mmol) and 2-aminopyridine-3-carbaldehyde (131 mg, 1.07 mmol) in EtOH (10 mL) was added L-proline (48 mg, 0.41 mmol). The mixture was refluxed at 85 °C for 12 h. LCMS indicated the reaction was complete. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (Hexanes/ethyl acetate = 1/1 to 1:3) to afford 2-(4-(benzyloxy)-3,3-difluorobutyl)-1,8-naphthyridine (160 mg, 59% yield) as a yellow solid. LCMS (ESI+): m/z = 328.14; [M+H]+ found 329.18.

[001236] Step 6: 2,2-difluoro-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-ol. A vial containing 2-(4-(benzyloxy)-3,3-difluorobutyl)-1,8-naphthyridine (160 mg, 0.49 mmol) was charged with Pd(OH)2 (20 wt% on carbon, 15 mg) and then diluted with MeOH (3 mL). The vial was evacuated and filled with H2 for 3 cycles and then stirred under an atmosphere of H2 for 15 h. The mixture was filtered through a pad of CELITE® and concentrated in vacuo to give 2,2-difluoro-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-ol which was used without further purification. LCMS (ESI+): m/z = 242.12; [M+H]+ found 243.024.

[001237] Step 7: 2,2-difluoro-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanal. To a solution of 2,2-difluoro-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-ol (35 mg, 145 μmol) in CH2Cl2 (2 ml) at room temperature was added Dess-Martin periodinane (64 g, 152 μmol) and the resulting mixture was stirred for an additional 2 h at room temperature. Next, 2-methoxyethan-1-amine (17 mg, 219 μmol) was added followed by sodium triacetoxyborohydride (77 mg, 364 μmol). The reaction mixture was stirred at RT for 15 h. The reaction mixture was concentrated and purified by reversed-phase chromatography to afford 2,2-difluoro-N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. LCMS (ESI+): m/z = 299.18; [M+H]+ found 300.833.

[001238] Step 8: (S)-2-(((benzyloxy)carbonyl)amino)-4-((2,2-difluoro-4-(5,6,7,8-tetrahydro-1,8 -naphthyridin-2-yl)butyl)(2-methoxyethyl)amino)methylbutanoate. The reaction solution of 2,2-difluoro-N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine ( 15 mg, 50 μmol), methyl (S)-2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (4 mg, 60 μmol) and sodium cyanoborohydride (4 mg, 60 μmol) in DCM /MeOH (1/0.5 ml) was stirred at room temperature for 12 h. The reaction mixture was concentrated and purified by reversed-phase chromatography to give (S)-2-(((benzyloxy)carbonyl)amino)-4-((2,2-difluoro-4-(5,6,7, Methyl 8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-methoxyethyl)amino)butanoate. LCMS (ESI+): m/z = 548.28; [M+H]+ found 549.337 .

[001239] Step 9: (S)-2-amino-4-((2,2-difluoro-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-methoxyethyl)amino)butanoic acid. To a solution of methyl (S)-2-(((benzyloxy)carbonyl)amino)-4-((2,2-difluoro-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-methoxyethyl)amino)butanoate (20 mg, 36 μmol) in 4:1:1 THF/MeOH/H2O (1.0 mL) was added LiOH (3 mg, 109 μmol) and the resulting mixture was stirred at room temperature for 2 h. The mixture was then neutralized with AcOH and purified by preparative reversed-phase HPLC to afford (S)-2-(((benzyloxy)carbonyl)amino)-4-((2,2-difluoro-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-methoxyethyl)amino)butanoic acid. LCMS (ESI+): m/z = 534.27; [M+H]+ found 535.184.

[001240] A flask containing (S)-2-(((benzyloxy)carbonyl)amino)-4-((2,2-difluoro-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-methoxyethyl)amino)butanoic acid (14 mg, 26 μmol) in MeOH (1 mL) was charged with Pd(OH)2 (20 wt % on carbon, 1 mg). The flask was evacuated and filled with H2 for 3 cycles and then shaken under an H2 atmosphere for 12 h. The mixture was filtered through a pad of CELITE® and concentrated in vacuo to afford (S)-2-amino-4-((2,2-difluoro-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-methoxyethyl)amino)butanoic acid. LCMS (ESI+): m/z = 400.23; [M+H]+ found 401.067.

[001241] Step 10: (S)-4-((2,2-difluoro-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid)(2 -methoxyethyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. A mixture of 4-chloroquinazoline (8 mg, 49 μmol), (S)-2-amino-4-((2,2-difluoro-4-(5,6,7,8-tetrahydro-1, 8-naphthyridine-2-yl)butyl)(2-methoxyethyl)amino)butanoic acid (13 mg, 33 μmol) and DIEA (17 μl, 97 μmol) in iPrOH (1 ml) was heated at 85 °C for 15 h. The mixture was then neutralized with AcOH and purified by preparative reversed-phase HPLC to afford (S)-4-((2,2-difluoro-4-(5,6,7,8-tetrahydro-1,8 -naphthyridin-2-yl)butyl)(2-methoxyethyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. LCMS (ESI+): m/z = 528.27; [M+H]+ found 529.415.1H NMR (500 MHz, Methanol-d4) δ 8.83 (s, 1H), 8.52 (d, J = 8.4 Hz, 1H), 8.12 (t, J = 7.8 Hz, 1H), 7.85 (t, J = 8.0 Hz, 2H), 7.57 (d, J = 7.3 Hz, 1H), 6.61 (d, J = 7.4 Hz, 1H), 5.32 (dd, J = 7.8, 5.0 Hz, 1H), 3.72 - 3.43 (m, 5H ), 3.28 - 2.94 (m, 9H), 2.93 - 2.67 (m, 4H), 2.63 - 2.10 (m, 3H), 2.04 - 1.79 (m, 2H).

[001242] Compound 676: (S)-2-((2-methyl-2H-pyrazol[4,3-d]pyrimidin-7-yl)amino acid)-4-((2-phenoxyethyl)(4-( 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2- amino-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (100 mg, 234 μmol) in 4 : 1 THF/H2O (2 ml) 7-chloro-2-methyl-2H-pyrazol[4,3-d]pyrimidine (43 mg, 258 μmol) and NaHCO3 (59 mg, 703 μmol) and the resulting mixture was heated at 70 °C for 1 h and then cooled to room temperature and concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 559.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.28 - 8.65 (m, 2 H) 7.57 (d, J = 7.34 Hz, 1 H) 7.26 (br t, J = 7.95 Hz, 2 H) 6.87 - 7.09 (m, 3 H) 6.65 (d, J = 7.34 Hz, 1 H) 5.11 (br dd, J = 8.50, 5.07 Hz, 1 H) 4.41 (br d, J = 4.52 Hz, 2 H) 4.07 ( s, 3 H) 3.37 - 3.86 (m, 8 H) 2.48 - 3.00 (m, 6 H) 1.69 - 2.17 (m, 6 H). SCHEME 48, COMPOUND 677:

[001243] Step 1: (S)-2-((4-Bromopyridin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (200 mg, 540 μmol) and 4-bromo-2-fluoropyridine (105 mg, 594 μmol) in DMSO (4 ml) was added K2CO3 (373 mg, 2.70 mmol), and the mixture was stirred at 100 °C for 2 h and then cooled to room temperature and concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 526.2 (M+H)+.

[001244] Step 2: (S)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyridin-2-ylamino)butanoic acid: To a mixture of (S)-2-((4-bromopyridin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (200 mg, 380 μmol) in MeOH (4 mL) was added 10 wt % Pd/C (80 mg), and the resulting mixture was stirred under an atmosphere of H 2 for 12 h and then filtered and concentrated vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 448.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 7.89 (dd, J = 5.14, 1.10 Hz, 1 H) 7.55 - 7.60 (m, 1 H) 7.40 (ddd, J = 8.62, 6.97, 1.90 Hz, 1 H) 7.30 (d, J = 7.34 Hz, 1 H) 6.50 - 6.57 (m, 1 H) 6.46 (dd, J = 10.51, 7.95 Hz, 2 H) 5.68 - 6.08 (m, 1 H) 4.25 (dd, J = 7.09, 4.89 Hz, 1 H) 3.33 - 3.39 (m, 2H) 2.50 - 2.84 (m, 10 H) 2.03 - 2.14 (m, 1 H) 1.92 - 2.03 (m, 1 H) 1.81 - 1.91 (m, 2 H) 1.68 - 1.80 (m, 2 H) 1.58 - 1.59 (m, 1 H) 1.48 - 1.59 (m, 1 H).

[001245] Compound 678: (S)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) acid )butyl)amino)-2-((2-methyl-2H-pyrazol[4,3-d]pyrimidin-7-yl)amino)butanoic acid. For a mixture of (S)-2-amino-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2 -yl)butyl)amino)butanoic acid (103 mg, 264 μmol) and 7-chloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (49 mg, 291 μmol) in THF (2 ml) were added NaHCO3 (111 mg, 1.32 mmol) and the resulting mixture was heated at 70 °C for 1 h and then cooled to room temperature and concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound title. LCMS (ESI+): m/z = 524.3

[001246] Compound 679: (S)-4-(((R)-2-methoxypropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-((2-methyl-2H-pyrazol[4,3-d]pyrimidin-7-yl)amino)butanoic: For a hydrochloride mixture (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl) acid amino)butanoic acid (100 mg, 231 μmol) and 7-chloro-2-methyl-2H-pyrazol[4,3-d]pyrimidine (43 mg, 254 μmol) in THF (2 ml) and H2O (0.5 ml) was added NaHCO3 (97 mg, 1.15 mmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 529.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.63 (br s, 1 H) 8.50 (s, 1 H) 7.59 (d, J = 7.34 Hz, 1 H) 6, 67 (d, J = 7.34 Hz, 1 H) 5.15 - 5.35 (m, 1 H) 5.08 (br dd, J = 8.38, 5.32 Hz, 1 H) 4.10 (s, 3 H) 3.54 - 3.75 (m, 6 H) 3.49 - 3.53 (m, 2 H) 3.41 (s, 5 H) 2.77 - 2.85 (m, 4 H) 2.53 - 2.74 (m, 2H) 1.79 - 1.99 (m, 6 H).

[001247] Compound 680: (S)-4-((2-fluoro-3-hydroxy-2-(hydroxymethyl)propyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. To a solution of (S)-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 (5 mg) in water (1 ml) was added sulfuric acid (0.1 ml). The reaction mixture was stirred at 80 °C for 6 h. The crude product was purified by reversed phase chromatography to afford (S)-4-((2-fluoro-3-hydroxy-2-(hydroxymethyl)propyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid as a TFA salt. LCMS theoretical m/z = 541.3; [M+H]+ found 541.24. 1H NMR (500 MHz, Methanol-d4) δ 8.84 (s, 1H), 8.50 (d, J = 8.3 Hz, 1H), 8.13 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.93 - 7.80 (m, 2H), 7.58 (d, J = 7.4 Hz, 1H), 6.62 (d, J = 7.3 Hz, 1H), 5.40 - 5.23 (m, 1H), 3.92 - 3.63 (m, 6H), 3.63 - 3.41 (m, 3H), 2.95 - 2.62 (m, 8H), 2.41 (s, 1H), 2.06 - 1.66 (m, 9H).

[001248] Compound 681: (S)-4-((3-hydroxypropyl)(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-aminopropan-1-ol, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 493.3. [M+H]+, found 493.2. SCHEME 49, COMPOUND 682:

[001249] Step 1: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 312 μmol) in 4:1 THF/H2O (3 ml) was added 5-bromo-4-chloropyrimidine (66 mg, 343 μmol) and NaHCOβ (79 mg, 936 μmol) and the resulting mixture was heated at 70 °C for 2 h and then cooled to room temperature and concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 614.9 (M+H)+.

[001250] Step 2: (S)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid: To a mixture of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (188 mg, 312 μmol) in MeOH (20 mL) was added 10 wt % Pd/C (200 mg), and the resulting mixture was stirred under an atmosphere of H 2 for 12 h and then evaporated to room temperature. filtered and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC column to give the title compound. LCMS (ESI+): m/z = 523.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.30 (s, 1 H) 7.90 (br s, 1 H) 7.29 (d, J = 7.02 Hz, 1 H) 6.90 - 7.01 (m, 2 H) 6.81 - 6.89 (m, 2 H) 6.46 (d, J = 7.45 Hz, 2 H) 4.49 (br s, 1 H) 4.15 (t, J = 5.26 Hz, 2 H) 3.34 - 3.41 (m, 2 H) 2.82 - 3.30 (m, 6 H) 2.59 - 2.80 (m, 4 H) 2.24 (br d, J = 5.26Hz, 1 H) 2.00 - 2.12 (m, 1 H) 1.66 - 1.96 (m, 6 H).

[001251] Compound 683: (R)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrazin-2-yl)amino)butanoic acid. From chiral SFC separation of Example 224. LCMS (ESI+): m/z = 533.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 14.42 (br s, 1 H) 9.87 - 10.12 (m, 1 H) 8.40 (s, 1 H) 8.15 (br s, 1 H) 8.01 - 8.10 (m, 3 H) 7.91 (br s, 1 H) 7.60 (br d, J = 6.84 Hz, 1 H) 7.40 - 7.53 (m, 3 H) 6.57 - 6.65 (m, 1 H) 4.53 (br s, 1 H) 3.84 (br s, 1 H) 3.42 (br s, 2 H) 3.28 (br s, 2 H) 3.25 (d, J = 3.09 Hz, 3 H) 3.17 (br s, 4 H) 2.71 (br d, J = 6.39 Hz, 4 H) 2.15 - 2.41 (m, 2 H) 1.64 - 1.86 (m, 6 H) 1.09 (br dd, J = 8.27, 6.28 Hz, 3 H).

[001252] Compound 684: (S)-4-((2-(2-oxopyrrolidin-1-yl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with 1-(2-aminoethyl)pyrrolidin-2-one, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 546.3. [M+H]+, found 546.3.

[001253] Compound 685: (S)-2-((3-cyanopyrazin-2-yl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-) naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (2S)-2-amino-4- [cyclopropyl-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]amino]butanoic acid (150 mg, 433 μmol) in i-PrOH (3 ml) was added 3-chloropyrazine-2-carbonitrile (66 mg, 476 μmol) and DIPEA (377 μl, 2.16 mmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 450.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4): δ ppm 8.24 (d, J = 2.43 Hz, 1 H) 7.85 (d, J = 2.43 Hz, 1 H) 7.35 ( d, J = 7.28 Hz, 1 H) 6.48 (d, J = 7.50 Hz, 1 H) 6.39 (d, J = 7.06 Hz, 1 H) 4.50 (t, J = 5.29 Hz, 1 H) 3.33 - 3.46 (m, 2 H) 3.00 - 3.17 ( m, 1 H) 2.53 - 2.95 (m, 7 H) 2.29 - 2.42 (m, 1 H) 2.15 (dq, J = 14.72, 5.02 Hz, 1 H) 1.58 - 2.00 (m, 7 H) 0.54 - 0.79 (m, 4 H).

[001254] Compound 686: (S)-2-((3-cyanopyrazin-2-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 337 μmol) in i-PrOH (3 ml) was added 3-chloropyrazine-2-carbonitrile (52 mg, 371 μmol) and DIPEA (294 μL, 1.69 mmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 548.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.18 (d, J = 2.43 Hz, 1 H) 7.81 (d, J = 2.43 Hz, 1 H) 7.31 (d, J = 7.28 Hz, 1 H) 6.78 - 7.01 (m, 4 H) 6.46 (d, J = 7.28 Hz, 1 H) 4.52 (t, J = 5.51 Hz, 1 H) 4.09 - 4.32 (m, 2 H) 3.33 - 3.44 (m, 2 H)) 2.76 - 3.29 (m, 6 H) 2.52 - 2.74 (m, 4 H) 2.23 - 2.42 (m, 1 H) 2.15 (dq, J = 14.75, 4.86 Hz, 1 H) 1.67 - 1.91 (m, 6 H)) SCHEME 50, COMPOUND 687:

[001255] Step 1: 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(benzo[ (S)-tert-butyl d]thiazol-2-ylamino)butanoate: A mixture of (S)-tert-butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoate (150 mg, 335 μmol) and 2-chlorobenzo[d]thiazole (47 mg, 279 μmol) in t-AmOH (3 ml) was added 2.0 M t-BuONa in THF (279 μl, 558 μmol), then t-BuXphosPd G3 (22 mg, 28 μmol) and the resulting mixture was heated at 100 °C for 15 h, cooled to room temperature and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 581.4 (M+H)+.

[001256] Step 2: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(benzo[d]thiazol-2-ylamino)butanoic acid: (S)-tert-Butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(benzo[d]thiazol-2-ylamino)butanoate (200 mg, 332 μmol) was taken up in 5:1 DCM/TFA (2 ml) and the resulting mixture was stirred at room temperature for 5 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 525.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.17 (br d, J = 5.62 Hz, 1 H) 7.75 (br t, J = 5.14 Hz, 1 H) 7.66 (d, J = 7.70 Hz, 1 H) 7.36 (d, J = 7.95 Hz, 1 H) 7.21 (t, J = 7.58 Hz, 1 H) 6.96 - 7.08 (m, 2 H) 6.72 (br s, 1 H) 6.24 (d, J = 7.21 Hz, 1 H) 4.38 (br d, J = 5.14 Hz, 1 H) 3.20 - 3.28 (m, 2 H) 3.06 - 3.18 (m, 2 H) 2.51 - 2.78 (m, 8 H) 2.41 (br t, J = 7.34 Hz, 2 H) 1.86 - 2.07 (m, 2 H) 1.68 - 1.83 (m, 5 H) 1.49 - 1.61 (m, 2 H) 1.35 - 1.47 (m, 2 H).

[001257] Compound 688: (S)-2-((1-methyl-1H-pyrazolo[3,4- d ]pyrimidin-4-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid (140 mg, 259 μmol) in THF (4 ml) and H2O (1 ml) was added 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (44 mg, 259 μmol) and NaHCO3 (109 mg, 1.29 mmol)) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 565.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (br d, J = 7.21 Hz, 1 H) 8.23 (s, 1 H) 8.18 (s, 1 H) 6.99 (d, J = 7.34 Hz, 1 H) 6.41 (br s, 1 H) 6.17 (d, J = 7.34 Hz, 1 H) 4.73 (br d, J = 5.26 Hz, 1 H) 3.98 (qd, J = 9.41, 1.71 Hz, 2 H) 3.89 (s, 3 H) 3.63 (br t, J = 5.81 Hz, 2 H) 3.22 (br t, J = 5.20 Hz, 2 H) 2.55 - 2.75 (m, 7 H) 2.42 - 2.48 (m, 1 H)) 2.34 (br t, J = 7.46 Hz, 2 H) 1.97 - 2.10 (m, 1 H) 1.87 (br d, J = 5.87 Hz, 1 H) 1.73 (q, J = 5.69 Hz, 2 H) 1.46 - 1.56 (m, 2 H) 1.37 (br d, J = 7.09 Hz, 2 H).

[001258] Compound 689: (S)-2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 362 µmol) in THF (1 ml) and H2O (0.25 ml) was added NaHCO3 (91 mg, 1.09 mmol) then 5-cyclopropyl-2-fluoropyrimidine (100 mg, 724 μmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 533.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.54 (br s, 2 H) 7.60 (d, J = 7.28 Hz, 1 H) 6.66 (d, J = 7.50 Hz, 1 H) 5.85 - 6.20 (m, 1 H) 4.82 - 4.87 (m, 1 H) 3.93 - 4.01 (m, 2 H) 3.79 (td, J = 14.77, 3.53 Hz, 2 H) 3.40 - 3.57 (m, 6 H) 3.32 - 3.40 (m, 2 H) 2.76 - 2.85 (m, 4 H) 2.32 - 2.65 (m, 2 H) 1.74 - 2.03 (m, 7 H) 1.04 - 1.12 (m, 2 H) 0.78 - 0.85 (m, 2 H).

[001259] Compound 690: (S)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 362 µmol) in THF (1 ml) and H2O (0.25 ml) was added NaHCO3 (91 mg, 1.09 mmol) then 4-chloro-6-phenylpyrimidine (138 mg, 724 μmol) and the resulting mixture was heated at 70 °C for 2 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 569.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.81 (s, 1H) 7.87 (d, J = 7.50 Hz, 2 H) 7.54 - 7.77 (m, 4 H) 7.29 (s, 1 H) 6.66 (d, J = 7.50 Hz, 1 H) 5.86 - 6.19 (m, 1 H) 5.09 (br s, 1 H) 3.98 (br s, 2 H) 3.79 (td, J = 14.72, 3.42 Hz, 2 H) 3.41 - 3.62 (m, 6 H) 3.34 (br d, J = 7.94 Hz, 2 H) 2.75 - 2.86 (m, 4 H) 2.35 - 2.66 (m, 2 H) 1.74 - 2.00 (m, 6 H). SCHEME 51, COMPOUND 691:

[001260] Step 1: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of 5-bromo-4-chloro-pyrimidine (77 mg, 398 μmol) and (S)-2-amino-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 362 μmol) in THF (2 ml), H2O (0.5 ml) was added NaHCO3 (152 mg, 1.81 mmol) and the resulting mixture was heated at 70 °C for 2 h, cooled to room temperature, and then concentrated in vacuo to give the title compound which was used without further purification. LCMS (ESI+): m/z = 571.3 (M+H)+.

[001261] Step 2: (S)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid. For a mixture of phenylboronic acid (38 mg, 315 μmol) and (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)( 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 262 μmol) in dioxane (1 ml) and H2O (0.25 ml ) Pd(dppf)Ch (19 mg, 26 μmol) and K2CO3 (73 mg, 525 μmol) were added and the resulting mixture was heated at 70 °C for 2 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 569.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (s, 1 H) 8.01 (s, 1 H) 7.40 - 7.57 (m, 5 H) 7.01 - 7, 09 (m, 2 H) 6.47 (br s, 1 H) 5.90 - 6.31 (m, 2 H) 4.34 (br d, J = 4.89 Hz, 1 H) 3.63 (td, J = 15.22, 3.79 Hz, 2 H) 3.55 (br t, J = 5.38 Hz , 2 H) 3.18 - 3.27 (m, 2 H) 2.53 - 2.93 (m, 8 H) 2.40 (t, J = 7.46 Hz, 2 H) 1.89 - 2.02 (m, 2 H) 1.68 - 1.78 (m, 2 H)) 1.22 - 1.58 (m, 4 H).

[001262] Compound 692: (S)-4-((2-(2,2-difluoroethoxy)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: To a mixture of (S)-2-amino-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 362 μmol) and 4-chloro-2-(3-pyridyl)quinazoline (96 mg, 398 μmol) in DMA (4 ml) was added DI-PEA (315 μL, 1.81 mmol) and the resulting mixture was heated at 70 °C for 12 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 620.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 9.56 (d, J = 1.54 Hz, 1 H) 8.84 (dt, J = 8.10, 1.79 Hz, 1 H) 8.62 (dd, J = 4.96, 1.65 Hz, 1 H) 8.11 (d, J = 8.38 Hz, 1 H) 7.75 - 7.91 (m, 2 H) 7.46 - 7.58 (m, 2 H) 7.15 (d, J = 7.28 Hz, 1 H) 6.29 - 6.38 (m, 1 H) 5.68 - 6.03 (m, 1 H) 4.91 - 4.93 (m, 1H) 3.83 (t, J = 5.07 Hz, 2 H) 3.58 - 3.69 (m, 1 H) 3.63 (td, J = 14.55, 3.75 Hz, 1 H) 3.33 - 3.40 (m, 1 H) 3.17 - 3.28 (m, 1 H) 3.02 - 3.15 (m, 1 H) 3.07 (br s, 1 H) 3.01 - 3.28 (m, 1 H)) 2.88 - 2.99 (m, 1 H) 2.51 - 2.64 (m, 4 H) 2.37 - 2.50 (m, 1 H) 2.25 - 2.37 (m, 1 H) 1.61 - 1.86 (m, 6 H).

[001263] Compound 693: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino acid)-4-((2-(2,2-difluoroethoxy)ethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of acid hydrochloride (S)-2-amino-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl )amino)butanoic acid (150 mg, 333 μmol) and 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (66 mg, 366 μmol) in DMA (4 ml) was added DIPEA (290 μl, 1.66 mmol) and the resulting mixture was heated at 70 °C for 12 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by HPLC reversed phase prep. to furnish the title compound. LCMS (ESI+): m/z = 559.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.50 (d, J = 2.43 Hz, 1 H) 8.31 (br s, 1 H) 7.74 (s, 1 H) 7, 13 - 7.24 (m, 1 H) 6.94 (s, 1 H) 6.51 (d, J = 2.21 Hz, 1 H) 6.42 (d, J = 7.28 Hz, 1 H) 5.77 - 6.13 (m, 1 H) 4.50 (br s, 1 H) 3.77 - 3, 87 (m, 2 H) 3.63 - 3.75 (m, 2 H) 3.33 - 3.43 (m, 2 H) 3.15 (br d, J = 9.48 Hz, 2 H) 2.83 - 3.07 (m, 4 H) 2.56 - 2.73 (m, 4 H) 2.18 - 2.31 (m, 1 H) 2 .03 - 2.16 (m, 1 H) 1.64 - 1.91 (m, 6 H). SCHEME 52, COMPOUND 694:

[001264] Step 1: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of 5-bromo-4-chloro-pyrimidine (77.00 mg, 398.08 μmol, 1.1 eq) and (S)-2-amino-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 362 μmol) in THF (2 ml), H2O (0.5 ml) was added NaHCO3 (152 mg, 1.81 mmol) and the resulting mixture was heated at 70 °C for 2 h, cooled to room temperature, and then concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 571.3 (M+H)+.

[001265] Step 2: (S)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid: To a mixture of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (150 mg, 262 μmol) in MeOH (3 mL) was added 10 wt % Pd/C (50 mg) and the resulting mixture was stirred under an atmosphere of H 2 for 5 h and then filtered and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 493.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (s, 1 H) 8.02 (br d, J = 5.62 Hz, 1 H) 7.51 (br s, 1 H) 7.02 (d, J = 7.21 Hz, 1 H) 6.57 (br s, 1 H) 6.39 (br s, 1 H) 5.91 - 6.29 (m, 2 H) 4.38 (br s, 1 H) 3.62 - 3.69 (m, 2 H) 3.56 - 3.60 (m, 2 H) 3.23 (br t, J = 5.38 Hz, 2 H) 2.52 - 2.78 (m, 8 H) 2.39 (t, J = 7.46 Hz, 2 H) 1.87 - 1.99 (m, 1 H) 1.68 - 1.83 (m, 3 H) 1.47 - 1.61 (m, 2 H) 1.33 - 1.46 (m, 1 H) 1.33 - 1.46 (m, 1 H). SCHEME 53, COMPOUND 695:

[001266] Step 1: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2) acid -yl)butyl)amino)-2-((2-methoxypyrimidin-4-yl)amino)butanoic acid: A mixture of 2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) (S)-tert-butyl butanoate (150 mg, 331 μmol) and 4-chloro-2-methoxy-pyrimidine (40 mg, 276 μmol) in t-AmOH (3 ml), then 2.0 M t-BuONa was added in THF (276 μL, 552 μmol) and t-BuXPhos-Pd-G3 (22 mg, 28 μmol) and the resulting mixture was heated to 100 °C for 15 h, cooled to room temperature, and then concentrated in vacuo to provide the title compound which was used without further purification. LCMS (ESI+): m/z = 561.5 (M+H)+.

[001267] Step 2: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methoxypyrimidin-4-yl)amino)butanoic acid: (S)-tert-Butyl 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methoxypyrimidin-4-yl)amino)butanoate (200 mg, 357 μmol) was taken up in 3:1 DCM/TFA (2 ml) and the resulting mixture was stirred at room temperature for 5 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 505.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 14.33 (br s, 1 H) 11.23 (br s, 1 H) 10.10 (br d, J=18.58 Hz, 1 H) 8.12 (br s, 1 H) 8.02 (d, J = 6.85 Hz, 1 H) 7.61 (d, J = 7.34 Hz, 1 H) 6.56 - 6.79 (m, 2 H) 5.20 - 5.51 (m, 1 H) 4.58 - 4.82 (m, 1 H) 4.01 (s, 3 H) 3.34 - 3.65 (m, 8 H) 3.31 (s, 3 H) 3.21 (br s, 2 H) 2.64 - 2.79 (m, 4 H) 2.41 (br d, J = 12.10 Hz, 1 H) 2.20 - 2.34 (m, 1 H) 1.63 - 1.85 (m, 6 H). SCHEME 54, COMPOUND 696:

[001268] Step 1: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2) acid -yl)butyl)amino)-2-((2-methoxypyrimidin-4-yl)amino)butanoic acid: A mixture of 2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) (S)-tert-butyl butanoate (150 mg, 331 μmol) and 6-chloro-N,N-dimethylpyrimidin-4-amine (44 mg, 276 μmol) in t-AmOH (3 ml) was added t-BuONa 2.0 M in THF (276 μl, 552 μmol) and t-BuXPhosPd G3 (22 mg, 28 μmol) and the resulting mixture was heated at 100 °C for 2.5 h, cooled to room temperature, and then concentrated in vacuo to give the title compound which was used without further purification. LCMS (ESI+): m/z = 574.5 (M+H)+.

[001269] Step 2: (S)-2-((6-(dimethylamino)pyrimidin-4-yl)amino acid)- 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5 ,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: 2-((6-(dimethylamino)pyrimidin-4-yl)amino)-4- (((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro- (S)-tert-butyl 1,8-naphthyridin-2-yl)butyl)amino)butanoate (200 mg, 349 μmol) was taken up in DCM/TFA 3: 1 (2 ml) and the resulting mixture was stirred at room temperature for 16 h, then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 518.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 14.07 - 14.49 (m, 1 H) 12.99 - 13.76 (m, 1 H) 11.24 (br s, 1 H) 8 .44 - 8.99 (m, 1 H) 8.48 (br d, J = 18.46 Hz, 1 H) 8.33 (s, 1 H) 8.10 (br s, 1 H) 7.60 (d, J = 7.34 Hz, 1 H) 6.64 (d, J = 7.34 Hz , 1 H) 5.87 (br s, 1 H) 5.25 - 5.49 (m, 1 H) 4.71 (br s, 1 H) 3.34 - 3.64 (m, 7 H) 3.31 (s, 3 H) 3.19 (br d, J = 3.55 Hz, 3 H) 3.12 (br s, 6 H) 2.64 - 2.79 (m, 4 H) 2.31 - 2.45 (m, 1 H) 2.21 (br s, 1 H) 1.64 - 1.87 (m, 6 H). SCHEME 55, COMPOUND 697:

[001270] Step 1: 2-((6-(tert-butyl)pyrimidin-4-yl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6, (S)-tert-butyl 7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: A mixture of 2-amino- (S)4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate )-tert-butyl (150 mg, 331 μmol) and 4-(tert-butyl)-6-chloropyrimidine (47 mg, 276 μmol) in t-AmOH (3 ml) was added 2.0 M t-BuONa in THF (276 μl, 552 μmol), then t-BuXPhosPd G3 (22 mg, 28 μmol) and the resulting mixture was heated at 100 °C for 2 ,5 h, cooled to room temperature and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 587.3 (M+H)+.

[001271] Step 2: (S)-2-((6-(tert-butyl)pyrimidin-4-yl)amino acid)-4- (((S)-2-fluoro-3-methoxypropyl)(4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: 2-((6-(tert-butyl)pyrimidin-4-yl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetra- (S)-tert-butyl hydro-1,8-naphthyridin-2-yl)butyl)amino) butanoate (200 mg, 341 μmol) was taken up at 3:1 DCM/TFA (2 ml) and the resulting mixture was stirred at room temperature for 16 and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 531.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 14.07 - 14.49 (m, 1 H) 12.99 - 13.76 (m, 1 H) 11.24 (br s, 1 H) 8 .44 - 8.99 (m, 1 H) 8.48 (br d, J = 18.46 Hz, 1 H) 8.33 (s, 1 H) 8.10 (br s, 1 H) 7.60 (d, J = 7.34 Hz, 1 H) 6.64 (d, J = 7.34 Hz , 1 H) 5.87 (br s, 1 H) 5.25 - 5.49 (m, 1 H) 4.71 (br s, 1 H) 3.34 - 3.64 (m, 7 H) 3.31 (s, 3 H) 3.19 (br d, J = 3.55 Hz, 3 H) 3.12 (br s, 6 H) 2.64 - 2.79 (m, 4 H) 2.31 - 2.45 (m, 1 H) 2.21 (br s, 1 H) 1.64 - 1.87 (m, 6 H). SCHEME 56, COMPOUND 698:

[001272] Step 1: 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl) (S)-tert-butyl amino)-2-((2-phenylpyrimidin-4- yl)amino)butanoate: A mixture of 2-amino-4- (((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (S)- tert-butyl (150 mg, 331 μmol) and 4-chloro-2-phenylpyrimidine (53 mg, 276 μmol) in t-AmOH (3 ml) were added t-BuONa 2.0 M in THF (276 μL, 552 μmol), then t-BuXPhosPd G3 (22 mg, 28 μmol) and the resulting mixture was heated at 100 °C for 5 h, cooled to room temperature and then concentrated in vacuo to give the title compound which was used without further purification. LCMS (ESI+): m/z = 607.2 (M+H)+.

[001273] Step 2: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-phenylpyrimidin-4-yl)amino)butanoic acid: (S)-tert-Butyl 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-phenylpyrimidin-4-yl)amino)butanoate (200 mg, 330 μmol) was taken up in DCM/TFA (2 ml) and the resulting mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 551.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (br d, J = 7.72 Hz, 2 H) 8.15 (br d, J = 6.39 Hz, 1 H) 7.37 - 7.46 (m, 3 H) 6.95 (br d, J = 7.06 Hz, 1 H) 6.48 (br s, 1 H) 6.15 (d, J = 7.28 Hz, 1 H) 4.50 - 4.76 (m, 2 H) 3.35 - 3.47 (m, 2 H) 3.12 - 3.21 (m, 5 H) 2.51 - 2.70 (m, 6 H) 2.28 - 2.46 (m, 4 H) 1.97 (br d, J = 7.28 Hz, 1 H) 1.80 (br s, 1 H) 1.65 - 1.74 (m, 2 H) 1.49 (br s, 2 H) 1.28 - 1.40 (m, 2 H). SCHEME 57, COMPOUND 699:

[001274] Step 1: 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl) (S)-tert-butyl amino)-2-((5-phenylpyrazin-2- yl)amino)butanoate: A mixture of 2-amino-4- (((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (S)- tert-butyl (150 mg, 331 μmol) and 4-chloro-2-phenylpyrimidine (53 mg, 276 μmol) in t-AmOH (3 ml) were added t-BuONa 2.0 M in THF (276 μL, 552 μmol) and t-BuXPhosPd G3 (22 mg, 28 μmol) and the resulting mixture was heated at 100 °C for 5 h, cooled to room temperature, and then concentrated in vacuo to furnish the title compound which was used without further purification. LCMS (ESI+): m/z = 607.2 (M+H)+.

[001275] Step 2: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrazin-2-yl)amino)butanoic acid: (S)-tert-Butyl 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrazin-2-yl)amino)butanoate (200 mg, 330 μmol) was taken up in 3:1 DCM/TFA (2 ml) and the resulting mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 551.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 14.30 (br s, 1 H) 10.95 (br s, 1 H) 8.56 (s, 1 H) 8.17 (s, 1 H) 8.10 (br s, 1 H) 7.92 (d, J = 7.28 Hz, 2 H) 7.78 (br s, 1 H) 7.58 (d, J = 7.28 Hz, 1 H) 7.38 - 7.49 (m, 2 H) 7.29 - 7.37 (m, 1 H) 6.62 (d, J = 7.06 Hz, 1 H) 5.22 - 5.48 (m, 1 H) 4.50 (br s, 1 H) 3.34 - 3.65 (m, 8 H) 3.31 (s, 3 H) 3.13 (s, 2 H) 2.64 - 2.79 (m, 4 H) 2.34 (br s, 1 H) 2.22 (br s, 1 H) 1.63 - 1.86 (m, 6 H). SCHEME 58, COMPOUND 700:

[001276] Step 1: 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl) (S)-tert-butyl amino)-2-((6-phenylpyrazin-2- yl)amino)butanoate: A mixture of 2-amino-4- (((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (S)- tert-butyl (150 mg, 331 μmol) and 2-chloro-6-phenylpyrazine (53 mg, 276 μmol) were added to t-AmOH (3 ml), in t-BuONa was then added 2.0 M in THF (276 μl, 552 μmol) and t-BuXPhosPd G3 (22 mg, 28 μmol) were added and the resulting mixture was heated to 100 °C for 5 h, cooled to room temperature, and then concentrated in vacuo to give the title compound which was used without further purification. LCMS (ESI+): m/z = 607.2 (M+H)+.

[001277] Step 2: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrazin-2-yl)amino)butanoic acid: (S)-tert-Butyl 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrazin-2-yl)amino)butanoate (200 mg, 330 μmol) was taken up in 3:1 DCM/TFA (2 mL) and the resulting mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 551.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (s, 1 H) 7.90 - 8.02 (m, 3 H) 7.37 - 7.46 (m, 3 H) 6.99 (d, J = 7.06 Hz, 1 H) 6.18 (dd, J = 7.28, 2.43 Hz, 1 H) 4.55 - 4.80 (m, 1 H) 4.43 (br d, J = 5.73 Hz, 1 H) 3.36 - 3.50 (m, 2 H) 3.09 - 3.24 (m, 5 H) 2.52 - 2.77 (m, 7 H) 2.29 - 2.47 (m, 3 H) 2.00 (br dd, J = 13.34, 6.50 Hz, 1 H) 1.77 - 1.88 (m, 1 H) 1.64 - 1.74 (m, 2 H) 1.45 - 1.56 (m, 2 H) 1.31 - 1.41 (m, 2 H).

[001278] Compound 701: (S)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid (140 mg, 259 μmol) in THF (4 ml) and H2O (1 ml) was added 2-chloro-5-(trifluoromethyl)pyrimidine (52 mg, 285 μmol) and NaHCO3 (109 mg, 1.29 mmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 579.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (s, 2 H) 8.18 (d, J = 7.21 Hz, 1 H) 7.02 (d, J = 7.34 Hz, 1 H) 6.44 (br s, 1 H) 6.19 - 6.27 (m, 1 H) 6.19 - 6.27 (m, 1 H) 4.38 - 4.46 (m, 1 H) 3.94 - 4.06 (m, 2 H) 3.65 (br s, 2 H) 3.20 - 3.28 (m, 2 H) 2.54 - 2.78 (m, 7 H) 2.42 - 2.48 (m, 1 H) 2.37 (t, J = 7.52 Hz, 2 H) 1.94 - 2.05 (m, 1 H) 1.81 - 1.91 (m, 1 H) 1.70 - 1.79 (m, 2 H) 1.53 (tq, J = 13.50, 6.61 Hz, 2 H) 1.32 - 1.43 (m, 2 H).

[001279] Compound 702: (S)-2-((5-cyanopyrimidin-2-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid (140 mg, 259 μmol) in THF (1 ml) and H2O (0.25 ml) was added 2-chloropyrimidine-5-carbonitrile (40 mg, 285 μmol) and NaHCO3 (109 mg, 1.29 mmol) and the resulting mixture was heated at 50 °C for 1 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 536.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) 8.66 - 8.73 (m, 2 H) 8.42 (d, J = 7.46 Hz, 1 H) 7.03 (d, J = 7.21 Hz, 1 H) 6.44 (br s, 1 H) 6.22 (d, J = 7.34 Hz, 1 H) 4.36 - 4.46 (m, 1 H) 3.96 - 4.07 (m, 2 H) 3.64 (t, J = 5.93 Hz, 2 H) 3.24 (br t, J = 5.20 Hz, 2 H) 2.54 - 2.79 (m, 8 H) 2.37 (t, J = 7.52 Hz, 2 H) 1.81 - 2.06 (m, 2 H) 1.75 (q, J = 5.90 Hz, 2 H) 1.46 - 1.59 (m, 2 H) 1.33 - 1.44 (m, 2 H).

[001280] Compound 703: (S)-2-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid: To a solution of (S)-2-amino-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid (140 mg, 259 μmol) in THF (1 ml) and H2O (0.25 ml) was added 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (44 mg, 285 μmol) and NaHCO3 (109 mg, 1.29 mmol) were added and the resulting mixture was heated at 70 °C for 9 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 551.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.42 (br s, 1 H) 8.31 (br d, J = 7.34 Hz, 1 H) 8.20 (d, J = 4.16 Hz, 2 H) 7.00 (d, J = 7.34 Hz, 1 H) 6.46 (br s, 1 H) 6.18 (d, J = 7.34 Hz, 1 H) 4.68 - 4.78 (m, 1 H) 3.92 - 4.07 (m, 2 H) 3.64 (t, J = 5.87 Hz, 2 H) 3.23 (br t, J = 5.38 Hz, 2 H) 2.52 - 2.78 (m, 7H) 2.41 - 2.49 (m, 1 H) 2.34 (t, J = 7.46 Hz, 2 H) 1.98 - 2.11 (m, 1 H) 1.88 (br d, J = 5.99 Hz, 1 H) 1.68 - 1.78 (m, 2 H) 1.46 - 1.58 (m, 2 H) 1.31 - 1.43 (m, 2 H))

[001281] Compound 704: (S)-2-((5-Bromopyrimidin-2-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid (140 mg, 259 μmol) in THF (4 ml) and H2O (1 ml) was added 5-bromo-2-chloro-pyrimidine (55 mg, 285 μmol) and NaHCO3 (109 mg, 1.29 mmol) and the resulting mixture was heated at 70 °C for 6 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 589.1 (M+H)+. 1H NMR (400 MHz, DMSO-d) H) 4.22 - 4.33 (m, 1 H) 4.01 (q, J = 9.41 Hz, 2 H) 3.64 (t br, J = 5.87 Hz, 2 H) 3.24 (br t, J = 5.07 Hz, 2 H) 2.53 - 2.79 (m, 7 H) 2.42 - 2.49 (m, 1H) 2.38 (br t, J = 7.52 Hz, 2 H) 1.79 - 2.00 (m, 2 H) 1.69 - 1.78 (m, 2 H) 1.47 - 1.59 (m, 2 H) 1.33 - 1.45 (m, 2 H).

[001282] Compound 705: (S)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid: To a solution of (S)-2-amino-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid (140 mg, 259 μmol) in THF (4 ml) and H2O (1 ml) was added 4-chloro-2-(trifluoromethyl)pyrimidine (52 mg, 285 μmol) and NaHCO3 (109 mg, 1.29 mmol) and the resulting mixture was heated at 70 °C for 9 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 579.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (br d, J = 5.75 Hz, 2 H) 7.03 (d, J = 7.21 Hz, 1 H) 6.82 (d, J = 5.99 Hz, 1 H) 6.55 (br s, 1 H) 6.23 (d, J = 7.21 Hz, 1 H) 4.43 (br d, J = 5.99 Hz, 1 H) 3.97 - 4.08 (m, 2 H) 3.66 (t, J = 5.69 Hz, 2 H) 3.24 (br t, J = 5.32 Hz, 2 H) 2.54 - 2.85 (m, 8 H) 2.34 - 2.44 (m, 2 H) 1.69 - 2.02 (m, 4 H) 1.49 - 1.58 (m, 2 H) 1.35 - 1.48 (m, 2 H).

[001283] Compound 706: (S)-2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid (140 mg, 259 μmol) in THF (4 ml) and H2O (1 ml) was added 1-cyclopropyl-4-fluorobenzene (39 mg, 285 μmol) and NaHCO3 (109 mg, 1.29 mmol) and the resulting mixture was heated at 70 °C for 6 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 551.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (s, 2 H) 6.96 - 7.10 (m, 2 H) 6.37 (br s, 1 H) 6.22 (d, J = 7.21 Hz, 1 H) 4.21 - 4.32 (m, 1 H) 3.95 - 4.07 (m, 2 H) 3.64 (t, J = 5.93 Hz, 2 H) 3.23 (br t, J = 5.20 Hz, 2 H) 2.52 - 2.79 (m, 7 H) 2.42 - 2.49 (m, 1 H) 2.38 (t, J = 7.46 Hz, 2 H) 1.78 - 1.99 (m, 2 H) 1.67 - 1.78 (m, 3 H) 1.48 - 1.60 (m, 2 H) 1.34 - 1.43 (m, 2 H) 0.81 - 0.90 (m, 2 H) 0.55 - 0.65 (m, 2 H).

[001284] Compound 707: (S)-2-((3-cyanopyrazin-2-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid (140 mg, 259 μmol) in i-PrOH (3 ml) was added 3-chloropyrazine-2-carbonitrile (40 mg, 285 μmol) and DIPEA (226 μl, 1.29 mmol) and the resulting mixture was heated at 70 °C for 1 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 536.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.25 (d, J = 2.08 Hz, 1 H) 7.89 (d, J = 2.08 Hz, 1 H) 7.33 (br d, J = 7.34 Hz, 1 H) 6.48 (d, J = 7.21 Hz, 1 H) 4.48 - 4.55 (m, 1 H) 3.90 - 4.02 (m, 4 H) 3.37 - 3.44 (m, 2 H) 3.15 - 3.27 (m, 2 H) 2.98 - 3.11 (m, 3 H) 2.84 - 2.92 (m, 1 H) 2.74 (br t, J = 5.99Hz, 2 H) 2.60 - 2.69 (m, 2 H) 2.12 - 2.34 (m, 2 H) 1.71 - 1.92 (m, 6 H).

[001285] Compound 708: (S)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid (140 mg, 259 μmol) in DMA (3 ml) was added 4-chloro-2-(pyridin-3-yl)quinazoline (77 mg, 285 μmol) and DIPEA (226 μL, 1.29 mmol) and the resulting mixture was heated at 70 °C for 2 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 638.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.59 (d, J = 1.47 Hz, 1 H) 8.55 - 8.76 (m, 3 H) 8.33 (d, J = 8.19 Hz, 1 H) 7.75 - 7.93 (m, 2 H) 7.46 - 7.62 (m, 2 H) 6.91 (d, J = 7.21 Hz, 1 H) 6.24 - 6.37 (m, 1 H) 6.09 (d, J = 7.21 Hz, 1 H) 4.73 - 4.82 (m, 1 H) 3.96 (q, J = 9.50 Hz, 2 H) 3.66 (t, J = 5.87Hz, 2 H) 3.20 (br t, J = 4.95 Hz, 2 H) 2.53 - 2.85 (m, 8 H) 2.29 (t, J = 7.46 Hz, 2 H) 2.04 - 2.19 (m, 2 H) 1.71 (q, J = 5.84 Hz, 2 H) 1.46 - 1.55 (m, 2 H) 1.40 (br d, J = 6.60 Hz, 2 H). SCHEME 59, COMPOUND 709:

[001286] Step 1: (S)-2-((6-Chloropyrimidin-4-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid (140 mg, 259 μmol) in THF (4 ml) and H2O (1 ml) was added 4,6-dichloropyrimidine (42 mg, 285 μmol) and NaHCO3 (109 mg, 1.29 mmol) and the resulting mixture was heated at 70 °C for 5 h, cooled to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 545.3 (M+H)+.

[001287] Step 2: (S)-2-((6-phenylpyrimidin-4-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid: To a mixture of (S)-2-((6-chloropyrimidin-4-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid (141 mg, 259 μmol) in dioxane (4 ml) and H2O (1 ml of acid) was added phenylboronic acid (47 mg, 388 μmol), K2CO3 (72 mg, 517 μmol), and Pd(dppf)Cl2 (19 mg, 26 μmol) were prepared and the resulting mixture was heated at 100 °C for 2 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 587.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (s, 1 H) 7.99 (br d, J = 5.38 Hz, 2 H) 7.60 (br s, 1 H) 7.45 - 7.53 (m, 3 H) 7.10 (br s, 1 H) 6.99 (d, J = 7.21 Hz, 1 H) 6.43 (br s, 1 H) 6.21 (d, J = 7.21 Hz, 1 H) 4.47 (br s, 1 H) 4.02 (q, J = 9.25 Hz, 2 H) 3.67 (br t, J = 5.75 Hz, 2 H) 3.22 (br t, J = 5.20Hz, 2 H) 2.53 - 2.83 (m, 7 H) 2.44 - 2.48 (m, 1 H) 2.39 (br t, J = 7.40 Hz, 2 H) 1.94 - 2.03 (m, 1 H) 1.84 (br dd, J = 13.02, 6.79 Hz, 1 H) 1.70 - 1.78 (m, 2 H) 1.54 (br d, J = 4.77 Hz, 2 H) 1.38 - 1.47 (m, 2 H). SCHEME 60, COMPOUND 710:

[001288] Step 1: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid (140 mg, 259 μmol) in THF (4 ml) and H2O (1 ml) was added 5-bromo-4-chloropyrimidine (55 mg, 285 μmol) and NaHCO3 (109 mg, 1.29 mmol) and the resulting mixture was heated at 70 °C for 3 h, cooled to room temperature, and then concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 589.1 (M+H)+.

[001289] Step 2: (S)-2-((5-phenylpyrimidin-4-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid: To a mixture of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid (152 mg, 258 μmol) in dioxane (4 ml) and H2O (1 ml) was added phenylboronic acid (47 mg, 387 μmol), K2CO3 (72 mg, 516 μmol), and Pd(dppf)Cl2 (19 mg, 26 μmol) were prepared and the resulting mixture was heated at 100 °C for 2 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 587.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (s, 1H) 8.02 (s, 1 H) 7.40 - 7.58 (m, 5 H) 7.06 (br dd, J = 13.27, 6.54 Hz, 2 H) 6.57 (br s, 1 H) 6.25 (d, J = 7.21 Hz, 1 H) 4.41 (br d, J = 5.62 Hz, 1 H) 4.00 (q, J = 9.41 Hz, 2 H) 3.60 (br t, J = 5.50 Hz, 2 H) 3.21 - 3.27 (m, 2 H) 2.54 - 2.85 (m, 8H) 2.40 (br t, J = 7.40 Hz, 2 H) 1.97 (br d, J = 5.38 Hz, 2 H) 1.69 - 1.80 (m, 2 H) 1.41 - 1.58 (m, 2 H) 1.22 - 1.40 (m, 2 H). SCHEME 61, COMPOUND 711:

[001290] Step 1: (S)-2-((5-Bromopyrimidin-4-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid (140 mg, 259 μmol) in THF (4 ml) and H2O (1 ml) was added 5-bromo-4-chloropyrimidine (55 mg, 285 μmol) and NaHCO3 (109 mg, 1.29 mmol) and the resulting mixture was heated at 70 °C for 6 h, cooled to room temperature, and then concentrated in vacuo to afford the title compound which was used without further purification. LCMS (ESI+): m/z = 589.1 (M+H)+.

[001291] Step 2: (S)-2-(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: To a mixture of (S)-2-((5-bromopyrimidin-4-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid (152 mg, 258 μmol) in MeOH (10 mL) was added 10 wt % Pd/C (200 mg), and the resulting mixture was stirred under an atmosphere of H 2 for 16 h and, then filtered and concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 511.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (s, 1 H) 8.03 (br d, J = 5.50 Hz, 1 H) 7.55 (br s, 1 H) 7.04 (d, J = 7.34 Hz, 1 H) 6.55 (br d, J = 19.56 Hz, 2 H) 6.23 (d, J = 7.21 Hz, 1 H) 4.40 (br s, 1 H) 4.01 (q, J = 9.46 Hz, 2 H) 3.65 (br t, J = 5.75 Hz, 2 H) 3.24 (br t, J = 5.38 Hz, 2 H) 2.55 - 2.76 (m, 8H) 2.40 (br t, J = 7.40 Hz, 2 H) 1.95 (br dd, J = 13.39, 6.54 Hz, 1 H) 1.71 - 1.84 (m, 3 H) 1.49 - 1.58 (m, 2 H) 1.35 - 1.45 (m, 2 H).

[001292] Compound 712: (S)-2-((6-(1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid (140 mg, 259 μmol) in DMA (3 ml) was added 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (51 mg, 285 μmol) and DIPEA (226 μL, 1.29 mmol) were added and the resulting mixture was heated at 70 °C for 2 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 577.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.54 (d, J = 2.32 Hz, 1 H) 8.35 (s, 1 H) 7.92 (br d, J = 5.75 Hz, 1 H) 7.84 (d, J = 0.98 Hz, 1 H) 7.07 (br s, 1 H) 6.99 (d, J = 7.21 Hz, 1 H) 6.54 - 6.58 (m, 1 H) 6.43 (br s, 1 H) 6.20 (d, J = 7.34 Hz, 1 H) 4.51 (br s, 1 H) 3.98 - 4.05 (m, 2 H) 3.65 (br t, J = 5.87 Hz, 2 H) 3.20 - 3.25 (m, 2 H) 2.55 - 2.78 (m, 8 H) 2.38 (br t, J = 7.40 Hz, 2 H) 1.94 - 2.03 (m, 1 H) 1.80 (br s, 1 H) 1.71 - 1.76 (m, 2 H) 1.49 - 1.58 (m, 2 H) 1.36 - 1.44 (m, 2 H).

[001293] Compound 713: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2) acid -yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid: A mixture of 2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) (S)-tert-butyl butanoate (152 mg, 336 μmol) and 2-chloro-5-methyl-pyrimidine (36 mg, 280 μmol) in t-AmOH (2 ml) 2.0 M t-BuONa in THF was added (280 μL, 560 μmol), then t-BuXPhos-Pd-G3 (22 mg, 28 μmol) and the resulting mixture was heated at 100 °C for 5 h, cooled to room temperature, and then concentrated in vacuum to provide a 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) -2-((5-methylpyrimidin-2-yl)amino)butanoate (S)-tert-butyl intermediate, LCMS (ESI+): m/z = 545.3 (M+H)+, which was used without purification additional. Of the intermediate butanoate, 180 mg, 330 μmol) was taken up in DCM (2 ml) and TFA (600 μl) and the resulting mixture was stirred at room temperature for 6 h and then concentrated in vacuo. The crude residue was purified by Prep. reversed-phase HPLC to furnish the title compound. LCMS (ESI+): m/z = 489.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 14.34 (br s, 1 H) 10.93 (br s, 1 H) 8.30 (s, 2 H) 8.13 (br s, 1 H) 7.82 (br s, 1 H) 7.60 (d, J = 7.34 Hz, 1 H) 6.63 (d, J = 7.34 Hz, 1 H) 5.24 - 5.44 (m, 1 H) 4.46 (br s, 1 H) 3.63 (br s, 1 H) 3 .49 - 3.59 (m, 2 H) 3.33 - 3.48 (m, 4 H) 3.31 (d, J = 0.98Hz, 3H) 3.14 - 3.27 (m, 3 H) 2.66 - 2.77 (m, 4 H) 2.14 - 2.37 (m, 2 H) 2.10 (s, 3 H) 1, 63 - 1.86 (m, 6 H).

[001294] Compound 714: (S)-2-((3-cyanopyrazin-2-yl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: To a mixture of (S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride (150 mg, 333 μmol) in i-PrOH (2 ml) was added DIPEA (290 μl, 1.66 mmol), then 3-chloropyrazine-2-carbonitrile (93 mg, 665 μmol) and the resulting mixture was heated at 70 °C for 2 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 518.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 14.13 (br s, 1 H) 10.22 (br s, 1 H) 8.37 (d, J = 2.43 Hz, 1 H) 8.03 (d, J = 2.43 Hz, 2 H) 7.84 - 7.90 (m, 1 H) 7.61 (d, J = 7.28 Hz, 1 H) 6.61 (d, J = 7.28 Hz, 1 H) 6.00 - 6.33 (m, 1 H) 4.54 - 4.66 (m, 1 H) 3.90 (br t, J = 4.74 Hz, 2 H) 3.75 (td, J = 15.27, 3.42 Hz, 2 H) 3.35 (br s, 4 H) 3.16 (br s, 4 H) 2.67 - 2.76 (m, 4 H) 2.28 - 2.41 (m, 2 H) 1.76 - 1.87 (m, 2 H) 1.63 - 1.75 (m, 4 H).

[001295] Compound 715: (S)-2-([4,4'-Bipyridin]-2-ylamino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2-((4-bromopyridin-2-yl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (50 mg, 88 μmol) and 4-pyridylboronic acid (32 mg, 263 μmol) in dioxane (2 ml) and H2O (0.5 To 100 μmol) were added Pd(dppf)Cl2.CH2Cl2 (7 mg, 9 μmol) and K2CO3 (36 mg, 262 μmol) and the resulting mixture was heated at 100 °C for 2 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 569.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 9.07 (d, J = 6.85 Hz, 2 H) 8.53 (d, J = 6.85 Hz, 2 H) 8.18 (d, J = 6.60 Hz, 1 H) 7.82 (d, J = 0.98 Hz, 1 H) 7.60 (d, J = 7.34 Hz, 1 H) 7.46 (dd, J = 6.72, 1.71 Hz, 1 H) 6.67 (d, J = 7.34 Hz, 1 H) 5.87 - 6.19 (m, 1 H) 4.92 - 4.96 (m, 1 H) 3.96 - 4.05 (m, 2 H) 3.80 (td, J = 14.70, 3.61 Hz, 2 H) 3.60 - 3.69 (m, 1 H) 3.51 (br dd, J = 10.94, 5.44 Hz, 5 H) 3.37 (br t, J = 7.89 Hz, 2 H) 2.78 - 2.85 (m, 4 H) 2.61 - 2.72 (m, 1 H) 2.41 - 2.53 (m, 1 H) 1.78 - 1.99 (m, 6 H). SCHEME 62, COMPOUND 716:

[001296] Step 1: (S)-2-((4-bromopyridin-2-yl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2- acid hydrochloride amino-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (500 mg, 1.11 mmol) in DMSO (4 ml) was added K2CO3 (766 mg, 5.54 mmol) and 4-bromo-2-fluoropyridine (234 mg, 1.33 mmol) and the resulting mixture was heated at 130°C for 1 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by prep. HPLC from reverse phase to furnish the title compound. LCMS (ESI+): m/z = 571.2 (M+H)+.

[001297] Step 2: (S)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((4-phenylpyridin-2-yl)amino)butanoic acid: To a mixture of (S)-2-((4-bromopyridin-2-yl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (50 mg, 88 μmol) and phenylboronic acid (32 mg, 263 μmol) in dioxane (2 ml) and H2O (0.5 ml) was added Pd(dppf)Cl2.CH2Cl2 (7 mg, 9 μmol) and K2CO3 (36 mg, 263 μmol) were prepared and the resulting mixture was heated at 100 °C for 2 h, cooled to room temperature, and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 568.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.00 (d, J = 6.60 Hz, 1 H) 7.81 - 7.86 (m, 2 H) 7.56 - 7.61 (m, 4 H) 7.45 (d, J = 1.34 Hz, 1 H) 7.35 (dd, J = 6.79, 1.65 Hz, 1 H) 6.65 (d, J = 7.34 Hz, 1 H) 5.86 - 6.17 (m, 1 H) 4.75 - 4.80 (m, 1 H) 3.95 - 4.03 (m, 2 H) 3.80 (td, J = 14.76, 3.61 Hz, 2H) 3.58 - 3.66 (m, 1 H) 3.47 - 3.56 (m, 5 H) 3.34 - 3.40 (m, 2 H) 2.76 - 2.84 (m, 4 H) 2.56 - 2.67 (m, 1 H) 2.34 - 2.46 (m, 1 H) 1.75 - 1.98 (m, 6H). SCHEME 63, COMPOUND 717:

[001298] Step 1: (S)-2-((5-bromopyridin-2-yl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7) ,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid: A mixture of (S)-2- acid hydrochloride amino-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (200 mg, 444 μmol) in DMSO (3 ml) was added

[001299] (306 mg, 2.22 mmol) and 5-bromo-2-fluoropyridine (94 mg, 532 μmol) were combined and the resulting mixture was heated at 130 °C for 15 h, cooled to room temperature, adjusted to pH = 6 by the addition of 1 M aq. HCl solution and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 571.2 (M+H)+.

[001300] Step 2: 2-((5-Phenylpyridin-2-yl)amino)butanoic acid: To a mixture of (S)-2-((5-bromopyridin-2-yl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (20 mg, 35 μmol) and phenylboronic acid (13 mg, 105 μmol) in dioxane (2 ml) and H2O (0.5 ml) was added Pd(dppf)Cl2.CH2Cl2 (3 mg, 4 μmol) and K2CO3 (15 mg, 105 μmol), and the resulting mixture was heated at 100 °C for 2 h. cooled to room temperature and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 568.3 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.36 (dd, J = 9.35, 2.26 Hz, 1 H) 8.18 (d, J = 1.83 Hz, 1 H) 7.62 - 7.67 (m, 2 H) 7.59 (d, J = 7.34 Hz, 1 H) 7.48 - 7.54 (m, 2 H) 7.42 - 7.47 (m, 1 H) 7.37 (d, J = 9.29 Hz, 1 H) 6.66 (d, J = 7.34 Hz, 1 H) 5.87 - 6.19 (m, 1 H) 4.79 (dd, J = 7.89, 5.44Hz, 1H) 3.95 - 4.05 (m, 2 H) 3.80 (td, J = 14.76, 3.61 Hz, 2 H) 3.57 - 3.65 (m, 1 H) 3.46 - 3.56 (m, 5 H) 3.34 - 3.40 (m, 2 H) 2.76 - 2.85 (m, 4 H) 2.57 - 2.68 (m, 1 H) 2.36 - 2.48 (m, 1 H) 1.77 - 1.99 (m, 6 H).

[001301] Compound 718: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2) acid -yl)butyl)amino)-2-((7-methyl-7H-pyrrol[2,3-d]pyrimidin-4-yl)amino)butanoic acid: A mixture of 2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) (S)-tert-butyl butanoate (150 mg, 331 μmol), 4-chloro-7-methyl-7H-pyrrol[2,3-d]pyrimidine (48 mg, 286) in t-AmOH (3 ml) was added 2.0 M t-BuONa in THF (286 μl, 572 μmol) then t-BuXPhos-Pd-G3 (23 mg, 29 μmol) and the resulting mixture was heated to 100 °C for 15 h, cooled to room temperature and then concentrated in vacuo to give a (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8 -tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)butanoate butyl intermediate, LCMS (ESI+): m/z = 584.4 (M+H)+, which was used without further purification. Of the intermediate butanoate, 80 mg, 141 μmol) was taken up in DCM (1 ml) and TFA (400 μl) and the resulting mixture was stirred at room temperature for 6 h and then concentrated in vacuo . The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 528.3 (M+H)+.

[001302] Compound 719: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2) acid -yl)butyl)amino)-2-((6-methylpyrazin-2-yl)amino)butanoic acid: A mixture of (S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) tert-butyl butyl)amino)butanoate (211 mg, 467 μmol) and 2-chloro-6-methyl-pyrazine (50 mg, 389 μmol) in t-AmOH (3 ml) 2.0M t-BuONa in THF was added (389 μL, 778 μmol) then t-BuXPhos-Pd-G3 (31 mg, 39 μmol) and the resulting mixture was heated at 100 °C for 15 h, cooled to room temperature, and then concentrated in vacuo to afford a (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino tert-Butyl )-2-((6-methylpyrazin-2-yl)amino)butanoate intermediate, LCMS (ESI+): m/z = 545.4 (M+H)+, which was used without further purification. Of the intermediate butanoate, 268 mg, 494 μmol, was taken up in DCM (2 ml) and TFA (1.5 ml) and the resulting mixture was stirred at room temperature for 6 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 489.3 (M+H)+.

[001303] Compound 720: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2) acid -yl)butyl)amino)-2-(quinoxalin-2-ylamino)butanoic acid: A mixture of (S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) tert-butyl butyl)amino)butanoate (211 mg, 467 μmol) and 2-chloroquinoxaline (64 mg, 389 μmol) in t-AmOH (3 ml) were added. of the 2.0 M t-BuONa in THF (389 μl, 778 μmol) then t-BuXPhos-Pd-G3 (31 mg, 39 μmol) and the resulting mixture was heated at 100 °C for 15 h, cooled to room temperature, and then concentrated in vacuo to furnish a ( S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- tert-Butyl 2-(quinoxalin-2-ylamino)butanoate intermediate, LCMS (ESI+): m/z = 581.4 (M+H)+, which was used without further purification. Of the intermediate butanoate, 309 mg, 533 μmol, was taken up in DCM (2 ml) and TFA (1.5 ml) and the resulting mixture was stirred at room temperature for 6 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 525.3 (M+H)+.

[001304] Compound 721: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2) acid -yl)butyl)amino)-2-((6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino)butanoic acid: A mixture of (S)-2-amino-4- (((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) tert-butyl butyl)amino)butanoate (211 mg, 467 μmol) and 4-chloro-6-methyl-2-(4-pyridyl)pyrimidine (80 mg, 389 μmol) in t-AmOH (3 mL) was added 2.0 M t-BuONa in THF (389 μL, 778 μmol) then t-BuXPhos-Pd-G3 (31 mg, 39 μmol) and the resulting mixture was heated at 100 °C for 15 h, cooled to room temperature and then concentrated in vacuo to give a (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8- tert-butyl tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino)butanoate -median, LCMS (ESI+): m/z = 622.4 (M+H)+, which was used without further purification. Of the butanoate intermediate, 270 mg, 447 μmol, was taken up in DCM (2 ml) and TFA (1.5 ml) and the resulting mixture was stirred at room temperature for 6 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 566.3 (M+H)+.

[001305] Compound 722: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2) acid -yl)butyl)amino)-2-((1-methyl-1H- indazol-3-yl)amino)butanoic acid: A mixture of (S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) tert-butyl butyl)amino)butanoate (109 mg, 240 μmol) and 3-bromo-1-methyl-IH-indazole (42 mg, 200 μmol) in THF (2 ml) was added t-BuONa 2.0 M in THF (200 μL, 400 μmol) was added, then t-BuXPhos-Pd-G3 (31 mg, 39 μmol) and the resulting mixture was heated at 100 °C for 15 h, cooled to room temperature and , then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish a (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6 ,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-indazol-3-yl)amino)butanoate tert-butyl intermediate, LCMS (ESI+): m/z = 583.4 (M+H)+. Of the intermediate butanoate, 150 mg, 258 μmol) was taken up in DCM (2 ml) and TFA (1.5 ml) and the resulting mixture was stirred at room temperature for 6 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 527.3 (M+H)+. SCHEME 64, COMPOUND 723:

[001306] Step 1: 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1 (S)-tert-butyl-methyl-1H-indazol-3-yl)amino)butanoate: A mixture of (S)-tert-butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoate (130 mg, 290 μmol) and 3-bromo-1-methyl-1H-indazole (61 mg, 290 μmol) in t-AmOH (3 ml) was added t-BuONa 2.0 M in THF (290 μl, 580 μmol), then t-Bu Xphos Pd G3 (23 mg, 29 μmol) and the resulting mixture was heated at 100 °C for 15 h, cooled to room temperature, and then concentrated in vacuo to furnish compound of the title that was used without further purification. LCMS (ESI+): m/z = 578.5 (M+H)+.

[001307] Step 2: (S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(benzo[d]thiazol-2-ylamino)butanoic acid: (S)-tert-Butyl 4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-indazol-3-yl)amino)butanoate (200 mg, 346 μmol) was taken up in 3:1 DCM/TFA (2 ml) and the resulting mixture was stirred at room temperature for 15 h and then concentrated in vacuo. The crude residue was purified by prep. HPLC. reverse phase to furnish the title compound. LCMS (ESI+): m/z = 522.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (br t, J = 5.40 Hz, 1 H) 7.70 (d, J = 8.16 Hz, 1 H) 7.24 - 7.34 (m, 2 H) 7.00 (d, J = 7.28 Hz, 1 H) 6.91 (t, J = 6.73 Hz, 1 H) 6.43 (br s, 1 H) 6.22 (d, J = 7.28 Hz, 1 H) 4.11 (t, J = 6.06 Hz, 1 H) 3.71 (s, 3 H) 3.22 (br t, J = 5.29 Hz, 2 H) 3.12 (dt, J = 12.68, 6.23 Hz, 2 H) 2.53 - 2.69 (m, 6 H) 2.31 - 2.46 (m, 4 H) 1.86 - 2.01 (m, 2 H) 1.71 - 1.77 (m, 5 H) 1.49 - 1.58 (m, 2 H) 1.35 - 1.45 (m, 2 H) 2H).

[001308] Compound 724: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2) acid -yl)butyl)amino)-2-(pyridin-3-ylamino)butanoic acid: A mixture of 2-amino-4-(((S)-2-fluoro-3- methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino) (S)-tert-butyl butanoate (151 mg, 334 μmol) and 3-bromopyridine (44 mg, 278 μmol) in t-AmOH (2 ml) was added 2.0 M t-BuONa in THF (278 μl, 556 μmol), then t-BuXPhos-Pd-G3 (22 mg, 28 μmol) and the resulting mixture was heated at 100 °C for 5 h, cooled to room temperature and then concentrated in vacuo to give a 4 -(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyridin (S)-tert-Butyl (3-ylamino)butanoate intermediate, LCMS (ESI+): m/z = 530.3 (M+H)+, which was used without further purification. Of the intermediate butanoate, 160 mg, 302 μmol, was taken up in DCM (2 ml) and TFA (600 μl) was added and the resulting mixture was stirred at room temperature for 6 h and then concentrated in vacuo. The crude residue was purified by reversed-phase prep. HPLC to furnish the title compound. LCMS (ESI+): m/z = 474.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90 (d, J = 2.45 Hz, 1 H) 7.74 (d, J = 4.40 Hz, 1 H) 7.02 - 7 .11 (m, 2 H) 6.85 (dd, J = 8.38, 1.53 Hz, 1 H) 6.25 (d, J = 7.34 Hz, 1 H) 4.55 - 4.82 (m, 1 H) 3.84 - 4.02 (m, 1 H) 3.45 - 3.49 ( m, 1 H) 3.39 - 3.43 (m, 1 H) 3.18 - 3.25 (m, 5 H) 2.64 - 2.69 (m, 4 H) 2.59 (br d, J = 6.72 Hz, 4 H) 2.30 - 2.42 (m, 2 H) 1.86 - 1.93 (m, 1 H) 1.67 - 1 .82 (m, 3 H) 1.46 - 1.59 (m, 2 H) 1.31 - 1.43 (m, 2 H).

[001309] Compound 725: (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)- 2-(naphthalen-1-ylamino)butanoic acid: A mixture of (S)-2-amino-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)tert-butanoate butyl (151 mg, 334 μmol) and 1-iodonaphthalene (70 mg, 278 μmol) in t-AmOH (2 ml) was added t-BuONa 2.0 M in THF (278 μl, 556 μmol) and then t-BuXPhos-Pd-G3 (22 mg, 28 μmol) and the resulting mixture was heated at 100 °C for 5 h, cooled to room temperature, and then concentrated in vacuo to furnish a 4-((2-methoxyethyl )(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(naphthalen-1-ylamino)butanoate tert-butyl intermediate, which was used without further purification. Of the intermediate butanoate, 160 mg, 302 μmol, was taken up in DCM (2 ml) and TFA (600 μl) and the resulting mixture was stirred at room temperature for 6 h and then concentrated in vacuo. The Crude residue was purified by reversed-phase prep. HPLC and then chiral SFC to furnish the title compound. LCMS (ESI+): m/z = 491.3 (M+H)+.

[001310] Compound 726: (S)-4-((2-morpholinoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with 2-morpholinoethan-1-amine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 548.3. [M+H]+, found 548.4.

[001311] Compound 727: (2S)-4-((2,3-dihydroxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl acid )amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with 3-aminopropane-1,2-diol, Procedure H with 4-chloroquinazoline, and Procedure P. 1H NMR (400 MHz, Methanol-d4) δ 8, 87 (s, 1H), 8.54 (dd, J = 8.7, 1.3 Hz, 1H), 8.19 - 8.05 (m, 1H), 7.97 - 7.79 (m, 2H), 7.58 (dd, J = 7.3, 1.2 Hz, 1H), 6.62 (dd, J = 7.3, 1.1 Hz, 1H), 5.37 (dd, J = 8.0, 5.9 Hz, 1H), 4.02 (d, J = 19.8 Hz, 1H), 3.70 - 3.43 (m, 6H), 2.81 (dt, J = 19.3, 6.9 Hz, 6H), 2.51 (m, 1H), 2.02 - 1 .67 (m, 8H). LCMS theoretical m/z = 509.3. [M+H]+, found 509.3

[001312] Compound 728: 4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)butyl)amino)-2-(naphthalen-1-ylamino)butanoic acid. From chiral SFC purification of Example 329. LCMS (ESI+): m/z = 491.3 (M+H)+.

[001313] Compound 729: (2S)-4-((3-fluoro-2-hydroxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with 1-amino-3-fluoropropan-2-ol, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 511.3. [M+H]+, found 511.3. 1H NMR (400MHz, Methanol-d4) δ 8.86 (d, J = 1.3Hz, 1H), 8.53 (d, J = 8.2Hz, 1H), 8.14 (dd, J = 8.4, 6.8Hz, 1H), 7.88 (t, J = 8.3Hz, 2H), 7.63 - 7.53 (m, 1H), 6.98 (t, J = 8.4 Hz, 1H), 6.63 (dd, J = 7.4, 2.2 Hz, 1H), 5.37 (d, J = 7.5 Hz, 1H), 4.50 (d, J = 3.7 Hz, 1H), 4.38 (d, J = 3.8 Hz, 1H), 4.29 (m, 1H), 3.79 - 3.45 (m, 6H), 2.93 - 2.62 (m, 6H), 2.04 - 1.71 (m, 7H).

[001314] Compound 730: (S)-2-(Quinazolin-4-ylamino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(thiazol-2-ylmethyl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with thiazol-2-ylmethanamine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 532.2. [M+H]+, found 532.3.

[001315] Compound 731: (S)-4-((2-(3-oxomorpholino)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with 4-(2-aminoethyl)morpholin-3-one, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 562.3. [M+H]+, found 562.3.

[001316] Compound 732: (S)-4-(benzyl(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 benzylamine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 525.3. [M+H]+, found 525.2.

[001317] Compound 733: (S)-4-(((R)-2-hydroxypropyl)(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 (R)-1-aminopropan-2-ol, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 493.3. [M+H]+, found 493.3.

[001318] Compound 734: (2S)-4-(((1,4-dioxan-2-yl)methyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with (1,4-dioxan-2-yl)methanamine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS [M+H]+ found 535.3. 1H NMR (400 MHz, Methanol-d4) δ 8.88 (s, 1H), 8.56 (dq, J = 8.5, 1.5 Hz, 1H), 8.20 - 8.07 (m, 1H), 7.88 (ddd, J = 7.2, 3.8, 2.5 Hz, 2H), 7.58 (d, J = 7.3 Hz, 1H), 6.62 (d, J = 7.3 Hz, 1H), 5.35 (ddd, J = 8.0, 6.1, 1.8 Hz, 1H), 4.06 (m, 1H), 3.84 - 3.66 (m, 4H), 3.66 - 3.40 (m, 5H), 3.29 - 3.17 (m, 2H), 2.80 (dt, J = 21.2, 6.8 Hz, 5H), 2.68 (dt, J = 16.3, 6.8 Hz, 1H), 2.49 (s, 1H), 2.02 - 1.64 (m, 8H).

[001319] Compound 735: (S)-4-(((S)-3-fluoro-2-hydroxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with 1-amino-3-fluoropropan-2-ol, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS [M+H]+ found 511.2. 1H NMR (400 MHz, Methanol-d4) δ 8.87 (s, 1H), 8.56 (dt, J = 8.8, 1.9 Hz, 1H), 8.14 (ddq, J = 8.4, 7.1, 1.1 Hz, 1H), 7.94 - 7.80 (m, 2H), 7.58 (dt, J = 7.4, 1.1 Hz, 1H), 6.62 (d, J = 7.3 Hz, 1H), 5.38 (dd, J = 8.3, 5.6 Hz, 1H), 4.50 (d, J = 4.3 Hz, 1H), 4.38 (d, J = 4.4 Hz, 1H), 4.27 (ddd, J = 18.6, 9.1, 4.3 Hz, 1H), 3.75 - 3.41 (m, 6H), 2.92 - 2.63 (m, 5H), 2.54 (d, J = 12.9 Hz, 1H), 2.11-1.65 (m, 7H).

[001320] Compound 736: (S)-4-(((S)-2-hydroxypropyl)(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 (S)-1-aminopropan-2-ol, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 493.3. [M+H]+, found 493.3.

[001321] Compound 737: (2S)-4-((morpholin-3-ylmethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with morpholin-3-ylmethanamine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS [M+H]+ found 534.2. 1H NMR (400 MHz, Methanol-d4) δ 8.85 (d, J = 4.2 Hz, 1H), 8.67 - 8.53 (m, 1H), 8.13 (ddt, J = 8.5, 7.2, 1.4 Hz, 1H), 7.87 (td, J = 8.1, 7.6, 1.7 Hz, 2H), 7.58 (dd, J = 7.3, 1.4 Hz, 1H), 6.62 (d, J = 7.3 Hz, 1H), 5.36 (ddd, J = 10.3, 8.3, 5.5 Hz, 1H), 3.98 (dt, J = 12.6, 3.3 Hz, 1H), 3.83 (dtd, J = 16.5, 12.5, 7.2 Hz, 2H), 3.63 - 3.40 (m, 4H), 3.24 - 3.05 (m, 3H), 2.96 (dd, J = 21.1, 13.3 Hz, 1H), 2.80 (dt, J = 26.9, 6.4 Hz, 5H), 2.62 - 2.26 (m, 2H), 2.09 - 1.88 (m, 7H)), 1.86 - 1.63 (m, 4H).

[001322] Compound 738: (2S)-4-((3,3-Difluoro-2-hydroxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with 3-amino-1,1-difluoropropan-2-ol, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 529.3. [M+H]+, found 529.3.

[001323] Compound 739: (S)-4-(((S)-2,3-dihydroxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with 3-amino-1,1-difluoropropan-2-ol, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS [M+H]+ found 509.2. 1H NMR (400 MHz, Methanol-d4) δ 8.86 (s, 1H), 8.64 - 8.48 (m, 1H), 8.22 - 8.06 (m, 1H), 7.95 - 7.80 (m, 2H), 7.58 (dd, J = 7.3, 1.1 Hz, 1H), 6.62 (d, J = 7.3 Hz, 1H), 5.36 (t, J = 6.9 Hz, 1H), 4.06 (s, 1H), 3.76 - 3.40 (m, 5H), 2.81 (dt, J = 18.5, 6.9 Hz, 6H), 2.49 (brs, 1H), 2.03 - 1.67 (m, 8H).

[001324] Compound 740: (S)-4-((2-Hydroxy-2-methylpropyl)(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 1-amino-2-methylpropan-2-ol, Procedure H with 4-chloropyrido[2,3-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 508.3. [M+H]+, found 508.3.

[001325] Compound 741: (S)-4-((2-Hydroxy-2-methylpropyl)(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 1-amino-2-methylpropan-2-ol, Procedure H with 4-chloropyrido[3,2-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 508.3. [M+H]+, found 508.3.

[001326] Compound 742: (S)-2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-hydroxy-2-methylpropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with 1-amino-2-methylpropan-2-ol, Procedure H with 1-amino-2-methylpropan-2-ol, and Procedure P. LCMS theoretical m/z = 539.3. [M+H]+, found 539.3.

[001327] Compound 743: (S)-4-((2-hydroxy-2-methylpropyl)(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 1-amino-2-methylpropan-2-ol, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 507.3. [M+H]+, found 507.3.

[001328] Compound 744: (S)-4-(((S)-2-fluoro-3-methoxypropyl)(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 B using Procedure F with (S)-2-fluoro-3-methoxypropan-1-amine, Procedure H with 4-chloropyrido[3,2-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 526.3. [M+H]+, found 526.3.

[001329] Compound 745: (S)-4-(Methoxy(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with O-methylhydroxylamine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS [M+H]+ found 465.2. 1H NMR (400 MHz, Methanol-d4) δ 8.83 (d, J = 0.9 Hz, 1H), 8.53 (dd, J = 8.6, 1.3 Hz, 1H), 8.12 (ddt, J = 8.4, 7.2, 1.2 Hz, 1H), 7.87 (ddd, J = 8.4, 6.7, 1.1 Hz, 2H), 7.55 (dd, J = 7.3, 1.2 Hz, 1H), 6.57 (d, J = 7.3 Hz, 1H), 5.41 (dd, J = 9.3, 4.7 Hz, 1H), 3.62 (d, J = 1.2 Hz, 3H), 3.50 (t, J = 5.7 Hz, 2H), 3.02 - 2.88 (m, 2H), 2.89 - 2.76 (m, 3H), 2.70 (t, J = 7.7 Hz, 2H), 2.50 (ddd, J = 14.6, 7.4, 5.1 Hz, 1H), 2.37 - 2.20 (m, 1H), 1.96 (p, J = 6.1 Hz, 2H), 1.81 - 1.47 (m, 4H).

[001330] Compound 746: (S)-4-((2-methoxy-2-methylpropyl)(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-methoxy-2-methylpropan-1-amine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 521.3. [M+H]+, found 521.3.

[001331] Compound 747: (S)-2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-methoxy-2-methylpropyl)(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-methoxy-2-methylpropan-1-amine, Procedure H with 4-chloro-7-fluoro-2-methylquinazoline, and Procedure P. LCMS theoretical m/z = 553.3. [M+H]+, found 553.3.

[001332] Compound 748: (S)-4-(((3-hydroxyoxetan-3-yl)methyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with 3-(aminomethyl)oxetan-3-ol, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS [M+H]+ found 521.2. 1H NMR (400 MHz, Methanol-d4) δ 8.81 (s, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.18 - 8.03 (m, 1H), 7.93 - 7.75 (m, 2H), 7.58 (d, J = 7.3 Hz, 1H), 6.63 (d, J = 7.3 Hz, 1H), 5.29 (dd, J = 8.8, 4.0 Hz, 1H), 4.69 (d, J = 10.4 Hz, 4H), 3.90 - 3.43 (m, 4H), 3.30 - 3.15 (m, 1H), 3.06 - 2.56 (m, 6H), 2.30 (s, 1H), 2.16 - 1.69 (m, 6H).

[001333] Compound 749: (S)-4-((2-methoxy-2-methylpropyl)(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-methoxy-2-methylpropan-1-amine, Procedure H with 4-chloropyrido[2,3-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 522.3. [M+H]+, found 522.3.

[001334] Compound 750: (S)-4-((2-methoxy-2-methylpropyl)(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-methoxy-2-methylpropan-1-amine, Procedure H with 4-chloropyrido[3,2-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 522.3. [M+H]+, found 522.3.

[001335] Compound 751: (S)-4-((2-methoxy-2-methylpropyl)(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-methoxy-2-methylpropan-1-amine, Procedure H with 4-chloro-2-methylquinazoline, and Procedure P. LCMS theoretical m/z = 535.3. [M+H]+, found 535.3.

[001336] Compound 752: (S)-4-(((1-cyanocyclopropyl)methyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with 1-(aminomethyl)cyclopropane-1-carbonitrile, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 514.3. [M+H]+, found 514.3.

[001337] Compound 753: (S)-4-(((S)-3-fluoro-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with (S)-3-fluoro-2-methoxypropan-1-amine, Procedure H with 4-chloroquinazoline, and Procedure P. LCMS theoretical m/z = 525.3. [M+H]+, found 525.3.

[001338] Compound 754: (S)-4-(((S)-3-fluoro-2-methoxypropyl)(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 B using Procedure F with (S)-3-fluoro-2-methoxypropan-1-amine, Procedure H with 4-chloro-2-methylquinazoline, and Procedure P. LCMS theoretical m/z = 539.3. [M+H]+, found 539.3.

[001339] Compound 755: (S)-4-(((S)-3-fluoro-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-fluoro-2-methylquinazolin-4-yl)amino)butanoic acid. Prepared according to Scheme B using Procedure F with (S)-3-fluoro-2-methoxypropan-1-amine, Procedure H with 4-chloro-7-fluoro-2-methylquinazoline, and Procedure P. LCMS theoretical m/z = 557.3. [M+H]+, found 557.3.

[001340] Compound 756: (S)-2-(Quinazolin-4-ylamino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a mixture of (S)-4-(benzyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (87 mg, 0.17 mmol) in MeOH (3 mL) was added 1 M aq. HCl (340 μL, 0.34 mmol) was added, then 20 wt % Pd(OH) 2 /C (12 mg) was added, and the resulting mixture was stirred under an atmosphere of H 2 for 6 h and then filtered and concentrated in vacuo. The crude residue was purified by preparative reversed-phase HPLC to furnish the title compound. Theoretical LCMS m/z = 435.2. [M+H]+, found 435.2.

[001341] Compound 757: (S)-2-((8-fluoroquinazolin-4-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with (R)-2-methoxypropan-1-amine, Procedure H with 4-chloro-8-fluoroquinazoline, and Procedure P. LCMS theoretical m/z = 525.3. [M+H]+, found 525.2.

[001342] Compound 758: (S)-2-((7-fluoroquinazolin-4-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with (R)-2-methoxypropan-1-amine, Procedure H with 4-chloro-7-fluoroquinazoline, and Procedure P. LCMS theoretical m/z = 525.3. [M+H]+, found 525.3.

[001343] Compound 759: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((8-methylquinazolin-4-yl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with (R)-2-methoxypropan-1-amine, Procedure H with 4-chloro-8-methylquinazoline, and Procedure P. LCMS theoretical m/z = 521.3. [M+H]+, found 521.3.

[001344] Compound 760: (S)-4-(((S)-3-fluoro-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-methylquinazolin-4-yl)amino)butanoic acid. Prepared according to Scheme B using Procedure F with (S)-3-fluoro-2-methoxypropan-1-amine, Procedure H with 4-chloro-7-methylquinazoline, and Procedure P. LCMS theoretical m/z = 539.3. [M+H]+, found 539.2.

[001345] Compound 761: (S)-4-(((S)-3-fluoro-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-fluoroquinazolin-4-yl)amino)butanoic acid. Prepared according to Scheme B using Procedure F with (S)-3-fluoro-2-methoxypropan-1-amine, Procedure H with 4-chloro-7-fluoroquinazoline, and Procedure P. LCMS theoretical m/z = 545.3. [M+H]+, found 545.2.

[001346] Compound 762: (S)-4-(((S)-3-fluoro-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((8-methylquinazolin-4-yl)amino)butanoic acid. Prepared according to Scheme B using Procedure F with (S)-3-fluoro-2-methoxypropan-1-amine, Procedure H with 4-chloro-8-methylquinazoline, and Procedure P. LCMS theoretical m/z = 539.3. [M+H]+, found 539.3.

[001347] Compound 763: (S)-4-(((S)-3-fluoro-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((8-fluoroquinazolin-4-yl)amino)butanoic acid. Prepared according to Scheme B using Procedure F with (S)-3-fluoro-2-methoxypropan-1-amine, Procedure H with 4-chloro-8-fluoroquinazoline, and Procedure P. LCMS theoretical m/z = 543.3. [M+H]+, found 543.3.

[001348] Compound 764: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-methylquinazolin-4-yl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with (R)-2-methoxypropan-1-amine, Procedure H with 4-chloro-7-methylquinazoline, and Procedure P. LCMS theoretical m/z = 521.3. [M+H]+, found 521.3.

[001349] Compound 765: (S)-2-((6-fluoroquinazolin-4-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with (R)-2-methoxypropan-1-amine, Procedure H with 4-chloro-6-fluoroquinazoline, and Procedure P. LCMS theoretical m/z = 525.3. [M+H]+, found 525.3.

[001350] Compound 766: (S)-4-(((S)-3-fluoro-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-fluoroquinazolin-4-yl)amino)butanoic acid. Prepared according to Scheme B using Procedure F with (S)-3-fluoro-2-methoxypropan-1-amine, Procedure H with 4-chloro-6-fluoroquinazoline, and Procedure P. LCMS theoretical m/z = 543.3. [M+H]+, found 545.3.

[001351] Compound 767: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(thieno[2,3-d]pyrimidin-4-ylamino)butanoic acid. Prepared according to Scheme A using Procedure A with (R)-2-methoxypropan-1-amine, Procedure H with 4-chlorothieno[2,3-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 513.3. [M+H]+, found 513.2.

[001352] Compound 768: (S)-4-(((S)-3-fluoro-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(thieno[2,3- d ]pyrimidin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with (S)-3-fluoro-2-methoxypropan-1-amine, Procedure H with 4-chlorothieno[2,3-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 531.3. [M+H]+, found 531.2.

[001353] Compound 769: (S)-4-(((S)-3-fluoro-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methylthieno[2,3- d ]pyrimidin-4-yl)amino)butanoic acid. Prepared according to Scheme B using Procedure F with (S)-3-fluoro-2-methoxypropan-1-amine, Procedure H with 4-chloro-6-methylthieno[2,3- d ]pyrimidine, and Procedure P. LCMS theoretical m/z = 545.3. [M+H]+, found 545.3.

[001354] Compound 770: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methylthieno[2,3-d]pyrimidin-4-yl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with (R)-2-methoxypropan-1-amine, Procedure H with 4-chloro-6-methylthieno[2,3-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 527.3. [M+H]+, found 527.3.

[001355] Compound 771: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(thieno[3,2-d]pyrimidin-4-yl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with (R)-2-methoxypropan-1-amine, Procedure H with 4-chlorothieno[3,2-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 513.3. [M+H]+, found 513.2.

[001356] Compound 772: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methylthieno[3,2-d]pyrimidin-4-yl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with (R)-2-methoxypropan-1-amine, Procedure H with 4-chloro-6-methylthieno[3,2-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 527.3. [M+H]+, found 527.3.

[001357] Compound 773: (S)-4-(((S)-3-fluoro-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(thieno[3,2- d ]pyrimidin-4-ylamino)butanoic acid. Prepared according to Scheme B using Procedure F with (S)-3-fluoro-2-methoxypropan-1-amine, Procedure H with 4-chlorothieno[3,2-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 531.3. [M+H]+, found 531.2.

[001358] Compound 774: (S)-4-(((S)-3-fluoro-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methylthieno[3,2- d ]pyrimidin-4-yl)amino)butanoic acid. Prepared according to Scheme B using Procedure F with (S)-3-fluoro-2-methoxypropan-1-amine, Procedure H with 4-chloro-6-methylthieno[3,2- d ]pyrimidine, and Procedure P. LCMS theoretical m/z = 545.3. [M+H]+, found 545.2.

[001359] Compound 775: (S)-4-(((S)-3-fluoro-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylthieno[2,3- d ]pyrimidin-4-yl)amino)butanoic acid. Prepared according to Scheme B using Procedure F with (S)-3-fluoro-2-methoxypropan-1-amine, Procedure H with 4-chloro-5-methylthieno[2,3- d ]pyrimidine, and Procedure P. LCMS theoretical m/z = 545.3. [M+H]+, found 545.2.

[001360] Compound 776: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylthieno[2,3-d]pyrimidin-4-yl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with (R)-2-methoxypropan-1-amine, Procedure H with 4-chloro-5-methylthieno[2,3-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 527.3. [M+H]+, found 527.2.

[001361] Compound 777: (S)-2-((7,8-Difluoroquinazolin-4-yl)amino)-4-(((S)-3-fluoro-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. Prepared according to Scheme B using Procedure F with (S)-3-fluoro-2-methoxypropan-1-amine, Procedure H with 4-chloro-7,8-difluoroquinazoline, and Procedure P. LCMS theoretical m/z = 561.3. [M+H]+, found 561.3.

[001362] Compound 778: (S)-2-((7,8-Difluoroquinazolin-4-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with (R)-2-methoxypropan-1-amine, Procedure H with 4,7-dichloroquinazoline, and Procedure P. LCMS theoretical m/z = 543.3. [M+H]+, found 543.3.

[001363] Compound 779: (S)-4-(((S)-3-fluoro-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-methylthieno[3,2- d ]pyrimidin-4-yl)amino)butanoic acid. Prepared according to Scheme B using Procedure F with (S)-3-fluoro-2-methoxypropan-1-amine, Procedure H with 4-chloro-7-methylthieno[3,2- d ]pyrimidine, and Procedure P. LCMS theoretical m/z = 545.3. [M+H]+, found 545.2.

[001364] Compound 780: (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-methylthieno[3,2-d]pyrimidin-4-yl)amino)butanoic acid. Prepared according to Scheme A using Procedure A with (R)-2-methoxypropan-1-amine, Procedure H with 4-chloro-7-methylthieno[3,2-d]pyrimidine, and Procedure P. LCMS theoretical m/z = 527.3. [M+H]+, found 527.3. BIOLOGICAL EXAMPLES EXAMPLE B1 - SOLID PHASE Avβ6 INTEGRIN BINDING ASSAY

[001365] Microplates were coated with recombinant human αvβ6 integrin (2 μg/ml) in PBS (100 μl/well at 25 °C, overnight). The coating solution was removed, washed with wash buffer (0.05% Tween 20; 0.5 mM MnCl2; in 1x TBS). The plate was blocked with 200 μl/well blocking buffer (1% BSA; 5% sucrose; 0.5 mM MnCl2; in 1x TBS) at 37 °C for 2 h. Dilutions of test compounds and recombinant TGFβi LAP (0.67 μg/ml) in binding buffer (0.05% BSA; 2.5% sucrose; 0.5 mM MnCl2; in 1x TBS) were added. The plate was incubated for 2 h at 25 °C, washed and incubated for 1 h with Biotin-Anti-hLAP. Bound antibody was detected by peroxidase-conjugated streptavidin. IC50 values for test compounds were calculated by a four-parameter logistic regression.

[001366] The IC50 values obtained for inhibition of αvββ integrin for a first series of selected exemplary compounds are shown in Table B-1. The IC50 values obtained for inhibition of αvββ integrin for a second series of selected exemplary compounds are shown in Table B-2. The compounds tested were compound samples prepared according to the procedures described in the Synthetic Examples section, with the stereochemical purity indicated in the Examples. The IC50 values in Tables B-1 and B-2 are presented in four ranges: below 50 nM; from 50 nM to 250 nM; above 250 nM to 1,000 nM; and above 1,000 nM. TABLE B-1 TABLE B-2

EXAMPLE B2 - DISCLOSED COMPOUNDS POTENTIALLY INHIBIT αvβ6 IN A SOLID PHASE ASSAY

[001367] A third series of exemplary compounds were selected for testing in the solid-phase αvβ6 integrin binding assay. The compounds tested were compound samples prepared according to the procedures described in the Synthetic Examples section, with the stereochemical purity indicated in the Examples. As in Example B1, microplates were coated with recombinant human αVβ6 integrin (2 μg/ml) in PBS (100 μl/well at 25 °C, overnight). The coating solution was removed, washed with wash buffer (0.05% Tween 20; 0.5 mM MnCl2; in 1x TBS). The plate was blocked with 200 μl/well of blocking buffer (1% BSA; 5% sucrose; 0.5 mM MnCl2; in 1x TBS) at 37 °C for 2 h. Dilutions of test compounds and recombinant TGFβ1 LAP (0.67 μg/ml) in binding buffer (0.05% BSA; 2.5% sucrose; 0.5 mM MnCl2; in 1x TBS) were added. The plate was incubated for 2 h at 25 °C, washed and incubated for 1 h with Biotin-Anti-hLAP. Bound antibody was detected by peroxidase-conjugated streptavidin. IC50 values for test compounds were calculated by a four-parameter logistic regression.

EXAMPLE B3 - DISCLOSED COMPOUNDS POTENTIALLY INHIBIT αvβi IN A SOLID PHASE ASSAY

[001368] A fourth series of exemplary compounds were selected for testing in a solid-phase αVβ1 integrin binding assay. The compounds tested were compound samples prepared according to the procedures described in the Synthetic Examples section, with the stereochemical purity indicated in the Examples. Similar to Examples B1 and B2, microplates were coated with recombinant human αvβ1 integrin (2 μg/ml) in PBS (100 μl/well at 25 °C, overnight). The coating solution was removed, washed with wash buffer (0.05% Tween 20; 0.5 mM MnCl2; in 1x TBS). The plate was blocked with 200 μl/well of blocking buffer (1% BSA; 5% sucrose; 0.5 mM MnCl2; in 1x TBS) at 37 °C for 2 h. Dilutions of test compounds and recombinant TGFβ1 LAP (0.67 μg/ml) in binding buffer (0.05% BSA; 2.5% sucrose; 0.5 mM MnCl2; in 1x TBS) were added. The plate was incubated for 2 h at 25 °C, washed and incubated for 1 h with Biotin-Anti-hLAP. Bound antibody was detected by peroxidase-conjugated streptavidin. IC50 values for test compounds were calculated by a four-parameter logistic regression.

EXAMPLE B4 - THE DISCLOSED COMPOUNDS POTENTIALLY INHIBIT HUMAN INTEGRIN αVβ6

[001369] A fifth series of exemplary compounds were selected for determination of biochemical potency using the ALPHASCREEN® (Perkin Elmer, Waltham, MA) proximity-based assay (a non-radioactive bead-based amplified luminescent proximity homogeneous assay) as previously described (Ullman EF et al., Luminescent oxygen channeling immunoassay: Measurement of particle binding kinetics by chemiluminescence. Proc. Natl. Acad. Sci. USA, Vol. 91, pp. 5426-5430, June 1994). To assess the potency of human αvβ6 integrin binding inhibitors, inhibitor compounds and integrin were incubated together with recombinant TGFβ1 LAP and biotinylated anti-LAP antibody plus acceptor and donor beads, following the manufacturer's recommendations. Donor beads were coated with streptavidin. Acceptor beads had a Ni-nitrilotriacetic acid chelator for binding to a 6xHis tag on human αvβ6 integrin. All incubations occurred at room temperature in 50 mM Tris-HCl, pH 7.5, 0.1% BSA supplemented with 1 mM CaCl2 and MgCl2 each. The order of reagent addition was as follows: 1. αVβ6 integrin, test inhibitor compound, LAP, biotinylated anti-LAP antibody, and acceptor beads were all added together. 2. After 2 h, donor beads were added. After an additional 30 min of incubation, samples were read.

[001370] Integrin binding was assessed by exciting donor beads at 680 nm and measuring the fluorescent signal produced between 520 and 620 nm using a Biotek Instruments (Winooski, VT, USA) SynergyNeo2 multimode plate reader. Compound potency was assessed by determining the inhibitor concentrations required to reduce fluorescent light output by 50%. Data analysis for IC50 determinations was performed by four-parameter nonlinear logistic regression analysis using Dotmatics ELN software (Core Informatics Inc., Branford, CT).

EXAMPLE B5 - THE DISCLOSED COMPOUNDS POTENTIALLY INHIBIT HUMAN INTEGRIN αVβ1

[001371] A sixth series of exemplary compounds were selected to determine biochemical potency using the ALPHASCREEN® proximity-based assay as described in Example B4. To assess the potency of inhibitors of binding to human αvβ1 integrin, inhibitor compounds and integrin were incubated together with biotinylated purified human fibronectin plus acceptor and donor beads, following the manufacturer's recommendations. Donor beads were coated with streptavidin. Acceptor beads had a Ni-nitrilotriacetic acid chelator for binding to a 6xHis tag on human αvβ1 integrin. All incubations occurred at room temperature in 50 mM Tris-HCl, pH 7.5, 0.1% BSA supplemented with 1 mM CaCl2 and MgCl2 each. The order of reagent addition was as follows: 1. Integrin αVβ1, test inhibitor compound, biotinylated fibronectin, and acceptor beads were all added together. 2. After 2 h, donor beads were added. After another 30 min of incubation, the samples were read.

[001372] Integrin binding was assessed by exciting donor beads at 680 nm and measuring the fluorescent signal produced between 520 and 620 nm using a Biotek Instruments (Winooski, VT, USA) SynergyNeo2 multimode plate reader. Compound potency was assessed by determining the inhibitor concentrations required to reduce fluorescent light output by 50%. Data analysis for IC50 determinations was performed by four-parameter nonlinear logistic regression analysis using Dotmatics ELN software (Core Informatics Inc., Branford, CT). COMBINED INHIBITION RESULTS FOR EXAMPLES B1, B2, B3, B4, AND B5

[001373] Table B-3 (Figure 2) shows the IC50 data for Examples B1, B2, B3, B4, and B5 for inhibition of αVβ1 and αVβ6 integrins in the solid phase assays and inhibition of human αVβ1 and αVβθ integrins in the ALPHASCREEN® assays. The IC50 data are presented in four ranges: below 50 nM; 50 nM to 250 nM; above 250 nM to 1,000 nM; and above 1,000 nM.

[001374] All references, such as publications, patents, patent applications, and published patent applications, are incorporated herein by reference in their entirety.

[001375] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims (24)

1. Compound, characterized by the fact that it presents the Formula (A) or a salt thereof wherein: R1 is C6-C14 aryl or 5- to 10-membered heteroaryl wherein the C6-C14 aryl and the 5- to 10-membered heteroaryl are optionally substituted by R1a; R2 is hydrogen; deuterium; C1-C6 alkyl optionally substituted by R2a; -OH; -O-C1-C6 alkyl optionally substituted by R2a; C3-C6 cycloalkyl optionally substituted by R2b; -O-C3-C6 cycloalkyl optionally substituted by R2b; 3- to 12-membered heterocyclyl optionally substituted by R2c; or -S(O)2R2d; with the proviso that any carbon atom bonded directly to a nitrogen atom is optionally substituted with a chemical moiety R2a other than halogen; each R1a is 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-C14 aryl, deuterium, halogen, -CN, -OR3, -SR3, -NR4R5, -NO2, -C=NH(OR3), - C(O)R3, -OC(O)R3, -C(O)OR3, -C(O)NR4R5, -NR3C(O)R4, - NR3C(O)OR4, -NR3C(O)NR4R5, -S(O)R3, -S(O)2R3, -NR3S(O)R4, - NR3S(O)2R4, -S(O)NR4R5, -S(O)2NR4R5, or -P(O)(OR4)(OR5), wherein each R1a is, whenever possible, independently optionally substituted by deuterium, halogen, oxo, -OR6, -NR6R7, -C(O)R6, -CN, -S(O)R6, -S(O)2R6, -P(O)(OR6)(OR7), C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-C14 aryl or C1-C6 alkyl optionally substituted by deuterium, oxo, OH or halogen; each R2a, R2b, R2c, R2e and R2f is independently oxo or R1a; R2d is C1-C6 alkyl optionally substituted by R2e or C3-C5 cycloalkyl optionally substituted by R2f; R3is independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R3are independently optionally substituted by halogen, deuterium, oxo, -CN, -OR8, -NR8R9, -P(O)(OR8)(OR9) or C1-C6 alkyl optionally substituted by deuterium, halogen, -OH, or oxo; R4 and R5 are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of R4 and R5 are independently optionally substituted by deuterium, halogen, oxo, -CN, -OR8, -NR8R9 or C1C6 alkyl optionally substituted by deuterium, halogen, -OH or oxo; or R4 and R5 are taken together with the atom to which they are attached to form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, -OR8, -NR8R9 or C1-C6 alkyl optionally substituted by deuterium, halogen, oxo or -OH; R6 and R7 are each independently hydrogen, deuterium, C1-C6 alkyl optionally substituted by deuterium, halogen or oxo, C2-C6 alkenyl optionally substituted by deuterium, halogen or oxo, or C2-C6 alkynyl optionally substituted by deuterium, halogen or oxo; or R6 and R7 are taken together with the atom to which they are attached to form a 3- to 6-membered heterocyclyl optionally substituted by deuterium, halogen, oxo or C1-C6 alkyl optionally substituted by deuterium, halogen or oxo; R8 and R9 are each independently hydrogen, deuterium, C1-C6 alkyl optionally substituted by deuterium, halogen, or oxo, C2-C6 alkenyl optionally substituted by deuterium, halogen, or oxo, or C2-C6 alkynyl optionally substituted by deuterium, halogen, or oxo; or R8 and R9 are taken together with the atom to which they are attached to 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 R10, R11, R12, and R13 are independently hydrogen or deuterium; R14 is deuterium; q is 0, 1, 2, 3, 4, 5, 6, 7, or 8; each R15 is independently selected from hydrogen, deuterium, or halogen; each R16 is independently selected from hydrogen, deuterium, or halogen; and p is 3, 4, 5, 6, 7, 8, or 9. 2. Compound according to claim 1, characterized by the fact that: R2 is C1-C6 alkyl optionally substituted by R2a; C3-C6 cycloalkyl optionally substituted by R2b; 3- to 12-membered heterocyclyl optionally substituted by R2c; or -S(O)2R2d; R is independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6C14 aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl of R3 are independently optionally substituted by halogen, deuterium, oxo, -CN, -OR8, -NR8R9, -P(O)(OR8)(OR9) or C1C6 alkyl optionally substituted by deuterium, halogen, OH, or oxo; each R15 is hydrogen; and each R16 is hydrogen; and in which the compound is represented by Formula (I): 3. The compound of claim 1 or 2, or a salt thereof, wherein at least one of R1a, R2a, R2b, R2c, R2e, R2f, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 or R14 is deuterium. 4. The compound of claim 1 or 2, or a salt thereof, wherein R10, R11, R12, R13 and R14 are hydrogen; p is 3; and wherein the compound is represented by Formula (II): 5. Compound according to any one of claims 1 to 4, or a salt thereof, characterized in that R1 is a 5- to 10-membered heteroaryl optionally substituted by R1a; or wherein R1 is: pyrimidinyl, quinazolinyl, pyrazolopyrimidinyl, pyrazinyl, quinolinyl, pyridopyrimidinyl, thienopyrimidinyl, pyridinyl, pyrrolopyrimidinyl, quinoxalinyl, indazolyl, benzothiazolyl, naphthalenyl, purinyl or isoquinolinyl; and is optionally substituted by deuterium, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 perhaloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, 5- to 10-membered heteroaryl, C6-C14 aryl, cyano, amino, alkylamino or dialkylamino; or wherein R1 is: pyrimidin-2-yl, pyrimidin-4-yl, quinazolin-4-yl, 1H-pyrazolo[3,4-d]pyrimidine-4-yl, 1H-pyrazolo[4,3-d]pyrimidine-7-yl, pyrazin-2-yl, quinoline-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 is optionally substituted by: one or more deuterium; methyl; cyclopropyl; fluorine; chlorine; bromine; difluoromethyl; trifluoromethyl; methyl and fluorine; methyl and trifluoromethyl; methoxy; cyano; dimethylamino; phenyl; pyridin-3-yl; or pyridin-4-yl; or wherein R1 is pyrimidin-4-yl optionally substituted by R1a; or wherein R1 is pyrimidin-4-yl optionally substituted by R1a wherein R1a is 5- to 10-membered heteroaryl or C1-C6 alkyl optionally substituted by halogen; or wherein R1 is pyrimidin-4-yl optionally substituted by pyrazolyl, methyl, difluoromethyl or trifluoromethyl; or wherein R1 is pyrimidin-4-yl substituted by methyl and trifluoromethyl; or wherein R1 is quinazolin-4-yl optionally substituted by R1a; or wherein R1 is quinazolin-4-yl optionally substituted by halogen, C1-C6 alkyl optionally substituted by halogen or C1-C6 alkoxy; or wherein R1 is quinazolin-4-yl optionally substituted by fluorine, chlorine, methyl, trifluoromethyl or methoxy. 6. A compound according to any one of claims 1, 3, 4 or 5, or a salt thereof, characterized in that R2 is: hydrogen; deuterium; hydroxy; or C1-C6 alkyl or C1-C6 alkoxy optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C6-C14 aryl, C6-C14 aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy, 3- to 12-membered heterocyclyl optionally substituted with oxo, -C(O)NR4R5, -NR3C(O)R4 or -S(O)2R3; or wherein R2 is: methyl, methoxy, ethyl, ethoxy, propyl, cyclopropyl or cyclobutyl; each of which is optionally substituted by one or more of: hydroxy, methoxy, ethoxy, acetamide, fluorine, fluoroalkyl, phenoxy, dimethylamide, methylsulfonyl, cyclopropoxy, 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 by 0, 1, 2 or 3 of deuterium, hydroxy, methyl, fluorine, cyano or oxo. 7. A compound according to any one of claims 1 to 5, or a salt thereof, characterized in that R2 is: (i) C1-C6 alkyl optionally substituted by R2a; optionally wherein R2a is: halogen; C3-C8 cycloalkyl optionally substituted by halogen; 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl; -NR4R5; -NR3C(O)R4; -S(O)2R3; or oxo; or optionally wherein R2a is: fluorine; fluorine-substituted cyclobutyl; methyl-substituted pyrazolyl; or -S(O)2CH3; (ii) C1-C6 alkyl optionally substituted by -OR3; optionally wherein R3 is: hydrogen; C1-C6 alkyl optionally substituted by halogen; C3-C6 cycloalkyl optionally substituted by halogen; C6-C14 aryl optionally substituted by halogen; or 5- to 6-membered heteroaryl optionally substituted by halogen or C1-C6 alkyl; or optionally wherein R3 is: hydrogen; methyl; ethyl; difluoromethyl; -CH2CHF2; -CH2CF3; cyclopropyl substituted by fluorine; phenyl optionally substituted by fluorine; or pyridinyl optionally substituted by fluorine or methyl; (iii) –CH2CH2OCH3; (iv) R2 is C1-C6 alkyl substituted by halogen and OR3, wherein R3 is C1-C6 alkyl; (v) R2 is C3-C6 cycloalkyl optionally substituted by R2b; or (vi) R2 is cyclopropyl. 8. Compound according to any one of claims 1 to 4, or a salt thereof, characterized in that: wherein m is 0, 1, 2 or 3 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are independently optionally substituted by deuterium; wherein each R1a is independently deuterium, alkyl, haloalkyl, or heteroaryl; (c) where m is 0, 1, 2 or 3 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are independently optionally substituted by deuterium; d) R1 is where m is 0, 1, 2, 3, 4, or 5 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R1a are independently optionally substituted by deuterium; optionally wherein R1 is where each R1a is independently deuterium, halogen, alkyl, haloalkyl, or alkoxy; (e) R1 where m is 0, 1, 2, 3, 4, or 5 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN, or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy, and heteroaryl of R1a are independently optionally substituted by deuterium; (f) wherein m is 0, 1, 2, 3 or 4, and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are independently optionally substituted by deuterium; optionally wherein R1 is selected from the group consisting of where m is 0, 1, 2, 3 or 4, and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are independently optionally substituted by deuterium; optionally wherein R1 is selected from the group consisting of wherein m is 0, 1, 2, 3 or 4, and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are independently optionally substituted by deuterium; optionally wherein R1 is selected from the group consisting of wherein m is 0, 1, 2, 3, 4, 5 or 6 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are independently optionally substituted by deuterium; (j) wherein m is 0, 1, 2, 3, 4, 5 or 6 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are independently optionally substituted by deuterium; (k) where m is 0, 1 or 2 and each R1a is, when applicable, independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R1a are independently optionally substituted by deuterium; (l) R1 is selected from the group consisting of and any of the preceding groups in which any one or more hydrogen atoms are replaced by a deuterium atom (or atoms); (m) R1 is selected from the group consisting of and any of the preceding groups in which any one or more hydrogen atoms are replaced by a deuterium atom (or atoms); (n) R1 is selected from the group consisting of and any of the preceding groups in which any one or more hydrogen atoms are replaced by a deuterium atom (or atoms); or (o) R1 is selected from the group consisting of and any of the preceding groups in which any one or more hydrogen atoms are replaced by an atom (or atoms) of deuterium. 9. Compound according to any one of claims 1 to 5 or 8, or a salt thereof, characterized in that wherein n is 1, 2, 3, 4, 5 or 6, and R3 is C1-C2 alkyl optionally substituted by fluorine; phenyl optionally substituted by fluorine; pyridinyl optionally substituted by fluorine or methyl; or cyclopropyl optionally substituted by fluorine; or wherein R2 is selected from the group consisting of and any of the preceding groups in which any one or more hydrogen atoms are replaced by a deuterium atom (or atoms); or in which R2 is selected from the group consisting of and any of the preceding groups in which any one or more hydrogen atoms are replaced by a deuterium atom (or atoms); or in which R2 is C1-C6 alkyl optionally substituted by -OR3 and R3 is phenyl optionally substituted by fluorine; or in which R2 is C1-C6 alkyl optionally substituted by -OR3 and R3 is pyridinyl optionally substituted by fluorine or methyl; or in which R2 is C1-C6 alkyl substituted by R2a, wherein R2a is halogen; or (ii) C1-C6 alkyl substituted by R2a, wherein R2a is deuterium; or (iii) C1-C6 alkyl substituted by R2a, wherein R2a is 3- to 12-membered heterocyclyl optionally substituted by oxo; or (iv) C1-C6 alkyl substituted with R2a, wherein R2a is 4- to 5-membered heterocyclyl optionally substituted by oxo; or (v) C1-C6 alkyl substituted with R2a, wherein R2a is C6-C14 aryl optionally substituted by halogen or -OR6; or (vi) C1-C6 alkyl substituted with R2a, wherein R2a is phenyl optionally substituted by halogen or -OR6; or (vii) C1-C6 alkyl substituted with R2a, wherein R2a is 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl; or (viii) C1-C6 alkyl substituted with R2a, wherein R2a is pyrazolyl optionally substituted by methyl; or (ix) C1-C6 alkyl substituted with R2a wherein R2a is C3-C8 cycloalkyl optionally substituted with -CN, halogen or –OR6; or (x) C1-C6 alkyl substituted with R2a wherein R2a is -S(O)2R3. 10. The compound of any one of claims 1 to 4, or a salt thereof, wherein R1 is pyridyl optionally substituted by R1a; or wherein R1 is indazolyl optionally substituted by R1a; or wherein R1 is 1H-pyrrolopyridyl optionally substituted by R1a; or wherein R1 is quinolinyl optionally substituted by R1a; or wherein R1 is phenyl optionally substituted by R1a; or wherein R1 is indanyl optionally substituted by R1a. 11. A compound, or a salt thereof, selected from Compounds Nos. 1 to 780 in Figure 1. 12. Compound according to claim 1, or a salt thereof, characterized in that the compound has Formula (II-B): where m is 0, 1, 2, 3, 4, or 5. 13. Compound according to claim 1, characterized in that the compound is selected from: (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; (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; (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; (S)-2-((6-fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; (S)-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; (S)-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; (2S)-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; (S)-4-(((S)-3-fluoro-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid; (S)-2-((8-fluoroquinazolin-4-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; (S)-2-((7-fluoroquinazolin-4-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((8-methylquinazolin-4-yl)amino)butanoic acid; (S)-2-((7,8-difluoroquinazolin-4-yl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; (S)-4-((2-phenoxy ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; (S)-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; (S)-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; (S)-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; (S)-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; (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; (S)-4-((2-ethylhydroxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; (S)-4-(((R)-2-hydroxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; and (S)-4-(((S)-2,3-dihydroxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a salt thereof. 14. The compound of claim 1, wherein the compound is (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a salt thereof. 15. Pharmaceutical composition, characterized by the fact that it comprises a compound, as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 16. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 15, for use in the treatment of a fibrotic disease. 17. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 15, for use in the treatment of fibrotic disease, wherein the fibrotic disease is pulmonary fibrosis, hepatic fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis. 18. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use in the treatment of idiopathic pulmonary fibrosis (IPF). 19. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use in the treatment of primary sclerosing cholangitis (PSC). 20. Use of a compound as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, characterized in that it is in the manufacture of a pharmaceutical composition, a medicament or a kit for the treatment of a fibrotic disease. 21. Use of a compound as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, characterized in that it is in the manufacture of a pharmaceutical composition, a medicament or a kit for the treatment of a fibrotic disease, in which the fibrotic disease is pulmonary fibrosis, hepatic fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis or biliary fibrosis. 22. Use of a compound as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, characterized in that it is in the manufacture of a pharmaceutical composition, a medicament or a kit for the treatment of idiopathic pulmonary fibrosis (IPF). 23. Use of a compound as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, characterized in that it is in the manufacture of a pharmaceutical composition, a medicament or a kit for the treatment of primary sclerosing cholangitis (PSC). 24. Invention, characterized by the fact that it is in any form of its embodiments or in any category of claim that can be claimed, for example, product, or process, or use covered by the object initially described, revealed, or illustrated in the patent application, Kit, comprising a compound as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, Article of manufacture, comprising a compound as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, Use of a compound, as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical composition, a medicament or a kit for the treatment of a disease, disorder or health condition in an individual and/or for the inhibition of integrin αvβ6 in an individual and/or for the activation of TGFβ in a cell and/or for the modulation of the activity of at least one integrin in an individual in need thereof. same.