WO2020076862A1 - Amino acid compounds and methods of use - Google Patents

Amino acid compounds and methods of use Download PDF

Info

Publication number
WO2020076862A1
WO2020076862A1 PCT/US2019/055252 US2019055252W WO2020076862A1 WO 2020076862 A1 WO2020076862 A1 WO 2020076862A1 US 2019055252 W US2019055252 W US 2019055252W WO 2020076862 A1 WO2020076862 A1 WO 2020076862A1
Authority
WO
WIPO (PCT)
Prior art keywords
tetrahydro
naphthyridin
homoserine
compound
ethyl
Prior art date
Application number
PCT/US2019/055252
Other languages
French (fr)
Inventor
Jacob CHA
Manuel Munoz
Maureen REILLY
Nicole Cooper
Katerina Leftheris
David J. Morgans Jr.
Timothy HOM
Yajun Zheng
Original Assignee
Pliant Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CN201980066146.7A priority Critical patent/CN113195053B/en
Priority to BR112021006620A priority patent/BR112021006620A2/en
Priority to JOP/2021/0056A priority patent/JOP20210056A1/en
Priority to MX2021004015A priority patent/MX2021004015A/en
Priority to KR1020217013781A priority patent/KR20210101205A/en
Priority to EP19870448.8A priority patent/EP3863711A4/en
Priority to EA202190967A priority patent/EA202190967A1/en
Application filed by Pliant Therapeutics, Inc. filed Critical Pliant Therapeutics, Inc.
Priority to CR20210224A priority patent/CR20210224A/en
Priority to JP2021544112A priority patent/JP7523450B2/en
Priority to PE2021000461A priority patent/PE20211463A1/en
Priority to CU2021000027A priority patent/CU24690B1/en
Priority to AU2019358041A priority patent/AU2019358041A1/en
Priority to SG11202103283RA priority patent/SG11202103283RA/en
Priority to CA3115643A priority patent/CA3115643A1/en
Publication of WO2020076862A1 publication Critical patent/WO2020076862A1/en
Priority to DO2021000054A priority patent/DOP2021000054A/en
Priority to IL282026A priority patent/IL282026A/en
Priority to CONC2021/0004279A priority patent/CO2021004279A2/en
Priority to PH12021550784A priority patent/PH12021550784A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This disclosure relates generally to therapeutic agents that may be useful as anb6 integrin inhibitors.
  • the therapeutic agents may be used in the treatment or prophylactic treatment of fibrosis such as idiopathic pulmonary fibrosis (1PF) and nonspecific interstitial pneumonia (NSIP).
  • fibrosis such as idiopathic pulmonary fibrosis (1PF) and nonspecific interstitial pneumonia (NSIP).
  • Fibrosis a pathologic feature of many diseases, is caused by a dysfunction in the body’s natural ability to repair damaged tissues. If left untreated, fibrosis can result in scarring of vital organs causing irreparable damage and eventual organ failure.
  • NASH nonalcoholic steatohepatitis
  • Fibrosis in the kidney characterized by glomerulosclerosis and tubulointerstitial fibrosis, is the final common manifestation of a wide variety of chronic kidney diseases (CKD). Irrespective of the initial causes, progressive CKD often results in widespread tissue scarring that leads to destruction of kidney parenchyma and end-stage renal failure, a devastating condition that requires dialysis or kidney replacement.
  • CKD chronic kidney diseases
  • Scleroderma encompasses a spectrum of complex and variable conditions primarily characterized by fibrosis, vascular alterations, and autoimmunity.
  • the scleroderma spectrum of disorders share the common feature of fibrosis, resulting in hardening or thickening of the skin. For some patients, this hardening occurs only in lim ited areas, but for others, it can spread to other major organs
  • Crohn’s Disease is a chronic disease of unknown etiology tending to progress even in tire setting of medical or surgical treatment. Intestinal fibrosis is among the most common complications of Crohn’s disease, resulting in stricture formation in the small intestine and colon.
  • Idiopathic pulmonary fibrosis is a chronic, progressive, fibrosing disease of unknown etiology, occurring in adults and limited to the lungs.
  • IPF the lung tissue becomes thickened, stiff, and scarred.
  • lung fibrosis progresses, it becomes more difficult for the lungs to transfer oxygen into the bloodstream and the organs do not receive the oxygen needed to function properly.
  • IPF currently affects approximately 200,000 people in the U.S., resulting in 40,000 deaths per year. Patients diagnosed with IPF experience progressive breathlessness and eventually, complete respiratory failure.
  • PBC Primary biliary cholangitis
  • primary' biliary cirrhosis is a chronic disease of the liver that causes damage and fibrosis in the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Over time, this leads to scarring and fibrosis in both the liver and biliary tract.
  • Nonspecific interstitial pneumonia is a rare disorder that affects the tissue that surrounds and separates the tiny air sacs of the lungs. These air sacs, called the alveoli, are where the exchange of oxygen and carbon dioxide takes place between the lungs and the bloodstream.
  • 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) might become inflamed as well .
  • Tire fibrotic form is defined by thickening and scarring of lung tissue. This scarring is known as fibrosis and is irreversible. When the lung tissue thickens or becomes scarred, it does not function as effectively. Breathing becomes less efficient, and there are lower levels of oxygen in the blood. (Kim et a!., Proc. Am. Thorac. Soc. (2006) 3:285-292; Lynch, D., Radiology (2001) 221 :583-584; Kinder et a , Am. I. Respir. Crit. Care Med. (2007) 176:691 -697)
  • a vailable courses of treatment are scarce, as there are currently no options on the market proven to have an effect on long-term patient survival or symptomatology. There remains a need for treatment of fibrotic diseases.
  • the anb ⁇ integrin is expressed m epithelial cells, and binds to the latency- associated peptide of transforming growth factor-b ⁇ (T ⁇ RbI) and mediates TORbI activation. Its expression level is significantly increased after injury to lung and
  • cholangiocytes and plays a critical in vivo role in tissue fibrosis. Increased levels are also associated with increased mortality in IFF and NSIP patients
  • PSC Primary sclerosing cholangitis
  • bile duct inflammation and fibrosis that obliterates the bile ducts.
  • the resulting impediment to the flow of bile to the intestines can lead to cirrhosis of the liver and subsequent complications such as liver failure and liver cancer.
  • Expression of anb6 is elevated in liver and bile duct of PSC patients.
  • the present disclosure provides for anb ⁇ integrin inhibitors that may be useful for treatment of fibrosis.
  • amino acid compounds that are anb6 integral inhibitors, compositions containing these compounds and methods for treating diseases mediated by anb ⁇ integrin such as a fibrotic disease
  • 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 earner or excipient
  • a method of treating a fibrotic disease or condition in an individual comprising admini stering to the individual a therapeutically effective amount of a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof.
  • the fibrotic disease or condition is pulmonary, liver, renal, cardiac, dermal, or gastrointestinal fibrosis.
  • the fibrotic disease or condition is idiopathic pulmonary fibrosis, interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease induced fibrosis, Alport syndrome, primary sclerosing cholangitis, primarily biliar cholangitis (also known as primary ' biliary cirrhosis), systemic sclerosis associated interstitial lung disease, scleroderma (also known as systemic sclerosis), diabetic nephropathy, diabetic kidney- disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn’s Disease.
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • alcoholic liver disease induced fibrosis Alport syndrome
  • primary sclerosing cholangitis primarily biliar cholangitis (also known as primary ' biliary
  • a method of delaying the onset and/or development of a fibrotic disease or condition in an individual (such as a human) who is at risk for developing a fibrotic disease or condition comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof.
  • the disease or condition is pulmonary, liver, renal, cardiac, dermal, or gastrointestinal fibrosis.
  • the fibrotic disease or condition is idiopathic pulmonary fibrosis, interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease induced fibrosis, Alport syndrome, primary' sclerosing cholangitis, primarily biliary cholangitis (also known as primary biliary cirrhosis), systemic sclerosis associated interstitial lung disease, scleroderma (also known as systemic sclerosis), diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn’s Disease.
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • alcoholic liver disease induced fibrosis Alport syndrome
  • primary' sclerosing cholangitis primarily biliary cholangitis (also known as primary biliary cirr
  • kits comprising a compound of formula (I), or any variation thereof de tailed herein, or a pharmaceutically acceptable sal t thereof.
  • the kit comprises instructions for use according to a method described herein, such as a method of treating a fibrotic disease in an individual.
  • FIG. 1 Table 2 shows chemical structures for various compounds disclosed herein .
  • Reference to compound numbers in the table in some instances depicts a particular stereoisomeric form of the compound number, as will be evident from the chemical structure depicted.
  • FIG. 2 Table B ⁇ 2 shows biological data for various compounds disclosed herein.
  • the invention provides, inter alia , compounds of formula (I), and variations thereof, pharmaceutical compositions comprising compounds of formula (I), and methods of using such compounds and compositions in treating fibrotic diseases.
  • Compounds and pharmaceutical compositions comprising salts of compounds of formula (I) are provided as well.
  • Reference to“about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to“about X” includes description of“X”. Likewise, reference to a value“X” also includes description of“about X”.
  • Alkyl refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbon atoms).
  • Particular alkyl groups are those having 1 to 20 carbon atoms (a“C1-C20 alkyl”), having 1 to 10 carbon atoms (a“C1-C10 alkyl”), having 6 to 10 carbon atoms (a“Ce-Cio alkyl”), having 1 to 6 carbon atoms (a“Ci ⁇ C& alkyl”), having 2 to 6 carbon atoms (a“Cr-Ce alkyl”), or having 1 to 4 carbon atoms (a“C1-C4 alkyl”).
  • alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyi, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n- pentyd, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
  • Alkylene as used herein refers to the same residues as alkyl, but having bivalency.
  • Particular alkylene groups are those having 1 to 20 carbon atoms (a“C1-C20 alkylene”), having 1 to 10 carbon atoms (a“C1-C10 alkylene”), having 6 to 10 carbon atoms (a“Ce-Cio alkylene”), having 1 to 6 carbon atoms (a“Ci-Ce alkylene”), 1 to 5 carbon atoms (a“C ] -C.-3 alkylene”), 1 to 4 carbon atoms (a“C1-C4 alkylene”) or 1 to 3 carbon atoms (a“Ci- C3 alkylene”).
  • alkylene examples include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH.3)-), butylene (-P NCi k K l l -). isobutylene (-C1 K l HU HP I. ⁇ -). pentylene ( -( 1 1 (C H ) A 1 1 ) hexylene (-C1 MCI t.fi iCi f ⁇ -). heptylene (-P f(0 EfiCi 1 -).
  • octylene (-P l.dC ' l f yCl i.-). and the like. It is understood that when alkylene is substituted (for example with a cycloalkyl group), the substituent is not one of the sites of bivalency. For example, propylene
  • substitution with cyclopropyl may provide hut does not provide , wherein the wavy line denotes a site of bi valency.
  • An alkenyl group may have“cis” or“trans” configurations, or alternatively have“E” or“Z” configurations.
  • Particular alkenyl groups are those having 2 to 20 carbon atoms (a“C2-C20 alkenyl”), having 6 to 10 carbon atoms (a“Ce-Cio alkenyl”), having 2 to 8 carbon atoms (a“Ci-Cs alkenyl”), having 2 to 6 carbon atoms (a“Ci-Ce alkenyl”), or having 2 to 4 carbon atoms (a“C 2 -C4 alkenyl”).
  • alkenyl groups include, but are not limited to, groups such as ethenyl (or vinyl), prop-l-enyl, prop-2 -enyl (or ally!), 2-methylprop-l-enyl, but- 1 -enyl, but-2-enyl, but-3-enyl, buta-l ,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.
  • groups such as ethenyl (or vinyl), prop-l-enyl, prop-2 -enyl (or ally!), 2-methylprop-l-enyl, but- 1 -enyl, but-2-enyl, but-3-enyl, buta-l ,3-dienyl, 2- methylbuta- 1 ,3-die
  • alkenylene refers to the same residues as alkenyl, but having bivalency.
  • Particular aikenylene groups are those having 2 to 20 carbon atoms (a“C2-C20 aikenylene”), having 2 to 10 carbon atoms (a“C2-C10 aikenylene”), having 6 to 10 carbon atoms (a“Ce-Cio aikenylene”), having 2 to 6 carbon atoms (a“C2-C6 aikenylene”), 2 to 4 carbon atoms (a“C2-C4 alkenylene”) or 2 to 3 carbon atoms (a“C2-C3 alkenylene”).
  • Alkynyl refers to and includes, unless otherwise stated, an unsaturated linear (2. e. , unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula CoC) and having the number of carbon atoms designated (i.e. , C2-C10 means two to ten carbon atoms).
  • Particular alkynyl groups are those having 2 to 20 carbon atoms (a“C2- C20 alkynyl”), having 6 to 10 carbon atoms (a“Ce-Cio alkynyl”), having 2 to 8 carbon atoms (a“C 2 ⁇ Cs alkynyl”), having 2 to 6 carbon atoms (a“C2-C6 alkynyl”), or having 2 to 4 carbon atoms (a“C2-C4 alkynyl”).
  • alkynyl group examples include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-l-ynyl, prop-2-ynyi (or propargyl), but-l-ynyl, but-2- ynyl, but-3-ynyl, and the like.
  • Alkynylene refers to the same residues as alkynyl, but having bivalency .
  • Particular alkyny lene 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“Ce-Cio alkynylene”), having 2 to 6 carbon atoms (a“Ci-Ce alkynylene”), 2 to 4 carbon atoms (a“C2-C4 alkynylene”) or 2 to 3 carbon atoms (a“C2-C3 alkynylene”).
  • alkynylene examples include, but are not limited to, groups such as ethynylene (or acetylenylene) (-CoC ⁇ ), propynylene (-OCCH2-), and the like.
  • Cycloalkyl refers to and includes, unless otherwise stated, saturated cyclic univalent hydrocarbon structures, having the number of carbon atoms designated (i.e., C3-C10 means three to ten carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. , 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 having from 3 to 8 annular carbon atoms (a "Cs-Cs cycloalkyl"), having 3 to 6 annular carbon atoms (a“C3-C6 cycloalkyl”), or having from 3 to 4 annular carbon atoms (a "C3-C4 cycloalkyl”).
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepty!, norbomyl, and the like.
  • Cycloaikylene refers to the same residues as cycloalkyl, but having bivalency. Cycloaikylene can consist of one ring or multiple rings which may be fused, spiro or bridged, or combinations thereof. Particular cycloaikylene groups are those having from 3 to 12 annular carbon atoms.
  • a preferred cycloaikylene is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "Cr-Cg cycloaikylene”), having 3 to 6 carbon atoms (a“C3 ⁇ Ce cycloaikylene”), or having from 3 to 4 annular carbon atoms (a "C 3 -C4 cycloaikylene”).
  • Examples of cycloaikylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, and the like.
  • a cycloaikylene may atach to the remaining structures via the same ring carbon atom (e.g., 1,1- cyclopropylene) or different ring carbon atoms (e.g., 1,2-cyclopropylene).
  • the connecting bonds may be cis or trans to each other (e.g., c/s- 1,2-cyclopropylene or trans- 1,2- cyclopropylene). If points of atachment are not specified, the moiety can include any chemically possible attachments.
  • cyclopropylene can indicate 1,1 - cyclopropylene or 1 ,2-cyclopropylene (e.g ⁇ , cis-l , 2-cyclopropylene, trans- 1,2- cyclopropylene, or a mixture thereof), or a mixture thereof.
  • Cycloalkenyl can consist of one ring, such as cyclohexenyl, or multiple rings, such as norbornenyl.
  • a preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a ( :-CN cycloalkenyi”). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cydohuienyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like.
  • Cyeloalkenyiene refers to the same residues as cycloalkenyi, but having bi valency.
  • Aryl or“Ar” as used herein refers to an unsaturated aromatic carbocydic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings are carbocydic and may or may not be aromatic, provided at least one ring in the multiple condensed ring structure is aromatic.
  • Particular aryl groups are those having from 6 to 14 annular carbon atoms (a“Ce-Cir 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 either an aromatic ring position or at a non-aromatic ring position.
  • 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.
  • arylene refers to the same residues as aryl, but having bivalency. Particular arylene groups are those having from 6 to 14 annular carbon atoms (a‘Ce-Cu arylene”).
  • Heteroaryl refers to an unsaturated aromatic cyclic group having from 1 to 14 annular carbon atoms and at least one annular 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 be carbocyclic or may contain one or more annular heteroatom and which may or may not be aromatic, provided at least one ring in the multiple condensed ring structure is both aromatic and contains at least one annular heteroatom.
  • 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.
  • particular heteroaryl groups are monocyclic aromatic 5-, 6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • particular heteroaryl groups are polycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • a heteroaryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position.
  • a heteroaryl 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.
  • a heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom.
  • Heteroarylene refers to the same residues as heteroaryl, but having bivalency.
  • leterocycle refers to a saturated or an unsaturated non-aromatic cyclic group 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 heterocyclic group may have a single ring (e.g. , pyrrolidinyl) or multiple condensed rings (e.g., decahydroisoquinolm-l -yl), which condensed rings may or may not be aromatic and which may be carbocylic or contain one or more annular heteroatoms, but which excludes heteroaryl rmgs.
  • a heterocycle comprising more than one ring may be fused, bridged or spiro, or any combination thereof.
  • one or more of the fused rings can be cycloalkyl or aryl, but excludes heteroaryl groups.
  • the heterocyclyl group may be optionally substituted independently with one or more substituents described herein.
  • Particular heterocyclyl 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 nitrogen, oxygen and sulfur.
  • heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 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.
  • heterocyclyl includes polycyclic non-aromatic rings having from I to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • Heterocyclylene refers to die same residues as heterocyclyl, but having bi valency .
  • Halo or“halogen” refers to elements of the Group 17 series having atomic number 9 to 85.
  • Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with one or more halogens, it may be referred to by using the prefix“halo,” e.g., haloaryl, haloalkyi, etc. refer to aryl and alkyl substituted with one or more halo groups, which in the case of two or more halo groups may be, but are not necessarily the same halogen.
  • a residue is substituted with more than one halogen, it m ay be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloary!, dihaloalkyl, trihaloaryl etc. refer to and and alkyl substituted with 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.
  • perhaloalkyl An alkyl group in which each hydrogen is replaced with a halo group is referred to as a“perhaloalkyl .”
  • a preferred haloalkyl, e.g., perhaloalkyl group is trifluoromethyl (-CF3).
  • perhaloalkoxy refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group.
  • An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).
  • Thiocarbonyl refers to the group C S.
  • D refers to deuterium ( 2 H).
  • Boc refers to ferf-butyloxycarhonyl.
  • HATU refers to l-[bis(dimelhylamino)methylene]-lH-l ,2,3-lriazolo[4,5- b jpy ridinium 3 -oxide hexaliuorophosphate .
  • BOP refers to benzotriazol - 1 -yloxytri s(diraetbylamino)phosphomum hexaliuorophosphate.
  • PyBOP refers to benzotriazol-l -yl-oxytripyrrolidinophosphonium
  • 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 in which the substituents may be the same of different.
  • an optionally substituted group has one substituent.
  • an optionally substituted group has two substituents.
  • an optionally substituted group has three substituents.
  • an optionally substituted group has four substituents.
  • an optionally substituted group has 1 to 2, 1 to 3, 1 to 4,
  • an optionally substituted group is unsubstituted.
  • an individual intends a mammal, including but not limited to a primate, human, bovine, horse, feline, canine, or rodent. In one variation, the individual is a human.
  • beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease, diminishing tire extent of the disease, stabilizing the di sease (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, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • treatment is a reduction of pathological consequence of fibrosis. The methods of the invention contemplate any one or more of these aspects of treatment.
  • an effective amount intends such amount of a compound of the invention which should be effective in a given therapeutic form.
  • 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 administering one or more therapeutic agents (e.g. , a compound, or 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 may be or is achieved.
  • Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
  • A“therapeutically effective amount” refers to an amount of a compound or salt thereof sufficient to produce a desired therapeutic outcome.
  • unit dosage form refers to physically discrete units, suitable as unit 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 fomis may contain a single or a combination therapy.
  • controlled release refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, with a “controlled release” formulation, administration does not result in 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, generally involving mixing the drug compound with carriers, polymers or other compounds having the desired release characteristics (e.g. , pH-dependent or non-pH-dependent solubility, different 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).
  • desired release characteristics e.g. , pH-dependent or non-pH-dependent solubility, different degrees of water solubility, and the like
  • pharmaceutically acceptable or“pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S Food and Drug Administration.
  • “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual .
  • Such salts 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 either is replaced by a metal ion, e.g. , an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • Acceptable organic bases include ethanolamme, diethanolamine,
  • Acceptable inorganic bases which can he used to prepared salts include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • Pharmaceutically acceptable salts can be prepared m 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 base or acid, respectively, and isolating the salt thus formed during subsequent purification
  • excipient means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient.
  • Vari ous substances may he embraced 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, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
  • suspending/gelling agents include, e.g., carrageenan, sodium starch glycoiate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.
  • substantially pure intends a composition that contains no more than 10% impurity, such as a composition comprising less than about 9%, 7%, 5%, 3%, 1%, 0.5% impurity.
  • composition when a composition is described as“consisting essentially of” the listed components, the composition contains the components expressly listed, and may contain other components which do not substantially affect the disease or condition being treated such as trace impurities. However, the composition either does not contain any other components which do substantially affect tire disease or condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the disease or condition being treated, the composition does not contain a sufficient concentration or amount of those extra components to substantially affect the disease or condition being treated.
  • the method contains the steps listed, and may contain other steps that do not substantially affect the disease or condition being treated, but the method does not contain any other steps which substantially affect the disease or condition being treated other than those steps expressly listed.
  • R ! is 5,6,7,8-tetrahydro ⁇ l,8 ⁇ naphthyridin ⁇ 2 ⁇ yl optionally substituted by R 4 , 1,2, 3,4- tetrahydro-l ,8-naphthyridin-2-yl optionally substituted by R 4 , 6-aminopyridin-2-yl optionally- substituted by R 4 , or (pyridin-2-yl)amino optionally substituted by R 4 ;
  • G is -C(0)R 2 or R 3 ;
  • R 2 is Ci-Ce alkyl optionally substituted by R 2a , C3-C8 cycloalkyl optionally substituted by R 2b , 3- to 12-membered heterocyclyl optionally substituted by R 2c , Ce-Cw aryl optionally substituted by R 2d , 5- to 10-membered heteroaryl optionally substituted by R 2e , -OR 2f , or
  • R 3 is Ci-C & alkyl optionally substituted by R 3a , C3-C8 cycloalkyl optionally substituted by R 3b , 3- to 12-membered heterocyclyl optionally substituted by R 3c , Ce-Cir aryl optionally substituted by R 3d , or 5- to 10-membered heteroaryl optionally substituted by R 3e ;
  • L 1 is C2-C4 alkylene optionally substituted by R 4 ;
  • L 2 is a bond or C1-C3 alkylene optionally substituted by R 4 ;
  • L 3 is C2-C4 alkylene optionally substituted by R 4 :
  • Y is a bond or C3-C5 cycloalkylene optionally substituted by Y a :
  • R 2i is Ci-Ce alkyl, C 3 -Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cir aryl, and 5- to 10-membered heteroaryl of R ⁇ ' 1 are independently optionally substituted by R 2 ‘;
  • R 2g and R 2h are each independently hydrogen, deuterium, C ⁇ -Ce alkyl,
  • each R 2a , R 2b , R 2c , R 2d , R 2® , R 21 , R 2 ⁇ *, R 3a , R 3b , R JC , R 3d , R 3e and Y a is independently oxo or R 4 ;
  • each R 4 is independently deuterium, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Cs-Cs cycloalkyl, 3- to 12-membered heterocyclyl, C6-C14 aryl, 5- to 10- membered heteroaryd,
  • Ci- Cfi alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Ci ary'l, and 5- to 10-membered heteroaryd of R 4 are independently optionally substituted by R 4a ; each R 4a is independently deuterium, halogen, oxo, -OR 8 , -NR 8 R 9 ,
  • each R 6 is independently hydrogen, deuterium, Ci-Ce alkyl, Cb-Ce alkenyl, Cr-Ce alkynyl, (b-Ce cycloalkyl, Ce-Cw aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the Ci-Ce alkyl, C2-G5 alkenyl, Cb-Ce alkynyl, Cb-Ce cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R 6 are independently optionally substituted by deuterium, halogen, oxo, -CN, -OR i0 ,
  • a compound of the formula (I), or a salt thereof wherein the carbon bearing the CO2I I and N(H)G moieties is in the“S” configuration.
  • a compound of the formula (I), or a salt thereof wherein the carbon bearing the CO2H and N(H)G moieties is in the“R” configuration.
  • Mixtures of a compound of the formula (I) are also embraced, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.
  • L 1 is unsubstituted C2-C4 alkylene.
  • L 1 is -CH2-CH2-, -CH2-CH2-CH2-, or --CH2--CH2---CH2---CH2-.
  • L 1 is --CH2--CH2- .
  • -Y- is a bond.
  • -Y - is a C3-C4 cycloalkylene.
  • Y is a C3 cycloalkylene.
  • Y is a C4 cycloalkylene.
  • L 3 are via the same carbon atom (e.g. , in another variation, the point of attachment of the C3-C4 cycloalkylene to L 2 and L 3 are via two different carbon atoms
  • the stereochemistry introduced at the C 3 -C4 cycloalkylene is trans (e.g., and in another variation, when the point of attachment of the C3-C4 cycloalkylene to L 2 and L 3 are via two different carbon atoms, the stereochemistry introduced at the C 3 -C4 cycloalkylene is cis
  • At least one of R3 ⁇ 4, R 2h , R 4 , R 4a , R 4b , R 5 , R 5a , R 6 , R 7 , R 8 , R 9 , R 10 , R n , or R i2 is deuterium.
  • -L 2 -Y-L 3 - are taken together to form a moiety selected from the group consisting of: -CH2CH2CH2-,
  • -Id-O-L 2 - Y-L 3 - are taken together to form a moiety selected from the group consisting of: .
  • -L ! -Q-L 2 ⁇ Y ⁇ L 3 - are taken together to form a moiety selected from the group consisting of: .
  • -L'-Q-lAY-L 3 - are taken together to form a moiety selected from the group consi sting of: [0081]
  • the compound of formula (!) or a salt thereof is pro vided wherein: R 1 is l,2,3,4 ⁇ tetrahydro-l,8-naphthyridin-2-yl; L !
  • R 2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haioaikyl.
  • the compound of formula (I) or a salt thereof is provided wherein: R 1 is l ,2,3,4-tetrahydro-l ,8-naphthyridin-2-yl; 1/ is -CH2CH2CH2-, Y is a bond, and L J is -CH2CH2CH2-; and G is -C(0)R 2 , wherein R 2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haioaikyl.
  • R 1 is l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl
  • L ! is -CH2CH2CH2CH2-
  • Y is a bond
  • L J is -CH2CH2-
  • G is -C(Q)R 2 , wherein R 2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haioaikyl.
  • R 1 is 1,2,3, 4-tetrahydro-l,8-naphthyridin-2-yl
  • L 1 is -CH2CH2-
  • Y is 1,3-cyclobutyl
  • L 3 is -CH2CH2-
  • G is -C(0)R 2 , wherein R 2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haioaikyl .
  • R 1 is 1 ,2,3,4-tetrahydro- l,8-naphthyridin-2-yl
  • L 1 is -CH2CH2-
  • Y is cvs-1,3- cyclobutyl
  • L 3 is -CH2CH2-
  • G is -C(0)R 2 , wherein R 2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 un saturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haioaikyl.
  • R 1 is l ,2,3,4-tetrahydro ⁇ l ,8 ⁇ naphthyridin ⁇ 2-yl
  • L 1 is -CH2CH2-
  • Y is tram- 1 ,3-cyclobutyl
  • L 3 is -CH2CH2-
  • G is -C(0)R 2 , wherein R 2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haioaikyl.
  • R 1 is l,2,3,4-tetrahydro-l,8-naphthyridin- 2-yl
  • L 1 is -CH2CH2-
  • Y is a bond
  • L 3 is -CH2CH2CH2CH2-
  • G is ---R 3 , wherein R 3 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce ha!oa!kyl.
  • R 1 is l,2,3,4-tetrahydro-l,8-naphthyridin- 2-yl
  • L 1 is -CH2CH2CH2-
  • Y is a bond
  • L 3 is -CH2CH2CH2-
  • G is -R 3 , wherein R 3 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haloalkyi.
  • R 1 is 1,2,3, 4-tetrahydro-l,8-naphthyridin- 2-yl
  • L 1 is -CH2CH2CH2CH2-
  • Y is a bond
  • L 3 is -CH2CH2-
  • G is -R 3 , wherein R 3 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI-CG alkyl, or Ci-C& haloalkyi.
  • R 1 is 1 ,2,3,4-tetrahydro-l ,8-naphthyridin- 2-yl
  • L 1 is -CH2CH2-
  • Y is 1,3-cyclobutyl
  • L 3 is -CH2CH2-
  • G is -R 3 , wherein R 3 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haloalkyi.
  • R 1 is l,2,3,4-tetrahydro-l,8-naphthyridin- 2-yl
  • L 1 is -CH2CH2-
  • Y is ds-l ,3-cyclobutyl
  • L J is -CH2CH2-
  • G is -R 3 , wherein R 3 is a six-membered heterocyclyl, and, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI -CG alkyl, or CI-CG haloalkyi.
  • R 1 is 1,2,3, 4-tetrahydro-l,8-naphthyridin- 2-yl
  • L 1 is -CH2CH2-, is irons- 1,3 -cyclobutyl
  • L 3 is -CH2CH2-
  • G is ---R 3 , wherein R 3 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI-CG alkyl, or CI-CG haloalkyi.
  • each preceding embodiment described in this paragraph a further embodiment is disclosed in which among the substitutable ring atoms in R 2 , one of: one saturated ring atom is substituted with CI-CG haloalkyi, e.g., -CF3; two aryl ring atoms are independently substituted with halogen; and 2 or 3 heteroaryl ring atoms are independently substituted with halogen or CI-CG alkyl, e.g., methyl.
  • each preceding embodiment described in this paragraph may be excluded from the compound represented by formula (I) and salts thereof.
  • the compound of formula (I) or a salt thereof is provided wherein: R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl; L ! is -CH2CH2-, Y is a bond, and L J is -CH2CH2CH2CH2-; and G is -C(0)R 2 , wherein R 2 is a six-membered heterocyclyl, axyl, or heteroaryl ring, wherein among the substitutable ring atoms in R-', 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI -CG alkyl, or CI-CG haioaikyl.
  • the compound of fonnula (I) or a salt thereof wherein: R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl; L 1 is -CH2CH2CH2-, is a bond, and L 3 is -CH2CH2CH2-; and G is -C(0)R 2 , wherein R 2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI-CG alkyl, or CI-CG haioaikyl .
  • R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl
  • L* is -CH2CH2CH2CH2-
  • Y is a bend
  • L 3 is -CH2CH2-
  • G is -C(0)R 2
  • R 2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI-CG alkyl, or CI-CG haioaikyl.
  • the compound of formula (I) or a salt thereof is provided wherein: R 1 is 5,6,7,8-tetrahydro ⁇ l,8 ⁇ naphthyridin ⁇ 2 ⁇ yl; L ! is -CH2CH2-, Y is 1,3-cyclobutyl, and L 3 is -CH2CH2-; and G is -C(0)R 2 , wherein R 2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI-CG alkyl, or CI-CG haioaikyl.
  • the compound of formula (I) or a salt thereof is provided wherein: R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl; L ’! is -CH2CH2-, Y is e/s-1,3- cyclobutyi, and L 3 is -CH2CH2-; and G is -C(0)R 2 , wherein R 2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI-CG alkyl, or CI-CG haioaikyl.
  • the compound of formula (I) or a salt thereof is provided wiierein: R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl; L 1 is -CH2CH2-, Y is tram- 1 ,3-cyclobutyl, and L 3 is -CH2CH2-; and G is -C(0)R 2 , wherein R 2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI-CG alkyl, or C I -CG haioaikyl.
  • R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl
  • L 1 is -CH2CH2-
  • Y is a bond
  • L 3 is -CH2CH2CH2CH2-
  • G is -R 3 , wherein R 3 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haloalkyl.
  • R 1 is 5,6,7,8-tetrahydro-l ,8-naphthyridin- 2-yl
  • L 1 is -CH2CH2CH2-
  • Y is a bond
  • L 3 is -CH2CH2CH2-
  • G is -R 3 , wherein R 3 is a six-membered heterocyclyl, aryl, or heteroaiyl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haloalkyl.
  • R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl
  • L 1 is -CH2CH2CH2CH2-
  • Y is a bond
  • L 3 is -CH2CH2-
  • G is -R 3 , wherein R 3 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haloalkyl.
  • R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl
  • L 1 is -CH2CH2-
  • Y is 1,3-cyclobutyl
  • L 3 is -CH2CH2-
  • G is -R 3 , wherein R 3 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI-CG alkyl, or Ci-C& haloalkyl.
  • R 1 is 5,6,7,8-tetrahydro-l ,8-naphthyridin- 2-yl
  • L 1 is -CH2CH2-
  • Y is cis- 1 ,3-cyclobutyl
  • L 3 is -CH2CH2-
  • G is -R 3 , wherein R J is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or CI-CG haloalkyl.
  • R 1 is 5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl
  • L 1 is -CH2CH2-
  • Y is fraH,v ⁇ j ,3 ⁇ eyciobutyL
  • L 3 is -CH2CH2-
  • G is -R 3 , wherein R 3 is a six-membered heterocyclyl, and, or heteroaryl ring, wherein among the substitutable ring atoms in R 2 , 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or CI-CG haloalkyl.
  • each preceding embodiment described in this paragraph a further embodiment is disclosed in which among the substitutable ring atoms in R 2 , one of: one saturated ring atom is substituted with CI-CG haloalkyl, e.g., -CF3; two and ring atoms are independently substituted with halogen; and 2 or 3 heteroaryl ring atoms are independently substituted with halogen or Ci-Cs alkyl, e.g., methyl.
  • each preceding embodiment described in this paragraph may be excluded from the compound represented by formula (I) and salts thereof.
  • the compound of formula (I) is of the formula (Ila):
  • R 2 is as defined for formula (1).
  • the compound of fonnula (I) is of the formula (lib):
  • R 3 is as defined for formula (I).
  • the compound of formula (I) is of the formula (111a):
  • R 2 is as defined for formula (I).
  • the compound of formula (I) is of the formula (Mb):
  • R 3 is as defined for formula (I).
  • the compound of formula (I) is of the formula (IVa):
  • the compound of formula (I) is of the formula (IVb):
  • R is as defined for formula (I).
  • the compound of formula (I) is of the formula (Va):
  • R 2 is as defined for formula (I).
  • the compound of formula (Va) is of the formula (Va-1):
  • R 2 is as defined for formula (I).
  • the compound of formula (Va) is of the formula (Va-2);
  • R 2 is as defined for formula (I).
  • the compound of formula (I) is of the formula (Vb):
  • the compound of formula (Vb) is of the formula (Vb-1):
  • the compound of formula (Vb) is of the formula (Vb-2):
  • R is as defined for formula (I).
  • the compound of formula (I) is of the formula:
  • the compound of formula (I) is of the formula:
  • the compound of formula (I) is of the formula:
  • the compound of formula (I) is of the formula:
  • the compound of formula (I) is of the formula:
  • the compound of formula (I) is of the formula:
  • the compound of formula (I) is of the formula:
  • the compound of formula (I) is of the formula:
  • the compound of formula (I) is of the formula:
  • the compound of formula (I) is of the formula:
  • the compound of formula (I) is of the formula:
  • the compound of formula (I) is of the formula:
  • j and k are respectively 2 and 4, 3 and 3, or 4 and 2,
  • the compound of formula (I) is of the formula:
  • the compound of formula (I) is of the formula:
  • Reference to formula (I) or any variation thereof includes reference to (11a), (11b), (Ilia), (Illb), (IVa), (IVb), (Va), (Va-1), (Va-2), (Vb), (Vb-1), (Vb-2), (GI-A-1), (II-A-2), (II- A-2i), (II-A-2ii), (P-A-la-l), (II-A-l a-2), (P- A- la-3), (TT-A-lb-1), (II-A-lb-2), (P-A-l c-l), (II-A-lc-2), (II-A-ld-1 ), (II-A-ld-2), (II-A-ld-3), (II-A-2a-l), (II-A-2a-2), (II-A-2a-3), (II-A- 2a-4), (II-A-2b-l), (II-A-2), (I
  • tire compound is selected from the group consisting of
  • the alpha-carbon of the amino acid can have either R or S absolute stereochemistry as indicated.
  • the alpha-carbon of the amino acid is in the S absolute stereochemistry.
  • the alpha-carbon of the amino acid is in the S absolute stereochemical configuration, in some embodiments such a compound is substantially isolated from the corresponding compound in which the amino acid is in the R absolute stereochemical configuration, such as when a composition comprising the compound in the S absolute stereochemical configuration comprises no more than 5% or 3% or 1% or 0.5% or 0.1 % by weight of the corresponding compound having the R absolute stereochemical configuration.
  • the alpha-carbon of the amino acid is in the R absolute stereochemistry.
  • such a compound is substantially isolated from the corresponding compound in which the amino acid is in the S absolute stereochemical configuration, such as when a composition comprising the compound in the R absolute stereochemical configuration comprises no more than 5% or 3% or 1% or 0.5% or 0.1% by weight of the corresponding compound having the S absolute stereochemical configuration.
  • a composition comprising a foregoing compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a composition comprising a mixture of a compound in winch the alpha-carbon of the amino acid is in the S stereochemical configuration and a compound in which the alpha-carbon of the amino acid is in the R stereochemical configuration.
  • a compound of formula (I), or a salt thereof wherein G is -C(0)R 2 and R 2 is Ci-Ce alkyl substituted by 0-5 R 2a groups.
  • R 2 is unsubstituted Ci-Ce alkyl (e.g., unsubstituted Cr- Ce alkyl).
  • the Ci-Ce alkyl of R 2 is straight-chain alkyl (e.g., n-butyl).
  • the Ci-Ce alkyl of R 2 is branched alkyl (e.g., iso-butyl).
  • R 2 is CI-CJ alkyl substituted by 1-5 R 2a groups, wherein each R 2a is independently selected from halogen, Ci-Ce alkyl, Ci-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cir aryl, 5- to lO-membered heteroaryl, -CN, -OR 3 , ⁇ NR 6 R 7 , -NR 3 C(0)0R 6 , and -SiCfhR 3 , wherein the Ci- Ce alkyl, (ri-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Ci4 aryl, and 5- to 10- membered heteroaryl of R 2a are independently optionally substituted by R 4a .
  • R 2 is C2-C5 alkyl substituted by 1-5 R 2a groups, wherein at least one of the R 2a groups is halogen (e.g., R 2 C5 alkyl substituted by 2-3 fluoro groups).
  • R 2 is Ci-Cs alkyl (e.g., C1-C 3 alkyl) substituted by 1-5 R 2a groups, wherein at least one of tire R 2a groups is CVCs cycloalkyl (e.g., cyclopropyl, cyclobutyl, and cyclohexyl).
  • R 2 is C1-C 3 alkyl substituted by (h-Ce cycloalkyl, wherein the Cb-Ce cycloalkyl is substituted by 0-5 groups selected from the group consisting of halogen, Ci-Ce alkyl (e.g., methyl), and -OR 5 (e.g., -OH and -OCH 3 ).
  • R 2 is Ci-Cs alkyl substituted by Cs-Ce cycloalkyl, wherein the Cs-Ce cycloalkyl unsubstituted.
  • R 2 is Ci-Cs alkyl substituted by 1-5 R 2a groups, wherein at least one of the R 2a groups is 3- to 12-membered heterocyclyl (e.g. R 2 is C; alkyl substituted by 6-membered heterocyclyl).
  • R 2 is C1-C5 alkyl substituted by 1-5 R 23 groups, wherein at least one of the R 2a groups is Ce- C14 aryl, wherein the Ce-Cw aryl is independently optionally substituted by halogen or Ci-Ce alkyl substituted by 0-5 halogen (e.g., R 2a is unsubstituted phenyl or phenyl substituted by 1-5 halogen.
  • R 2 is C2-C5 alkyl (e.g., Cs alkyl) substituted by 1-5 R 2a groups, wherein at least one of the R 2a groups is 5- to 10-membered heteroaryi substituted by 0-5 R 4a groups (e.g., R 2a is unsubstituted pyridinyl).
  • R 2 is C1-C5 alkyl substituted by 1-5 R 23 groups, wherein at least one of the R 2a groups is -OR 5 , wherein each R 5 is independently selected from hydrogen, Ci-Ce alkyl, and Ce-Cu aryl (e.g.
  • R 5 is C&-Ci4 aryl substituted by 0-5 halogen).
  • R 2 is Ci ⁇ Cs alkyl substituted by 1-5 R 2a groups, wherein at least one of the R 2a groups is -CN, -NR 6 R 7 , -NR 5 C(0)0R 6 , or -S(0)2R 5 .
  • R 2 is C1-C5 alkyl substituted by 2-5 R 2a groups, wherein each R 2a is independently selected from halogen, Ci-Ce alkyl, Cs-Cs cycloalkyl, 5- to 10- membered heteroaryl, Ce-Ci4 aryl, -CN, -OR 5 , and -NR 3 C(0)0R 6 .
  • R 2 is C1-C5 alkyl substituted by 2-5 R 2a groups, wherein at least one R 2a group is phenyl substituted by 0-5 halogen and at least one R 2a group is OR 5 , wherein each R 5 is independently selected from hydrogen and Ci-Ce alkyl .
  • C(0)R 2 and R 2 is selected from the group consisting of:
  • a compound of formula (I), or a salt thereof wherein G is -C(0)R 2 and R 2 is C3-C cycloalkyl substituted by 0-5 R 2b groups.
  • the Ci-Cs cycloalkyl of R 2 is monocyclic.
  • the Cb-Cs cycloalkyl of R 2 is bicyclic (e.g., fused, spiro, or bridged).
  • R 2 is unsubstituted CiwCs cycloalkyl (e.g. , bicycle[2.2.2]octanyl).
  • R 2 is Cb-Cs cycloalkyl substitu ted by 1 -5 R 2b groups, wherein each R 2b is independently selected from halogen, Ci-Ce alkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, and -OR 5 .
  • R 2 is C3-C6 cycloalkyl (e.g. , cyclopropyl or cyclohexyl) substituted by 1-5 R 2b groups, wherein at least one of the R 2b groups is halogen (e.g., fluoro).
  • R 2 is Ci-Ce cycloalkyl substituted by 1-5 R 2b groups, wherein at least one of the R 2b groups is Ci-Ce alkyl, wherein the Ci-Cs alkyl of R 2b is substituted by 0-5 R 4a groups (e.g., R 2b is C1-C2 alkyl substituted by 1-5 R 4a groups, wherein each R 4a groups is independently selected from phenyl substituted by 0-5 halogen and 6- membered heteroaryl substituted by 0-5 halogen).
  • R 2 is Cb-Cs cycloalkyl substituted by 1-5 R ib groups, wherein at least one of the R 2b groups is 3- to 12-membered heterocyclyl (e.g., tetrahydro-2 f-pyranyl or benzodioxo!yl).
  • R 2 is C3-C4 cycloalkyl substituted by 1 -5 R 2b groups, wherein at least one of the R 2b groups is Ce-Cw aryl substituted by 0-5 R 4a groups, wherein each R 4a is independently selected from halogen, Ci-Ce alkyl, and -OR 8 (e.g., R 2b is unsubstituted phenyl or R 2b is phenyl substituted by fluoro, methyl, tert-butyl, or -OCF3).
  • R 2b is unsubstituted phenyl or R 2b is phenyl substituted by fluoro, methyl, tert-butyl, or -OCF3
  • R 2 is C3-C7 cycloalkyl substituted by 1-5 R 2b groups, wherein at least one of the R 2b groups is 5- to 10-membered heteroaryl (e.g., pyridinyl or isoquinolinyl).
  • R 2 is C3-C& cycloalkyl substituted by 2-5 R 2b groups, wherein each R 2D is independently selected from halogen (e.g., fluoro), Ce-Cir aryl (e.g., phenyl), and -OR 5 (e.g., -OH).
  • R 2 is C3-C6 cycloalkyl substituted by 2-5 R 2b groups, wherein at least one R 2b group is halogen (e.g., fluoro) and at least one R 2b group is phenyl substituted by 0-5 Ci-Ce alkyl (e.g., -CH3).
  • halogen e.g., fluoro
  • Ci-Ce alkyl e.g., -CH3
  • C(0)R 2 and R 2 is selected from the group consisting of:
  • n 0, 1, 2, or 3.
  • n is 0.
  • n is 1.
  • n is 2.
  • n is 3.
  • a compound of formula (I), or a salt thereof wherein G is -C(0)R 2 and R 2 is 3- to 12-membered heterocyclyl substituted by 0-5 R 2c groups.
  • the 3- to 12-membered heterocyclyl of R 2 is monocyclic.
  • the 3- to 12-membered heterocyclyl of R 2 is bicyclic (e.g., fused, spiro, or bridged).
  • R 2 unsubstituted 4- to 10-membered heterocyclyl (e.g., azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyi, tetrahydropyranyl, oxabicy clohexanyl, oxabicy clooctanyl , tetrahydro-2H-thiopyranyl, morpholinyl,
  • heterocyclyl e.g., azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyi, tetrahydropyranyl, oxabicy clohexanyl, oxabicy clooctanyl , tetrahydro-2H-thiopyranyl, morpholinyl,
  • R 2 is 3- to 12-membered heterocyclyl substituted by 1-5 R 2c groups, wherein each R 2c is independently selected from oxo, halogen, Ci-Ce alkyl, Ce- Ci 4 aryl, 5- to 10-membered heteroaryl, -CN, -OR 5 , -C(0)R 5 , -C(Q)QR 5 , and -S(0)2.R 3
  • R 2 is 4- to 6-membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, or azetidinyl) substituted by 1-5 R 2c groups, wherein at least one of the R 2c groups is Ci-Ce alkyl, wherein the Ci-Ce alkyl of
  • R 2c is C1-C2 alkyl substituted by 1-5 R 4a groups, wherein each R 4a groups is independently selected from halogen; phenyl substituted by 0-5 halogen; 6-membered heteroaryl (e.g., pyridinyl or pyrimidimy!) substituted by 0-5 halogen; and ⁇ NR 8 C(0)0R 10 (e.g. -NHC(O)O-r-butyl).
  • R 2 is 4- to 6-membered heterocyclyl substituted by 1-5 R 2c groups, wherein at least one of the R 2c groups is unsubstituted Ce-Cu aryl (e.g., phenyl).
  • R 2 is 4- to 6-membered heterocyclyl (e.g., 5- membered heterocyclyl) substituted by 1-5 R 2c groups, wherein at least one of the R 2c groups is 5- to 10-membered heteroaryl substituted by 0-5 Ci-Ce alkyl (e.g., R 2c is pyrazolyl substituted by -CH3).
  • R 2 is 4- to 6-membered heterocyclyl substituted by 1-5 R 2c groups, wherein at least one R 2c group is ⁇ C(0)R 5 , -C(())()R 3 , or -S(0)2R 3 , wherein each R 3 is independently Ci-Ce alkyl.
  • R 2 is 4- to 6-membered heterocyclyl (e.g., 1,2-dihydropyridinyl) substituted by 1-5 R 2c groups, wherein at least one R 2c group is oxo.
  • R 2 is 4- to 6-membered heterocyclyl substituted by 2-5 R 2c groups, wherein each R 2c is independently selected from halogen, Ci-Ce alkyl, -C(Q)R 5 ,
  • R is 4- to 6-membered heterocyclyl substituted by 2-5 R 2c groups, wherein at least one R 2c group is Ci-Ce alkyl substituted by 0-5 halogen and at least one R-' c group is -C(0)R 5 or -C(0)OR 3 .
  • R 2 is azetidinyl, pyrrohdinyi, pipendinyl, oxetanyl, tetrahydrofuranyi, tetrahydropyranyl, oxabicyclohexanyl, oxabicy clooctanyl, tetrahydro-2H- thiopyranyl, morpholinyl, or benzodioxanyl, each of which is substituted by 0-5 R-' c groups.
  • G is azetidinyl, pyrrohdinyi, pipendinyl, oxetanyl, tetrahydrofuranyi, tetrahydropyranyl, oxabicyclohexanyl, oxabicy clooctanyl, tetrahydro-2H- thiopyranyl, morpholinyl, or benzodioxanyl, each of which is substituted by 0-5 R-
  • C(Q)R Z and R 2 is selected from the group consisting of:
  • n is 0, 1, 2, or 3
  • n is 0.
  • n is 1
  • n is 2.
  • n is 3.
  • one of the R 2c groups can replace the hydrogen atom of the -N(H)- moiety (e.g., n is ).
  • a compound of formula (I), or a salt thereof wherein G is -C(0)R 2 and R 2 is Ce-Cir aryl substituted by 0-5 R 2d groups.
  • R 2 is unsubstituted Ce-Cio aryl (e.g, phenyl, indanyl, or 1,2,3,4-tetrahydronaphthalenyl).
  • R 2 is Ce-Cio aryl substituted by 1 -5 R 2d groups, wherein each R 2d is independently selected from halogen, Ci-Ce alkyl, Cs-Cs cycloalkyl, 3- to 12-membered heterocyclyl, 5- to lO-membered heteroaryl, -CN, and -OR 5 , wherein the Ci-Ce alkyl, C3-Cs cycloalkyl, 3- to 12-membered heterocyclyl and 5- to lO-membered heteroaryl of R 2d are each independently substituted by 0-5 halogen, Ci-Ce alkyl or OR 8 .
  • R 2 is Ce-Cio aryl substituted by 1-5 R 2d groups, wherein at least one of the R 2d groups is halogen (e.g. , fluoro or ehloro).
  • R 2 is Ce-Cio aryl substituted by 1 -5 R 2d groups, wherein at least one of the R 2d groups is Ci-Ce alkyl, wherein the Ci-Ce alkyl of R 2a is substituted by 0-5 R 4a groups (e.g., R 2d is -CH ).
  • R 2d is C1-C2 alkyl substituted by 1-5 R 4a groups, wherein each R 4a groups is independently selected from halogen and OR 8 (e.g., R 2d is -CHblQH), or -CF3).
  • R 2 is Ce-Cio aryl (e.g, phenyl) substituted by 1-5 R 2d groups, wherein at least one of the R 2d groups is Cb-Ce cycloalkyl (e.g., cyclopropyl).
  • R 2 is Ce-Cio aryl (e.g, phenyl) substituted by 1-5 R 2d groups, wherein at least one of the R 2d groups is 6-membered heterocye!yl (e.g , morpholinyl).
  • R 2 is Ce-Cio aryl (e.g, phenyl) substituted by 1-5 R 2d groups, wherein at least one of the R 2d groups is 5- to 6- membered heteroaryl (e.g., pyrazolyl, thiazoiyl, or pyridinyl), w'herein the heteroaryl of R 2d is substituted by 0-5 Ci-Ce alkyl groups (e.g., -CHs).
  • heteroaryl e.g., pyrazolyl, thiazoiyl, or pyridinyl
  • R 2 is Ce-Cio and (e.g, phenyl) substituted by 1 -5 R 2a groups, wherein at least one of the R 2d groups is -OR 5 , wherein each R 5 is independently selected from Ci-C 2 alkyl substituted by 0-5 groups selected from halogen (e.g., fluoro) and -OR 10 (e.g., -0( 1 b).
  • R 2 is Ce-Cio and (e.g, phenyl) substituted by 2-5 R 2d groups, w'herein each R-' a is independently selected from halogen, Ci-Ce alkyl, -CN, and -OR 5 .
  • R 2 is Ce-Cio aryl (e.g, phenyl) substituted by 2-5 R 2d groups, wherein at least two of the R 2d groups are halogen (e.g., fluoro or chloro).
  • R 2 is Ce-Cio aryl (e.g, phenyl) substituted by 2-5 R 2d groups, w'herein at least one of the R 2d groups is Ci-Ce alkyl and at least one of the R 2d groups is selected from the group consisting of halogen, -CN, and -OR 5 in another aspect of the foregoing embodiment, R 2 is phenyl, indanyl, or 1 , 2,3,4- tetrahydronaphthalenyl, each of which is substituted by 0-5 R 2d groups.
  • C(0)R 2 and R 2 is selected from the group consisting of: , wherein R 2d is as defined for formula (I), and n is 0, 1,
  • n is 0. In another variation, n is 1 In another variation, n is 2. In yet another variation, n is 3.
  • a compound of formula (I), or a salt thereof wherein G is -C(0)R 2 and R 2 is 5 - to 10-membered heteroaryl substituted by 0-5 R 2e groups.
  • R 2 is un substituted 5- to 10- membered heteroaryl (e g., pyridinyl, pyrrolopyridinyl, quino!inyl, or 4,5,6,7-tetrahydro- indazolyS).
  • R 2 is 5- to lO-membered heteroaryl substituted by 1-5 R 2e groups, wherein each R 2s is independently selected from halogen, Ci-Ce alkyl, and -OR 5 .
  • R 2 is 5- to lO-membered heteroaryl (e.g., pyridinyl) substituted by 1 -5 R 2e groups, wherein at least one of the R 2e groups is halogen.
  • R 2 is 5- to 10- membered heteroaryl (e.g., pyridinyl, pyrimidinyl, pyrrolopyridinyl, or indazolyl) substituted by 1-5 R 2e groups, wherein at least one of the R 2e groups is Ci-Cr alkyl, wherein the Ci- C.4 alkyl of R 2e is substituted by 0-5 halogen groups (e.g. R 2e is -CHs or -CFri).
  • heteroaryl e.g., pyridinyl, pyrimidinyl, pyrrolopyridinyl, or indazolyl
  • R 2 is 5- to lO-membered heteroaryl substituted by 2-5 R 28 groups, wherein each R 28 is independently selected from halogen, CI-CG alkyl, and -CN.
  • R 2 is 5- to 10-membered heteroaryl substituted by 2-5 R 28 groups, wherein at least two of the R 2e groups are halogen.
  • R 2 is 5- to lO-membered heteroaryl substituted by 2-5 R 2e groups, wherein at least two of the R 2e groups are Ci-Ce alkyl.
  • R 2 is 5- to 10-membered heteroaryl (e.g.
  • R 2 is 5- to 10-membered heteroaryl (e.g., pyridinyl or pyrimidinyl) substituted by three -Ctb groups.
  • R 2 is 5- to 10-membered heteroaryl (e.g., pyridinyl or pyrimidinyl) substituted by two -Ctb groups and one halogen group.
  • R 2 is pyrazolyl, pyridyl, pyrimidinyl, indazolyl, pyrrolopyridinyl, quinolinyl, or 4,5,6,7-tetrahydro-indazolyl, each of which is substituted by 0-5 R 28 groups.
  • C(Q)R 2 and R 2 is selected from the group consisting of:
  • n is 0, 1, 2, or 3.
  • n is 0.
  • n is 1.
  • n is 2
  • n is 3.
  • R 2f is selected from the group consisting of Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cir and, and 5- to lO-membered heteroaryl.
  • Also provided in another embodiment is a compound of formula (I), or a salt thereof, wherein G is -C(0)R 2 , R 2 is -GR 2i , and R 2f is Ci-Ce alkyl substituted by 0-5 R 2 ‘ groups.
  • R 21 is unsubstituted Ci-Ce alkyl.
  • R 2f is Ci-Ce alkyl substituted by 1-5 R 2 groups, wherein each R 21 is independently selected from the group consisting of halogen, Ci-Ce alkyl, C 3 -C.8 cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cw aryl, 5- to 10-membered heteroaryl, -OR 5 , ⁇ NR 5 C(0)R 6 , and -NR 5 C(0)0R 6 , wherein the Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Ci aiyl, and 5- to 10-membered heteroaryl of R 21 is substituted by 0-5 groups selected from the group consisting of halogen, -CN, -OR 8 , and Ci- C fi alkyl optionally substituted by halogen.
  • R 2f is Ci-Ce alkyl substituted by 1-5 R 2 groups, wherein at least one of the R 2 ' groups is halogen. In another aspect of the foregoing embodiment, R 2f is Ci-Ce alkyl substituted by 1-5 R 21 groups, wherein at least one of the R 21 groups is phenyl. In another aspect of the foregoing embodiment, R 2f is Ci-Ce alkyl substituted by 1-5 R 2! groups, wherein at least one of the R 2 ' groups is -NR 5 C(0)OR b , wherein R 5 is hydrogen and R 6 is Ci-Ce alkyl (e.g, R 21
  • R 2t is Ci-Ce alkyl substituted by 1-5 R 21 groups, wherein at least one of the R 2i groups is ⁇ NR 5 C(0)R 6 , wherein R 5 is hydrogen and R 6 is Ci-Ce alkyl (e.g., R 2 * is -NHC(0)CH3).
  • C(0)R 2 and R 2 is selected from the group consisting of:
  • R 2 ' is as defined for formula (I).
  • a compound of formula (I), or a salt thereof wherein G is -C(0)R 2 , R 2 is -OR 2 and R 2f is Cs-Cs cycloalkyl substituted by 0-5 R 21 groups.
  • R 2l is unsubstituted Cs-Cs cycloalky] (e.g., cyclopentyl, cylcohexyl, or spiro[2.3]hexanyl).
  • R 2f is C3-C8 cycloalkyl substituted by 1-5 R 2s groups, wherein each R 21 is independently selected from the group consisting of halogen, Ci-Ce alkyl, Ci-Ce alkynyl, Ce- C 14 and, and 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C -Ce alkynyl, Ce- Ci4 aryl, and 5- to lO-membered heteroaryl of R 2i are substituted by 0-5 groups selected from the group consisting of Ci-Ce alkyl and Ce-Cu aryl.
  • R 2f is Cs-Ce cycloalkyl (e.g., cyclopropyl or cyclobutyl) substituted by 1 -5 R 21 groups, wherein at least one R 21 group is Ci alkyl.
  • R 2t is C Ce cycloalkyl substituted by 1-5 R 21 groups, wherein at least one R 21 group is C2 alkynyl substituted by 0-1 phenyl group.
  • R 2f is Ci-Ce cycloalkyl substituted by 1-5 R 2s groups, wherein at least one R 2 ' group is phenyl substituted by 0-3 Ci-Ce alkyl groups or is pyrazolyl substituted by 0-3 Ci- Ce alkyl groups, which Ci-Ce alkyl groups on phenyl or pyrazolyl of R 2s may he the same or different
  • R 2i is as defined for formula (I) and n is 0, 1, or 2. In one variation, n is 0. In another variation, n is 1. In yet another variation, n is 2.
  • Also provided in another embodiment is a compound of fonnula (I), or a salt thereof, wherein G is -C(0)R 2 , R 2 is -QR 2f , and R 2t is 3- to 12-membered heterocyclyl substituted by 0-5 R 2 ‘ groups.
  • R 2f is unsubstituted 3- to 12-membered heterocyclyl (e.g. , azetidinyl or pyrrol idinyl).
  • R 2f is 3- to 12-membered heterocyclyl substituted by 1-5 R 2 ‘ groups, wherein each R 2 ’ is independently selected from the group consisting of Ci- Ce alkyl, Cr-Ce alkynyl, Ce-Cu aryl, -C(Q)R 3 , -C(0)OR 5 , and -S(Q)2R 5 .
  • R 2f is 3- to 12-membered heterocyclyl substituted by 1-5 R 2 * groups, wherein at least one R 2 ' group is Ci-Ce alkyl or Ci-Ce alkynyl, each of which is unsubstituted or substituted by a phenyl group.
  • R 2f is 3- to 12-membered heterocyclyl substituted by 1-5 R 21 groups, wherein at least one R 2! group is Ce-Cr aryl (e.g., phenyl) substituted by 0-5 R 4a groups, wherein each R 4a is independently selected from the group consisting of halogen and Ci-Ce alkyl (e.g., isopropyl).
  • R 21 is 3- to 12-membered heterocyclyl (e.g., azetidinyl or pyrroiidinyl) substituted by 1-5 R 21 groups, wherein at least one R 21 group is -C(0)R 5 , wherein R 5 is Ci-Cs alkyl (e.g, R 2i is -C(0)CH3).
  • R 2f is 3- to 12-membered heterocyclyl substituted by 1-5 R 21 groups, wherein at least one R 21 group is ⁇ C(0)OR 5 , wherein R 3 is Ci-Ce alkyl (e.g. , R 2 ' is - C(O)O-t-butyd).
  • R 2f is 3- to 12-membered heterocyclyl (e.g., azetidinyi or pyrrolidinyi) substituted by 1-5 R 2 ‘ groups, wherein at least one R 21 group is -S(0)2R 5 , wherein R 5 is Ci-Ce alkyl (e.g., R 21 is -S(0)2GHb).
  • R 2f is 3- to 12-membered heterocyclyl substituted by 2-5 R 21 groups, wherein at least one R 21 group is -C(0)R 5 , -C(0)OR 5 , or -S(0)2R 5 , wherein R 5 is Ci-Ce alkyl (e.g., R 3 is - CHs or t-butyl).
  • R 21 is azetidinyi, pyrrolidinyi, or tetrahydropyranyl, each of which is optionally substituted by 0- 5 R 2 ’.
  • C(0)R 2 and R 2 is selected from the group consisting of:
  • R 2i is as defined for formula (I) and n is 0, 1, or 2. In one variation, n is 0. In another variation, n is 1. In yet another variation, n is 2. In the above structures that depict an -N(H)- moiety and n is 1 or 2, it is understood that one of the R 21 groups can replace the hydrogen
  • R 21 is unsubstituted C&-C14 aryl (e.g. , indanyl or l ,2,3,4-tetrahydronaphthaienyi).
  • C(Q)R 2 and R 2 is selected from the group consisting of:
  • R 21 is as defined for fonnula (I) and n is 0, 1 , or 2. In one variation, n is 0. In another variation, n is 1. In yet another variation, n is 2. [0130] Also provided in another embodiment is a compound of formula (1), or a salt thereof, wherein G is -C(Q)R 2 , R 2 is -QR 2i , and R 2f is 5- to lO-membered heteroaryl substituted by 0-5 R 2 ⁇ 1 groups. In another aspect of the foregoing embodiment, R 21 is unsubstituted 5- to 10-membered heteroaryl.
  • Also provided in another embodiment is a compound of formula (I), or a salt thereof, wherein G is -C(0)R 2 and R 2 is -NR 2g R 2h .
  • R 2g is hydrogen and R 2h is Ci-Ce alkyl substituted by 0-5 halogen.
  • R 2g is Ci-Ce alkyl substituted by 0-5 halogen and R 2h is Ci-Ce alkyl substituted by 0-5 halogen.
  • R 2 is selected from the group consisting of:
  • C(0)R 2 and R 2 is selected from the group consisting of:
  • R 3 is 5- to 10-membered heteroaryl (e.g., pyrimidinyl or quinazolinyl) substituted by 0-5 R 3e groups, wherein each R 3e group is independently selected from halogen; Ci-Ce alkyl optionally substituted by halogen; 5- to 10-membered heteroaryl optionally substituted by halogen or Ci-Ce alkyl; and Ci-Ce alkoxy.
  • R 3 is unsubstituted 5- to 10-membered heteroaryl.
  • R 3 is 5- to 10-membered heteroaryl substituted by 1-5 R 3e groups, wherein each R 3s group is independently selected from halogen, Ci-C& alkyl, and C&-C14 aryl.
  • R 3 is 5- to 10-membered heteroaryl substituted by 1 -5 R 3e groups, wherein at least one R 3e group is halogen.
  • R 3 is 5- to 10-membered heteroaryl substituted by 1-5 R Je groups, wherein at least one R 3e group is C1-C4 alkyl.
  • R 3 is 5- to 10-membered heteroaryl substituted by 1-5 R 3e groups, wherein at least one R 3e group is phenyl.
  • R 3 is 5- to 10-membered heteroaryl substituted by 2-5 R 3e groups, wherein at least one R 3e group is Ci-Ce alkyl, and wherein at least one R 3e group is CS-CM aryl.
  • R 3 is selected from the group consisting of:
  • each R 3e is independently R 4 .
  • the - moiety is present as shown and the structure it substituted by at least one R 3e group, it is understood that one of the R 3e groups can replace the hydrogen atom of the -N(H)- moiety
  • wiierein G is R 3 and
  • R 3 is selected from the group consisting of:
  • R 3 is selected from the group consisting of:
  • R 3 is selected from the group consisting of:
  • a compound of formula (I), or a salt thereof wherein G is selected from the group consisting of: [0142]
  • a compound of formula (I) or a salt thereof, wherein the compound has any one or more of the following features:
  • CI-CG alkyl optionally substituted by R 23 , such as methyl, ethyl,
  • heterocyciyl optionally substituted by R 2e , such as 4- to 6-membered heterocyciyl containing 1 or 2 heteroatoms selected from O and N (e.g., azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl), each of which is substituted by 0-5 R 2c groups;
  • R 2S 5- to 10-membered heteroaryl optionally substituted by R 2S , such as pyridinyl, pyrimidinyl, indazolyl, or qumolmyl, each of which is substituted by 0-5 R 2e groups;
  • each R 2a , R 2b , R 2d , and R 2s is independently R 4 , R 2c is oxo or R 4 , and R 4 is halogen, Ci-C& alkyl, Cs-Cs cycloalkyl, 3- to 12-membered heterocyciyl, Ce-CA and, 5- to 10-membered heteroaryl, -CN, -OR 3 , -C(0)R 5 , -C(0)OR 5 , -C(0)NR 6 R 7 , -NR 5 C(0)0R 6 , or -S(0) 2 R 5 , wherein the Ci-Ce alkyl, CVCs cycloalkyl, 3 ⁇ to 12-membered heterocyclyl, Cb- C14 aryl . and 5- to 10-membered heteroaryl of R 4 are independently optionally substituted by R 43 , wherein R 4a is halogen, -OR*,
  • R 8 is hydrogen or Ci-Ce alkyl optionally substituted by halogen
  • R 9 is hydrogen
  • R 10 is Ci-Ce alkyl optionally substituted by halogen
  • Ci-Cb alkyl optionally substituted by R Ja , such as methyl or ethyl, each of which is substituted by 1 R 3a group, wherein R 3a is pheny l or quinazolinyl; or
  • R 3e 5- to 10-membered heteroaryl optionally substituted by R 3e , such as pyrimidinyl, quinazolinyl, or pyrazolopyrimidinyl, each of which is substituted by 0-5 R 3e groups;
  • (1) and (11) apply, and G is -C(0)R 2 .
  • (I) and (II) apply, and G is R 3
  • (I) and (II) apply, G is - C(Q)R 2 , and (i) applies.
  • (I) and (II) apply, G is -C(Q)R 2 , and (ii) applies.
  • (1) and (II) apply, G is -C(0)R 2 , and (iii) applies.
  • (I) and (II) apply, G is -C(0)R 2 , and (iv) applies.
  • G is -C(0)R 2 , and (v) applies.
  • (I) and (II) apply, G is R 3 , and (vi) applies.
  • (I) and (II) apply, G is R 3 , and (vii) applies.
  • R 2 is Ci-Ce alkyl optionally substituted by R 23 , Ci-Cs cycloalkyl optionally substituted by R 2b , 3- to 12-membered heterocyclyl optionally substituted by R 2c , Cb-Ci4 aryl optionally substituted by R 2d , or 5- to !Q-membered heteroaryl optionally substituted by R 2e , wherein each R 2a , R 2b , R 2c , R 2a , and R 2e is independently R 4 , wherein each R 4 is
  • each R 4a is independently halogen, -OR 8 , -NR 8 R 9 , -C(0)0R 8 , -NR 8 C(0)0R 10 , -CN, 5- to 10-membered heteroaryl, Ce- Ci4 aryl, or Ci-C& alkyl, wherein R 8 , R 9 , and R 10 are as defined for formula (I), and n is 0, 1, or 2. In one variation, n is 0. In another variation, n is 1. In yet another variation, n is 2.
  • G is - C(0)R 2
  • R 2 is Ci-Ce alkyl optionally substituted by R 2a , Ca-Cs cycloalkyl optionally substituted by R 20 , 3- to 12-membered heterocyclyl optionally substituted by R 2c , Ce-Cir aryl optionally substituted by R 2d , or 5- to 10-rnernbered heteroaryl optionally substituted by R 2s , wherein each R 2a , R 2b , R 2c , R 2d , and R 2e is independently R 4 , wherein each R 4 is
  • the moiety ' can be attached to the rest of the structure at any available position.
  • 3-chloro-5-methylpyridinyl may be attached to the rest of the structure at the 2-, 4-, or 6-position (i.e., 3-chloro-5- methylpyridin-2-yl, 3-chioro-5-methylpyridin-4-yl or 3-chloro-5-methylpyridin-6-yl, respectively).
  • R 2 and R 3 groups described herein are shown as attached at specific positions (e.g., pyrimid-4-yl, quinazolin-4-yl, or isoquinolin-l-yl) but they can also be attached via any other available valence (e.g., pyrimid-2-yl, quinazolin-2-yl, or isoquinolin-3- yl, respectively).
  • Table 2 Additional representative compounds are shown in Table 2 (FIG. 1).
  • a compound selected from the compounds depicted in Table 2 or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof ⁇ , or a salt thereof.
  • the compound is a salt of a compound selected from the compounds depicted in Table 2, or a stereoisomer thereof.
  • The“flat” versions of all compounds depicted in Table 2 are also contemplated in this disclosure, including flat versions of any specific stereoisomeric forms in the Table.
  • Compound 185 is a specific stereochemical form of Compound 185, in particular the form produced by Example 365.
  • the compound detailed herein is selected from the group consisting of:
  • the compound detailed herein is selected from the group consisting of: N-(2-chloro-3-fluorobenzoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserine; N-(I -methy]-lH-indazole-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)homoserine; N-(4,4-difluorocyclohexane-l-carbonyl)-0-(4-(5, 6,7,8- tetraliydro-l,8-naphthyridin ⁇ 2-yl)butyl)homoserine; N-pentanoyl-0-(4-(5,6,7,8-tetrahydro- l,8-
  • a composition such as a pharmaceutical composition
  • the composition comprises a compound selected from the group consisting of one or more of the compounds depicted in Table 1 , or a stereoisom er thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof.
  • the composition comprises a compound selected from the group consisting of a salt of one or more of the compounds depicted in Table 1
  • the composition is a
  • composition that further comprises a pharmaceutically acceptable carrier
  • a composition such as a pharmaceutical composition
  • the composition comprises a compound selected from the group consisting of one or more of the compounds depicted in Table 2, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof.
  • the composition comprises a compound selected from the group consisting of a salt of one or more of the compounds depicted in Table 2.
  • the composition is a
  • composition that further comprises a pharmaceutically acceptable carrier
  • the invention also includes all salts of compounds referred to herein, such as pharmaceutically acceptable salts.
  • the invention also includes any or all of the
  • stereochemical forms including any enantiomeric or diastereorneric forms, and any tautomers or other forms of the compounds described. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of a compound depicted. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also described and embraced by the invention. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. It is also understood that prodrugs, solvates and metabolites of the compounds are embraced by this disclosure.
  • compositions comprising a compound of the in v ention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof.
  • Compositions comprising a mixture of compounds of the invention in any ratio are also embraced by the invention, including mixtures of two or more stereochemical forms of a compound of the inv ention in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced.
  • the N-oxides are also provided and described.
  • Compounds described herein are anb ⁇ integrin inhibitors. In some instances, it is desirable for the compound to inhibit other integrins in addition to anb6 integrin. In some embodiments, the compound inhibits anb ⁇ integrin and one or more of anb ⁇ , anb3, anb5, a2b1, a3b1, a ⁇ b ⁇ integrin, a7b1 and a 11 b 1. In some embodiments, the compound inhibits anb ⁇ integrin and anb ⁇ integrin. In some embodiments, the compound inhibits anb ⁇ integrin, anb3 integrin and anb5 integrin. In some embodiments, the compound inhibits anb6 integrin and a2b1 integrin.
  • the compound inhibits anb ⁇ integrin, a2b1 integrin and a3b1 integrin. In some embodiments, the compound inhibits anb ⁇ integrin and a ⁇ b ⁇ integrin. In some embodiments, the compound inhibits anb6 integrin and a7b1 integrin. In some embodiments, the compound inhibits anb6 integrin and a ⁇ Ib ⁇ integrin.
  • the compound is a selective anb ⁇ integrin inhibitor. In some embodiments, the compound does not inhibit substantially a4b1, anb8 and/or a2b3 integrin. In some embodiments, tire compound inhibits anb6 integrin but does not inhibit substantially a4b1 integrin. In some embodiments, the compound inhibits anb ⁇ integrin but does not inhibit substantially anb8 integrin. In some embodiments, the compound inhibits anb6 integrin but does not inhibit substantially a2b3 integrin. In some embodiments, the compound inhibits anb ⁇ integrin but does not inhibit substantially the anb8 integrin and the a4b!
  • the invention also intends isotopically-labeled and/or isotopically-enriched forms of compounds described herein.
  • the compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or variations thereof described herein, where one or more atoms are replaced by an isotope of the same element.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2 H, 3 H, n C, 13 C, i4 C i3 N, i5 0, 17 Q, 32 P, 35 S, 18 F, 36 Cl.
  • Incorporation of heavier isotopes such as deuterium ( 2 H or D) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances.
  • the compounds of formula (I) may have one or more of the hydrogen atoms replaced by deuterium, such as any of the hydrogens in one or more of the moieties G, L ! , L 2 , Y, L 3 , and R ! .
  • Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in tire art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically- labeled reagents in place of the corresponding non -labeled reagent.
  • the invention also includes any or all metabolites of any of the compo unds described.
  • the metabolites may include any chemical species generated by a
  • 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, preloaded syringe, i.v. bag, and the like.
  • the compounds detailed herein are orally bioavailahle.
  • the compounds may also be formulated for parenteral (e.g., intravenous) administration.
  • One or several compounds described herein can 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.
  • a pharmacologically acceptable carrier which are known in the art.
  • the carrier may be in various forms.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provides in the Examples below).
  • the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.
  • a particular stereoisomer of a compound may be accomplished from a corresponding mixture of stereoisomers using any suitable conventional procedure for separating stereoisomers or resolving enantiomers.
  • diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound.
  • Tire diastereomers may then he separated by any convenient means, for example by crystallization, and the desired enantiomer recovered.
  • a racemate may be separated using chiral High Performance Liquid Chromatography.
  • a particular stereoisomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
  • Chromatography, recrystallization and other conventional separation procedures may also he used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
  • Solvates and/or polymorphs of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated. Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are often formed during the process of
  • Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually 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
  • X 1 is a leaving group the like); and X 2 is another leaving group (e.g , -Cl, -Br, -I, -QTf and the like).
  • X ’! is a leaving group the like); and X 2 is another leaving group (e.g., -Cl, -Br, -I, -OTf, and the like).
  • X 1 is a leaving group
  • X 2 is another leaving group (e.g., -Cl, -Br, -I, -OTf, and the like).
  • compound 14D (i.e., second eluting isomer from Scheme D-1) to an appropriate acid gives compound 14D, wherein the wavy line in compound 14D refers to the isomer obtained when either Isomer Dl or Isomer D2 is reacted.
  • X 1 is a leaving group
  • X 2 is another leaving group (e.g., -Cl, -Br, -I, -OTf, and the like).
  • X ’! is a leaving group the like); and X 2 is another leaving group (e.g., -Cl, -Br, -I, -OTf, and the like).
  • X 1 is a leaving group i
  • X 2 is another leaving group (e.g., -Cl, -Br, -1, -OTf, and the like).
  • Compound 14A can he separated using chiral SFC to afford Isomer G1 and Isomer G2.
  • X 1 is a leaving group the like); and X 2 is another leaving group (eg , -Cl, -Br, -I, -OTf. and the like).
  • compositions of any of the compo unds detailed herein including compounds of the formulae (I), (Ha).. (lib), (Ilia), (IHb), (IVa), (FVb), (Va), (Va-l), (Va-2), (Vb), (Vb-1), and (Vb-2), or a salt thereof, or compounds depicted in Table 1 , or a salt thereof, or mixtures thereof, are embraced by this invention.
  • the invention includes pharmaceutical compositions comprising a compound of the in vention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • tire pharmaceutically acceptable salt is tin acid addition salt, such as a salt formed with an inorganic or organic acid.
  • compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
  • the pharmaceutical composition are prepared from mixtures of any of the compounds detailed herein, or salts thereof.
  • the pharmaceutical composition is a composition for controlled release of any of the compounds detailed herein.
  • compositions of any of the compounds detailed herein including compounds of the formulae (I), (Ha).. (lib), (Ilia), (IHb), (IVa), (FVb), (Va), (Va-l), (Va-2), (Vb), (Vb-1), (Vb-2), (P-A-1), (II-A-2), (P-A-2 ⁇ ), (P-A-2 ⁇ ), (IT-A-la-I), (II-A-la-2), (GG-A- la-3), (II-A-lb-l), (II-A-lb-2), (II-A-lc-1), (II-A-lc-2), (II-A-ld-1), (II-A-ld-2), (II-A-ld- 3), (II-A-2a-l), (H-A-2a-2), (II-A-2a-3), (H-A-2a-4), (II-A-2b-l), (I)
  • compositions comprising a compound in purified forms are detailed herein.
  • 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 Table 1 may contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound of Table 1 or a salt thereof.
  • compositions may contain no more than 25% impurity. In one embodiment, compositions may contains no more than 20% impurity.
  • 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.
  • a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 10% impurity.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 9% impurity.
  • a composition of substantially pure compound or a salt thereof wherein the composition contains or no more than 7% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 5% impurity . In another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no 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 no more than 0.5% impurity.
  • a composition of substantially pure compound means that the composition contains no more than 10% or preferably no more than 5% or more preferably no more than 3% or even more preferably no more than 1% impurity or most preferably no more than 0.5% impurity, which impurity may be the compound in a different stereochemical form.
  • a composition of substantially pure (5) compound means that the composition contains no more than 10% or no more than 5% or no more than 3% or no more than 1 % or no more than 0.5% of the (R) form of the compound.
  • the purified forms and substantially pure forms of the compounds apply to any compounds of the formulae (I), (Ila), (lib), (Ilia), (IHb), (IVa),
  • the compounds herein are synthetic compounds prepared for administration to an individual such as a human.
  • compositions are provided containing a compound in substantially pure form.
  • the invention embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable earner or excipient.
  • methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compo unds are suitable for any compound or form thereof detailed herein.
  • the compound de tailed herein or salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g , intramuscular, subcutaneous or intravenous), topical or transdermal delivery form.
  • oral, mucosal e.g., nasal, sublingual, vaginal, buccal or rectal
  • parenteral e.g , intramuscular, subcutaneous or intravenous
  • topical or transdermal delivery form e.g., topical or transdermal delivery form.
  • a compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
  • suitable carriers include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultic
  • One or several compounds described herein or a salt thereof can 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.
  • a pharmaceutically acceptable carrier such as those mentioned above.
  • the carrier may be various forms.
  • phamiaceutical formulations may contain preservatives, solubilizers, stabilizers, re- wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • Formulations comprising die compound may also contain other substances which have valuable therapeutic properties.
  • compositions may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g. in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21 st ed. (2005), which is incorporated herein by reference.
  • Compounds as 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 in soft shell, emulsions or suspensions.
  • oral compositions such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions.
  • carriers which may be used for the preparation of such compositions, are lactose, com starch or its derivatives, talc, stearate or its salts, etc.
  • Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a pharmaceutically acceptable salt thereof can be formulated as a 10 mg tablet.
  • compositions comprising a compound provided herein are also described.
  • the composition comprises a compound and a pharmaceutically acceptable carrier or excipient.
  • a composition of substantially pure compound is provided.
  • the composition is for use as a human or veterinary medicament.
  • the composition is for use in a method described herein.
  • the composition is for use in the treatment of a disease or disorder described herein.
  • Compounds and compositions of the invention such as a pharmaceutical composition containing a compound of any formula provided herein or a sal t thereof and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein.
  • the compounds and compositions may 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 conducting quality control assays
  • a method of treating a fibrotic disease in an individual in need thereof comprising administering to the individual a therapeutically effecti ve amount of a compound of formula (I), or any variation thereof, e.g., a compound of formula (I), (Ha), (lib), (Ilia), (Mb), (IVa), (IVb), (Va), (Va-1), (Va-2), (Vb), (Vb-1), or (Vb-2), a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof, or a
  • the individual is a human.
  • the individual such as a human, may be in need of treatment, such as a human who has or is suspected of having a fibrotic disease.
  • a variation of the compounds includes any stereoisomer thereof
  • a method of treating a fibrotic disease in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of formulae (I), (Ila), (lib), (Ilia), (Mb), (IVa), (IVb), (Va), (Va-1 ), (Va-2), (Vb), (Vb-1), (Vb-2), (II-A-1 ), (P-A-2), (P-A-2 ⁇ ), (II-A-2ii), (II-A-Ia-1 ), (II- A-la-2), (II -A- la-3), (II-A-lb-1), (II-A-lb-2), (II-A-lc-1 ), (II-A-lc-2), (II-A-ld-1), (II-A-ld-
  • the individual is a human.
  • the individual such as a human, may be in need of treatment, such as a human who has or is suspected of having a fibrotic disease.
  • a variation of the compounds includes any stereoisomer thereof.
  • a method of delaying the onset and/or development of a fibrotic disease in an individual (such as a human) who is at risk for dev eloping a fibrotic disease. It is appreciated that delayed development may encompass prevention in the event 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-age or older adults), the presence of inflammation, having one or more genetic component associated with development of a fibrotic disease, medical history such as treatment with a drug or procedure believed to be associated with an enhanced 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 development of a fibrotic disease.
  • age e.g., middle-age or older adults
  • medical history such as treatment with a drug or procedure believed to be associated with an enhanced susceptibility to fibrosis (e.g., radiology) or a medical condition believed to be associated with fibrosis
  • a history of smoking e.g., the presence of occupational and/or environmental factors such as exposure to pollutants associated with development of a fibrotic disease.
  • 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, NS1P, PSC, PBC, or is an individual who has had or is suspected of having had a myocardial infarction
  • the fibrotic disease is fibrosis of a tissue such as the lung (pulmonary fibrosis), the liver, the skin, the heart (cardiac fibrosis), the kidney (renal fibrosis), or the gastrointestinal tract (gastrointestinal fibrosis).
  • the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skm fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or bibary fibrosis (such as PBC).
  • the fibrotic disease is a pulmonary fibrosis, e.g., idiopathic pulmonary fibrosis (IPF), interstitial lung disease, systemic sclerosis-associated interstitial lung disease, or radiation-induced pulmonary fibrosis.
  • the individual at risk for developing a fibrotic disease is an individual who has or is suspected of having a history of viral lung infections
  • the fibrotic disease is a primary sclerosing cholangitis, or biliary fibrosis.
  • the fibrotic disease is fibrotic nonspecific interstitial pneumonia (NSIP)
  • 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 liver disease induced fibrosis, alcoholic steatosis induced liver fibrosis, nonalcoholic fatty liver disease, and cirrhosis.
  • infectious liver fibrosis from pathogens such as HCV, HBV or parasites such as schistosomiasis
  • NASH alcoholic liver disease induced fibrosis
  • alcoholic steatosis induced liver fibrosis alcoholic steatosis induced liver fibrosis
  • nonalcoholic fatty liver disease cirrhosis
  • the fibrotic disease is biliary tract fibrosis
  • the fibrotic disease is renal fibrosis, e.g. , diabetic kidney' disease, diabetic nephrosclerosis, hypertensive nephrosclerosis, diabetic nephropathy, focal segmental glomerulosclerosis (“FSGS”), Alport syndrome, chronic kidney disease, and acute kidney injury from contrast induced nephropathy.
  • renal fibrosis e.g. , diabetic kidney' disease, diabetic nephrosclerosis, hypertensive nephrosclerosis, diabetic nephropathy, focal segmental glomerulosclerosis (“FSGS”), Alport syndrome, chronic kidney disease, and acute kidney injury from contrast induced nephropathy.
  • the fibrotic disease is systemic and local sclerosis or scleroderma, keloids and hypertrophic scars, or post surgical adhesions.
  • the fibrotic disease is atherosclerosis or restenosis.
  • the fibrotic disease is a gastrointestinal fibrosis, e.g. ,
  • the fibrotic disease is cardiac fibrosis, e.g., post myocardial infarction induced fibrosis and inherited cardiomyopathy.
  • a compound of formula (I), or any variation thereof e.g. , a compound of formula (I), (Ha), (lib), (Ilia), (Illb), (IVa), (IVb), (Va), (Va-1), (Va-2), (Vb), (Vb-l ), or (Vb-2), a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a fibrotic disease .
  • a compound of formula (I), or any variation thereof e.g., a compound of formula (II), a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.
  • a method of inhibiting anb ⁇ integrin in an individual comprising administering a compound of formula (I), or any variation thereof, e.g., a compound of formula (Ila), (Tib), (Ilia), (Tllb), (IVa), (IVb), (Va), (Va-I), (Va-2), (Vb), (Vb-l ), or (Vb-2), a stereoisomer thereof, or a compound selected from the compounds depicted in Table l, or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I), or any variation thereof e.g., a compound of formula (Ila), (Tib), (Ilia), (Tllb), (IVa), (IVb), (Va), (Va-I), (Va-2), (Vb), (Vb-l ), or (Vb-2), a stereoisomer thereof, or a compound selected from the compounds depicted in Table l, or a pharmaceutically acceptable salt thereof.
  • Also provided is a method of inhibiting TORb activation in a cell comprising administering to the cell a compound of formula (1), or any variation thereof, e.g., a compound of formula (Ila), (lib), (Ilia), ( I II b). (IVa), (IVb), (Va), (Va-1), (Va-2), (Vb), (Vb- 1 ), or (Vb-2), a compound selected from the compounds depicted in Table 1, or a
  • the compound is a selective anb6 integral inhibitor.
  • the compound does not inhibit substantially a4b1, anb8 and/or a2b3 integrin.
  • the compound inhibits anb6 integrin but does not inhibit substantially a4b1 integrin. In still another such method, the compound inhibits anb ⁇ integrin but does not inhibit substantially anb8 integrin. In a further such method, the compound inhibits anb ⁇ integrin but does not inhibit substantially a2b3 integrin. In one embodiment is provided a method of inhibiting anb6 integrin and one or more of anb ⁇ , anb3, anb5, a2b1, a3b1, a ⁇ b1 integrin, «7bI and a ⁇ Ib ⁇ h an individual in need thereof. In another embodiment is provided a method of inhibiting anb ⁇ integrin and anb ⁇ integrin.
  • a method of inhibiting anb6 integrin, anb3 integrin and anb5 integrin In another embodiment is provided a method of inhibiting anb6 integrin and a2b1 integrin. In another embodiment is provided a method of inhibiting anb6 integrin, a2b1 integrin and a3b1 integrin. In another embodiment is provided a method of inhibiting anb ⁇ integrin and a ⁇ b ⁇ integrin. In another embodiment is provided a method of inhibiting anbd integrin and a7b1 integrin. In another embodiment is provided a method of inhibiting anb ⁇ integrin and a 11 b 1 integrin.
  • the method of inhibition is for an individual in need thereof, such as an individual who has or is suspected of having a fibrotic disease, and wherein the method comprises administering to the individual a compound of formula (I), or any variation thereof, e.g., a compound of formula (Ila), (lib), (Ilia), (ITTb), (IVa), (IVb), (Va), (Va-1), (Va- 2), (Vb), (Vb-1), or (Vb-2), a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • a compound of formula (Ila), (lib), (Ilia), (ITTb), (IVa), (IVb), (Va), (Va-1), (Va- 2), (Vb), (Vb-1), or (Vb-2 a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • a method of modulating at least one integrin in a subject comprising an ⁇ xv subunit, the method comprising administering to the subject an effective amount of the compound of formula (I), or any variation thereof, e.g., a compound of formula (Ila), (lib), (Ilia), (Tllb), (IVa), (IVb), (Va), (Va-1), (Va-2), (Vb), (Vb- 1), or (Vb-2), a stereoisomer thereof, or a compound selected from the compounds depicted m Table 1, or a pharmaceutically acceptable salt thereof.
  • the modulating comprising inhibiting the at least one integrin in the subject.
  • the at least one integrin comprising at least one of anbi integrin and anbb integrin.
  • the subject has or is at risk of a fibrotic disease selected from the group consisting of: idiopathic pulmonary ' fibrosis (IFF), interstitial lung disease, radiation-induced pulmonary ' fibrosis.
  • IFF idiopathic pulmonary ' fibrosis
  • interstitial lung disease idiopathic pulmonary ' fibrosis
  • radiation-induced pulmonary ' fibrosis idiopathic pulmonary ' fibrosis
  • nonalcoholic fatty liver disease NASH
  • nonalcoholic steatohepatitis NASH
  • alcoholic liver disease induced fibrosis Alport syndrome
  • primary sclerosing cholangitis PSC
  • primary biliary cholangitis biliar ' atresia
  • systemic sclerosis associated interstitial lung disease scleroderma, diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn’s Disease
  • tire method comprises inhibiting one or both of anbi integrin and anb ⁇ integrin in the subject, thereby treating the fibrotic disease in the subject.
  • the subject being in need of treatment for NASH, the effective amount administered to the subject being effective to inhibit at least anbi integrin, thereby treating the subject for NASH.
  • the sub j ect being in need of treatment for IPF, the effective amount administered to the subject being effective to inhibit at least anbd integrin, thereby treating the subject for IPF.
  • the subject being in need of treatment for PSC, the effective amount administered to the subject being effective to inhibit at least one of anbi integrin and anbb integrin, thereby treating the subject for PSC.
  • a method of modulating TGFp activation in a cell comprising contacting the cell with the compound of formula (I), or any variation thereof, e.g., a compound of formula (Ila), (lib), (Ilia), (IKb), (IVa), (IVh), (Va), (Va-1), (Va-2), (Vb), (Vb- 1), or (Vb-2), a stereoisomer thereof, or a compound selected from the compounds depicted in Table 1, or a pharmaceutically acceptable salt thereof.
  • the modulating comprising inhibiting TORb activation in the cell.
  • the TORb activation being mediated in the cell by at least one of anbi integrin and anbd integrin.
  • Vb (Va), (Va-1), (Va-2), (Vb), (Vb-l), or (Vb-2), a stereoisomer thereof, or a compound selected from the compounds depicted in Table 1 , or a pharmaceutically acceptable salt thereof, wherein the subject has at least one tissue in need of therapy and the tissue has at least one elevated level of: TORb activation and/or expression; anbi integrin activity and/or expression; or anb ⁇ integrin activity and/or expression; wherein the at least one elevated level is elevated compared to a healthy state of the tissue.
  • the method selectively inhibits anbi integrin compared to anbb integrin in the subject.
  • the method selectively inhibits anbd integrin compared to anbi integrin in the subject. In some aspects, the method inhibits both of anbi integrin and anbd integrin in the subject. In some aspects, the method selectively inhibits both anbi integrin and anbb integrin compared to at least one other an-containing integrin in the subject. In some aspects, the anbi integrin is inhibited in one or more fibroblasts in the subject. In some aspects, the anb ⁇ . integrin is inhibited in one or more epithelial cells in the subject. In some aspects, the at least one tissue in the subject comprises one or more of: lung tissue, liver tissue, skin tissue, cardiac tissue, kidney tissue, gastrointestinal tissue, gall bladder tissue, and bile duet tissue.
  • a compound of formula (I), or any variation thereof e.g. , a compound of formulae (I), (Ila), (lib), (Ilia), (I Ib), (IVa), (IVb), (Va), (Va-l), (Va-2), (Vb), (Vb-1 ), (Vb-2), (II-A-l), (P-A-2), (P-A-2 ⁇ ), (II ⁇ A ⁇ 2ii), (II-A-la-1 ), flI-A-la-2), (P-A- la-3), (II-A-lb-l ), (II-A-lb-2), (II-A-lc-1), (II-A-lc-2), (II-A-ld-1), (II-A-ld-2), (H-A-ld- 3), (II-A-2a-l), (H-A-2a-2), (U-A-2a-3), (III),
  • a method of inhibiting anb ⁇ integrin in an individual comprising administering a compound of formulae (I), (Ila), (lib), (Ilia), (IHb), (IVa), (IVb), (Va), (Va-l), (Va-2), (Vb), (Vb-1 ), (Vb-2), (II-A-l), (II-A-2), (II-A-2 ⁇ ), (II-A- 2ii), (II-A-la-1), (ll-A-la-2), (II-A-la-3), (11-A-lb-l), (ll-A-lb-2), (U-A-lc-1), (II-A-lc-2), (II-A-ld-1), (II-A-ld-2), (II-A-ld-3), (II-A-2a-l), (II-A-2a-2), (II-A-2a-3), (II-A-A-2a-l), (II
  • Also provided is a method of inhibiting TORb activation in a cell comprising administering to the cell a compound of formulae (I), (11a), (11b), (Ilia), (Ilib), (IV a), (IVb), (Va), (Va-l), (Va-2), (Vb), (Vb-1), (Vb-2), (P-A-1), (P-A-2), (P-A-2 ⁇ ), (II ⁇ A ⁇ 2ri), (II-A-la- 1), (H-A-Ia-2), (II-A-la-3), (P-A-lb-l), (TI-A-lb-2), (P-A-lc-l), (II-A-lc-2), (P-A-ld-l ), (II-A-ld-2), (II-A-ld-3), (II-A-2a-l ), (II-A-2a-2), (II-A-2a-3), (lI-A-A-2
  • the compound is a selective anb ⁇ integrin inhibitor.
  • the compound does not inhibit substantially a4b1, anb8 and/or a2b3 integrin.
  • the compound inhibits anb6 integrin but does not inhibit substantially a4b! integrin.
  • the compound inhibits anb ⁇ integrin but does not inhibit substantially anb8 integrin.
  • the compound inhibits anb ⁇ integrin but does not inhibit substantially a2b3 integrin.
  • a method of inhibiting anb6 integrin and anb ⁇ integrin is pro vided.
  • a method of inhibiting anb6 integrin, anb3 integrin and anb5 integrin is provided.
  • a method of inhibiting anb6 integrin and a2b1 integrin is provided.
  • a method of inhibiting anb ⁇ integrin, a2b1 integrin and a3b1 integrin In another embodiment is provided a method of inhibiting anb6 integrin and a ⁇ b ⁇ integrin. In another embodiment is provided a method of inhibiting anb ⁇ integrin and a7b1 integrin. In another embodiment is provided a method of inhibiting anb ⁇ integrin and ori Ib ⁇ integrin.
  • the method of inhibition is for an individual in need thereof, such as an indi vidual who has or is suspected of having a fibrotic di sease, and wherein the method comprises administering to the individual a compound of formulae (I), (Ila), (lib), (Ilia), (lllb), (IV a), (IVb), (Va), (Va-1), (Va-2), (Vb), (Vb-1), (Vb-2), (P-A-1), (P-A-2), (P-A-2 ⁇ ), (II-A-2ii), (II-A-la-1), (II-A-la-2), (II-A-la-3), (II-A-lb-1), (D-A-lb-2), (II-A-lc-l), (P-A- lc-2), (II-A-ld-1), (II-A-ld-2), (II-A-ld-3), (II-A-2a-l
  • the modulating comprising inhibiting the at least one integrin in the subject.
  • the at least one integrin comprising at least one of anbi integrin and anbb integrin.
  • the subject has or is at risk of a fibrotic disease selected from the group consisting of: idiopathic pulmonar fibrosis (IFF), interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease induced fibrosis, Alport syndrome, primary sclerosing cholangitis (PSC), primary biliary' cholangitis, biliary atresia, systemic sclerosis associated interstitial lung disease, scleroderma, diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn’s Disease; and the method comprises inhibiting one or both of anbiopathic pulmonar fibros
  • the subject being in need of treatment for NASH, the effective amount administered to the subject being effective to inhibit at least anbi integrin, thereby treating the subject for NASH.
  • the subject being in need of treatment for IPF, the effective amount administered to the subject being effective to inhibit at least anbb integrin, thereby treating the subject for IPF.
  • the subject being in need of treatment for PSC, the effective amount administered to the subject being effective to inhibit at least one of anbi integrin and avpe integrin, thereby treating the subject for PSC.
  • a method of modulating TORb activation in a cell comprising contacting the cell with the compound of formulae (I), (Ila), (lib), (Ilia), (Ilib), (IVa), (IVb), (Va), (Va-l), (V a-2), (Vb), (Vb-1), (Vb-2), (II-A-1), (II-A-2), (H-A-2 ⁇ ), (II-A-2u), (II-A-la- 1), (II-A-1 a-2), (II -A- la-3), (H-A-!b-i), (II-A-lb-2), (D-A-lc-1), (H-A-lc-2), (II-A-ld-1), (TI-A-ld-2), (II-A-l d-3), (II ⁇ A ⁇ 2a-I), (II-A-2a-2), (II-A-2a-3), (II-A-A-A), (II
  • the method selectively inhibits anbi integrin compared to anbd integrin in the subject. In some aspects, the method selectively inhibits anbd integrin compared to anbi integrin in the subject. In some aspects, the method inhibits both of anbi integrin and anbb integrin in the subject. In some aspects, the method selectively inhibits both anbi integrin and anbb integrin compared to at least one other av-containing integrin the subject. In some aspects, the anbi integrin is inhibited in one or more fibroblasts in the subject. In some aspects, the anb & integrin is inhibited in one or more epithelial cells in the subject. In some aspects, the at least one tissue the subject comprises one or more of: lung tissue, liver tissue, skin tissue, cardiac tissue, kidney tissue,
  • the individual is a human, such as a human in need of the method.
  • the individual may be a human who has been diagnosed with or is suspected of having a fibrotic disease.
  • the individual may be a human who does not have detectable disease but who has one or more risk factors for developing a fibrotic disease.
  • kits for carrying out the methods of the invention which comprises one or more compounds described herein, or a salt thereof, or a
  • kits may employ any of the compounds disclosed herein.
  • 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
  • Kits generally comprise suitable packaging.
  • the kits may comprise one or more containers comprising any compound described herein.
  • Each component if there is more than one component
  • One or more components of a kit may be sterile and/or may be contained within sterile packaging.
  • kits may be in unit dosage forms, bulk packages (e.g. , multi-dose packages) or sub-unit doses.
  • 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 a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • 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).
  • kits may optionally include a set of instractions, generally written
  • kits although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention.
  • the instructions included with the kit generally include information as to the components and their administration to an individual.
  • reactions of functional groups on a compound containing a trans-cyclobutyl group can also be performed on a compound containing a cis-cyclobutyl group, or on a mixture of a compound containing a cis-cyclobutyl group and a compound containing a trans-cyclobutyl group.
  • reactions of functional groups on a compound containing a cycloalkyl Y group can also be performed on a compound lacking a Y group (i.e., where the linker is -Li- O-L2-L3- as defined in Formula (I)), or on a mixture of a compound containing a cycloalkyl group and a compound lacking a Y group.
  • Some of the following general procedures use specifi c 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 can be carried out on other specific compounds having the same functional group (e.g., a different compound having a protected amine where the Boc-protecting group can be removed using acid in the same manner) as long as 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 reacti on on those 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).
  • reaction mixture was diluted watli sat NaHCCb and H2O and stirred for 15 minutes and then filtered through a coarse fritted funnel and the filter cake was rinsed with 4: 1 DCM/'/PrOH.
  • the layers were separated and the aqueous layer w r as extracted with 4: 1 DCM/zPrOH and the combined organic extracts were dried over MgSOy filtered, and concentrated in vacuo to give 2 ⁇ ((!s,3r)-3-(2-(l,8- naphthyridin-2-yl)ethyl)cyclobutoxy)acetaldehyde.
  • R is R 2t as defined for formula (I), or any applicable variations detailed herein, can be performed as exemplified below.
  • R 2f is as defined for formula (I), or any applicable variations detailed herein, can be performed as exemplified below.
  • reaction mixture vcas concentrated in vacuo and purified by normal phase silica gel column chromatography to afford tert-butyl 3-(((l -methoxy-l-oxo-4-(trans-3-(2-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobutoxy)butan-2-yl)carbamoyl)oxy)-3-methylazetidine-l- carboxylate.
  • n 0 or 1
  • L ! and R 2 are as defined for formula (I), or any applicable variations detailed herein, can be performed as exemplified below.
  • Z is an alkylene moiety and R is hydrogen.
  • Z is taken together with the adjacent “NR” group to fonn a heterocyclic ring.
  • n 0 or 1
  • L 1 and R 2 are as defined for formula (I), or any applicable variations detailed herein, can be performed as exemplified below.
  • Z is an alkyiene moiety and R is hydrogen.
  • Z is taken together with the adjacent “NR” group to form a heterocyclic ring.
  • the organic layer was concentrate to give tert-butyl 7-(4-oxobutyl)-3,4-dihydro-l,8-naphthyridine-l(2H)- carboxylate that was used without further purification.
  • tert-butyl 3-hydroxy-3-(4-isopropylphenyl)az tidine-l-carboxylate A solution of tert-butyl 3 -oxoazetidine- 1 -carboxylate (793 mg, 4.63 mmol) in THF (4 mL) at -78 °C was added (4-isopropylpheny])magnesium bromide (0.5 M in THF, 5 mL, 5.0 mmol) dropwise and the resulting mixture was stirred for 30 minutes at -78 °C. The mixture was diluted with sat. aq. NH4CI and extracted with EtOAc.
  • Example la To a mixture of compound la-e (500 mg, 864.94 umol) was added HC1 (4 M, 3.24 mL, 15 eq). Tie mixture was stirred at 70 °C for 10 hrs. LCMS indicated desired M+H + was detected. The mixture was freeze-dried directly to give Example la (304.47 mg, 587.12 umol, 67.88% yield, 96.492% purity, HC1) which was delivered without any further purification.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The invention relates to compounds of formula (I), or a salt thereof, wherein R1, G, L1L2, L3, and Y are as described herein. Compounds of formula (I) and pharmaceutical compositions thereof are inhibitors of one, or both of, ανβ1 integrin and ανβ6 integrin that are useful for treating fibrosis such as in nonalcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IFF) and nonspecific interstitial pneumonia (NSTP).

Description

AMINO ACID COMPOUNDS AND METHODS OF USE
RELATED APPLICATIONS
[0001] Tliis application claims the benefit of priority to U.S Provisional Pat. App. No. 62/742,901, filed October 8, 2018, the entire contents of which are incorporated by reference herein.
FIELD OF THE INVENTION
[0002] This disclosure relates generally to therapeutic agents that may be useful as anb6 integrin inhibitors. The therapeutic agents may be used in the treatment or prophylactic treatment of fibrosis such as idiopathic pulmonary fibrosis (1PF) and nonspecific interstitial pneumonia (NSIP).
BACKGROUND
[0003] Fibrosis, a pathologic feature of many diseases, is caused by a dysfunction in the body’s natural ability to repair damaged tissues. If left untreated, fibrosis can result in scarring of vital organs causing irreparable damage and eventual organ failure.
[QQ04] Patients with nonalcoholic fatty liver disease (NAFLD) may progress from simple steatosis to nonalcoholic steatohepatitis (NASH) and then fibrosis. While liver fibrosis is reversible in its initial stages, progressive liver fibrosis can lead to cirrhosis.
[0005] Fibrosis in the kidney, characterized by glomerulosclerosis and tubulointerstitial fibrosis, is the final common manifestation of a wide variety of chronic kidney diseases (CKD). Irrespective of the initial causes, progressive CKD often results in widespread tissue scarring that leads to destruction of kidney parenchyma and end-stage renal failure, a devastating condition that requires dialysis or kidney replacement.
[0006] Scleroderma encompasses a spectrum of complex and variable conditions primarily characterized by fibrosis, vascular alterations, and autoimmunity. The scleroderma spectrum of disorders share the common feature of fibrosis, resulting in hardening or thickening of the skin. For some patients, this hardening occurs only in lim ited areas, but for others, it can spread to other major organs
[QQ07] Following myocardial infarction, cardiac structural remodeling is associated with an inflammatory reaction, resulting in scar formation at the site of the infarction. This scar formation is a result of fibrotic tissue deposition which may lead to reduced cardiac function and disruption of electrical activity within the heart.
[0008] Crohn’s Disease is a chronic disease of unknown etiology tending to progress even in tire setting of medical or surgical treatment. Intestinal fibrosis is among the most common complications of Crohn’s disease, resulting in stricture formation in the small intestine and colon.
[0009] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing disease of unknown etiology, occurring in adults and limited to the lungs. In IPF, the lung tissue becomes thickened, stiff, and scarred. As lung fibrosis progresses, it becomes more difficult for the lungs to transfer oxygen into the bloodstream and the organs do not receive the oxygen needed to function properly. IPF currently affects approximately 200,000 people in the U.S., resulting in 40,000 deaths per year. Patients diagnosed with IPF experience progressive breathlessness and eventually, complete respiratory failure.
[0010] Primary biliary cholangitis (PBC), also known as primary' biliary cirrhosis, is a chronic disease of the liver that causes damage and fibrosis in the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Over time, this leads to scarring and fibrosis in both the liver and biliary tract.
[0011] Nonspecific interstitial pneumonia (NSIP) is a rare disorder that affects the tissue that surrounds and separates the tiny air sacs of the lungs. These air sacs, called the alveoli, are where the exchange of oxygen and carbon dioxide takes place between the lungs and the bloodstream. 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) might become inflamed as well . There are two primary' forms of NSIP - cellular and fibrotic. The cellular form is defined mainly by inflammation of the ceils of the interstitium. Tire fibrotic form is defined by thickening and scarring of lung tissue. This scarring is known as fibrosis and is irreversible. When the lung tissue thickens or becomes scarred, it does not function as effectively. Breathing becomes less efficient, and there are lower levels of oxygen in the blood. (Kim et a!., Proc. Am. Thorac. Soc. (2006) 3:285-292; Lynch, D., Radiology (2001) 221 :583-584; Kinder et a , Am. I. Respir. Crit. Care Med. (2007) 176:691 -697)
7 [0012] A vailable courses of treatment are scarce, as there are currently no options on the market proven to have an effect on long-term patient survival or symptomatology. There remains a need for treatment of fibrotic diseases.
[0013] The anbό integrin is expressed m epithelial cells, and binds to the latency- associated peptide of transforming growth factor-bΐ (TΌRbI) and mediates TORbI activation. Its expression level is significantly increased after injury to lung and
cholangiocytes, and plays a critical in vivo role in tissue fibrosis. Increased levels are also associated with increased mortality in IFF and NSIP patients
[0014] Primary sclerosing cholangitis (PSC) involves bile duct inflammation, and fibrosis that obliterates the bile ducts. The resulting impediment to the flow of bile to the intestines can lead to cirrhosis of the liver and subsequent complications such as liver failure and liver cancer. Expression of anb6 is elevated in liver and bile duct of PSC patients.
[0015] The present disclosure provides for anbό integrin inhibitors that may be useful for treatment of fibrosis.
SUMMARY
[0016] Disclosed are amino acid compounds that are anb6 integral inhibitors, compositions containing these compounds and methods for treating diseases mediated by anbό integrin such as a fibrotic disease
[QQ17] In one aspect, provided is a compound of formula (I), or any variation thereof, or a salt thereof ( e.g . , a pharmaceutically acceptable salt thereof), as detailed herein
[0018] 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 earner or excipient
[QQ19] In another aspect, provided is a method of treating a fibrotic disease or condition in an individual (such as a human) in need thereof comprising admini stering to the individual 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 or condition is pulmonary, liver, renal, cardiac, dermal, or gastrointestinal fibrosis. In other embodiments the fibrotic disease or condition is idiopathic pulmonary fibrosis, interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease induced fibrosis, Alport syndrome, primary sclerosing cholangitis, primarily biliar cholangitis (also known as primary' biliary cirrhosis), systemic sclerosis associated interstitial lung disease, scleroderma (also known as systemic sclerosis), diabetic nephropathy, diabetic kidney- disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn’s Disease.
[0020] In another aspect, provided is a method of delaying the onset and/or development of a fibrotic disease or condition in an individual (such as a human) who is at risk for developing a fibrotic disease or condition comprising administering to the individual 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 disease or condition is pulmonary, liver, renal, cardiac, dermal, or gastrointestinal fibrosis. In oilier embodiments the fibrotic disease or condition is idiopathic pulmonary fibrosis, interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease induced fibrosis, Alport syndrome, primary' sclerosing cholangitis, primarily biliary cholangitis (also known as primary biliary cirrhosis), systemic sclerosis associated interstitial lung disease, scleroderma (also known as systemic sclerosis), diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn’s Disease.
[0021] 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.
[0022] Also provided is use of a compound of formula (1), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a fibrotic disease.
[0023] Further provided is a kit comprising a compound of formula (I), or any variation thereof de tailed herein, or a pharmaceutically acceptable sal t thereof. In some embodiments, the kit comprises instructions for use according to a method described herein, such as a method of treating a fibrotic disease in an individual.
[0024] In another aspect, provided is a method of making a compound of formula (I) or any variation thereof Also provided are compound intermediates useful in synthesis of a compound of formula (I), or any variation thereof.
[0025] It is understood that aspects and variations described herein also include‘consisting” and/or‘’consisting essentially of’ aspects and variations. BRIEF DESCRIPTION OF THE FIGURES
[0026] FIG. 1, Table 2 shows chemical structures for various compounds disclosed herein . Reference to compound numbers in the table in some instances depicts a particular stereoisomeric form of the compound number, as will be evident from the chemical structure depicted.
[0027] FIG, 2, Table B~2 shows biological data for various compounds disclosed herein.
DETAILED DESCRIPTION
[QQ28] The invention provides, inter alia , compounds of formula (I), and variations thereof, pharmaceutical compositions comprising compounds of formula (I), and methods of using such compounds and compositions in treating fibrotic diseases. Compounds and pharmaceutical compositions comprising salts of compounds of formula (I) are provided as well.
Definitions
[0029] For use herein, unless clearly indicated otherwise, use of the terms“a”,“an” and the like refers to one or more.
[QQ3Q] Reference to“about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to“about X” includes description of“X”. Likewise, reference to a value“X” also includes description of“about X”.
[0031] “Alkyl” as used herein refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbon atoms). Particular alkyl groups are those having 1 to 20 carbon atoms (a“C1-C20 alkyl”), having 1 to 10 carbon atoms (a“C1-C10 alkyl”), having 6 to 10 carbon atoms (a“Ce-Cio alkyl”), having 1 to 6 carbon atoms (a“Ci~C& alkyl”), having 2 to 6 carbon atoms (a“Cr-Ce alkyl”), or having 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-propyi, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n- pentyd, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. [0032] “Alkylene” as used herein refers to the same residues as alkyl, but having bivalency. Particular alkylene groups are those having 1 to 20 carbon atoms (a“C1-C20 alkylene”), having 1 to 10 carbon atoms (a“C1-C10 alkylene”), having 6 to 10 carbon atoms (a“Ce-Cio alkylene”), having 1 to 6 carbon atoms (a“Ci-Ce alkylene”), 1 to 5 carbon atoms (a“C]-C.-3 alkylene”), 1 to 4 carbon atoms (a“C1-C4 alkylene”) or 1 to 3 carbon atoms (a“Ci- C3 alkylene”). Examples of alkylene include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH.3)-), butylene (-P NCi k K l l -). isobutylene (-C1 K l HU HP I.· -). pentylene ( -( 1 1 (C H ) A 1 1 ) hexylene (-C1 MCI t.fi iCi f·-). heptylene (-P f(0 EfiCi 1 -). octylene (-P l.dC'l f yCl i.-). and the like. It is understood that when alkylene is substituted (for example with a cycloalkyl group), the substituent is not one of the sites of bivalency. For example, propylene
substitution with cyclopropyl may provide
Figure imgf000007_0001
hut does not provide
Figure imgf000007_0002
, wherein the wavy line denotes a site of bi valency.
[QQ33] “Alkenyl” as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefimc unsaturation (i. e. , having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms). An alkenyl group may have“cis” or“trans” configurations, or alternatively have“E” or“Z” configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a“C2-C20 alkenyl”), having 6 to 10 carbon atoms (a“Ce-Cio alkenyl”), having 2 to 8 carbon atoms (a“Ci-Cs alkenyl”), having 2 to 6 carbon atoms (a“Ci-Ce alkenyl”), or having 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-l-enyl, prop-2 -enyl (or ally!), 2-methylprop-l-enyl, but- 1 -enyl, but-2-enyl, but-3-enyl, buta-l ,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.
[0034] “Aikenylene” as used herein refers to the same residues as alkenyl, but having bivalency. Particular aikenylene groups are those having 2 to 20 carbon atoms (a“C2-C20 aikenylene”), having 2 to 10 carbon atoms (a“C2-C10 aikenylene”), having 6 to 10 carbon atoms (a“Ce-Cio aikenylene”), having 2 to 6 carbon atoms (a“C2-C6 aikenylene”), 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 vinyl ene) (-CH=CH~), propenylene (-CH=CHCH2-), i,4-but-l-enylene (-CH=CH-CH2CH2-), 1 ,4-but-2-enylene ( -(Ί I t 1 1 ( ! !( ! ! -}. 1,6-hex- 1-enylene ( ·< ! ! ( 1 1-({ 1 1 ) (Ί I -}_ and the like.
[0035] “Alkynyl” as used herein refers to and includes, unless otherwise stated, an unsaturated linear (2. e. , unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula CºC) and having the number of carbon atoms designated (i.e. , C2-C10 means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a“C2- C20 alkynyl”), having 6 to 10 carbon atoms (a“Ce-Cio alkynyl”), having 2 to 8 carbon atoms (a“C2~Cs alkynyl”), having 2 to 6 carbon atoms (a“C2-C6 alkynyl”), or having 2 to 4 carbon atoms (a“C2-C4 alkynyl”). Examples of alkynyl group include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-l-ynyl, prop-2-ynyi (or propargyl), but-l-ynyl, but-2- ynyl, but-3-ynyl, and the like.
[0036] “Alkynylene” as used herein refers to the same residues as alkynyl, but having bivalency . Particular alkyny lene 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“Ce-Cio alkynylene”), having 2 to 6 carbon atoms (a“Ci-Ce 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 acetylenylene) (-CºC~), propynylene (-OCCH2-), and the like.
[0037] “Cycloalkyl” as used herein refers to and includes, unless otherwise stated, saturated cyclic univalent hydrocarbon structures, having the number of carbon atoms designated (i.e., C3-C10 means three to ten carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. , 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 having from 3 to 8 annular carbon atoms (a "Cs-Cs cycloalkyl"), having 3 to 6 annular carbon atoms (a“C3-C6 cycloalkyl”), or having from 3 to 4 annular carbon atoms (a "C3-C4 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepty!, norbomyl, and the like. [QQ38] “Cycloaikylene” as used herein refers to the same residues as cycloalkyl, but having bivalency. Cycloaikylene can consist of one ring or multiple rings which may be fused, spiro or bridged, or combinations thereof. Particular cycloaikylene groups are those having from 3 to 12 annular carbon atoms. A preferred cycloaikylene is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "Cr-Cg cycloaikylene"), having 3 to 6 carbon atoms (a“C3~Ce cycloaikylene”), or having from 3 to 4 annular carbon atoms (a "C3-C4 cycloaikylene"). Examples of cycloaikylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, and the like. A cycloaikylene may atach to the remaining structures via the same ring carbon atom (e.g., 1,1- cyclopropylene) or different ring carbon atoms (e.g., 1,2-cyclopropylene). When a cycloaikylene attaches to the remaining structures via two different ring carbon atoms, the connecting bonds may be cis or trans to each other (e.g., c/s- 1,2-cyclopropylene or trans- 1,2- cyclopropylene). If points of atachment are not specified, the moiety can include any chemically possible attachments. For example, cyclopropylene can indicate 1,1 - cyclopropylene or 1 ,2-cyclopropylene (e.g·, cis-l , 2-cyclopropylene, trans- 1,2- cyclopropylene, or a mixture thereof), or a mixture thereof.
[0039] “Cydoalkenyr refers to and includes, unless otherwise stated, an unsaturated cyclic non-aromatic univalent hydrocarbon structure, having at least one site of olefmic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C3-C10 means three to ten carbon atoms). Cycloalkenyl can consist of one ring, such as cyclohexenyl, or multiple rings, such as norbornenyl. A preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a ( :-CN cycloalkenyi”). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cydohuienyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like.
[OO40] “Cyeloalkenyiene” as used herein refers to the same residues as cycloalkenyi, but having bi valency.
[0041] “Aryl” or“Ar” as used herein refers to an unsaturated aromatic carbocydic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings are carbocydic and may or may not be aromatic, provided at least one ring in the multiple condensed ring structure is aromatic. Particular aryl groups are those having from 6 to 14 annular carbon atoms (a“Ce-Cir 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 either 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.
[0042] “Arylene” as used herein refers to the same residues as aryl, but having bivalency. Particular arylene groups are those having from 6 to 14 annular carbon atoms (a‘Ce-Cu arylene”).
[QQ43] “Heteroaryl” as used herein refers to an unsaturated aromatic cyclic group having from 1 to 14 annular carbon atoms and at least one annular 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 be carbocyclic or may contain one or more annular heteroatom and which may or may not be aromatic, provided at least one ring in the multiple condensed ring structure is both aromatic and contains at least one annular heteroatom. 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 one variation, particular heteroaryl groups are monocyclic aromatic 5-, 6- or 7-membered rings having from 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 having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. A heteroaryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, a heteroaryl 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. A heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom.
[0044] “Heteroarylene” as used herein refers to the same residues as heteroaryl, but having bivalency.
[QQ45] ' leterocycle”,‘lieterocyclic”, or‘lieterocyclyl” as used herein refers to a saturated or an unsaturated non-aromatic cyclic group 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 heterocyclic group may have a single ring (e.g. , pyrrolidinyl) or multiple condensed rings (e.g., decahydroisoquinolm-l -yl), which condensed rings may or may not be aromatic and which may be carbocylic or contain one or more annular heteroatoms, but which excludes heteroaryl rmgs. A heterocycle comprising more than one ring may be fused, bridged or spiro, or any combination thereof. In fused ring systems, one or more of the fused rings can be cycloalkyl or aryl, but excludes heteroaryl groups. The heterocyclyl group may be optionally substituted independently with one or more substituents described herein.
Particular heterocyclyl 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 nitrogen, oxygen and sulfur. In one variation, heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 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 polycyclic non-aromatic rings having from I to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
[0046] “Heterocyclylene” as used herein refers to die same residues as heterocyclyl, but having bi valency .
[QQ47] “Halo” or“halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with one or more halogens, it may be referred to by using the prefix“halo,” e.g., haloaryl, haloalkyi, etc. refer to aryl and alkyl substituted with one or more halo groups, which in the case of two or more halo groups may be, but are not necessarily the same halogen. Where a residue is substituted with more than one halogen, it m ay be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloary!, dihaloalkyl, trihaloaryl etc. refer to and and alkyl substituted with 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 with a halo group is referred to as a“perhaloalkyl .” A preferred haloalkyl, e.g., 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 making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).
[0048] “Carbonyl” refers to the group C=G.
[0049] “Thiocarbonyl” refers to the group C S.
[0050] “Oxo” refers to the moiety =0.
[0051] “D” refers to deuterium (2H).
[0052] “Boc” refers to ferf-butyloxycarhonyl.
[0053] “Cbz” refers to carboxy benzyl.
[0054] “HATU” refers to l-[bis(dimelhylamino)methylene]-lH-l ,2,3-lriazolo[4,5- b jpy ridinium 3 -oxide hexaliuorophosphate .
[0055] “BOP” refers to benzotriazol - 1 -yloxytri s(diraetbylamino)phosphomum hexaliuorophosphate.
[0056] “PyBOP” refers to benzotriazol-l -yl-oxytripyrrolidinophosphonium
hexafl u oropho ph ate .
[0057] “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 in which the substituents may be the same of 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.
I I [QQ58] Unless clearly indicated otherwise,“an individual” as used herein intends a mammal, including but not limited to a primate, human, bovine, horse, feline, canine, or rodent. In one variation, the individual is a human.
[0059] As used herein,“treatment” or“treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this invention, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease, diminishing tire extent of the disease, stabilizing the di sease (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, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival. Also encompassed by “treatment” is a reduction of pathological consequence of fibrosis. The methods of the invention contemplate any one or more of these aspects of treatment.
[0060] As used herein, the term“effective amount” intends such amount of a compound of the invention which should be effective in a given therapeutic form. 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 administering one or more therapeutic agents (e.g. , a compound, or 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 may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
[0061] A“therapeutically effective amount” refers to an amount of a compound or salt thereof sufficient to produce a desired therapeutic outcome.
[0062] As used herein,“unit dosage form” refers to physically discrete units, suitable as unit 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 fomis may contain a single or a combination therapy. [QQ63] As used herein, the term‘"controlled release” refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate,
Figure imgf000014_0001
with a “controlled release” formulation, administration does not result in 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, generally involving mixing the drug compound with carriers, polymers or other compounds having the desired release characteristics (e.g. , pH-dependent or non-pH-dependent solubility, different 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).
[0064] As used herein, by“pharmaceutically acceptable” or“pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S Food and Drug Administration.
[0065] “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual . 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 either is replaced by a metal ion, e.g. , an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamme, diethanolamine,
triethanolamine and the like. Acceptable inorganic bases which can he used to prepared salts include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Pharmaceutically acceptable salts can be prepared m 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 base or acid, respectively, and isolating the salt thus formed during subsequent purification
[0066] The term“excipient"’ as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient. Vari ous substances may he embraced 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, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthaJate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.: compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc =“directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycoiate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally m combination with aspartame or cellulose), etc.;
suspending/gelling agents include, e.g., carrageenan, sodium starch glycoiate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.
[0067] Unless otherwise stated, "substantially pure" intends a composition that contains no more than 10% impurity, such as a composition comprising less than about 9%, 7%, 5%, 3%, 1%, 0.5% impurity.
[0068] It is understood that aspects and embodiments described herein as“comprising” include“consisting of” and“consisting essentially of” embodiments.
[0069] When a composition is described as“consisting essentially of” the listed components, the composition contains the components expressly listed, and may contain other components which do not substantially affect the disease or condition being treated such as trace impurities. However, the composition either does not contain any other components which do substantially affect tire disease or condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the disease or condition being treated, the composition does not contain a sufficient concentration or amount of those extra components to substantially affect the disease or condition being treated. When a method is described as “consisting essentially of” the listed steps, the method contains the steps listed, and may contain other steps that do not substantially affect the disease or condition being treated, but the method does not contain any other steps which substantially affect the disease or condition being treated other than those steps expressly listed.
Compounds
[0070] In one aspect, provided is a compound of formula (I):
Figure imgf000016_0001
or a salt thereof, wherein:
R! is 5,6,7,8-tetrahydro~l,8~naphthyridin~2~yl optionally substituted by R4, 1,2, 3,4- tetrahydro-l ,8-naphthyridin-2-yl optionally substituted by R4, 6-aminopyridin-2-yl optionally- substituted by R4, or (pyridin-2-yl)amino optionally substituted by R4;
G is -C(0)R2 or R3;
R2 is Ci-Ce alkyl optionally substituted by R2a, C3-C8 cycloalkyl optionally substituted by R2b, 3- to 12-membered heterocyclyl optionally substituted by R2c, Ce-Cw aryl optionally substituted by R2d, 5- to 10-membered heteroaryl optionally substituted by R2e, -OR2f, or
R3 is Ci-C& alkyl optionally substituted by R3a, C3-C8 cycloalkyl optionally substituted by R3b, 3- to 12-membered heterocyclyl optionally substituted by R3c, Ce-Cir aryl optionally substituted by R3d, or 5- to 10-membered heteroaryl optionally substituted by R3e;
L1 is C2-C4 alkylene optionally substituted by R4;
L2 is a bond or C1-C3 alkylene optionally substituted by R4;
L3 is C2-C4 alkylene optionally substituted by R4: Y is a bond or C3-C5 cycloalkylene optionally substituted by Ya:
R2i is Ci-Ce alkyl, C3-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cir aryl, and 5- to 10-membered heteroaryl of R·'1 are independently optionally substituted by R2‘;
R2g and R2h are each independently hydrogen, deuterium, C\-Ce alkyl,
C3-Cg cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cw aryl, or 5- to 10-membered heteroary , wherein the Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl,
(V.-C : aryl, and 5- to 10-membered heteroaryl of R2g and R2h are independently optionally substituted by R2*:
each R2a, R2b, R2c, R2d, R2®, R21, R2·*, R3a, R3b, RJC, R3d, R3e and Ya is independently oxo or R4;
each R4 is independently deuterium, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Cs-Cs cycloalkyl, 3- to 12-membered heterocyclyl, C6-C14 aryl, 5- to 10- membered heteroaryd,
-C(0)0R5, -C(0)NR6
Figure imgf000017_0001
-NR5S(0)R6, -NR5S(0)2R6, -S(0)NR6R7, -S(0)2NR6R7, or -P(0)(0R5)(0R6), wherein the Ci- Cfi alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Ci ary'l, and 5- to 10-membered heteroaryd of R4 are independently optionally substituted by R4a; each R4a is independently deuterium, halogen, oxo, -OR8, -NR8R9,
-C(0)R8, -C(0)0R8, -NR8C(0)0R10, -CN, -S(0)R8, -S(0)2R8, -P(0)(0R8)(0R9), CVCK cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6~Ci4 aryl, or Ci-Ce alkyl, wherein the 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Ce- Ci4 aryl, and Ci-Ce alkyl of R4a are independently optionally substituted by R4b; each R4b is independently deuterium, oxo, -OH, -0(2H), halogen, or Ci-Ce alkyl optionally substituted by deuterium, halogen, -OH, -Q(2H), or oxo; each R5 is independently hydrogen, deuterium, Ci-Ce alkyl, C2-Ce alkenyl, Ci-Ce alkynyl, C3-C6 cycloalkyl, Ce-Cir aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce cycloalkyl, C&-Ci4 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl of R5 are each independently optionally substituted by R33; each R3a is independently halogen, deuterium, oxo, -CN, -OR10, -NRnR12,
-P(0)(0Rn)(0R12), 3- to 12-memhered heterocyclyl, or Ci-Ce alkyl optionally substituted by deuterium, halogen, -OH, ~0(2H), or oxo; each R6 is independently hydrogen, deuterium, Ci-Ce alkyl, Cb-Ce alkenyl, Cr-Ce alkynyl, (b-Ce cycloalkyl, Ce-Cw aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the Ci-Ce alkyl, C2-G5 alkenyl, Cb-Ce alkynyl, Cb-Ce cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R6 are independently optionally substituted by deuterium, halogen, oxo, -CN, -ORi0, -NRUR 2, or Ci-Ce alkyl optionally substituted by deuterium, halogen, -OH, -0(2H), or oxo; each R7 is independently hydrogen, deuterium, Ci-Ce alkyl, Cb-Ce alkenyl, (b-Ce alkynyl, C3-C6 cycloalkyl, Ce-Ci4 aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cb-Ce cycloalkyl, Ce-Cir aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R7 are independently optionally substituted by deuterium, halogen, oxo, -CN, -OR10, -NRUR12, or Ci-Ce alkyl optionally substituted by deuterium, halogen, -OH, -Q(2H), or oxo; or R6 and R7 are taken together with the atom to which they are attached to form a 3 - to 10-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, -OR10, -NR! iR12, or Ci-Ce alkyl optionally substituted by deuterium, halogen, oxo, -OH, or -
0(2H); each Rs is independently hydrogen, deuterium, Ci-Ce alkyl optionally substituted by- deuterium, halogen, or oxo, Cb-Ce alkenyl optionally substituted by deuterium, halogen, or oxo, or C2-C6 alkynyl optionally substituted by deuterium, halogen, or oxo; each R9 is independently hydrogen, deuterium, Ci-Ce alkyl optionally substituted by deuterium, halogen, or oxo, C2-C& alkenyl optionally substituted by deuterium, halogen, or oxo, or Cr-Ce alkynyl optionally substituted by deuterium, halogen, or oxo; each Ri0 is independently hydrogen, deuterium, Ci-Cs alkyl optionally substituted by deuterium, halogen, or oxo, C2-C& alkenyl optionally substituted by deuterium, halogen, or oxo, or C2-C6 alkynyl optionally substituted by deuterium, halogen, or oxo; each R11 is independently hydrogen, deuterium, Ci-Ce alkyl optionally substituted by deuterium, halogen, or oxo, Ci-Ce alkenyl optionally substituted by deuterium, halogen, or oxo, or C2-C6 alkynyl optionally substituted by deuterium, halogen, or oxo; and each R!2is independently hydrogen, deuterium, Ci-Ce alkyl optionally substituted by deuterium, halogen, or oxo, Ci-Ce alkenyl optionally substituted by deuterium, halogen, or oxo, or C2-C6 alkynyl optionally substituted by deuterium, halogen, or oxo; or R1 1 and R12 are taken together with the atom to which they are attached to form a 3- 6 membered heterocyclyl optionally substituted by deuterium, halogen, oxo or Ci-Ce alkyl optionally substituted by deuterium, oxo, or halogen.
[QQ71] In one variation is provided a compound of the formula (I), or a salt thereof, wherein the carbon bearing the CO2I I and N(H)G moieties is in the“S” configuration. In another variation is provided a compound of the formula (I), or a salt thereof, wherein the carbon bearing the CO2H and N(H)G moieties is in the“R” configuration. Mixtures of a compound of the formula (I) are also embraced, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.
[0072] In the descriptions herein, it is understood that every description, variation, embodiment or aspect of a moiety may be combined with every description, variation, embodiment or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, every description, variation, embodiment or aspect provided herein with respect to G of formula (I) may be combined with every description, variation, embodiment or aspect of L!, L2, Y, L2 and/or R1 the same as if each and every combination were specifically and individually listed. It is also understood that all descriptions, variations, embodiments or aspects of formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, tire same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. For example, all descriptions, variations, embodiments or aspects of formula (I), where applicable, apply equally to any of formulae (Ila), (lib), (Ilia), (Hlb), (IVa), (IVb), (Va), (Va-I), (Va-2), (Vb), (Vb-1), and (Vb-2) detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae
[0073] In some embodiments of the compound of formula (I), or a salt thereof, L1 is unsubstituted C2-C4 alkylene. In a particular variation, L1 is -CH2-CH2-, -CH2-CH2-CH2-, or --CH2--CH2---CH2---CH2-. In another variation, L1 is --CH2--CH2- .
[Q074] In some embodiments of the compound of formula (I), or a salt thereof, -L2- is a bond.
[0075] In some embodiments of the compound of formula (I), or a salt thereof, -Y- is a bond.
[QQ76] In some embodiments of the compound of formula (1), or a salt thereof, -Y - is a C3-C4 cycloalkylene. In one aspect, Y is a C3 cycloalkylene. In another aspect, Y is a C4 cycloalkylene. In one variation, the point of attachment of the C3-C4 cycloalkylene to L2 and
L3 are via the same carbon atom (e.g. ,
Figure imgf000020_0001
In another variation, the point of attachment of the C3-C4 cycloalkylene to L2 and L3 are via two different carbon atoms
(e.g.,
Figure imgf000020_0002
In another variation, when the point of attachment of the C3-C4 cycloalkylene to L2 and L3 are via two different carbon atoms, the stereochemistry introduced at the C3-C4 cycloalkylene is trans (e.g.,
Figure imgf000020_0003
and
Figure imgf000020_0004
In another variation, when the point of attachment of the C3-C4 cycloalkylene to L2 and L3 are via two different carbon atoms, the stereochemistry introduced at the C3-C4 cycloalkylene is cis
Figure imgf000020_0005
[0077] In some embodiments of the compound of formula (I), or a salt thereof, at least one of R¾, R2h, R4, R4a, R4b, R5, R5a, R6, R7, R8, R9, R10, Rn, or Ri2 is deuterium.
[0078] In some embodiments of the compound of formula (I), or a salt thereof, -L2-Y-L3- are taken together to form a moiety selected from the group consisting of: -CH2CH2CH2-,
Figure imgf000021_0001
wherein the wavy lines denote attachment points to the parent molecule.
[0079] In some embodiments of the compound of formula (I), or a salt thereof, -L'-O-L2- Y-L3- are taken together to form a moiety selected from the group consisting of:
-C2-C4 alkylene— O-C2-C7 alkylene
Figure imgf000021_0002
j— C2-C4 alkylene- O-C0-C3 alkylene -C2-C4 alkylene
Figure imgf000021_0004
Figure imgf000021_0003
wherein
Figure imgf000021_0005
a C3-C5 eycloalkylene optionally substituted by Ya, and
-C2-C4 alkylene-
Figure imgf000021_0006
4 alkylene
Figure imgf000021_0007
wherein
Figure imgf000021_0008
a C3-C5 eycloalkylene optionally substituted by Ya.
[0080] In some embodiments of the compound of formula (I), or a salt thereof, -Id-O-L2- Y-L3- are taken together to form a moiety selected from the group consisting of:
Figure imgf000021_0009
Figure imgf000021_0010
. in another variation, -L!-Q-L2~Y~L3- are taken together to form a moiety selected from the group consisting of:
Figure imgf000021_0011
Figure imgf000021_0012
Figure imgf000021_0013
. In another particular variation, -L'-Q-lAY-L3- are taken together to form a moiety selected from the group consi sting of:
Figure imgf000021_0014
Figure imgf000021_0015
[0081] In an embodiment, the compound of formula (!) or a salt thereof is pro vided wherein: R1 is l,2,3,4~tetrahydro-l,8-naphthyridin-2-yl; L! is -CH2CH2-, Y is a bond, and L3 is -CH2CH2CH2CH2-; and G is -C(0)R2, wherein R2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haioaikyl. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is l ,2,3,4-tetrahydro-l ,8-naphthyridin-2-yl; 1/ is -CH2CH2CH2-, Y is a bond, and LJ is -CH2CH2CH2-; and G is -C(0)R2, wherein R2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haioaikyl. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl; L! is -CH2CH2CH2CH2-, Y is a bond, and LJ is -CH2CH2-; and G is -C(Q)R2, wherein R2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haioaikyl. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is 1,2,3, 4-tetrahydro-l,8-naphthyridin-2-yl; L1 is -CH2CH2-, Y is 1,3-cyclobutyl, and L3 is -CH2CH2-; and G is -C(0)R2, wherein R2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haioaikyl . In an embodimen t, the compound of formula (I) or a salt thereof is provided wherein: R1 is 1 ,2,3,4-tetrahydro- l,8-naphthyridin-2-yl; L1 is -CH2CH2-, Y is cvs-1,3- cyclobutyl, and L3 is -CH2CH2-; and G is -C(0)R2, wherein R2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 un saturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haioaikyl. In an embodiment, the compound of formula (!) or a salt thereof is provided wherein: R1 is l ,2,3,4-tetrahydro~l ,8~naphthyridin~2-yl; L1 is -CH2CH2-, Y is tram- 1 ,3-cyclobutyl, and L3 is -CH2CH2-; and G is -C(0)R2, wherein R2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haioaikyl. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is l,2,3,4-tetrahydro-l,8-naphthyridin- 2-yl; L1 is -CH2CH2-, Y is a bond, and L3 is -CH2CH2CH2CH2-; and G is ---R3, wherein R3 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce ha!oa!kyl. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is l,2,3,4-tetrahydro-l,8-naphthyridin- 2-yl; L1 is -CH2CH2CH2-, Y is a bond, and L3 is -CH2CH2CH2-; and G is -R3, wherein R3 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haloalkyi. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is 1,2,3, 4-tetrahydro-l,8-naphthyridin- 2-yl; L1 is -CH2CH2CH2CH2-, Y is a bond, and L3 is -CH2CH2-; and G is -R3, wherein R3 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI-CG alkyl, or Ci-C& haloalkyi. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is 1 ,2,3,4-tetrahydro-l ,8-naphthyridin- 2-yl; L1 is -CH2CH2-, Y is 1,3-cyclobutyl, and L3 is -CH2CH2-; and G is -R3, wherein R3 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haloalkyi. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is l,2,3,4-tetrahydro-l,8-naphthyridin- 2-yl; L1 is -CH2CH2-, Y is ds-l ,3-cyclobutyl, and LJ is -CH2CH2-; and G is -R3, wherein R3 is a six-membered heterocyclyl, and, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI -CG alkyl, or CI-CG haloalkyi. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is 1,2,3, 4-tetrahydro-l,8-naphthyridin- 2-yl; L1 is -CH2CH2-, is irons- 1,3 -cyclobutyl, and L3 is -CH2CH2-; and G is ---R3, wherein R3 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI-CG alkyl, or CI-CG haloalkyi. For each individual preceding embodiment described in this paragraph, a further embodiment is disclosed in which among the substitutable ring atoms in R2, one of: one saturated ring atom is substituted with CI-CG haloalkyi, e.g., -CF3; two aryl ring atoms are independently substituted with halogen; and 2 or 3 heteroaryl ring atoms are independently substituted with halogen or CI-CG alkyl, e.g., methyl. Further, in various embodiments, each preceding embodiment described in this paragraph may be excluded from the compound represented by formula (I) and salts thereof.
[0082] In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl; L! is -CH2CH2-, Y is a bond, and LJ is -CH2CH2CH2CH2-; and G is -C(0)R2, wherein R2 is a six-membered heterocyclyl, axyl, or heteroaryl ring, wherein among the substitutable ring atoms in R-', 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI -CG alkyl, or CI-CG haioaikyl. In an embodiment, the compound of fonnula (I) or a salt thereof is provided wherein: R1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl; L1 is -CH2CH2CH2-, is a bond, and L3 is -CH2CH2CH2-; and G is -C(0)R2, wherein R2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI-CG alkyl, or CI-CG haioaikyl . In an embodimen t, the compound of formula (I) or a salt thereof is provided wherein: R1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl; L* is -CH2CH2CH2CH2-, Y is a bend, and L3 is -CH2CH2-; and G is -C(0)R2, wiierein R2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI-CG alkyl, or CI-CG haioaikyl. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is 5,6,7,8-tetrahydro~l,8~naphthyridin~2~yl; L! is -CH2CH2-, Y is 1,3-cyclobutyl, and L3 is -CH2CH2-; and G is -C(0)R2, wherein R2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI-CG alkyl, or CI-CG haioaikyl. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl; L’! is -CH2CH2-, Y is e/s-1,3- cyclobutyi, and L3 is -CH2CH2-; and G is -C(0)R2, wherein R2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI-CG alkyl, or CI-CG haioaikyl. In an embodiment, the compound of formula (I) or a salt thereof is provided wiierein: R1 is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl; L1 is -CH2CH2-, Y is tram- 1 ,3-cyclobutyl, and L3 is -CH2CH2-; and G is -C(0)R2, wherein R2 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI-CG alkyl, or CI-CG haioaikyl. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is 5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl; L1 is -CH2CH2-, Y is a bond, and L3 is -CH2CH2CH2CH2-; and G is -R3, wherein R3 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haloalkyl. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is 5,6,7,8-tetrahydro-l ,8-naphthyridin- 2-yl; L1 is -CH2CH2CH2-, Y is a bond, and L3 is -CH2CH2CH2-; and G is -R3, wherein R3 is a six-membered heterocyclyl, aryl, or heteroaiyl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haloalkyl. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is 5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl; L1 is -CH2CH2CH2CH2-, Y is a bond, and L3 is -CH2CH2-; and G is -R3, wherein R3 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or Ci-Ce haloalkyl. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is 5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl; L1 is -CH2CH2-, Y is 1,3-cyclobutyl, and L3 is -CH2CH2-; and G is -R3, wherein R3 is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, CI-CG alkyl, or Ci-C& haloalkyl. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is 5,6,7,8-tetrahydro-l ,8-naphthyridin- 2-yl; L1 is -CH2CH2-, Y is cis- 1 ,3-cyclobutyl, and L3 is -CH2CH2-; and G is -R3, wherein RJ is a six-membered heterocyclyl, aryl, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or CI-CG haloalkyl. In an embodiment, the compound of formula (I) or a salt thereof is provided wherein: R1 is 5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl; L1 is -CH2CH2-, Y is fraH,v~j ,3~eyciobutyL and L3 is -CH2CH2-; and G is -R3, wherein R3 is a six-membered heterocyclyl, and, or heteroaryl ring, wherein among the substitutable ring atoms in R2, 1 saturated ring atom, or 2 or 3 unsaturated ring atoms are independently substituted with halogen, Ci-Ce alkyl, or CI-CG haloalkyl. For each individual preceding embodiment described in this paragraph, a further embodiment is disclosed in which among the substitutable ring atoms in R2, one of: one saturated ring atom is substituted with CI-CG haloalkyl, e.g., -CF3; two and ring atoms are independently substituted with halogen; and 2 or 3 heteroaryl ring atoms are independently substituted with halogen or Ci-Cs alkyl, e.g., methyl. Further, in various embodiments, each preceding embodiment described in this paragraph may be excluded from the compound represented by formula (I) and salts thereof.
[0083] In some embodiments, the compound of formula (I) is of the formula (Ila):
Figure imgf000026_0001
or a salt thereof, wherein R2 is as defined for formula (1).
[0084] In some embodiments, the compound of fonnula (I) is of the formula (lib):
Figure imgf000026_0002
or a salt thereof, wherein R3 is as defined for formula (I).
[QQ85] In some embodiments, the compound of formula (I) is of the formula (111a):
Figure imgf000026_0003
or a salt thereof, wherein R2 is as defined for formula (I).
[QQ86] In some embodiments, the compound of formula (I) is of the formula (Mb):
Figure imgf000026_0004
or a salt thereof, wherein R3 is as defined for formula (I).
[0087] In some embodiments, the compound of formula (I) is of the formula (IVa):
Figure imgf000026_0005
or a salt thereof, wherein R2 is as defined for formula (I). [0088] In some embodiments, the compound of formula (I) is of the formula (IVb):
Figure imgf000027_0001
or a salt thereof, wherein R : is as defined for formula (I).
[0089] In some embodiments, the compound of formula (I) is of the formula (Va):
Figure imgf000027_0002
or a salt thereof, wherein R2 is as defined for formula (I).
[0090] In some embodiments, the compound of formula (Va) is of the formula (Va-1):
Figure imgf000027_0003
or a salt thereof, wherein R2 is as defined for formula (I).
[0091] In some embodiments, the compound of formula (Va) is of the formula (Va-2);
Figure imgf000027_0004
or a salt thereof, wherein R2 is as defined for formula (I).
[0092] In some embodiments, the compound of formula (I) is of the formula (Vb):
Figure imgf000027_0005
In some embodiments, the compound of formula (Vb) is of the formula (Vb-1):
Figure imgf000028_0001
or a salt thereof, wherein
Figure imgf000028_0002
is as defined for formula (I).
In some embodiments, the compound of formula (Vb) is of the formula (Vb-2):
Figure imgf000028_0003
or a salt thereof, wherein R : is as defined for formula (I).
[0095] In some embodiments, the compound of formula (I) is of the formula:
Figure imgf000028_0004
wherein) and k are respectively 2 and 4, 3 and 3, or 4 and 2,
or a salt thereof.
[0096] In some embodiments, the compound of formula (I) is of the formula:
Figure imgf000028_0005
or a salt thereof. [QQ97] In some embodiments, the compound of formula (I) is of the formula:
Figure imgf000029_0001
or a salt thereof.
[QQ98] In some embodiments, the compound of formula (I) is of the formula:
Figure imgf000029_0002
lc-1)
Figure imgf000029_0003
(!I-A- l c-2) or a salt thereof
[0099] In some embodiments, the compound of formula (I) is of the formula:
Figure imgf000029_0004
(ll-A-ld-3) or a salt thereof.
[0100] In some embodiments, the compound of formula (I) is of the formula:
Figure imgf000030_0001
or a salt thereof.
[0101] In some embodiments, the compound of formula (I) is of the formula:
Figure imgf000030_0002
or a salt thereof.
[0102] In some embodiments, the compound of formula (I) is of the formula:
Figure imgf000030_0003
or a salt thereof.
[0103] In some embodiments, the compound of formula (I) is of the formula:
Figure imgf000031_0001
or a salt thereof.
In some embodiments, the compound of formula (I) is of the formula:
Figure imgf000031_0002
Figure imgf000032_0001
or a salt thereof.
[0105] In some embodiments, the compound of formula (I) is of the formula:
Figure imgf000032_0002
i
Figure imgf000033_0001
or a salt thereof.
[0106] In some embodiments, the compound of formula (I) is of the formula:
Figure imgf000033_0002
wherein j and k are respectively 2 and 4, 3 and 3, or 4 and 2,
or a salt thereof.
[0107] In some embodiments, the compound of formula (I) is of the formula:
Figure imgf000033_0003
salt thereof. [0108] In some embodiments, the compound of formula (I) is of the formula:
Figure imgf000034_0001
or a salt thereof.
[0109] Reference to formula (I) or any variation thereof includes reference to (11a), (11b), (Ilia), (Illb), (IVa), (IVb), (Va), (Va-1), (Va-2), (Vb), (Vb-1), (Vb-2), (GI-A-1), (II-A-2), (II- A-2i), (II-A-2ii), (P-A-la-l), (II-A-l a-2), (P- A- la-3), (TT-A-lb-1), (II-A-lb-2), (P-A-l c-l), (II-A-lc-2), (II-A-ld-1 ), (II-A-ld-2), (II-A-ld-3), (II-A-2a-l), (II-A-2a-2), (II-A-2a-3), (II-A- 2a-4), (II-A-2b-l), (II-A-2b-2), (Il-A-2c-l), (U-A-2c-2), (II-A-2c-3), (II-A-2c-4), (II-A-2d-l), (II-A-2d-2), (II-A-2d-3), (II-A-2d-4), (II-A-2d-5), (II-A-2d-6), (P-A-2e~1), (H-A-2e-2), (II- A-2e-3), (II-A-2e-4), (D-A-2e-5), (II-A-2e-6), (P-A-2e-7), (II-A-2e-8), (II-A-2f-l), ( 11 -L-2G·· 2), (P-A-2G-3), (II-A-2f-4), (II-A-2f-5), (II-A-2f-6), (K-A-2f-7), (H-A-2f-8), (II-A-2I-9), (II- A-2f-10), (P-B-1), (P-B-2), (P-B-3), (II-B-la), ( ! !-B-2a) (II-B-2b), (Il-B-3a), or (II-B-3b), a compound of Table 1 or Table 2, or any one of compounds 1-329. [0110] In some embodiments of the compound of formula (1), or a salt thereof, tire compound is selected from the group consisting of
Figure imgf000035_0001
pharmaceutically acceptable salt thereof, wherein G is as defined for formula (I), or any applicable variation thereof, and the alpha- carbon of the amino acid can have either R or S absolute stereochemistry as indicated. In one such embodiment, the alpha-carbon of the amino acid is in the S absolute stereochemistry. When the alpha-carbon of the amino acid is in the S absolute stereochemical configuration, in some embodiments such a compound is substantially isolated from the corresponding compound in which the amino acid is in the R absolute stereochemical configuration, such as when a composition comprising the compound in the S absolute stereochemical configuration comprises no more than 5% or 3% or 1% or 0.5% or 0.1 % by weight of the corresponding compound having the R absolute stereochemical configuration. In another such embodiment, the alpha-carbon of the amino acid is in the R absolute stereochemistry. When the alpha- carbon of the amino acid is in the R absolute stereochemical configuration, in some embodiments such a compound is substantially isolated from the corresponding compound in which the amino acid is in the S absolute stereochemical configuration, such as when a composition comprising the compound in the R absolute stereochemical configuration comprises no more than 5% or 3% or 1% or 0.5% or 0.1% by weight of the corresponding compound having the S absolute stereochemical configuration. In another embodiment is provided a composition comprising a foregoing compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one such embodiment is provided a composition comprising a mixture of a compound in winch the alpha-carbon of the amino acid is in the S stereochemical configuration and a compound in which the alpha-carbon of the amino acid is in the R stereochemical configuration.
[0111] Also provided in another embodiment is a compound of formula (I), or a salt thereof, wherein G is -C(0)R2 and R2 is Ci-Ce alkyl substituted by 0-5 R2a groups. In one aspect of the foregoing embodiment, R2 is unsubstituted Ci-Ce alkyl (e.g., unsubstituted Cr- Ce alkyl). In one aspect of tire foregoing embodiment, the Ci-Ce alkyl of R2 is straight-chain alkyl (e.g., n-butyl). In another aspect of the foregoing embodiment, the Ci-Ce alkyl of R2 is branched alkyl (e.g., iso-butyl). In another aspect of the foregoing embodiment, R2 is CI-CJ alkyl substituted by 1-5 R2a groups, wherein each R2a is independently selected from halogen, Ci-Ce alkyl, Ci-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cir aryl, 5- to lO-membered heteroaryl, -CN, -OR3, ~NR6R7, -NR3C(0)0R6, and -SiCfhR3, wherein the Ci- Ce alkyl, (ri-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Ci4 aryl, and 5- to 10- membered heteroaryl of R2a are independently optionally substituted by R4a. In another aspect of the foregoing embodiment, R2 is C2-C5 alkyl substituted by 1-5 R2a groups, wherein at least one of the R2a groups is halogen (e.g., R2 C5 alkyl substituted by 2-3 fluoro groups). In another aspect of the foregoing embodiment, R2 is Ci-Cs alkyl (e.g., C1-C3 alkyl) substituted by 1-5 R2a groups, wherein at least one of tire R2a groups is CVCs cycloalkyl (e.g., cyclopropyl, cyclobutyl, and cyclohexyl). In another aspect of the foregoing embodiment, R2 is C1-C3 alkyl substituted by (h-Ce cycloalkyl, wherein the Cb-Ce cycloalkyl is substituted by 0-5 groups selected from the group consisting of halogen, Ci-Ce alkyl (e.g., methyl), and -OR5 (e.g., -OH and -OCH3). In another aspect of the foregoing embodiment, R2 is Ci-Cs alkyl substituted by Cs-Ce cycloalkyl, wherein the Cs-Ce cycloalkyl unsubstituted. In another aspect of the foregoing embodiment, R2 is Ci-Cs alkyl substituted by 1-5 R2a groups, wherein at least one of the R2a groups is 3- to 12-membered heterocyclyl (e.g. R2 is C; alkyl substituted by 6-membered heterocyclyl). In another aspect of the foregoing embodiment, R2 is C1-C5 alkyl substituted by 1-5 R23 groups, wherein at least one of the R2a groups is Ce- C14 aryl, wherein the Ce-Cw aryl is independently optionally substituted by halogen or Ci-Ce alkyl substituted by 0-5 halogen (e.g., R2a is unsubstituted phenyl or phenyl substituted by 1-5 halogen. In another aspect of the foregoing embodiment, R2 is C2-C5 alkyl (e.g., Cs alkyl) substituted by 1-5 R2a groups, wherein at least one of the R2a groups is 5- to 10-membered heteroaryi substituted by 0-5 R4a groups (e.g., R2a is unsubstituted pyridinyl). In another aspect of the foregoing embodiment, R2 is C1-C5 alkyl substituted by 1-5 R23 groups, wherein at least one of the R2a groups is -OR5, wherein each R5 is independently selected from hydrogen, Ci-Ce alkyl, and Ce-Cu aryl (e.g. , R5 is C&-Ci4 aryl substituted by 0-5 halogen). In another aspect of the foregoing embodiment, R2 is Ci~Cs alkyl substituted by 1-5 R2a groups, wherein at least one of the R2a groups is -CN, -NR6R7, -NR5C(0)0R6, or -S(0)2R5. In another aspect of the foregoing embodiment, R2 is C1-C5 alkyl substituted by 2-5 R2a groups, wherein each R2a is independently selected from halogen, Ci-Ce alkyl, Cs-Cs cycloalkyl, 5- to 10- membered heteroaryl, Ce-Ci4 aryl, -CN, -OR5, and -NR3C(0)0R6. In another aspect of tire foregoing embodiment, R2 is C1-C5 alkyl substituted by 2-5 R2a groups, wherein at least one R2a group is phenyl substituted by 0-5 halogen and at least one R2a group is OR5, wherein each R5 is independently selected from hydrogen and Ci-Ce alkyl .
[0112] Also provided is a compound of formula (I), or a salt thereof, wherein G is -
R2a
C(0)R2 and R2 is selected from the group consisting of:
Figure imgf000037_0001
Figure imgf000037_0002
, wherein each R2a is
independently as defined for formula (I).
[0113] Also provided in another embodiment is a compound of formula (I), or a salt thereof, wherein G is -C(0)R2 and R2 is C3-C cycloalkyl substituted by 0-5 R2b groups. In another aspect of the foregoing embodiment, the Ci-Cs cycloalkyl of R2 is monocyclic. In another aspect, the Cb-Cs cycloalkyl of R2 is bicyclic (e.g., fused, spiro, or bridged). In another aspect, R2 is unsubstituted CiwCs cycloalkyl (e.g. , bicycle[2.2.2]octanyl). In another aspect of the foregoing embodiment, R2 is Cb-Cs cycloalkyl substitu ted by 1 -5 R2b groups, wherein each R2b is independently selected from halogen, Ci-Ce alkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, and -OR5. In another aspect of the foregoing embodiment, R2 is C3-C6 cycloalkyl (e.g. , cyclopropyl or cyclohexyl) substituted by 1-5 R2b groups, wherein at least one of the R2b groups is halogen (e.g., fluoro). In another aspect of the foregoing embodiment, R2 is Ci-Ce cycloalkyl substituted by 1-5 R2b groups, wherein at least one of the R2b groups is Ci-Ce alkyl, wherein the Ci-Cs alkyl of R2b is substituted by 0-5 R4a groups (e.g., R2b is C1-C2 alkyl substituted by 1-5 R4a groups, wherein each R4a groups is independently selected from phenyl substituted by 0-5 halogen and 6- membered heteroaryl substituted by 0-5 halogen). In another aspect of the foregoing embodiment, R2 is Cb-Cs cycloalkyl substituted by 1-5 Rib groups, wherein at least one of the R2b groups is 3- to 12-membered heterocyclyl (e.g., tetrahydro-2 f-pyranyl or benzodioxo!yl). In another aspect of the foregoing embodiment, R2 is C3-C4 cycloalkyl substituted by 1 -5 R2b groups, wherein at least one of the R2b groups is Ce-Cw aryl substituted by 0-5 R4a groups, wherein each R4a is independently selected from halogen, Ci-Ce alkyl, and -OR8 (e.g., R2b is unsubstituted phenyl or R2b is phenyl substituted by fluoro, methyl, tert-butyl, or -OCF3). In another aspect of the foregoing embodiment, R2 is C3-C7 cycloalkyl substituted by 1-5 R2b groups, wherein at least one of the R2b groups is 5- to 10-membered heteroaryl (e.g., pyridinyl or isoquinolinyl). In another aspect of the foregoing embodiment, R2 is C3-C& cycloalkyl substituted by 2-5 R2b groups, wherein each R2D is independently selected from halogen (e.g., fluoro), Ce-Cir aryl (e.g., phenyl), and -OR5 (e.g., -OH). In another aspect of the foregoing embodiment, R2 is C3-C6 cycloalkyl substituted by 2-5 R2b groups, wherein at least one R2b group is halogen (e.g., fluoro) and at least one R2b group is phenyl substituted by 0-5 Ci-Ce alkyl (e.g., -CH3).
[0114] Also provided is a compound of formula (I), or a salt thereof wherein G is -
C(0)R2 and R2 is selected from the group consisting of:
Figure imgf000038_0001
Figure imgf000038_0002
, wherein R2b is as defined for formula (I), and n is 0, 1, 2, or 3. In one variation, n is 0. In another variation, n is 1. In another variation, n is 2. In yet another variation, n is 3.
[0115] Also provided in another embodiment is a compound of formula (I), or a salt thereof, wherein G is -C(0)R2 and R2 is 3- to 12-membered heterocyclyl substituted by 0-5 R2c groups. In another aspect of the foregoing embodiment, the 3- to 12-membered heterocyclyl of R2 is monocyclic. In another aspect of the foregoing embodiment, the 3- to 12-membered heterocyclyl of R2 is bicyclic (e.g., fused, spiro, or bridged). In another aspect of the foregoing embodiment, R2 unsubstituted 4- to 10-membered heterocyclyl (e.g., azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyi, tetrahydropyranyl, oxabicy clohexanyl, oxabicy clooctanyl , tetrahydro-2H-thiopyranyl, morpholinyl,
benzodioxanyl, 3-oxabicyclo[3.1.0]hexanyl, or 8-oxabicyclo[3.2.1]octanyl). In another aspect of the foregoing embodiment, R2 is 3- to 12-membered heterocyclyl substituted by 1-5 R2c groups, wherein each R2c is independently selected from oxo, halogen, Ci-Ce alkyl, Ce- Ci4 aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -C(0)R5, -C(Q)QR5, and -S(0)2.R3 In another aspect of the foregoing embodiment, R2 is 4- to 6-membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, or azetidinyl) substituted by 1-5 R2c groups, wherein at least one of the R2c groups is Ci-Ce alkyl, wherein the Ci-Ce alkyl of R2c is substituted by 0-5 R4a groups. In another aspect of the foregoing embodiment, R2c is C1-C2 alkyl substituted by 1-5 R4a groups, wherein each R4a groups is independently selected from halogen; phenyl substituted by 0-5 halogen; 6-membered heteroaryl (e.g., pyridinyl or pyrimidimy!) substituted by 0-5 halogen; and ~NR8C(0)0R10 (e.g. -NHC(O)O-r-butyl). In another aspect of the foregoing embodiment, R2 is 4- to 6-membered heterocyclyl substituted by 1-5 R2c groups, wherein at least one of the R2c groups is unsubstituted Ce-Cu aryl (e.g., phenyl). In another aspect of the foregoing embodiment, R2 is 4- to 6-membered heterocyclyl (e.g., 5- membered heterocyclyl) substituted by 1-5 R2c groups, wherein at least one of the R2c groups is 5- to 10-membered heteroaryl substituted by 0-5 Ci-Ce alkyl (e.g., R2c is pyrazolyl substituted by -CH3). In another aspect of the foregoing embodiment, R2 is 4- to 6-membered heterocyclyl substituted by 1-5 R2c groups, wherein at least one R2c group is ~C(0)R5, -C(())()R3, or -S(0)2R3, wherein each R3 is independently Ci-Ce alkyl. In another aspect of the foregoing embodiment, R2 is 4- to 6-membered heterocyclyl (e.g., 1,2-dihydropyridinyl) substituted by 1-5 R2c groups, wherein at least one R2c group is oxo. In another aspect of the foregoing embodiment, R2 is 4- to 6-membered heterocyclyl substituted by 2-5 R2c groups, wherein each R2c is independently selected from halogen, Ci-Ce alkyl, -C(Q)R5,
and -C(Q)Q 5 In another aspect of the foregoing embodiment, R is 4- to 6-membered heterocyclyl substituted by 2-5 R2c groups, wherein at least one R2c group is Ci-Ce alkyl substituted by 0-5 halogen and at least one R-'c group is -C(0)R5 or -C(0)OR3. In another aspect of the foregoing embodiment, R2 is azetidinyl, pyrrohdinyi, pipendinyl, oxetanyl, tetrahydrofuranyi, tetrahydropyranyl, oxabicyclohexanyl, oxabicy clooctanyl, tetrahydro-2H- thiopyranyl, morpholinyl, or benzodioxanyl, each of which is substituted by 0-5 R-'c groups. [0116] Also provided is a compound of formula (I), or a salt thereof, wherein G is
C(Q)RZ and R2 is selected from the group consisting of:
Figure imgf000040_0001
Figure imgf000040_0002
d for formula (I), and n is 0, 1, 2, or 3 In one variation, n is 0. In another variation, n is 1 . In another variation, n is 2. In yet another variation, n is 3. In the above structures that depict an -N(H)- moiety and n is 1, 2, or 3, it is understood that one of the R2c groups can replace the hydrogen atom of the -N(H)- moiety (e.g., n is
Figure imgf000040_0003
).
[0117] Also provided in another embodiment is a compound of formula (I), or a salt thereof, wherein G is -C(0)R2 and R2 is Ce-Cir aryl substituted by 0-5 R2d groups. In another aspect of the foregoing embodiment, R2 is unsubstituted Ce-Cio aryl (e.g, phenyl, indanyl, or 1,2,3,4-tetrahydronaphthalenyl). In another aspect of the foregoing embodiment, R2 is Ce-Cio aryl substituted by 1 -5 R2d groups, wherein each R2d is independently selected from halogen, Ci-Ce alkyl, Cs-Cs cycloalkyl, 3- to 12-membered heterocyclyl, 5- to lO-membered heteroaryl, -CN, and -OR5, wherein the Ci-Ce alkyl, C3-Cs cycloalkyl, 3- to 12-membered heterocyclyl and 5- to lO-membered heteroaryl of R2d are each independently substituted by 0-5 halogen, Ci-Ce alkyl or OR8. In another aspect of the foregoing embodiment, R2 is Ce-Cio aryl substituted by 1-5 R2d groups, wherein at least one of the R2d groups is halogen (e.g. , fluoro or ehloro). In another aspect of the foregoing embodiment, R2 is Ce-Cio aryl substituted by 1 -5 R2d groups, wherein at least one of the R2d groups is Ci-Ce alkyl, wherein the Ci-Ce alkyl of R2a is substituted by 0-5 R4a groups (e.g., R2d is -CH ). In another aspect of tire foregoing embodiment, R2d is C1-C2 alkyl substituted by 1-5 R4a groups, wherein each R4a groups is independently selected from halogen and OR8 (e.g., R2d is -CHblQH), or -CF3). In another aspect of the foregoing embodiment, R2 is Ce-Cio aryl (e.g, phenyl) substituted by 1-5 R2d groups, wherein at least one of the R2d groups is Cb-Ce cycloalkyl (e.g., cyclopropyl). In another aspect of the foregoing embodiment, R2 is Ce-Cio aryl (e.g, phenyl) substituted by 1-5 R2d groups, wherein at least one of the R2d groups is 6-membered heterocye!yl (e.g , morpholinyl). In another aspect of the foregoing embodiment, R2 is Ce-Cio aryl (e.g, phenyl) substituted by 1-5 R2d groups, wherein at least one of the R2d groups is 5- to 6- membered heteroaryl (e.g., pyrazolyl, thiazoiyl, or pyridinyl), w'herein the heteroaryl of R2d is substituted by 0-5 Ci-Ce alkyl groups (e.g., -CHs). In another aspect of the foregoing embodiment, R2 is Ce-Cio and (e.g, phenyl) substituted by 1 -5 R2a groups, wherein at least one of the R2d groups is -OR5, wherein each R5 is independently selected from Ci-C 2 alkyl substituted by 0-5 groups selected from halogen (e.g., fluoro) and -OR10 (e.g., -0( 1 b). In another aspect of the foregoing embodiment, R2 is Ce-Cio and (e.g, phenyl) substituted by 2-5 R2d groups, w'herein each R-'a is independently selected from halogen, Ci-Ce alkyl, -CN, and -OR5. In another aspect of the foregoing embodiment, R2 is Ce-Cio aryl (e.g, phenyl) substituted by 2-5 R2d groups, wherein at least two of the R2d groups are halogen (e.g., fluoro or chloro). In another aspect of the foregoing embodiment, R2 is Ce-Cio aryl (e.g, phenyl) substituted by 2-5 R2d groups, w'herein at least one of the R2d groups is Ci-Ce alkyl and at least one of the R2d groups is selected from the group consisting of halogen, -CN, and -OR5 in another aspect of the foregoing embodiment, R2 is phenyl, indanyl, or 1 , 2,3,4- tetrahydronaphthalenyl, each of which is substituted by 0-5 R2d groups.
[0118] Also provided is a compound of formula (I), or a salt thereof, wherein G is -
C(0)R2 and R2 is selected from the group consisting of:
Figure imgf000041_0001
Figure imgf000041_0002
, wherein R2d is as defined for formula (I), and n is 0, 1,
2, or 3. In one variation, n is 0. In another variation, n is 1 In another variation, n is 2. In yet another variation, n is 3.
[0119] Also provided in another embodiment is a compound of formula (I), or a salt thereof, wherein G is -C(0)R2 and R2 is 5 - to 10-membered heteroaryl substituted by 0-5 R2e groups. In another aspect of the foregoing embodiment, R2 is un substituted 5- to 10- membered heteroaryl (e g., pyridinyl, pyrrolopyridinyl, quino!inyl, or 4,5,6,7-tetrahydro- indazolyS). In another aspect of the foregoing embodiment, R2 is 5- to lO-membered heteroaryl substituted by 1-5 R2e groups, wherein each R2s is independently selected from halogen, Ci-Ce alkyl, and -OR5. In another aspect of the foregoing embodiment, R2 is 5- to lO-membered heteroaryl (e.g., pyridinyl) substituted by 1 -5 R2e groups, wherein at least one of the R2e groups is halogen. In another aspect of the foregoing embodiment, R2 is 5- to 10- membered heteroaryl (e.g., pyridinyl, pyrimidinyl, pyrrolopyridinyl, or indazolyl) substituted by 1-5 R2e groups, wherein at least one of the R2e groups is Ci-Cr alkyl, wherein the Ci- C.4 alkyl of R2e is substituted by 0-5 halogen groups (e.g. R2e is -CHs or -CFri). In another aspect of the foregoing embodiment, R2 is 5- to lO-membered heteroaryl substituted by 2-5 R28 groups, wherein each R28 is independently selected from halogen, CI-CG alkyl, and -CN. In another aspect of the foregoing embodiment, R2 is 5- to 10-membered heteroaryl substituted by 2-5 R28 groups, wherein at least two of the R2e groups are halogen. In another aspect of the foregoing embodiment, R2 is 5- to lO-membered heteroaryl substituted by 2-5 R2e groups, wherein at least two of the R2e groups are Ci-Ce alkyl. In another aspect of the foregoing embodiment, R2 is 5- to 10-membered heteroaryl (e.g. , pyridinyl or pyrimidinyl) substituted by 3-5 R2e groups, wherein each R2e is independently selected from halogen, Ci- CG alkyl, and -CN. In another aspect of the foregoing embodiment, R2 is 5- to 10-membered heteroaryl (e.g., pyridinyl or pyrimidinyl) substituted by three -Ctb groups. In another aspect of the foregoing embodiment, R2 is 5- to 10-membered heteroaryl (e.g., pyridinyl or pyrimidinyl) substituted by two -Ctb groups and one halogen group. In another aspect of the foregoing embodiment, R2 is pyrazolyl, pyridyl, pyrimidinyl, indazolyl, pyrrolopyridinyl, quinolinyl, or 4,5,6,7-tetrahydro-indazolyl, each of which is substituted by 0-5 R28 groups.
[0120] Also provided is a compound of formula (I), or a salt thereof, wherein G is -
C(Q)R2 and R2 is selected from the group consisting of:
Figure imgf000042_0001
Figure imgf000042_0002
, , wherein R2e is as defined for formula (I), and n is 0, 1, 2, or 3. In one variation, n is 0. In another variation, n is 1. In another variation, n is 2 In yet another variation, n is 3.
[0121] Also provided in another embodiment is a compound of formula (I), or a salt thereof, wherein G is -C(Q)R2 and R2 is -OR2f . In another aspect of the foregoing embodiment, R2f is selected from the group consisting of Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cir and, and 5- to lO-membered heteroaryl.
[0122] Also provided in another embodiment is a compound of formula (I), or a salt thereof, wherein G is -C(0)R2, R2 is -GR2i, and R2fis Ci-Ce alkyl substituted by 0-5 R2‘ groups. In another aspect of the foregoing embodiment, R21 is unsubstituted Ci-Ce alkyl. In another aspect of the foregoing embodiment, R2f is Ci-Ce alkyl substituted by 1-5 R2 groups, wherein each R21 is independently selected from the group consisting of halogen, Ci-Ce alkyl, C3-C.8 cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cw aryl, 5- to 10-membered heteroaryl, -OR5, ~NR5C(0)R6, and -NR5C(0)0R6, wherein the Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Ci aiyl, and 5- to 10-membered heteroaryl of R21 is substituted by 0-5 groups selected from the group consisting of halogen, -CN, -OR8, and Ci- Cfi alkyl optionally substituted by halogen. In another aspect of the foregoing embodiment, R2fis Ci-Ce alkyl substituted by 1-5 R2 groups, wherein at least one of the R2' groups is halogen. In another aspect of the foregoing embodiment, R2f is Ci-Ce alkyl substituted by 1-5 R21 groups, wherein at least one of the R21 groups is phenyl. In another aspect of the foregoing embodiment, R2fis Ci-Ce alkyl substituted by 1-5 R2! groups, wherein at least one of the R2' groups is -NR5C(0)ORb, wherein R5 is hydrogen and R6 is Ci-Ce alkyl (e.g, R21
is -NHC(O)O-t-butyl). In another aspect of the foregoing embodiment, R2t is Ci-Ce alkyl substituted by 1-5 R21 groups, wherein at least one of the R2i groups is ~NR5C(0)R6, wherein R5 is hydrogen and R6 is Ci-Ce alkyl (e.g., R2* is -NHC(0)CH3).
[0123] Also provided is a compound of formula (I), or a salt thereof, wherein G is -
C(0)R2 and R2 is selected from the group consisting of:
Figure imgf000043_0001
wherein R2' is as defined for formula (I).
[0124] Also provided in another embodiment is a compound of formula (I), or a salt thereof, wherein G is -C(0)R2, R2 is -OR2 and R2fis Cs-Cs cycloalkyl substituted by 0-5 R21 groups. In another aspect of the foregoing embodiment, R2l is unsubstituted Cs-Cs cycloalky] (e.g., cyclopentyl, cylcohexyl, or spiro[2.3]hexanyl). In another aspect of the foregoing embodiment, R2f is C3-C8 cycloalkyl substituted by 1-5 R2s groups, wherein each R21 is independently selected from the group consisting of halogen, Ci-Ce alkyl, Ci-Ce alkynyl, Ce- C 14 and, and 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C -Ce alkynyl, Ce- Ci4 aryl, and 5- to lO-membered heteroaryl of R2i are substituted by 0-5 groups selected from the group consisting of Ci-Ce alkyl and Ce-Cu aryl. In another aspect of the foregoing embodiment, R2fis Cs-Ce cycloalkyl (e.g., cyclopropyl or cyclobutyl) substituted by 1 -5 R21 groups, wherein at least one R21 group is Ci alkyl. In another aspect of the foregoing embodiment, R2t is C Ce cycloalkyl substituted by 1-5 R21 groups, wherein at least one R21 group is C2 alkynyl substituted by 0-1 phenyl group. In another aspect of the foregoing embodiment, R2f is Ci-Ce cycloalkyl substituted by 1-5 R2s groups, wherein at least one R2' group is phenyl substituted by 0-3 Ci-Ce alkyl groups or is pyrazolyl substituted by 0-3 Ci- Ce alkyl groups, which Ci-Ce alkyl groups on phenyl or pyrazolyl of R2s may he the same or different
[0125] Also provided is a compound of formula (I), or a salt thereof, wherein G is -
selected from the group consisting of:
Figure imgf000044_0001
Figure imgf000044_0002
, wherein R2i is as defined for formula (I) and n is 0, 1, or 2. In one variation, n is 0. In another variation, n is 1. In yet another variation, n is 2.
[0126] Also provided in another embodiment is a compound of fonnula (I), or a salt thereof, wherein G is -C(0)R2, R2 is -QR2f, and R2t is 3- to 12-membered heterocyclyl substituted by 0-5 R2‘ groups. In another aspect of the foregoing embodiment, R2f is unsubstituted 3- to 12-membered heterocyclyl (e.g. , azetidinyl or pyrrol idinyl). In another aspect of the foregoing embodiment, R2f is 3- to 12-membered heterocyclyl substituted by 1-5 R2‘ groups, wherein each R2’ is independently selected from the group consisting of Ci- Ce alkyl, Cr-Ce alkynyl, Ce-Cu aryl, -C(Q)R3, -C(0)OR5, and -S(Q)2R5. In another aspect of the foregoing embodiment, R2fis 3- to 12-membered heterocyclyl substituted by 1-5 R2* groups, wherein at least one R2' group is Ci-Ce alkyl or Ci-Ce alkynyl, each of which is unsubstituted or substituted by a phenyl group. In another aspect of the foregoing embodiment, R2f is 3- to 12-membered heterocyclyl substituted by 1-5 R21 groups, wherein at least one R2! group is Ce-Cr aryl (e.g., phenyl) substituted by 0-5 R4a groups, wherein each R4a is independently selected from the group consisting of halogen and Ci-Ce alkyl (e.g., isopropyl). In another aspect of the foregoing embodiment, R21 is 3- to 12-membered heterocyclyl (e.g., azetidinyl or pyrroiidinyl) substituted by 1-5 R21 groups, wherein at least one R21 group is -C(0)R5, wherein R5 is Ci-Cs alkyl (e.g, R2i is -C(0)CH3). In another aspect of the foregoing embodiment, R2fis 3- to 12-membered heterocyclyl substituted by 1-5 R21 groups, wherein at least one R21 group is ~C(0)OR5, wherein R3 is Ci-Ce alkyl (e.g. , R2' is - C(O)O-t-butyd). In another aspect of the foregoing embodiment, R2f is 3- to 12-membered heterocyclyl (e.g., azetidinyi or pyrrolidinyi) substituted by 1-5 R2‘ groups, wherein at least one R21 group is -S(0)2R5, wherein R5 is Ci-Ce alkyl (e.g., R21 is -S(0)2GHb). In another aspect of the foregoing embodiment, R2f is 3- to 12-membered heterocyclyl substituted by 2-5 R21 groups, wherein at least one R21 group is -C(0)R5, -C(0)OR5, or -S(0)2R5, wherein R5 is Ci-Ce alkyl (e.g., R3 is - CHs or t-butyl). In another aspect of the foregoing embodiment, R21 is azetidinyi, pyrrolidinyi, or tetrahydropyranyl, each of which is optionally substituted by 0- 5 R2’.
[0127] Also provided is a compound of formula (I), or a salt thereof, wherein G is -
C(0)R2 and R2 is selected from the group consisting of:
Figure imgf000045_0001
wherein R2i is as defined for formula (I) and n is 0, 1, or 2. In one variation, n is 0. In another variation, n is 1. In yet another variation, n is 2. In the above structures that depict an -N(H)- moiety and n is 1 or 2, it is understood that one of the R21 groups can replace the hydrogen
atom of the -N(H)- moiety
Figure imgf000045_0002
[0128] Also provided in another embodiment is a compound of formula (I), or a salt thereof, wherein G is -C(0)R2, R2 is -OR2i, and R2f is Ce-Cu aryl substituted by 0-5 R2’ groups. In another aspect of the foregoing embodiment, R21 is unsubstituted C&-C14 aryl (e.g. , indanyl or l ,2,3,4-tetrahydronaphthaienyi).
[0129] Also provided is a compound of formula (I), or a salt thereof, wherein G is -
C(Q)R2 and R2 is selected from the group consisting of:
Figure imgf000045_0003
wherein R21 is as defined for fonnula (I) and n is 0, 1 , or 2. In one variation, n is 0. In another variation, n is 1. In yet another variation, n is 2. [0130] Also provided in another embodiment is a compound of formula (1), or a salt thereof, wherein G is -C(Q)R2, R2 is -QR2i, and R2fis 5- to lO-membered heteroaryl substituted by 0-5 R2·1 groups. In another aspect of the foregoing embodiment, R21 is unsubstituted 5- to 10-membered heteroaryl.
[0131] Also provided in another embodiment is a compound of formula (I), or a salt thereof, wherein G is -C(0)R2 and R2 is -NR2gR2h. In another aspect of the foregoing embodiment, R2g is hydrogen and R2h is Ci-Ce alkyl substituted by 0-5 halogen. In another aspect of the foregoing embodiment, R2g is Ci-Ce alkyl substituted by 0-5 halogen and R2h is Ci-Ce alkyl substituted by 0-5 halogen.
[0132] Also provided is a compound of formula (I), or a salt thereof, wherein G is C(0)R2
and R2 is selected from the group consisting of:
Figure imgf000046_0001
Figure imgf000046_0002
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
50
Figure imgf000052_0001
Figure imgf000053_0001
[0133] Also provided is a compound of formula (I), or a salt thereof, wherein G is -C(Q)R2 and R2 is selected from the group consisting of:
Figure imgf000053_0002
Figure imgf000053_0003
Figure imgf000054_0001
[0134] Also pro vided is a compound of formula (1), or a salt thereof, wherein G is -C(0)R2 and R2 is selected from the group consisting of:
Figure imgf000054_0002
Figure imgf000054_0003
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
[0135] Also provided is a compound of formula (I), or a salt thereof, wherein G is
C(0)R2 and R2 is selected from the group consisting of:
Figure imgf000057_0002
Figure imgf000057_0003
[0136] Also provided in another embodiment is a compound of formula (I), or a salt thereof, wherein G is R3. In one aspect, R3 is 5- to 10-membered heteroaryl (e.g., pyrimidinyl or quinazolinyl) substituted by 0-5 R3e groups, wherein each R3e group is independently selected from halogen; Ci-Ce alkyl optionally substituted by halogen; 5- to 10-membered heteroaryl optionally substituted by halogen or Ci-Ce alkyl; and Ci-Ce alkoxy. In one aspect, R3 is unsubstituted 5- to 10-membered heteroaryl. In one aspect, R3 is 5- to 10-membered heteroaryl substituted by 1-5 R3e groups, wherein each R3s group is independently selected from halogen, Ci-C& alkyl, and C&-C14 aryl. In one aspect, R3 is 5- to 10-membered heteroaryl substituted by 1 -5 R3e groups, wherein at least one R3e group is halogen. In one aspect, R3 is 5- to 10-membered heteroaryl substituted by 1-5 RJe groups, wherein at least one R3e group is C1-C4 alkyl. In one aspect, R3 is 5- to 10-membered heteroaryl substituted by 1-5 R3e groups, wherein at least one R3e group is phenyl. In one aspect, R3 is 5- to 10-membered heteroaryl substituted by 2-5 R3e groups, wherein at least one R3e group is Ci-Ce alkyl, and wherein at least one R3e group is CS-CM aryl.
[0137] Also provided is a compound of formula (I), or a salt thereof, wherein G is R3 and
R3 is selected from the group consisting of:
Figure imgf000058_0001
Figure imgf000058_0002
Figure imgf000058_0003
, wiierein each R3e is independently R4. In the above structures wherein the - moiety is present as shown and the structure it substituted by at least one R3e group, it is understood that one of the R3e groups can replace the hydrogen atom of the -N(H)- moiety
Figure imgf000058_0004
[0138] Also provided is a compound of formula (I), or a salt thereof, wiierein G is R3 and
R3 is selected from the group consisting of:
Figure imgf000058_0005
Figure imgf000059_0001
[0139] Also provided is a compound of formula (I), or a salt thereof, wherein G is R3 and
R3 is selected from the group consisting of:
Figure imgf000059_0002
Figure imgf000060_0001
[0140] Also provided is a compound of formula (I), or a salt thereof, wherein G is R3 and
R3 is selected from the group consisting of:
Figure imgf000060_0002
Figure imgf000060_0003
[0141] Also provided is a compound of formula (I), or a salt thereof, wherein G is selected from the group consisting of:
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
[0142] In one aspect, provided is a compound of formula (I) or a salt thereof, wherein the compound has any one or more of the following features:
Figure imgf000064_0001
(II) -Ld-O-LAY-L3- are taken together to form a moiety selected from the group
Figure imgf000064_0002
(III) G is -C(0)R2 or R3 wherein:
(A) R2 is:
(i) CI-CG alkyl optionally substituted by R23, such as methyl, ethyl,
isopropyl, or tert-butyl, each of which is substituted by 0-5 R2a groups;
(ii) Cb-C s cycloalkyl optionally substituted by R2b, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or spiro[3.3]heptanyl, each of w'hich is substituted by 0-5 R2b groups;
(iii) 3- to 12-membered heterocyciyl optionally substituted by R2e, such as 4- to 6-membered heterocyciyl containing 1 or 2 heteroatoms selected from O and N (e.g., azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl), each of which is substituted by 0-5 R2c groups;
(iv) Cfi-Ci4 aryl optionally substituted by R2d, such as phenyl substituted by 0-5 R2d groups; or
(v) 5- to 10-membered heteroaryl optionally substituted by R2S, such as pyridinyl, pyrimidinyl, indazolyl, or qumolmyl, each of which is substituted by 0-5 R2e groups; and
wherein each R2a, R2b, R2d, and R2s is independently R4, R2c is oxo or R4, and R4 is halogen, Ci-C& alkyl, Cs-Cs cycloalkyl, 3- to 12-membered heterocyciyl, Ce-CA and, 5- to 10-membered heteroaryl, -CN, -OR3, -C(0)R5, -C(0)OR5, -C(0)NR6R7, -NR5C(0)0R6, or -S(0)2R5, wherein the Ci-Ce alkyl, CVCs cycloalkyl, 3~ to 12-membered heterocyclyl, Cb- C14 aryl . and 5- to 10-membered heteroaryl of R4 are independently optionally substituted by R43, wherein R4a is halogen, -OR*,
-NR8R9, -C(0)0R®, -NR8C(O)OR]0, -CN, 5- to 10-membered heteroaryl, Ce-Ci4 aryl, or Ci-Cb alkyl, wherein
R8 is hydrogen or Ci-Ce alkyl optionally substituted by halogen,
R9 is hydrogen, and
R10 is Ci-Ce alkyl optionally substituted by halogen; and
(B) R3 is:
(vi) Ci-Cb alkyl optionally substituted by RJa, such as methyl or ethyl, each of which is substituted by 1 R3a group, wherein R3a is pheny l or quinazolinyl; or
(vii) 5- to 10-membered heteroaryl optionally substituted by R3e, such as pyrimidinyl, quinazolinyl, or pyrazolopyrimidinyl, each of which is substituted by 0-5 R3e groups;
In one aspect of this variation, (1) and (11) apply, and G is -C(0)R2. In another aspect of this variation, (I) and (II) apply, and G is R3 In another variation, (I) and (II) apply, G is - C(Q)R2, and (i) applies. In another variation, (I) and (II) apply, G is -C(Q)R2, and (ii) applies In another variation, (1) and (II) apply, G is -C(0)R2, and (iii) applies. In another variation, (I) and (II) apply, G is -C(0)R2, and (iv) applies. In another variation, (I) and (II) apply, G is -C(0)R2, and (v) applies. In another variation, (I) and (II) apply, G is R3, and (vi) applies. In another variation, (I) and (II) apply, G is R3, and (vii) applies.
[0143] Also provided is a compound of formula (I), or a salt thereof, wherein G is -
C(Q)R2, R2 is Ci-Ce alkyl optionally substituted by R23, Ci-Cs cycloalkyl optionally substituted by R2b, 3- to 12-membered heterocyclyl optionally substituted by R2c, Cb-Ci4 aryl optionally substituted by R2d, or 5- to !Q-membered heteroaryl optionally substituted by R2e, wherein each R2a, R2b, R2c, R2a, and R2e is independently R4, wherein each R4 is
independently selected from the group consisting of:
Figure imgf000065_0001
Figure imgf000066_0001
, wherein each R4a is independently halogen, -OR8, -NR8R9, -C(0)0R8, -NR8C(0)0R10, -CN, 5- to 10-membered heteroaryl, Ce- Ci4 aryl, or Ci-C& alkyl, wherein R8, R9, and R10 are as defined for formula (I), and n is 0, 1, or 2. In one variation, n is 0. In another variation, n is 1. In yet another variation, n is 2.
[0144] Also provided is a compound of formula (I), or a salt thereof, wherein G is - C(0)R2, R2 is Ci-Ce alkyl optionally substituted by R2a, Ca-Cs cycloalkyl optionally substituted by R20, 3- to 12-membered heterocyclyl optionally substituted by R2c, Ce-Cir aryl optionally substituted by R2d, or 5- to 10-rnernbered heteroaryl optionally substituted by R2s, wherein each R2a, R2b, R2c, R2d, and R2e is independently R4, wherein each R4 is
Cl CH3 CF3 CN OH independently selected from the group consisting of:
Figure imgf000066_0002
Figure imgf000066_0003
[0145] When a moiety is contemplated, it is understood that the moiety' can be attached to the rest of the structure at any available position. For example, 3-chloro-5-methylpyridinyl may be attached to the rest of the structure at the 2-, 4-, or 6-position (i.e., 3-chloro-5- methylpyridin-2-yl, 3-chioro-5-methylpyridin-4-yl or 3-chloro-5-methylpyridin-6-yl, respectively). The R2 and R3 groups described herein are shown as attached at specific positions (e.g., pyrimid-4-yl, quinazolin-4-yl, or isoquinolin-l-yl) but they can also be attached via any other available valence (e.g., pyrimid-2-yl, quinazolin-2-yl, or isoquinolin-3- yl, respectively).
[0146] Representative compounds are listed in Table 1. Table 1
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
[0147] The structures in Table 1 are drawn without stereochemistry. Atoms which can be stereocenters are noted by an asterisk (*). The structures are intended to embrace all possible stereoisomers of the compound depicted, as well as mixtures of stereoisomers in any proportion. Thus, racemic mixtures, scaiemic mixtures, mixtures of enantiomers in any proportion, mixtures of diastereomers in any proportion, and mixtures of enantiomers and diastereomers m any proportion are embraced, as well as individual, stereochemically pure compounds.
[0148] In some embodiments, provided is a compound selected from the compounds depicted in Table 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 the compounds depicted in Table 1, or a stereoisomer thereof.
[0149] Additional representative compounds are shown in Table 2 (FIG. 1). In some embodiments, provided is a compound selected from the compounds depicted in Table 2, 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 the compounds depicted in Table 2, or a stereoisomer thereof. The“flat” versions of all compounds depicted in Table 2 are also contemplated in this disclosure, including flat versions of any specific stereoisomeric forms in the Table.
[0150] Regarding the structures in FIG. 1, Table 2, reference to compound numbers in the table in some instances depicts a particular stereoisomeric form of the compound number, as will be evident from the chemical structure depicted. For example, Table 2 lists
Figure imgf000080_0001
as Compound 185. It is appreciated that the compound depicted is a specific stereochemical form of Compound 185, in particular the form produced by Example 365.
[0151] In one variation, the compound detailed herein is selected from the group consisting of:
N~(l -methyl-lH-indazole-4-carhony])-Q-(4~(5,6,7,8-tetrahydro-l ,8~naphthyridin~2- yl)butyl)homoserine;
N-(2-chIoro-3-fluorobenzoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yljbutyl )homoserine ;
N-(2-ethylbutanoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)homoserine;
N-benzoyl-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)homoserine; N -(4,4-difluorocyclohexane- 1 -carbonyl)-0-(4-(5,6,7,8-tetrahydro- l,8-naphthyridin-2- yljbutyi )homoserine ;
N-pentanoyl-0-(4-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)but l)homoserine;
N-(3-fluoro-5-(trifluoromethyl)benzoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yi)butyI)homosenne ;
2-(2-ethylbutanamido)-5-(3-(5,6,7,8-tetraliydrol,8-naphthyridin-2-yl)propoxy)pentanoic acid;
2-(2-chloro-3-iluorobenzamido)-5~(3-(5,6,7,8-tetrahydro-L8-naphthyridin-2- yl)propoxy)pentanoic acid;
2-(l-methyl-lH-indazo]e-4-carboxamido)-5-(3-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)propoxy)pentanoic acid;
2-(3-(l-methyl-lH-pyrazol-4-yl)benzaimdo)-5-(3-(5,6,7,8-tetrahydiO-l,8-naphthyndin-2~ yl)propoxy)pentanoic acid;
2-(2-ch]oro-3-fluorobenzamido)-6-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethoxy)hexanoic acid;
2-(3-(l-methyl-lH-pyrazol-4-yl)benzamido)-6-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethoxy)hexanoic acid;
N-(2-chloro-3-fluorobenzo}d)-0-(3-(2 -(5,6,7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(3-fluoro-5-(trifluoromethyl)benzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
2-(2-ethylbutanamido)-6-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethox ')hexanoic acid; 2-( 1 -methyl- lH-indazole-4-carboxamido)-6-(2-(5, 6,7, 8-tetrahydro- 1 ,8-naphthyridin-2- yl)ethoxy)hexanoic acid;
N-pentanoyl-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine;
N-(tert-butoxycarbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyc3obuty!)homoserine;
2-((tert-butox\ arbonyl)amino)-5-(3-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)propoxy)pentanoic acid;
N-benzoyl-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(tert-butoxycarbonyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yi)butyd)homoserine; 2-((tert-butoxycarbonyl)amino)-6-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethoxy)hexanoic acid; N-(4-fluofobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridm-2- yl)etiiyl)cyclobutyl)homoserine;
N-(4-chlorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)etliy3)cyclobutyl)homoserine;
N~(3 iliiorobenzoyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphtliyridin~2- yl)ethy!)cyc3obuty!)homoserine;
N~(3-chlorobenzoy])-0-(3~(2-(5,6,7,8~tetrahydro-l,8-naphthyridm-2- yl)ethyi)cyclobutyl)homoserine;
N-(2~eli3orobenzoyI)-Q-(3-(2~(5,6,7,8-tei.raliydro~l,8~napfat:liyridm~2~ yl)ethy!)cyclobuty])homoserine;
N-(2-fluorobenzoyl)-0-(3-(2-(5,6,7,8-tetra ydro-l,8-naphthyridin-2- yi)eiliyl)cyc3obuiyl)3iomoserine;
N-(2,3-difluorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyc3obutyl)homoserine;
N-(2,4-difiuorobenzoyl)-0-(3-(2 -(5,6,7, 8-tetrabydro-l, 8-naph1byridin-2- yl)ethyi)cyclobutyl)homoserine;
N-(2-chloro-4-fluorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)etliy3)cyclobutyl)homoserine;
N-(3-chloiO-5-fluorobenzoyl)-0-(3-(2-(5,6,7,8-ieirahydiO-l,8-napht3iyndm-2- yl)ethy3)cyc3obutyI)liomoserine;
N-(3-chloro-2-fluorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridm-2- yl)ethyl)cyc3obutyl)homoserine;
]N-(3,5-difluorobenzoyl)-0-(3-(2-(5,6,7,8-teira3iydro-l,8-napht3iyridm-2- yl)ethy3)cyc3obutyl)homoserine;
N-(3,4-difluorobenzoyl)-()-(3-(2-(5,6,7,8-tetrahydro-l,8-naphihyridin-2- yi)eiliyl)cyc3obuiyl)3iomoserine;
N-(2,3-dichlorobenzoyl)-0-(3-(2-(5,6,7,8~tetrahydro-l,8-naphthyndin-2- yl)ethyl)cyc!obutyl)homoserine;
N-(2-chIoro-6-fluorobenzoyl)-()-(3-(2-(5,6,7,8-tetrahydro-l,8-naphihyridin-2- yl)ethyi)cyclobutyl)homoserine;
N-(2,6-difluorobenzoyl)~0~(3-(2-(5,6,7,8-tetraliydro-l,8-naphtliyridin-2- yl)ethy!)cyclobuty])homoserine; N-(2,5-difluorobenzo} )-0-(3-(2-(5,6,7,8-tetrahydfo-l,8-naphthyridin-2- yl)ethy3)cyclobutyl)homoserine;
N-(3,4-dichlorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)etliy3)cyclobutyl)homoserine;
N-picolinoyl-0-(3-(2-(5,6,7,8-tetraliydrc>-l,8-naphthyridin-2-yl)ethyl)cyciobiityl)homoserme;
N-nicotinoy3-0-(3~(2-(5,6,7,8-tetrahydro-L8-naplithyridin-2-yI)etliy3)cyciobi3ty3)homoserine;
N-isonicotinoyl-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphthyridin-2- yl)ethyi)cyclobutyl)homoserine;
N-(l-methyl-lH-indazole-4-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yi)ethy!)cyclobutyl)homoserme;
N-(2-methyl-2H-indazole-6-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(2-methyl-2H-indazole-5-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(l-methyl-lH-pyrrolo[2,3-b]pyridine-4-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8- naphthyridin-2-yl)ethyl)cyciobutyl)homoserme;
N-(3-hydroxy-2-phenylpropanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin~2- yl)ediy3)cyclobutyl)homoserine;
N-(2-ethylbutanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethy3)cyc3obuty!)homoserine;
N-(3-ediylpentanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(l-methyl-lH-pyrrolo[2,3-b]pyridine-5-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyI)cyclobutyl)homoserine;
0-(3-(2-(5,6,7,8-tetrahydrc>-l ,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-(3-(thiazol-5- yi)benzoyi)homoserine:
N-(3-(hydroxymethyl)benzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyl)cyc!obutyl)homoserine;
N-(quinoline-5-carbonyl)-0-(3-(2-(5, 6,7, 8-tetrahydro-l,8-naphthyri din-2- yl)ethyi)cyclobutyl)homoserine;
N-(2-cyclopropylbenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethy!)cyclobuty])homoserine; N-(quinoline-7-carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(quinoline-6-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)etliyl)cyclobutyl)homoserine;
N-(quinoline-8-carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphthyridin-2- yl)ethyl)cyc3obuty!)homoserine;
N-(3-cyclopropylbenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(4-cyclopropylbenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethy!)cyclobutyl)homoserine;
N-(3-(l-methyl-lH-pyrazoI-4-yl)benzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-L8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(2-hydroxy-2-phenyiacetyi)-0-(4-(5,6,7,8-tetraliydro-l,8-naphtliyridin-2- yl)butyl)homoserine;
N-(2-hydroxy-2-phenylace )-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyi)cyclobutyl)homoserine;
N-(3-(l-methyl-lH-pyrazol-4-yl)benzoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridm-2- yl)butyl)homoserine;
N~( 1 -phenylcyclopropane- 1 -carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro- 1 ,8-naphtliyridm-2- yl)ethy3)cyc3obuty!)homoserine;
N~(2-methyi-2-phenylpropanoy!)-0-(3-(2-(5,0,7,8-tetrahydrc ~] ,8-naphthyri din-2- yl)ethyl)cyclobutyl)homoserine;
N -( 1 -pheny icy ciobutane- 1 -carbonyl)-0-(3 -(2-(5 ,6,7, 8-tetrahydro- 1 ,8-naphthyndin-2~ yl)ethy3)cyc3obutyl)homoserine;
N-(2,2-dimethyl-3-phenylpropanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(2-(4-fluorophenyl)-2-methylpropanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(3-methy oxetane-3-carbonyl)-0-(3-(2-(5, 6, 7, 8-tetrahydro- l,8-naphthyridin-2- yl)ethyi)cyclobutyl)homoserine;
N-(3-hydrox -2,2-dimethylpropanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethy])cyclobutyl)homoserine; N-(3-methoxy-2,2-dimethylpfopanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)etiiyl)cyclobutyl)homoserine;
N-(2-methyl-2-(pyridin-3-y])propanoy])-0-(3-(2-(5,6,7,8-tetraJhydro-l,8-naphthyridin-2- yl)etliy3)cyclobuiyl)homoserine;
N-(2,3-dihydro-lH-indene-2-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethy3)cyc3obutyI)liomoserine;
N-(3-cyano-2,2-dimethylpropanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyi)cyclobutyl)homoserine;
N-pivaloyl-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naplithyridin-2-yl)etliyl)cyclobutyl)homoserine;
N-(2,3-dihydro-lH-indene-l-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)etliyl)cyclobutyl)homoserine;
N~((neopentyloxy)carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphtliyridin-2- yl)ethy3)cyc3obuty!)homoserine;
N-((l -methylcyclopropoxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
-(( 1 -methylcyclobutoxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro- 1 ,8-naphthyridin-2- yl)etiiyl)cyclobutyl)homoserine;
0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)eth} )cyclobut> )-N-(((l, l, l-trifluoro-2- methylpropan-2-yl)oxy)carbony3)homoserine;
N-(isopropoxycarbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyl)cyc!obutyl)homoserine;
N-(diethylcarbamoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyi)cyclobutyl)homoserine;
N-(tert-butylcarbamoyl)-0-(3-(2-(5,6,7,8-tetrahydiO-l,8-naphthyridin-2- yl)etliyl)cyclobutyl)homoserine;
N~(tert-buty3(metliyl)carbamoyl)-0-(3-(2-(5,6,7,8 teirahydro-l,8-naphthyndin-2~ yl)ethy3)cyc3obutyI)liomoserine;
N-(isopropyl(methy])carbamoy])-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N -(diisopropylcarbamoyl)-0-(3 -(2-(5 ,6,7, 8-tetraliy dro- 1 , 8-naphthy ridin-2- yl)etiiyl)cyclobutyl)homoserine;
N-(3,3-dimethylbutanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)etliyl)cyclobutyl)homoserine; N-(3-methylbutanoyl)-0-(3-(2-(5,6,7,8-tetxahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(2-cyclobuty]acetyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridm-2- yl)etliyl)cyclobutyl)homoserine;
N-(2-(l-methylcyclopropyl)acetyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyc3obutyl)liomoserine;
N-(2-cyclopropylacetyr)-0-(3~(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyi)cyclobutyl)homoserine;
N-(((l-(tert-butoxycarbonyl)-3-methylazetidin-3-yl)oxy)carbonyl)-0-(3-(2-(5, 6,7,8- tetrahydro- 1 ,8-naphthyridin-2-y!)ethyi)cyclobutyi)homoserine;
N-(((3-methyl-l -(meihylsulfonyl)azetidin-3-yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-teirahydro- 1 , 8 -naphtiiy ridin-2-yl)eiliy l)cy ciobuty l)homoserine ;
N-(((l-acetyl-3~niethy3azetidin-3-yl)oxy)carbonyl)-0-(3~(2-(5,6,7,8-tetrahydro-L8- naphthyridi n -2-y] )eth yl)cyclobutyl)homoserine ;
N-(((3-meihylazetidin-3-yI)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphihyridin-2- yl)ethyi)cyclobutyl)homoserine;
N-((cycIohexyloxy)carbonyI)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphtliyridin-2- yl)etliy3)cyclobuiyl)homoserine;
N~(isobutoxycarbonyi)-0-(3-(2 (5,6,7,8-tetrahydro-l,8 naphthyridin-2- yl)ethy3)cyc3obutyI)liomoserine;
N-(((l -(tert-butoxycarbonyl)pyrro3idm-3-yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8~ naphthyridin-2-yl)ethyl)cyc3obutyl)homoserine;
]N-((pyrro3idin~3~y3oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphtliyridin~2~ yl)ethy3)cyc3obutyl)homoserine;
N-(4-(methylsuIfonyl)bui£inoyI)-0-(3 -(2-(5 ,6,7, 8-tetrahydro- 1 , 8-naphthyridin-2 - yl)ethyl)cyclobutyl)homoserine;
N-(((l-(methy3suIfonyl)pyrroIidin-3-yI)oxy)caibony3)-0-(3~(2-(5,6,7,8-tetrahydro-L8- naphthyridi n -2-y] )eth yl)cyc!obutyl)homoserine ;
N-(((l-acetylpyrrc lidin-3-yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphthyridin-2- yl)ethyi)cyclobutyl)homoserine;
N-((l-phenylethox )carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethy!)cyclobutyl)homoserine; N-((2-phenylcyclobutoxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyfidin-2- yl)etiiyl)cyclobutyl)homoserine;
N-((3-phenylcyclobutoxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ediyl)cyclobutyl)homoserine;
N~(((2-phenyIcyciohexyI)oxy)carbonyi)-0-(3~(2-(5,6,7,8-tetrahydro-l,8-naphihyridin~2- yl)ethy3)cyc3obutyi)liomoserine;
2-((tert-butoxycarbonyl)amir!o)-3-methyl-4-(3-(2-(5,6,7,8~tetrahydro-l,8-naphthyridin-2- yl)ethyi)cyclobutoxy)butanoic acid:
N-(((l-(tert-biitoxycaibony3)azetidin-3-yl)oxy)carbonyi)-0-(3-(2-(5,6/7,8-tetrahydro-l,8- naphthyridin-2 -yljethy! )cy clobutyl )hom oseri n e ;
N-(((4-phenylcyclohexyl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(((l-acetylazetidin-3-yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(((l-acetamidoprc pan-2-yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydrc -l,8-naphthyridin-2- yl)ethyi)cyclobutyl)homoserine;
N-(((l-((tert-butoxycarbonyl)amino)propan-2-yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine;
N-(((2-(3,5-dimethyl-lH-pyrazol-l-yl)cyclopen†yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine;
N-(((2-(3,5-dimethyl-lH-pyrazol-l -yl)cyclohexyl)oxy)carbony])-0-(3-(2-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine;
N-(((l-(tert-butoxycarbonyl)-3-(3-chlorophenyl)azetidin-3-yl)oxy)carbonyl)-0-(3-(2-
(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine;
N-((( i-(tert-butoxycarbonyl)-3-(4-isopropylphenyl)azetidin-3-yl)oxy)carbonyl)-0-(3-(2-
(5 ,6, 7, 8-teiraliydfo- 1 , 8-naphthyridin-2-yl)ediy l)cyclobuty l)homoserine ;
N (((l (tert-butoxycarbonyl)-3-(phenylethynyl)azetidin-3-yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine;
N-(l-(tert-butoxycarbonyl)piperidine-4-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine;
N-(3,3-difluorocyclohexane-l-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naph†hyridm-2- yl)eti y])cyclobutyl)homoserine; N-(2-ethyi-4,4-difluorobutano}d)-0-(3-(2-(5,6,7,8-tetfahydro-l,8-naphthyridin-2- yl)ethy3)cyclobutyl)homoserine;
N-(((2-(phenylethynyl)cyclohexyl)ox\)carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8- naphthyridin-2-yl)eihyl)cyclobutyl)homoserine;
N-(4-methyltetraliydfo-2H-pyran-4-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-
2-yl)ethyl)cyclobutyl)homoserine;
N-(2-cyclohexyl-2-methy]propanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyi)cyclobutyl)homoserine;
N-(2-(pyridin-2-yl)benzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethy!)cyclobutyl)homoserine;
N-(2-ethyl-4,4,4-trifluorobutanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(2-morpholinobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphth5Tidin-2- yl)ethyl)cyclobutyl)homoserine;
N-(2-ethyl-2-phenylbutanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(lH-pyrrolo[3,2-b]pyridine-7-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ediy3)cyclobuiyl)homoserine;
N~(4-cyanotetraliydro-2H-pyran-4-carbony3)~0-(3-(2-(5,6,7,8-tetrahydro-L8-naphthyridin-2- yl)ethy3)cyc3obutyI)liomoserine;
N-(l -(tert-butox\ arbonyl)-3-methy]azetidine-3-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine;
N-(l-(tert-butoxycarbonyl)azetidine-3-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridm-2-yl)ethy!)cyclobuty!)homoserine;
0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)ethyl)cyclobut> )-N-(4-
(trifluoromeiliyl)tetraiiydro-2H-pyran-4-carbonyl)homoserine;
N-(l-(methylsulfonyl)piperidine-3-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-(4,5,6,7-tetrahydro- lH-indazole-6-carbonyl)homoserine;
0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-(4,5,6,7-tetrahydro- 1 H-indazole-7-carbonyl )homoserine; N-(l-methyl-4,5,6,7-tetrahydro-lH-indazole-6-carbon}4)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridm-2-yl)ethy!)cyclobuty!)homoserine;
N-(l-ethyl-4,4-difluorocyclohexane-l-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)eihyl)cyclobutyl)homoserine;
N~(l-(6-methylindoline-l-carbonyl)cyclopropane-l-carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine;
N-(4-(((tert-butoxycarbonyl)amino)methyl)tetrahydro-2H-pyran-4-carbonyl)-0-(3-(2- (5,6,7,8~tetrahydro-L8-naphthyridin-2-yl)etliyl)cyclobutyl)homoserine;
N-(l-(pyridin-3-ylmethyl)cyclopropane-l-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2 -yl)ethyl )cy clobuty ! )hom oseri n e ;
N-(3-chloro-5-methylisonicotinoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserme ;
N-(4-methyltetrahydro-2H-pyran-4-carbonyl)-0-(4-(5,6,7,8-tetraliydro-l,8-naphtliyridin-2- yl)butyl)homoserine;
N-(2,6-dichlorobenzoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)biit> )homoserine;
N-(3,5-dichloroisomcotinoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyi )homoserine ;
N-( 1 -(4-(tert-butyl)phenyl)cyclobutane- 1 -carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro- 1 ,8- naphtliyridin-2-yl)eihyl)cyc3obutyl)homoserine;
N-(3,5-dimetliylisonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyc!obutyl)homoserine;
N-(3-chloro-5-methylisonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(3,5-dichIoroisonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naplithyridin-2- yl)etliy3)cyclobutyl)homoserine;
N-(bicyclo[2.2.2]octane-2-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobuty!)homoserine;
N-(2-methyl-l,2,3,4-tetrahydronaphthalene-2-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyc3obutyl)homoserine;
N-((methylsulfon}4)prolyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(2,4-dimethylnicotinoyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphtliyridm-2- yl)etliyl)cyclobutyl)homoserine; N-(4-phenyltetrahydro-2H-pyran-4-carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphthyridin-
2-yl)ethyl)cyclobutyl)homoserine;
N-(4-cyano-2,6-dimethylbenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-:naphthyridm-2- yl)etliyl)cyclobuiyl)homoserine;
0-(3 (2-(5,6,7,8 tetrahydiO-l,8-naphthyndin-2-yl)etliyl)cyclobiityI) N (2,4,6~
trimethylpyrimidine-5-carbonyl)homoserine;0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphtliyridin-2- yl)ethyl)cyclobutyl)-N-(2,4,6-trimethylnicotinoyl)homoserine;
N-(3-chloro-5-fluoroisonicotinoyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphthyridm-2- yl)ethyl)cyclobutyl)homoserine;
N-(l-(isoquino]in-l -yl)cyc]opropane-l-carbony])-0-(3-(2-(5,6,7,8-tetraliydro-l,8- naphthyridin-2-yl)eihyl)cyclobutyl)homoserine;
N-(2-(pyridin-2-yl)spiro[3.3]heptane-2-carbon}d)-0-(3-(2-(5,6,7,8-tetrahydfo-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine;
N-(2-(l -methyl- lH-pyrazol-4-yl)tetrahydrofuran-2-carbony])-0-(3-(2 -(5,6, 7, 8-tetrabydro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine;
N-(2,4-dimethyl-6-oxo-l,6-dihydropyridine-3-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyI)cyclobutyl)homoserine;
N-(4,6-dimethylpyrimidine-5-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(2,6-dichloro-4-(trifluoromethyl)benzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(l-(2-fluorophenyl)cyclopropane-l-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine;
N-(l-(benzo[d][l,3]dioxol-5-yl)cyclohexane-l-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)eihyl)cyclobutyl)homoserine;
N-(2,2-difluoro- 1 -(m-toly l)cyclopropane- 1 -carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro- 1,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine;
0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyc]obutyl)-N-(l -(tetrahydro-2H- pyran-2-yl)cyclopropane- 1 -carbonyl )homoserine;
N-(4-methoxy-2,6-dimethylbenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(l-acetyl-4-(trifluoromethy])piperidine-4-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)eihyl)cyclobutyl)homoserine; N-(2,3-dihydrobenzo[b][l,4]dioxine-2-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyI)cyclobutyl)homoserine;
N-(l-(3-chlorobenz\l)cyclopentane-l -carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)eihyl)cyclobutyl)homoserine;
0-(3 (2-(5,6,7,8-tetrahydiO-l,8-naphthyndin-2-yl)etliyl)cyclobiityI)-N-(l-(3-
(trifluoromethoxy)phenyl)cyclopropane-l-carbonyl)homoserine;
N-(4-f!uoro-2,6-dimethylbenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(4-cyanotetrahydro-2H-pyran-4-carbonyl)-0-(4-(5,6,7,8-tetraliydro-l,8-naphtliyridin-2- yl)butyl)homoserme;
0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-} )butyl)-N-(4-(trifluorometh} )tetrahydro-2H- pyran-4~carbonyl)homoserine;
N-(quinazolin-4-yl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(8-fluoroquinazolin-4-yl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(7-fluoroquinazolin-4-yl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ediyl)cyclobutyl)homoserine;
N~(7-iiiethylquinazolin-4-yl)-0-(3-(2~(5,6,7,8-tetraliydro-l,8-naphtliyridm~2- yl)ethy!)cyc3obuty!)homoserine;
N-(6-f!uoroqiiinazolin-4-yl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(5-fluoroquinazolin-4-yl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethy3)cyc3obutyl)homoserine;
N-(6-methylquinazolin-4-yl)-0-(3-(2-(5,6,7,8-tetrahydrc -l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(6-(tert-butyl)-2-phenylpyrimidin-4-yl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine;
N-(6-(tert-butyl)pyrimidin-4-yl)-0-(3-(2-(5,6,7,8-tetrahydrc -l,8-naphthyridin-2- yl)ethyi)cyclobutyl)homoserine;
N-(2-(tert-but>d)pyrimidin-4-yl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cydobuty])homoserine; N-(4-(tert-butyl)pyrimidin-2-yl)-Q-(3-(2-(5,6 ,8-ieifaliydfo-l,8-naphthyridin-2- y!)ethy3)eyclobi!tyl)homoserine;
N-(8~oxabicyclo[3.2.1 ]octane-3~carbonyl)-0-(4-(5,6,7,8~tetrahydro-l,8-naphthyridin-2- yl)butyI)homoserine;
N~(2-(dimethylamino)-3,5-dimethylisonicotinoy3)-0-(4~(5,6,7,8-tetraliydro-l,8~naphiliyridm~
2~y3)butyI)liomoserine;
N-(5-chloro-2-(dimethylamino)-3-methylisonicotinoyl)-0-(4-(5,6,7,8-tetrahydro-l,8- napiiihyridin-2-yl)butyi)homoserine:
N-(3-cyciopropyl-5-fluoroisonicotinoyl)~0~(4-(5,6,7,8-tetrahydro-L8-naplitliyridin-2- yl)butyl)homoserme;
N-(4 (( l,3-dimethyl iH pyrazo3 5-yl)meihy3)-2,6-dimeihylbenzoyl) 0 (4-(5,6,7,8- tetrahydro-L8-napiithyridin-2-yl)butyi)homoserm;e
N-(5-chioro-2-methoxy~3-iTiethylisonicotinoyl)-0-(4-(5,6,7,8-tetrabydro~l ,8~naphthyridin-2~ yl)butyl)homoserine;
N-(3-eihyl-5-fluoiOisonicoiinoyI)-0-(4-(5,6,7,8-tetrahydro-l,8-naphihyridin-2- yl)butyl)homoserine:
N-(4-((l, 3-dimethyl- lH-pyrazol-5-yl)methyl)-2-fluoro-6-metliylbenzoyl)-0-(4-(5, 6, 7, 8- tetrahydro-l,8-naphthyridin-2-yl)butyl)homoserine;
N-(3-chloro-5-fluoroisonicotinoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserine;
N-(5-fluoro-3-methylpyridazine-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserine;
N-(2,4-dimethyl-6-oxo-l,6-dihydropyridine-3-carbonyl)-0-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)homoserine;
N-(2,4-dimethyl-6-oxo-l-(2,2,2-trifluoroethyl)-l,6-dihydropyridine-3-carbonyl)-0-(4- (5 ,6, 7, 8-tetraliydro- 1 , 8-naphthyridin-2-yl)biityl)homoserme;
N-(3,5-dimethylisonicotinoyl)-0-(4-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)butyl)homoserine;
N-(3,5-dimethylpyridazine-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserine:
0-(4-(5,6,7,8-tetraliydro- 1 ,8-naphthyridin-2-yl)butyl)-N-( 1 ,2,4-trimethyl-6-oxo- 1,6- dihydropyridine-3-carbonyl)homoserine; N-(4-cyano-2-fluoro-6-methylbenzoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yljbutyi )homoserine ;
N-(3,5-dimethylmorpholine-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserine;
N-(5-chloro-3-methylpyridazine-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserine;
N-(6-methoxy-2,4-dimethylnicotinoyl)-0-(4-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)butyi)homoserine:
N-(2-chloro-4-cyano-6-fluorobenzoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)but\l)homoserine; and
N-(2,6-dichlorobenzoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)homoserine.
[0152] In one variation, the compound detailed herein is selected from the group consisting of: N-(2-chloro-3-fluorobenzoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserine; N-(I -methy]-lH-indazole-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)homoserine; N-(4,4-difluorocyclohexane-l-carbonyl)-0-(4-(5, 6,7,8- tetraliydro-l,8-naphthyridin~2-yl)butyl)homoserine; N-pentanoyl-0-(4-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)butyl)homoserme; N-(3-fluoro-5-(trifluorometliyl)benzoyl)-0-(4- (5 ,6,7, 8-te trahydro- 1 , 8-naphthyridin-2-yl)but}d)homoserine ; N-(3 -fl uoro-5 - (trifluoromethyl)benzoyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphtliyridm~2- yl)ethyl)cyc3obuty!)homoserine; N-pentanoyl-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl)ethyi)cyclobut i)homoserine; N-(tert-butoxycarbonyl)-0-(4-(5,6,7,8-tetrahydro-l ,8- naphthyridin-2-yl)butyl)homoserine; N-(4-fluorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(4-chlorobenzoyl)-0-(3-(2-(5,6,7,8- tetrahydro~l,8-naphthyridin-2~y3)ethyi)cyclobutyi)homoserine; N-(3-fluorobenzoyl)-0-(3-(2- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethy3)cyclobuty3)homoserine; N-(3-chlorobenzoy3)- 0-(3-(2-(5,6,7,8-tetrahydro-i,8-naphthyridin-2-yl)ethyl)cyclobiityi)homoserme; N-(2- chlorobenzoy3)-0-(3-(2~(5,6,7,8-tetrabydro~l ,8~naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(2~fluorobenzoyl)~0~(3-(2-(5,6,7,8~tetrahydro-i,8- naphthyridin-2-yl)ethyl)cyc3obutyl)honioserine; N-(2, 3-difluorobenzoyl)-0-(3-(2-(5, 6,7,8- tetraliydro-l,8-naphthyridm~2-yl)ethyl)cyclobutyl)homoserine: N-(2,4-difluorobenzoyl)-0- (3-(2~(5,6,7,8-tetrahydro-l ,8~naphthyridin-2-yl)ethyl)cyc!obutyl)homoserine; N-(2-chloro-4- fluorobenzoyi)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridm-2- yl)ethy 3)cyclobutyl)homoserine ; N -(3 -chioro-5 -fluorobenzoyl)-0-(3 -(2-(5 ,6,7, 8-tetrahydro- 1.8-naphthyridm-2-yl)ethyl)cyclobutyl)homoserine; N-(3-chloro-2-fluorobenzoyl)-0-(3-(2- (5 ,6,7, 8-tetrahydro- 1 , 8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine ; N~(3 ,5 - difluorobenzoyl)~0~(3-(2-(3, 6,7, 8-tetrahydro- 1, 8-naphthyridin-2~
yl)eiliyl)cyclobuiyl)homoserine; N-(2,3-dichlorobenzoyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8- naphtliyridin-2-yl)eihyl)cyclobuiyl)homoserine; N-(2~chloro-6-fluorobenzoyl)-0-(3~(2- (5,6,7,8-tetrahydro~!,8~naphthyridm~2~y})ethyl)cyelohutyl)homGS6rffle; N-(2,6- difluorobenzoyl)-0-(3-(2 -(5,6, 7, 8-tetrahydro- 1 ,8-naphth yridin-2- yl)ethyl)cyclobutyl)homoserine; N-(2, 5-difluorobenzoyl)-0-(3-(2-(5,6, 7, 8-tetrahydro- 1,8- naphthyridm-2-yl)ethy!)cyclobuty!)homoserine; N~(3,4~dich3orobenzoyl)~Q~(3-(2~(5, 6,7,8- tetrahydro~l ,8~naphthyridin~2~y!)ethyi)cyc!obutyi)homoserme; N-picolinoyl-0-(3-(2- (5,6,7, 8-tetrahydro-l,8-naphthyridin-2-yl)ethy3)cyclobuty3)homoserine; N-nicotinoyl-0-(3- (2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(l-methyl-lH- indazole-4-carbonyl)-0-(3-(2-(5, 6,7, 8-tetrahydro- l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(2-methyl-2H-indazole-6-carbonyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(2-methyl-2H-indazole-5- carbonyi)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N- (l-methyl-lH-pyrrolo[2,3-b]pyridine-4-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(2 -ethylbutanoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyi)cyciobiityi)homoserme; N-( l-methyl-lH-pyrrolo[2,3- b]pyridine-5-carbonyl)-0-(3-(2-(5, 6, 7, 8-tetrahydro- l,8-naphthyridin-2- yl)ethyl)cyc!obutyl)hornoserine; N-(3-(hydroxymethyl)benzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-
1.8-naphthyridin-2-yl)ethyl)cyc3obutyl)homoserine; N-(quinoline-5-carbonyl)-0-(3-(2- (5,6,7,8-tetrahydro-l,8-nap3ithyridin-2-yl)ethy3)cyciobutyi)homoserine; N-(2- cyelopropy!benzoyl)~0~(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(quinoline-7-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyc3obutyl)homoserine; N-(qidnoline-6-carbonyi)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(quino3ine-8-carbonyl)-0- (3-(2-(5, 6,7, 8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyc]obutyl)homoserine; N-(3- cyclopropylbenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethy3)cyclobutyl)homoserine; N-(4-cyclopropylbenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-isonicotinoyl-0-(3-(2-(5, 6, 7, 8-tetrahydro-
1.8-naphthyridin-2-yl)ethyl)cyclobuty])-homoserine; N-(3-ethylpentanoyl)-0-(3-(2-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserine; N-(2-chloro-3- fluorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethy3)cyclobutyl)homoserine; N-(3,4-difluorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(3-ethylpentanoyl)-0-(3-(2-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobiityl)homoserine; N-isonicotinoyl-0-(3-(2- (5,6,7,8-tetraliydro-l,8-naphtiiyridin-2-yl)elliyl)cycIobutyl)homoserine; 0-(3-(2-(5, 6,7,8- tetrahydro-L8-naphthyridin-2-y3}etliy3)eyclobutyl)~N~(3-(thiazo!~5-y3)benzoy3)homoserine; N-(3-hydroxy-2-phenylpropanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(3-(l-methyl-lH-pyrazol-4-yl)benzoyl)-0-(3-(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)cyclobutyl)homoserine; N-(3-(l -methyl- lH-pyrazol- 4-yl)benzoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)homoserine; N-(2- hydroxy-2-phenylacetyl)-0-(4-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)butyl)homoserine; N-(2-ltydroxy-2-phenylacetyi)-0-(4-(5,6,7,8-tetrahydro-l,8-iiaphthyridin-2-yl)biityl)- homoserine; N-(2-hydroxy-2-phenylacetyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(l-phenylcyclopropane-l-carbonyl)-0-(3-(2-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(2-methyl-2- plienylpropanoy3)-0-(3-(2-(5,6,7,8-tetrahydro-L8-naphthyridin-2- yl)ethyl)eyclobutyl)homoserine; N-(l -phenylcyclobutane-l-carbonyl)-0-(3-(2-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobiityl)homoserine; N-(2,2-dimethyl-3- phenyipropanoyl)-Q-(3-(2-(5,6/7,8-teirahydfo-l,8-naphtliyridm-2- yl)ethyl)cyelobuty!)homoserine; N-(tert-butoxycarbonyl)-0-(3-(2-(5,6,7,8-†etrahydro-l ,8- naphthyridin-2-y])ethyl)cyclobutyl)homoserine; N-(2-(4-fIuorophenyl)-2-methylpropanoyl)- 0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(3- methyloxetane-3-carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8~naphtliyridin~2- yl)ethyl)cyclobutyl)homoserine; N-(3-hydroxy-2,2-dimethylpropanoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobiityl)homoserine; N-(3-methoxy-2,2- dimethylpropanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyelobuty!)homoserine; N-(2-methyl-2-(pyridin-3-yl)propanoyl)-0-(3-(2-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(2,3-dihydro-lH-indene-2- carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N- (3-cyano-2,2-diinet3iylpropanoy3)-0-(3-(2-(5,6,7,8-tetrahydiO-L8-naphthyridin-2- yl)ethyI)cyclobutyl)homoserine; N-pivaloyi-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobuty])homoserine; N-(2, 3-dihydro- IH-indene- 1 -carbonyl)-0-(3-(2 -(5,6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cYclobutyl)homoserine; N-((neopentyloxy)carbonyl)- 0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyi)homoserme; N-((l- methylcyclopropoxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyiidin-2- yl)ethyl)cyclobuty])hornoserine; N-((l -methylcyclobutoxy)carbonyl)-0-(3-(2-(5,6,7,8- tetrahydro-L8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; 0-(3-(2-(5,6,7,8-tetrahydro-
1.8-naphthyridin-2-yl)ethyl)cyclobuty 1)-N -((( 1, 1,1 -trifluoro-2-methylpropan-2- yl)oxy)carbonyl)homoserine; N-(isopropoxycarbonyl)-0-(3-(2-(5, 6,7, 8-tetrahydro-l, 8- naphthyridm-2~y])ethyi)cyclobutyl)homoserine; N-(diethylcarbamoyl)-0-(3-(2-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine: N-(tert-butylcarbamoyi)-0- (3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(tert- buty](methyl)carbamoyl)-0-(3-(2-(5, 6,7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(isopropyl(methyl)carbamoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-L8-naphthyridin-2-yl)ethyl)cyciobiityl)homoserme; N-(diisopropyicarbamoyl)-0- (3-(2-(5, 6,7, 8-tetrahydro-l, 8-naphthyridm-2-yl)ethyl)cyclobutyl)homoserine; N-(3,3- dimethylbutanoy])-0-(3-(2 -(5,6,7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(3-methylbutanoyl)-0-(3-(2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(2-cyclobutylacetyl)-0-(3-(2-(5,6,7,8- tetrahydro- 1 ,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoseiine; N~(2~( 1 - methylcyclopropyl)acet>'l)-0-(3-(2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(2-cyclopropylacetyl)-0-(3-(2-(5, 6,7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl)cyc3obutyl)homoserine; N-(((l-(tert-butoxycarbonyl)-3- methylazetidin-3-yl)oxy)carbonyl)-0-(3-(2 -(5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(((3-methyl-l-(methylsulfonyl)azetidin-3- yl)oxy)carbonyl)-0-(3-(2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(((l-acetyl-3-methylazetidin-3-yl)oxy)carbonyl)-0-(3-(2- (5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethy3)cyclc buty3)homoseriiie; N-(((3- methylazetidin-3-yl)oxy)carbonyl)-0-(3-(2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl)cyclobuty!)homoserine; N-((cyclohexyloxy)carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro-
1.8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserme; N-(isobutoxycarbonyl)-0-(3-(2-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(((pyrrolidin-3- yl)oxy)carbonyl)-0-(3-(2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(4-(methylsulfonyl)butanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-
1.8-naphth\Tidin-2-yl)ethyl)cyclobuty])homoserine; N-(((l-(methylsulfonyl)pyrrolidin-3- yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(((l-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)carbonyl)- 0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(((l- acetylpyrrolidin-3-yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-((l-phenylethoxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro- l,8~naphthyridin-2-yl)eiliyl)cyclobutyl)homoserine; N-((2-phenylcyclobutoxy)carbonyl)-0- (3-(2-(5,6,7,8-tetraliydro-l,8-naphtliyridin-2-yl)ethyl)cyclobutyl)homoserine; N-((3- phenylcyclobutoxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; 2-((tert-butoxycarbonyl)amino)-3-methyl-4-(3-(2-(5,6,7,8- tetrahydro- 1 ,8-naphthyridin-2~y3)ethyi)cyclobutoxy)butanoic acid; N-(((2- phenylcyclohexyl)oxy)carbonyl)-0-(3-(2 -(5,6,7, 8-tetrahydro-l, 8-naphthyridin-2- yl)etliyl)cyclobutyl)homoserine; N-(((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)carbonyl)-0- (3-(2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl)cyclobiityl)homoserme; N-(((4- phenyicyclohexyl)oxy)carbonyl)~0~(3-(2-(5,6,7,8-tetrahydro-l,8-naphtliyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(((l-acetyiazetidm-3-yl)oxy)carbonyl)-0-(3-(2-(5, 6,7,8- tetrahydro- 1 ,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-((( 1 -((tert- butoxycarbonyi)amino)propan-2-yi)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8- naplithyridin-2-yl)ethy3)cyclobut} )homoserine; N-(((l-acetamidopropan-2-yl)oxy)carbonyl)- 0-(3-(2-(5, 6, 7, 8-tetrahydro-l , 8-naphthyridin-2-yl)ethyl)cyclobut}d)homoserine; N-(((2-(3,5- dimethyl-lH-pyrazo3-l-yl)cyclopentyl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-L8- naphthyridm-2-yl)ethyl)cyclobutyl)-homoserine; N -(((2-(3 ,5 -dimetiiyl- IH-py razol- 1 - yl)cyclohexyl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyl)cyclobutyl)-homoserine; N-(((l-(tert-butoxycarbonyl)-3-(3-chlorophem )azetidin-3- yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-L8-naphthyridin-2- yl)ethy3)cyc3obutyl)homoserine; N-(((l-(tert-butoxycarbonyl)-3-(4-isopropylphenyl)azetidin- 3-yl)oxy)carbonyl)-0-(3-(2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yi)etliyl)cyc3obutyl)homoserine; N-(((l-(tert-butoxycarbonyl)-3-(phenylethynyl)azetidin-3- yl)oxy)carbony!)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(l-(tert-butoxycarbonyl)piperidine-4-carbonyl)-0-(3-(2- (5,6,7,8-tetrahydro-L8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(3,3- difluorocyclohexane-l-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(2 -ethyl-4, 4-difluorobutanoyl)-0-(3-(2-(5,6, 7,8- tetrahydro-l ,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserine; N-(((2- (phenyletliynyl)cyclohexyl)oxy)carbonyl)-0-(3-(2 -(5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yd)ethyl)cyclobutyl)-homoserine; N-(2-cyclohexyl-2-methylpropanoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(2-(pyridin-2-yl)benzoyl)- 0-(3-(2~(5,6,7,8-tetrahydro~l ,8~naphthyridin~2-yl)ethyl)cyc!obutyi)homoserine; N-(2-ethyl- 4,4,4-trifiuorobuianoyl)-0-(3-(2-(5,6,7,8-teirahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(2-morpholinobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(2-ethyl-2-phenylbutanoyl)-0-(3-(2- (5,6,7,8-tetrahydro-l ,8-naphthyridin-2-y])ethyl)cyclobutyl)homoserine; N-(lH-pyrrolo[3,2- b]pyridine-7 -carbonyl)-0-(3 -(2-(5 ,6,7, 8-tetrahydro- 1 , 8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(4-cyanotetrahydro-2H-pyTan-4-carbony3)-0-(3-(2- (5,6,7,8-tetrahydro-l,8-naphthyridm-2-yl)ethy!)cydobuly!)hoiT!Oserine; N-(l -(tert- butoxycarbonyl)-3-methylazetidine-3-carbonyl)-0-(3-(2-(5, 6,7, 8-tetrahydro- 1,8- naphthyridin-2-yl)eihyl)cyc3obutyl)hornoserine; N-(l-(tert-butoxycarbonyl)azetidine-3- carbonyl)~0~(3-(2-(5,6,7,8-tetraliydro-l,8-naphtliyridin-2-yl)ethy!)cyc3obuty!)homoserine; N- (l -(methylsulfonyl)piperidine-3-carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)-homoserine; 0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethy3)cyclobutyl)-N-(4,5,6,7-tetra3iydro-lH-indazole-6-carbonyl)-3iomoserine; 0-(3-(2- (5,6,7,8-tetrahydro-L8-naplithyridin-2-y!)etliy3)cyciobut}d)-N-(4,5,6,7-tetrahydro-lH- indazole-7-carbonyl)homoserine; N-(4-methyltetrahydro-2H-pyran-4-carbonyl)-0-(3-(2- (5 ,6,7, 8-tetrahydro- 1 , 8-naphtliyridin-2-yl)ethy l)cycIobuty 1) homoserine ; N-(1 -methyl-4,5,6,7- tetrahydro-lH-indazole-6-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)-homoserine; N-(l-ethyl-4,4-difluorocyc]ohexane-l-carbonyl)-0-(3-(2- (5 ,6,7, 8-tetrahydro- 1 , 8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine ; N-( 1 -(6- methylindoline- 1 -carbony l)cyciopropane- 1 -carbonyl)-0-(3-(2-(5, 6, 7, 8-tetrahydro- 1,8- naphtliyridin-2-y!)ethy3)eyciobuty3)homoserine; N-(4-(((tert- butoxycarbonyl)amino)methyl)tetrahydro-2H-pyran-4-carbonyl)-0-(3-(2-(5, 6, 7, 8-tetrahydro-
1.8-napht3iyiidin-2-yi)etliyl)cyc3obutyl)homoserine; N-(l-(pyridin-3-ylmethyl)cyclopropane- l~carbony3)-0-(3-(2-(5,6,7,8-tetrabydro-l,8-naphthyridin-2~y3)etliyi)cyelobutyi)homoserine; N-(3-chioro-5-methylisonicotmoy3)-0-(4-(5, 6,7, 8-tetrahydro- l,8-naphthyridin-2- yl)butyl)homoserine; N-(4-methyltetrahydro-2H-pyran-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro- L8-napiithyridin-2-yl)butyl)homoserine: N-(2,6-dichlorobenzoyl)-0-(4-(5,6,7,8-tetrahydro-
1.8-naphthyridin-2-yl)butyi)homoserine; N-(3,5-dichioroisonicotmoyl)~0-(4-(5, 6,7,8- tetrahydro-l ,8-naphthyridin-2-yl)butyl)homoserine; N-(l-(4-(tert-butyl)phenyl)cyclobutane- l-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(4-methyltetrahydro-2H-pyran-4-carbon}d)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl)ethyl)cyclobutyl)homoserine; 0-(3-(2-(5,6,7,8-tetrahydiO-l,8-naphthyridin-2- yl)ethyl)cyclobuty])-N-(4-(trifluoromethyi)tetrahydro-2H-pyran-4-carbonyl)homoserine; N- (3-chloro-5-methylisonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(3,5-dichloroisonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-
1.8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(bicyclo[2.2.2]octane-2-carbonyl)-0- (3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyc]obutyl)homoserine; N-(2-methy!~ l,2,3,4-tetrahydronaphthalene-2-carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N~((methylsulfonyl)prolyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(2,4-dimethylnicotinoyl)-0-(3-(2-(5,6,7,8- tetrahydro-L8-naphthyridin-2-y3)ethyl)cyclobutyl)homoserine; N-(4-phenyltetrahydro-2H- pyran-4-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(4-cyano-2, 6-dimethylbenzoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; 0-(3-(2-(5,6,7,8-tetrahydro-
1.8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-(2,4,6-trimethylpyrimidine-5- carbonyi)homoserine: 0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)c}7clobutyl)-N- (2,4,6-trimethyinicotinoyl)homoserine; N-(3-chloro-5-fluoroisonicotinoyl)-0-(3-(2-(5, 6,7,8- tetrahydro- L8-naphthyridin-2-y3)ethyI)cyclobutyI)homoserine; N-( 1 -(isoquinolin- 1 - yl)cyclopropane- 1 -carbonyl)-0-(3-(2-(5,6,7,8-tetraltydro- 1 ,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(2-(pyridin-2-yl)spiro[3.3]heptane-2-carbonyl)-0-(3-(2- (5,6,7,8-tetrahydro-l ,8-naphthyridin-2-y])ethyl)cyclobu1yl)homoserine; N-(2-(l -methyl-lH- pyrazol-4-yl)tetrahydrofuran-2-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyi)cyclobutyl)homoserine; N-(2,4-dimethyl-6-oxo-l,6-dihydropyridine-3-carbonyl)-0- (3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N~(4,6~ dimethylpyrimidine-5-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yDetliy l)cyclobutyl)homoserine ; N -(2,6-dichloro-4-(trifluoromethyl)benzoyl)-0-(3 -(2- (5 ,6, 7, 8-tetrahydro- 1 , 8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine ; N-( 1 -(2- fluorophenyl)cyclopropane-l-carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(l-(benzo[d][ l,3]dioxol-5-yl)cyclohexane-l-carbonyl)-0- (3-(2-(5,6,7,8-tetraliydro-l,8-naphiliyridm-2-yI)ethyi)cyclobutyi)homoserine: N-(2,2- difluoro-l -(m-tolyl)cyclopropane-l-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin- 2-yl)ethyl)cyclobutyl)homoserine; 0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)-N-(l-(tetrahydro-2H-pyran-2-yl)cyclopropane-l -carbonyl )homoserine; N-(4-methoxy-2,6-dimethylbenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(l-acetyl-4-(trifluoromethyl)piperidine-4-carbonyl)-0-(3- (2-(5,6,7,8-tetraliydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(2,3- dihydrobenzo[b] | l,4]dioxine-2-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethy l)cyclobutyl)homoserine ; N-( 1 -(3 -chlorobenzy l)cyclopentane- 1 -carbonyl)-0-(3-(2- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; 0-(3-(2-(5,6,7,8- tetrahydro- 1 ,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-( 1 -(3- (trifluoiOmethoxy)phenyl)cyclopropane-l-carbonyl)homoserine; N-(4-fluoro-2,6- dimethylbenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobut>d)homoserine; N-(3,5-dimethylisonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-
1.8-naphthyridin-2-yl)etliyl)cyclobutyl)homoserine; N-(2-(tert-butyl)pyrimidin-4-yl)-0-(3-(2- (5 ,6, 7, 8-tetraliydro- 1 , 8-naphthyridin-2-yl)eihy l)cyclobut l)homoserine ; N -(4-(tert- butyl)pyrimidm-2~yl)-0-(3-(2-(5,6,7,8-tetrahydro-L8-naphthyridin-2- yl)ethyl)cyc!obutyl)homoserine; Q-(3~(2-(l ,8-naphthyridm~2-yi)ethy])cyclobutyl)-N- (quinazolin-4-yl)homoserine; N-(6-(tert-butyl)pyrimidin-4-yl)-0-(3-(2-(5,6,7,8-tetrahydro- L8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; 2-[(4-amino-2,6-dichloro- benzoyl)amino]-4-[3-[2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; N-(4-chloro-2,6-dimethylnicotinoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-L8-naphthyridin-2-yl)etliyl)cyciobutyl)-homoserme; 2-[(3-chloro-6-methyl- pyridine-2-carbonyl)amino]-4-[3-[2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; N-(2,6-dimethylpiperidine-l -carbonyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserine; N-(2,5-dimethylpyrrolidine- l-carbonyl)~0-(3-(2-(5,6,7,8-tetraliydiO-L8-naphthyridin-2-yl)etliyl)cyciobiityl)-homoserme; N-{2,6-dicbloro-4-cyanobenzoyl)~0~(3-{2-(5,6,7,8-tetraliydro-l,8-naphtliyridin-2- yl)ediyl)cyclobutyl)-homoserine; N-(2,6-dichloro-3-nitrobenzoyl)-0-(3-(2-(5,6,7,8- tetrahydro-L8-naphthyridin-2-yl)etliyl)cyciobutyl)-homoserme; 4-[3-[2-(5,6,7,8-tetrahydro-
1.8-naph&yridm-2~yl)ethyl]cyc!obutoxy]-2-[(l,2,4-trimethyl-6oxo-pyridine-3- carbonyl)amino]butanoic acid; N-(2-chloro-4-cyano-6-methylbenzoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserine; N-(3-bromo-5-chloro-2- fluoiOisonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-L8-naphthyridin-2-yl)etliyI)cyclobutyl)- homoserine; 0-(3-(2-(5, 6,7, 8-tetrahydro-l,8-naphthyridin-2-yl)e1hyl)cyclobutyl)-N-(5, 6,7,8- tetrahydronaphthalene-l-carbony])-homoserine; N-(3-bromo-2,6-dimethylbenzoyl)-0-(3-(2- (5,6,7, 8-tetrahydro-l,8-naphthyridin-2-yl)eiliyl)cyclobutyl)-hornoserine; 2-f(3-chloro-5- methoxy-pyridine-4-carbonyl)amino]-4-[3-[2-(5, 6,7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; 2-[(2,6-dichloro-4-fluoro-benzoyl)amino]-4-[3-[2- (5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl]cyclobutoxy]butanoic acid; 2-[(2-chloro-6- fluoro-benzoyl)amino]-4-[3-|2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; N-(3-bromo-2-chloro-6-fluorobenzoyl)-0-(3-(2-(5, 6,7,8- tetrahydro- 1 ,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserine; N -(2,4-dimethyl-6-oxo- 1 - phenyl-l,6-dihydropyridine-3-carbonyl)-0-(3-(2-(5, 6,7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl)cyclobutyl)-homoserine; N-(5-bromo-2-hydroxyisonicotinoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridm-2~y3)ethy3)cyclobuty3)-homoserine; N-(3-chloro-5- cyclopropylisonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)etliyl)cyclobutyl)-homoserine; N-(3-chloro-5-ethylisonicotinoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-L8-naphthyridin-2-yl)et3iy3)cyclobuty3)-homoserme; N-(3-cyano-2,6- dimethylbenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)etliyl)cyclobutyl)- homoserine; N-(3-bromo-5-fluoroisonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8- naphthyridin-2-yl)ethyl)cyc3obutyl)-homoserine; N-(2-methoxy-3,5-dimeihy3isonicotinoyl)- 0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridm-2-yI)ethyi)cyclobutyl)-homoserine; N-(3- chloro-5-(trifluoromethyl)isonicotinoyl)-0-(3-(2 -(5,6,7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ediyl)cyclobutyl)-homoserine; N-(3-bromo-5-chloroisonicotinoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-L8-naphthyridin-2-yl)et3iy3)cyclobuty3)-homoserme; N-(2-(dimethylamino)-3,5- dimethylisonicotinoyl)-0-(3-(2-(5,6,7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl)cyclobutyl)- homoserine; N-(3-ch]oro-5-fiuoro-2-methylisonicotinoyi)-0-(3-(2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl)cyc3obutyl)-homoserine; N-(2,6-dichloro-3-cyanobenzoyl)-0-(3-(2- (5 ,6,7, 8-tetrahydro- 1 , 8-nap3ithyridin-2-yl)ethy3)cyclobutyl)-homoserme ; N -(3 -methyl-5 - (trifluoromethyl)isonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridm-2- yl)etliyl)cyclobutyl)-homoserine; N-(2 -hydroxy-3, 5-dimethylisonicotinoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-L8-naphthyridin-2-yl)etliyl)cyciobutyl)-homoserme; lN-(3-cyano-2-liydroxy-6- metby!isonicotinoy!)-0-(3-(2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-y3)ethyi)cyclobutyi)- homoserine; N-(5-ch]oro~3-fiuoro-2-methyiisonicotinoy!)-0~(3-(2-(5, 6,7, 8-tetrahydro- 1,8- naphthyridin-2-yl)ethyl)cyc3obutyl)-homoserine; 2-[(6-methoxy-2,4-dimethyl-pyridine-3- carbonyl)amino]-4-[3-[2-(5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)etliyl]cyclobutoxy]butanoic acid; 2-[[2,6-dimethyl-4-[(4-methylpiperazin-l- yl)methyl]benzoyl]amino]-4-[3-[2-(5, 6, 7, 8-tetrahydro-l , 8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; N-(3,5-dimethylmorpholine-4-carbonyl)-0-(3-(2- (5 ,6,7, 8-tetrahydro 1 , 8-naphthyridin-2-yl)ethyl)cyclobutyl)-homosenne ; 2-[ [5 -chloro-3- fiuoro-2~[(4-rnethyipiperazin~l -y!)methyl]pyridme-4-carbonyl]arnmo]-4~[3-[2-(5,6,7,8~ tetrahydro- 1 ,8-naphthyridin~2-yl)ethyl]cyclobutoxy]butanoic acid; methyl 2-[(7~chloro-5- oxo-2,3-dihydiO-lH-indolizine-8-carbonyl)amino]-4-[3-f2-(5,6,7,8-tetraliydro-l,8- naphtliyridin-2-yl)ethyljcyclobutoxy]butanoate: 2~[(2,6-diiluoro-4-liydroxy-benzoyl)aimno]- 4~[3-[2~(5,6,7,8-tetrahydro~l,8~naphthyridin~2~yl)ethyl]cyelobutoxy]butanoie acid; 2~[(4~ chioro-2-methyl~pyrazole-3-carbonyl)ammo]-4-[3-[2-(5,6,7,8~tetrahydro-l,8-naphthyridm-2- yl)ethyl]cyclobutoxy |butanoic acid: 2~[(2-methylpyrazoie-3-carbonyl)aminoj-4-| 3~ 2 (5,6,7,8-tetrahydro-L8-naplithyridin-2-yi)etliy3]cyciobutoxy]biitanoic acid; N-(l- (phenylsulfonyl)piperidine-2-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yi)ethyl)cyclobutyl)-homoserine; 2-(3,3-dimethylbutanoylamino)-4-j 3-[2-(5,6,7,8-teirahydro- l,8-naphtIiyridm-2-yl)ethyljcyciobutoxy]butanoic acid; 2-| (2~phenylacetyl)amino]-4-[3-[2~ (5,6,7,8-tetrahydro~!,8~naphthyridin~2~yl}ethyl]cyelobutoxy]butanoie acid; 4-[3~[2-{5,6,7,8- tetrahydro-l,8-naphthyridm-2-yl)ethy!]cydobutoxy]-2~[(4, 4, 4~trifluoro~3, 3-dimethyl- butanoyl)amino ] butanoic acid; 2- (4,4-difluoro-3,3-dimethyl-butanoyl)amino|-4-| 3-[2- (5 ,6,7, 8-tetrahydro- 1 ,8-naphthyridin-2-yl)ethyl] cyclobutoxy] butanoic acid; 2-[[2- phenylpropanoyl]aiiiino]-4-[3-[2-(5,6,7,8~tetrahydro-l,8-r!aphthyridiii-2- yl)etliyl]cyclobutoxy]butanoic acid; 2-| | 2-(3,5-difluorophenyl)acetyl]amino |-4-|3-[2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)etliyi]cyciobiitoxy]butanoic acid; 2-[[2-(tert- butoxycaibonylamino)- 1 -methyl-ethoxy]carbonylainino] -4-[3-[2-(5 ,6,7, 8-tetrahydro- 1,8- naphthyridm-2~y])ethyl]cyc!obutoxy]butanoic acid; 2-[(3,6~dimethylpyridme-2~
carbonyi)aminoj-4-j 3-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl]cyclobutoxy |butanoic acid: 2-[(6-fluoiOchromane-2-carbonyi)aminoj-4-j 3-[2- (5,6,7,8-tetrahydro-l,8-naplithyridin-2-yi)ethyl]cyciobutoxy]biitanoic acid; 4-[3-[2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl]cyclobutoxy]-2-[2-[3-
(tiifluoroniethyl)phenyl]butanoylamino]butanoic acid: 2-[(3-chloro-5-methyl-pyridine-4- carbonyl)amino]-4-[3-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; 2-[(3-chloro-5-fluoro-pyridine-4-carbonyl)amino]-4-[3- [2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl]cyclobutoxy]butanoic acid; 2-[(4-cyano- 2,6-diniethyl-benzoyl)amino]-4-[3-| 2-(5,6,7,8-tetraliydro-l,8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; 2-[[4-(2-chlorophenyl)tetrahydropyran-4- carbonyl]amino]-4-[3-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; 2-[(2-hydroxyindane-2-carbonyl)amino]-4-[3-[2- (5,6,7,8~tetrahydro-L8-naphthyridin-2-yl)etliyl]cyclobutoxy]biitanoic acid; 2-[(l- cyclopropylcyclopropanecarbonyl)amino]-4-[3-[2-(5,6,7,8-tetrahydro-l ,8-iiaphthyridin-2- yl)ethyl]cyclobutoxy]birtanoic add; 2-[[3-(difluoromethyl)-5,6,7,8-tetrahydro- fl,2,4]triazolo[4,3-a]pyridine-6-carbonyl]amino]-4-[3-f2-(5,6,7,8-tetrahydro-l,8- naptithyridin-2-yl)eihyl|cyclobuioxyJbutanoic acid; 2-| ( 1- cyciopropylcyclobutanecarbonyl)amino]-4-[3-[2-(5,6,7,8-tetrahydio-l,8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; 2-[[ 1 -(4-isopropylphenyl)cyclopentanecarbonyl]amino] - 4-| 3-[2-(5,6,7,8~tetrahydro-L8-naphthyridin-2-yl)ethyl]cydobutoxy]biitanoic acid; 2- (bicyclo[2.2.2]octane-4-caibonylamino)-4-[3-[2-(5,6,7,8-tetrahydro-l,8-naphtliyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; 2-(3,4,5,6,7,7a-hexahydro-2H-benzofuran-3a- carbomdamino)-4-[3-[2 -(5,6,7, 8-tetrahydro-l, 8-naphthyridin-2- yi)etliyl]cyclobutoxy]butanoic acid; 2-[[l-(2-phenylethyi)cyclopropanecarbonyl]amino]-4-[3- [2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl]cyclobutoxy]butanoic acid; 2-[[4-(3- methylisoxazol-5-yl)tetrahydropyran-4-carbonyl]amino]-4-[3-[2-(5,6,7,8-tetrahydro-l,8- naphthyridm-2-yl)ethyllcyclobutoxy]butanoic acid; 2-[[l- (benzenesulfonyl)cyclopropanecarbonyi]amino]-4-[3-[2-(5,6,7,8-tetrahydro-l,8- naplithyridin-2-y!)ethyl]cyclobutoxy]butanoic acid; 2-[( 1- phenylcycloheptanecarbonyl)amino]-4-[3-|2-(5,6,7,8-tetrahydro-i,8-naphthyridin-2- yl)eiliyl]cyclobutoxy]butanoic acid; 2-| (4-meiliylsuifonyitetraliydropyran-4-carbonyl)aimno]- 4-[3-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl]cyclobutoxy]butanoic acid; 2-[[l-(4- suifamoylphenyl)cyclopropanecarbony!]amino]-4-[3-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl)ethyI]cyclobutoxy]butanoic acid; N-((phenylsulfonyl)prolyl)-0-(3-(2-(5, 6,7,8- tetraiiydro-l,8-naphthyridm~2-yl)eihyi)cyclobutXi)-homoserine; N-(5-chloro-3-fluoro-2-((4- methylpiperazin-l-yl)methyi)isonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ediyl)cyclobuiyl)-homoserine; N-(3-chloro-5-fluoro-2-((4-methylpiperazin-l- yi)methyl)isonicotinoyI)-0-(3-(2-(5,6,7,8-ietrahydiO-l,8-naphthyndin-2~yi)ethyl)cyclobutyl)- homoserine; 2-(pyrimidin-4-ylamino)-5-(3-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)propoxy)pentanoic acid; 2-[(3-chloro-5-methyl-pyridine-4-carbonyl)amino]-4-[4-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butoxy]butanoic acid; 2-[(2,4-dimethylpyridine-3- carbonyi)amino]-4-|4-(5,6,7,8-tetraliydro-l,8-naphtiiyridin~2-yl)butoxy]butanoic acid; 2-[(4- cyano-2,6-dimethyl-benzoyl)amino]-4-[4-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)butoxy]butanoic acid; 2-[(3,5-dich]oropyridine-4-carbonyl)amino]-4-[4-(5, 6,7,8- tctrahydro-l,8-naphihyridin-2-yl)butoxy]butanoic acid; 2-[(3-chloro-5-fluoro-pyridine-4- carbonyi)aminoi-4-|4-(5,6,7,8-tetraliydro-l,8-naphtliyridin~2~yl)butoxy]butanoic acid; N-
(3,5-dimethylmorpholme-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naph†hyridm-2-yi)butyl)- homoserine; N-(2,6-dichlorobenzoy])-0-(4-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)butyl)- homoserine; N-(3,5-dimethylisonicotinoyl)-0-(4-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yi)butyI)-homoserme; 2-[(2,4-dichloro-6-fluoro-benzoyl)amino]-4-[4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butoxy]butanoic acid; 2-[(2,4-dimethyl-6-oxo-lH-pyridine-3- carbonyl)amino]-4-[4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butoxy]butanoic acid; N-(3- chloro-5-methoxyisonicotinoyi)-0-(4-(5,6,7,8-tetrahydfo-l,8-naphthyridin-2-yl)butyl)- homoserine; 2-[(2-chloro-6-fluoro-benzoyl)amino]-4-[4-(5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl)butoxy]butanoic acid; N-(tert-butoxycarbony])-0-(4-(5,6,7,8-tetrahydro- 1 ,8- naphthyridin-2-yl)butyl)-homoserine; N-(5-bromo-2-hydroxyisonicotinoyl)-0-(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)-homoserine; N-(3-bromo-5-chloro-2- fluoroisonicotmoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridm-2-yl)butyl)-homoserine; N~ (2,4-dimethyl-6-oxo-l-phenyl-I ,6-dihydropyridme-3-carbonyl)-0-(4-(5,6,7,8-tetrahydro-I ,8- naphthyridin-2-yl)butyl)-homoserine; 0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)- N-(5,6,7,8-tetrahydronaphthalene-l-carbonyl)-homoserine; N-(3-bromo-2,6- dimethylbenzoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridm-2-yl)butyl)-homoserine; N~(3- chloro-5-fluoroisonicotinoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)- homoserme; N-(3-bromo-2-chloro-6-fluorobenzoyl)-0-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-homoserine; 2-[(3-chloro-5-methoxy-pyridine-4-carbonyl)amino]-4- [2-methyl-4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butoxy]butanoic acid; 2-[(3-chloro-5- fluoro-pyridine-4-carbonyl)amino]-4-[2-methyl-4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butoxy]butanoic acid; N-(3-chloro-5-fluoroisonicotinoyl)-0-(2-methyl-4-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2~y3)butyl)-homoserine; N-(2,6-dichlorobenzoyl)-0-(2-methyl- 4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)-homoserine; N-(2-chloro-6- fluorobenzoyl)-0-(2-methyl-4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)biityl)-homoserine; N-(4-fluoro-2-metliy3nicotinoyl)-0-(2-methy3-4-(5,6,7,8-tetrahydro-L8-naphthyridin-2- yl)butyl)-homoserine; 2-[(3-chloro-5-fluoro-pyridine-4-carbonyl)amino]-4-[2-hydroxy-4- (5 ,6,7, 8-tetrahydro- 1 , 8-naph thyridin-2-yl)butoxy jbutanoic acid; 2-( 1 -methyl- 1 H-indazoie-4- carboxamido)-5-(3-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-}4)propoxy)pentanoic acid; 2-(3- (l-methyl-lH-pyrazol-4-yl)benzamido)-5-(3-(5,6,7,8-tetrahydro-l,8-naph†hyridm-2- yl)propoxy)pentanoic add; 2-(2-ch]oro-3-fluorobenzamido)-6-(2-(5,6,7,8-tetrahydro-l ,8- naphthyridin-2-yl)ethoxy)hexanoic acid; 2-(3-( l-methyl-lH-pyrazol-4-yl)benzamido)-6-(2- (5,6,7,8-tetrahydro-L8-napMiyridin-2-yl)ethoxy)hexanoic acid; 2-(2-ethylbutanamido)-6-(2- (5,6,7,8~tetrahydro-L8-naphthyridin-2-yi)ethoxy)hexanoie acid; 2-(l -methyl- lH-indazole-4- carboxamido)-6-(2-(5,6,7,8-tetrahydro- 1 ,8-naphthyridin-2-yl)ethoxy)hexanoic acid; 2-((tert- butoxycarbonyl)amino)-5-(3-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)propoxy)pentanoic acid; N-benzoyl-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(quinazolin-4y d)-0-(3~(2~(5, 6, 7, 8-tetrahydro- 1 ,8- naphthyridin-2~yl)ethyl)cyc!obutyl)homoserine; N-(8-fluoroquinazolin-4-yl)-0-(3-(2- (5 ,6,7, 8-tetrahydro 1 , 8-naphthyridin-2-yl)ethy3)cyciobutyi)homoserine ; N-(7- fluoroqumazolin-4-yl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethy!)cyclobutyl)homoserine; N-(7-methylquinazolin-4-yl)-0-(3-(2-(5,6,7,8-tetrahydro-
1.8-naphihyridin-2-yl)etiiyl)cyclobutyl)homoserine; N-(6-fluoroquinazolin-4-yl)-0-(3-(2- (5 ,6, 7, 8-tetrahydro- 1 , 8-naphthyridin-2-\i)ethy l)cyclobuty l)homoserine ; N-(5 - fluoroquinazolin-4-yl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyc!obutyl)homoserine; N-(6-methylquinazolin-4-yl)-0-(3-(2 -(5,6,7, 8-tetrahydro-
1.8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; and N-(6-(tert-butyl)-2-phenylpyrimidin- 4-yl)-Q-(3-(2-(5,6,7,8-tetrahydro-I,8-naphthyfidin-2-yi)ethyi)cyclobutyi)-homoserine.
[0153] 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 the compounds depicted in Table 1 , or a stereoisom er 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 the compounds depicted in Table 1 In one aspect, the composition is a
pharmaceutical composition that further comprises a pharmaceutically acceptable carrier
[0154] 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 the compounds depicted in Table 2, 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 the compounds depicted in Table 2. In one aspect, the composition is a
pharmaceutical composition that further comprises a pharmaceutically acceptable carrier
[0155] The invention also includes all salts of compounds referred to herein, such as pharmaceutically acceptable salts. The invention also includes any or all of the
stereochemical forms, including any enantiomeric or diastereorneric forms, and any tautomers or other forms of the compounds described. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of a compound depicted. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also described and embraced by the invention. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. It is also understood that prodrugs, solvates and metabolites of the compounds are embraced by this disclosure.
Compositions comprising a compound of the in v ention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof. Compositions comprising a mixture of compounds of the invention in any ratio are also embraced by the invention, including mixtures of two or more stereochemical forms of a compound of the inv ention in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced. Where one or more tertiary amine moiety is present in the compound, the N-oxides are also provided and described.
[0156] Compounds described herein are anbό integrin inhibitors. In some instances, it is desirable for the compound to inhibit other integrins in addition to anb6 integrin. In some embodiments, the compound inhibits anbό integrin and one or more of anbΐ, anb3, anb5, a2b1, a3b1, aόbΐ integrin, a7b1 and a 11 b 1. In some embodiments, the compound inhibits anbό integrin and anbΐ integrin. In some embodiments, the compound inhibits anbό integrin, anb3 integrin and anb5 integrin. In some embodiments, the compound inhibits anb6 integrin and a2b1 integrin. In some embodiments, the compound inhibits anbό integrin, a2b1 integrin and a3b1 integrin. In some embodiments, the compound inhibits anbό integrin and aόbΐ integrin. In some embodiments, the compound inhibits anb6 integrin and a7b1 integrin. In some embodiments, the compound inhibits anb6 integrin and aΐ Ibΐ integrin.
[0157] In some instances, it is desirable to avoid inhibition of other integrins. In some embodiments, the compound is a selective anbό integrin inhibitor. In some embodiments, the compound does not inhibit substantially a4b1, anb8 and/or a2b3 integrin. In some embodiments, tire compound inhibits anb6 integrin but does not inhibit substantially a4b1 integrin. In some embodiments, the compound inhibits anbό integrin but does not inhibit substantially anb8 integrin. In some embodiments, the compound inhibits anb6 integrin but does not inhibit substantially a2b3 integrin. In some embodiments, the compound inhibits anbό integrin but does not inhibit substantially the anb8 integrin and the a4b! integrin. [0158] The invention also intends isotopically-labeled and/or isotopically-enriched forms of compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or variations thereof described herein, where one or more atoms are replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2H, 3H, nC, 13C, i4C i3N, i50, 17Q, 32P, 35S, 18F, 36Cl. Incorporation of heavier isotopes such as deuterium (2H or D) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances. In some embodiments, provided herein is an isotopically enriched form of any of the formulae described herein, wherein the compound comprises one or more deuterium atoms. In some embodiments, the compounds of formula (I) may have one or more of the hydrogen atoms replaced by deuterium, such as any of the hydrogens in one or more of the moieties G, L!, L2, Y, L3, and R!.
[0159] Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in tire art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically- labeled reagents in place of the corresponding non -labeled reagent.
[0160] The invention also includes any or all metabolites of any of the compo unds described. The metabolites may include any chemical species generated by a
biotransformation of any of the compounds described, such as intermediates and products of metabolism of the compound.
[0161] 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, preloaded syringe, i.v. bag, and the like.
[0162] Preferably, the compounds detailed herein are orally bioavailahle. However, the compounds may also be formulated for parenteral (e.g., intravenous) administration.
[0163] One or several compounds described herein can 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 medication, the carrier may be in various forms.
GENERAL SYNTHETIC METHODS
[0164] The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provides in the Examples below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.
[0165] Where it is desired to obtain a particular stereoisomer of a compound, this may be accomplished from a corresponding mixture of stereoisomers using any suitable conventional procedure for separating stereoisomers or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. Tire diastereomers may then he separated by any convenient means, for example 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 stereoisomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
[0166] Chromatography, recrystallization and other conventional separation procedures may also he used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
[0167] Solvates and/or polymorphs of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated. Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are often formed during the process of
crystallization. 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 usually 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
recrystal! izati on solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate. [0168] Compounds provided herein may be prepared according to General Schemes A,
B, C, D-2, E-2, F-2, G-2, and H; Schemes D-l, E-l, F-l , and G-l; General Procedures A, B
C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, and R; and Examples 1 -226
[0169] Compounds of formula 18A can be prepared according to General Scheme A, wherein G, R2, and R3 are as defined for formula (I), or any applicable variations detailed
herein; X1 is a leaving group
Figure imgf000109_0001
the like); and X2 is another leaving group (e.g , -Cl, -Br, -I, -QTf and the like).
General Scheme A
Issey e
Figure imgf000109_0002
Figure imgf000109_0003
Figure imgf000109_0004
Figure imgf000109_0005
[0170] Silylation of compound 1A gives compound 2A, which can be reduced with a suitable reducing agent to give compound 3A. Iodination of 3 A gives compound 4A, which can be alkylated with compound 5A under basic conditions to give compound 6A
Condensation of compound 6A with compound 7 A in the presence of an appropriate catalyst gives compound 8 A, which can be alkylated with an alkyl halide to give compound 9A. Oxidative cleavage of 9 A gives compound 10A, which can be treated with compound 11A under basic conditions to afford compound 12A. Reduction of compound 12A gives compound 13 A, which can be exposed to an appropriate acid to give compound 14A.
Coupling of compound 14A with compound of formula 15A or 16A gives rise to compound 17A, which can be hydrolyzed in the presence of a suitable hydroxide source to give compound 18 A.
[0171] Reaction conditions for the transformations of General Scheme A are provided in the General Procedures that follow , in particular General Procedures D, E, F, H, I, K, and N. Exemplary reaction conditions for the transformations of General Scheme A are provided in General Procedure A, omitting the chiral separation step at the end of General Procedure A.
[0172] Compounds of formula 18B can be prepared according to General Scheme B, wherein G, R2, and R3 are as defined for formula (1), or any applicable variations detailed
herein; X’! is a leaving group
Figure imgf000110_0001
the like); and X2 is another leaving group (e.g., -Cl, -Br, -I, -OTf, and the like).
General Scheme B
Figure imgf000110_0002
Figure imgf000111_0001
[0173] Silylation of compound IB gives compound 2B, which can be reduced with a suitable reducing agent to give compound 3B. lodination of 3B gives compound 4B, which can be alkylated with compound 5 A under basic conditions to give compound 6B.
Condensation of compound 6B with compound 7 A in the presence of an appropriate catalyst gives compound 8B, which can be alkylated with an alkyl halide to give compound 9B. Oxidative cleavage of 9B gives compound 10B, which can be treated with compound 11A under basic conditions to afford compound 12B. Reduction of compound 12B gives compound 13B, which can be exposed to an appropriate acid to give compound 14B.
Coupling of compound 14B with compound of formula 15A or 16A gives rise to compound G7B, which can be hydrolyzed in the presence of a suitable hydroxide source to give compound 18B.
[0174] Reaction conditions for the transformations of General Scheme B are provided in the General Procedures that follow in particular General Procedures D, E, F, H, L K, and N. Exemplary reaction conditions for the transformations of General Scheme B are provided in General Procedure B, omitting the chiral separation step at the end of General Procedure B.
[0175] Compounds of formula 12C can be prepared according to General Scheme C, wherein G, R2 and R3 are as defined for formula (I), or any applicable variations detailed herein; X1 is a leaving group
Figure imgf000112_0001
the like); and X2 is another leaving group (e.g , -Cl, -Br, -I, -OTf. and the like).
General Scheme C
Figure imgf000112_0002
[0176] Reduction of compound 1C gives compound 2C, which can be alkylated with an alkyl halide to give compound 3C Oxidative cleavage of 3C gives compound 4C, which can be treated with compound 11A under basic conditions to afford compound 6C. Reduction of compound 6C gives compound 7C, which can be exposed to an appropriate acid to give compound 8C. Coupling of compound 8C with compound of formula 15A or 16A gives rise to compound of formula 11C, which can be hydrolyzed in the presence of a suitable hydroxide source to give compound 12C.
[0177] Reaction conditions for the transformations of General Scheme C are provided in the General Procedures that follow, in particular General Procedures D, E, F, H, I, K, and N. Exemplar reaction conditions for the transformations of General Scheme C are provided in General Procedure C, omitting the chiral separation step at the end of General Procedure C. [0178] Compounds of formula 18D can be prepared according to Scheme D-i followed by General Scheme D-2, wherein G, R2 and RJ are as defined for formula (I), or any
applicable variations detailed herein; X1 is a leaving group
Figure imgf000113_0001
the like); and X2 is another leaving group (e.g., -Cl, -Br, -I, -OTf, and the like).
Scheme D-l
Figure imgf000113_0002
the
Figure imgf000113_0004
Figure imgf000113_0005
Figure imgf000113_0003
isomer D1 Isomer D2
[0179] Silylation of compound 1A gives compound 2A, which can be reduced with a suitable reducing agent to give compound 3A. lod nation of 3 A gives compound 4A, which can be alkylated with compound 5 A under basic conditions to give compound 6A.
Condensation of compound 6A with compound 7A in the presence of an appropriate catalyst gives compound 8 A, wliich can be alkylated with an alkyl halide to give compound 9A. Oxidative cleavage of 9A gives compound 10A, which can he treated with compound 11 A under basic conditions to afford compound 12A. Reduction of compound 12A gives compound 13 A, which can be separated using chiral SFC to afford Isomer Dl and Isomer D2.
Genera! Scheme D-2
Figure imgf000114_0001
[0180] Exposure of Isomer Dl (i.e., first eluting isomer from Scheme D-1) or Isomer D2
(i.e., second eluting isomer from Scheme D-1) to an appropriate acid gives compound 14D, wherein the wavy line in compound 14D refers to the isomer obtained when either Isomer Dl or Isomer D2 is reacted. Coupling of compound 14D with compound of formula 15A or 16A gives rise to compound 17D, which can be hydrolyzed in the presence of a suitable hydroxide source to give compound 18D.
[0181] Reaction conditions for the transformations of General Scheme D-2 are provided in the General Procedures that follow, in particular General Procedures D, E, F, H, I, K, and N. Exemplary reaction conditions for the transformations of Scheme D-1 are provided in General Procedure A.
[0182] Compounds of formula 18E can be prepared according to Scheme E~1 followed by General Scheme E-2, wherein G, R2 and R3 are as defined for formula (I), or any
applicable variations detailed herein; X1 is a leaving group (
Figure imgf000114_0002
the like); and X2 is another leaving group (e.g., -Cl, -Br, -I, -OTf, and the like).
Figure imgf000115_0001
Figure imgf000115_0002
Figure imgf000115_0003
isomer E1 isomer E2
[0183] Silylation of compound IB gives compound 2B, which can he reduced with a suitable reducing agent to give compound 3B lodination of 3B gives compound 4B, which can be alkylated with compound 5 A under basic conditions to give compound 6B.
Condensation of compound 6B with compound 7A in the presence of an appropriate catalyst gives compound 8B, which can be alkylated with an alkyl halide to give compound 9B. Oxidative cleavage of 9B gives compound 1 OB, which can be treated with compound 1 1 A under basic conditions to afford compound 12B. Reduction of compound 12B gives compound 13B, which can be separated via supercritical fluid chromatography (SFC) into Isomer El and Isomer E2. General Scheme E-2
Figure imgf000116_0004
Figure imgf000116_0001
[0184] Exposure of isomer El (i.e., first eluting isomer from Scheme E-1) or Isomer E2 (i.e., second eluting isomer from Scheme E-1) to an appropriate acid gives compound 14E, wherein the wavy line in compound 14E refers to the isomer obtained when either Isomer El or Isomer E2 is reacted. Coupling of compound 14E with compound of formula 15A or 16A gives rise to compound 17E, which can be hydrolyzed in the presence of a suitable hydroxide source to give compound 18E.
[0185] Reaction conditions for the transformations of General Scheme E-2 are provided in the General Procedures that follow, in particular General Procedures D, E, F, H, I, K, and N. Exemplary reaction conditions for the transformations of Scheme E-1 are provided in General Procedure B.
[0186] Compounds of formula 12F can be prepared according to Scheme F-l followed by General Scheme F-2, wherein G, R2 and R3 are as defined for formula (1), or any applicable
variations detailed herein; X’! is a leaving group
Figure imgf000116_0002
the like); and X2 is another leaving group (e.g., -Cl, -Br, -I, -OTf, and the like).
Scheme F-l
Figure imgf000116_0003
Figure imgf000117_0001
Figure imgf000117_0003
Isomer F2
[0187] Reduction of compound 1C gives compound 2C, which can be alkylated with an alkyl halide to give compound 3C. Oxidative cleavage of 3C gives compound 4C, which can be treated with compound 11 A under basic conditions to afford compound 6C. Reduction of compound 6C gives compound 7C, which can be separated via supercritical fluid chromatography (SFC) into Isomer FI and Isomer F2.
General Scheme F-2
Figure imgf000117_0002
[0188] Exposure of Isomer FI (i.e., first eluting isomer from Scheme F-l) or Isomer F2 (i.e., second eluting isomer from Scheme F-l) to an appropriate acid gives compound 8F, wherein the wavy line in compound 8F refers to the isomer obtained when either Isomer FI or Isomer F2 is reacted. Coupling of compound 8F with compound of formula 15A or 16A gives rise to compound of formula 1 IF, which can be hydrolyzed in the presence of a suitable hydroxide source to give compound 12F.
[0189] Reaction conditions for the transformations of General Scheme F-2 are provided in tire General Procedures that follow', in particular General Procedures D, E, F, H, I, K, and N. Exemplary reaction conditions for the transformations of Scheme F-l are provided in General Procedure C.
[0190] Compounds of formula 18G can be prepared according to Scheme G-l followed by General Scheme G-2, wherein G, R2 and R3 are as defined for formula (I), or any
applicable variations detailed herein; X1 is a leaving group i
Figure imgf000118_0001
the like); and X2 is another leaving group (e.g., -Cl, -Br, -1, -OTf, and the like).
Scheme G-l
Figure imgf000118_0002
isomer 01 isomer G2
[0191] Silylation of compound 1A gives compound 2A, which can be reduced with a suitable reducing agent to give compound 3A. lodmation of 3A gives compound 4A, which can be alkylated with compound 5 A under basic conditions to give compound 6A.
Condensation of compound 6A with compound 7A in the presence of an appropriate catalyst gives compound 8 A, wliieh can be alkylated with an alkyl halide to give compound 9A. Oxidative cleavage of 9A gives compound 10A, which can he treated with compound 11 A under basic conditions to afford compound 12A. Reduction of compound 12A gives compound 13 A, which can be exposed to an appropriate acid to give compound 14A.
Compound 14A can he separated using chiral SFC to afford Isomer G1 and Isomer G2.
General Scheme G-2
Figure imgf000119_0003
Figure imgf000119_0004
[0192] Coupling of Isomer G1 (i.e., first eluting isomer from Scheme G-1) or Isomer G2 (i.e., second eluting isomer from Scheme G-1) with compound of formula 15A or 16A gives compound 17G, wherein the wavy line in compound I7G refers to the isomer obtained when either Isomer G1 or Isomer G2 is reacted. Compound 17G can be hydrolyzed in the presence of a suitable hydroxide source to give compound 18G.
[0193] Reaction conditions for the transformations of Scheme G-1 and General Scheme G-2 are provided in the General Procedures that follow, in particular General Procedures D, E, F, H, I, K, and N. Exemplary reaction conditions for the transformations of Scheme G-1 are provided in General Procedure A.
[0194] Compounds of formula 18H can be prepared according to General Scheme H, wherein G, R2 and R3 are as defined for fonnula (I), or any applicable variations detailed
herein; X1 is a leaving group
Figure imgf000119_0001
the like); and X2 is another leaving group (eg , -Cl, -Br, -I, -OTf. and the like).
Figure imgf000119_0002
. 2M
Figure imgf000120_0002
Figure imgf000120_0001
[0195] Allylation of compound 1A gives compound 2H, which can be reduced with a suitable reducing agent to give compound 3H. lodination of 3H gives compound 4H, which can be alkylated with compound 5A under basic conditions to give compound 6H.
Condensation of compound 6H with compound 7A in the presence of an appropriate catalyst gives compound 9H, which can be alkylated with an alkyl halide to give compound 9H Oxidative cleavage of 9H followed by treating with compound 1 1 A under basic conditios affords compound 1211 Reduction of compound 12H gives compound 13H, which can be exposed to an appropriate acid to give compound 14H. Coupling of compound 14H with compound of formula 15 A or 16A gives rise to compound 17H, which can be hydrolyzed in the presence of a sui table hydroxide source to give compound 18H.
[0196] Reaction conditions for the transformations of General Scheme H are provided in the General Procedures that follow , in particular General Procedures D, E, F, H, I, K, and N.
[0197] It is understood that tire schemes above 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.
[0198] Additional methods of preparing compounds according to formula (I), and salts thereof, are provided in the Examples. As a skilled artisan 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 which would provide a desired compound.
Pharmaceutical Compositions and Formulations
[0199] Pharmaceutical compositions of any of the compo unds detailed herein, including compounds of the formulae (I), (Ha).. (lib), (Ilia), (IHb), (IVa), (FVb), (Va), (Va-l), (Va-2), (Vb), (Vb-1), and (Vb-2), or a salt thereof, or compounds depicted in Table 1 , or a salt thereof, or mixtures thereof, are embraced by this invention. Thus, the invention includes pharmaceutical compositions comprising a compound of the in vention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, tire pharmaceutically acceptable salt is tin acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation. In one embodiment, the pharmaceutical composition are prepared from mixtures of any of the compounds detailed herein, or salts thereof. In one embodiment, the pharmaceutical composition is a composition for controlled release of any of the compounds detailed herein.
[020Q] Pharmaceutical compositions of any of the compounds detailed herein, including compounds of the formulae (I), (Ha).. (lib), (Ilia), (IHb), (IVa), (FVb), (Va), (Va-l), (Va-2), (Vb), (Vb-1), (Vb-2), (P-A-1), (II-A-2), (P-A-2Ϊ), (P-A-2ΪΪ), (IT-A-la-I), (II-A-la-2), (GG-A- la-3), (II-A-lb-l), (II-A-lb-2), (II-A-lc-1), (II-A-lc-2), (II-A-ld-1), (II-A-ld-2), (II-A-ld- 3), (II-A-2a-l), (H-A-2a-2), (II-A-2a-3), (H-A-2a-4), (II-A-2b-l), (II-A-2b-2), (H-A-2c-l), (II-A-2c-2), (II-A-2c-3), (II-A-2c-4), (II-A-2d-l), (II-A-2d-2), (II-A-2d~3), (II-A-2d-4), (II-A- 2d-5), (II-A-2d-6), (II-A-2e-l), (II-A-2e-2), (II-A-2e-3), (II-A-2e-4), (II-A-2e~5), (II-A-2e-6), (II-A-2e-7), (II-A-2e-8), (H-A-2f-l), (II-A-2f-2), (Il-A-2f-3), (II-A-2f-4), (II-A-2f-5), (U-A- 2f-6), (II-A-2f-7), (II-A-2f-8), (II-A-2f-9), (II-A-2f-10), (II-B-1), (G1-B-2), (IΪ-B-3), (II-B-la), (II-B-2a), (II-B-2b), (II-B-3a), or (II-B-3b), a compound of Table 1 or Table 2, or any one of compounds 1-329; or a salt thereof, or mixtures thereof, are also embraced by this invention. [0201] 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, 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 Table 1 may contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound of Table 1 or a salt thereof. In one embodiment, compositions may contain no more than 25% impurity. In one embodiment, compositions may contains no more than 20% impurity. In still further 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 still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 9% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 7% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 5% impurity . In another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no 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 no more than 0.5% impurity. In yet other variations, a composition of substantially pure compound means that the composition contains no more than 10% or preferably no more than 5% or more preferably no more than 3% or even more preferably no more than 1% impurity or most preferably no more than 0.5% impurity, which impurity may be the compound in a different stereochemical form. For instance, a composition of substantially pure (5) compound means that the composition contains no more than 10% or no more than 5% or no more than 3% or no more than 1 % or no more than 0.5% of the (R) form of the compound. [Q202] In further embodiments, the purified forms and substantially pure forms of the compounds apply to any compounds of the formulae (I), (Ila), (lib), (Ilia), (IHb), (IVa),
(IVb), (Va), (Va-l), (Va-2), (Vb), (Vb-1), (Vb-2), (II-A-1), (II-A-2), (II-A-2Ϊ), (P-A-2ϋ), (II- A-la-1), (II-A-la-2), (II-A-la-3), (P-A-lb-l), (D-A-lb-2), (II-A-lc-1), (II-A-lc-2), (II-A-ld- 1), (II-A-1 d-2), (II-A-ld-3), (II-A-2a-l), (H-A-2a-2), (II-A-2a-3), (II-A-2a-4), (H-A-2b-l), (II-A-2b-2), (iI-A-2c-l), (II-A-2c-2), (II-A-2c-3), (n~A~2e-4), (II-A-2d-l), (II-A-2d-2), (II-A- 2d-3), (II-A-2d-4), (II-A-2d-5), (II-A-2d-6), (II-A-2e~l), (II-A-2e-2), (II-A-2e-3), (II-A-2e-4), (II-A-2e-5), (II-A-2e-6), (H-A-2e-7), (P-A-2e-8), (II-A-2f-l), (II-A-2f-2), (H-A-2f-3), (P-A- 2f-4), (ii-A-2f-5), (II-A-2f-6), (II-A-2f-7), (P~A~2ί~8), (P-A-2ί-9), (II-A-2f-10), (II-B-1), (II- B-2), (II-B-3), (II-B-la), (II-B-2a), (II-B-2b), (II-B-3a), or (II-B-3b), a compound of Table 1 or Table 2, or any one of compounds 1-329
[0203] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual such as a human. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the invention embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable earner or excipient. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compo unds are suitable for any compound or form thereof detailed herein.
[0204] The compound de tailed herein or salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g , intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
[0205] One or several compounds described herein or a salt thereof can 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 be various forms. In addition, phamiaceutical formulations may contain preservatives, solubilizers, stabilizers, re- wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising die compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g. in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st ed. (2005), which is incorporated herein by reference.
[0206] Compounds as 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 in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, com starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
[0207] Any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a pharmaceutically acceptable salt thereof can be formulated as a 10 mg tablet.
[0208] 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 the treatment of a disease or disorder described herein.
Methods of Use
[0209] Compounds and compositions of the invention, such as a pharmaceutical composition containing a compound of any formula provided herein or a sal t thereof and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. The compounds and compositions may 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 conducting quality control assays
[0210] In one aspect, provided is a method of treating a fibrotic disease in an individual in need thereof comprising administering to the individual a therapeutically effecti ve amount of a compound of formula (I), or any variation thereof, e.g., a compound of formula (I), (Ha), (lib), (Ilia), (Mb), (IVa), (IVb), (Va), (Va-1), (Va-2), (Vb), (Vb-1), or (Vb-2), a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof, or a
pharmaceutically acceptable salt thereof In one aspect, the individual is a human. The individual, such as a human, may be in need of treatment, such as a human who has or is suspected of having a fibrotic disease. In one embodiment, a variation of the compounds includes any stereoisomer thereof
[0211] In a further aspect, provided is a method of treating a fibrotic disease in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of formulae (I), (Ila), (lib), (Ilia), (Mb), (IVa), (IVb), (Va), (Va-1 ), (Va-2), (Vb), (Vb-1), (Vb-2), (II-A-1 ), (P-A-2), (P-A-2Ϊ), (II-A-2ii), (II-A-Ia-1 ), (II- A-la-2), (II -A- la-3), (II-A-lb-1), (II-A-lb-2), (II-A-lc-1 ), (II-A-lc-2), (II-A-ld-1), (II-A-ld-
2), (H-A-ld-3), (II-A-2a-l), (ll-A-2a-2), (II-A-2a-3), (H-A-2a-4), (U-A-2b-l), (H-A-2b-2), (II-A-2c-l), (II-A-2c-2), (II-A-2c-3), (II-A-2c-4), (II-A-2d-l), (D-A-2d-2), (II-A-2d-3), (P-A- 2d-4), (II-A-2d-5), (II-A-2d-6), (II-A-2e-l), (IT-A-2e-2), (II-A-2e-3), (II-A-2e-4), (II-A-2e-5), (II-A-2e-6), (II-A-2e-7), (II-A-2e-8), (II-A-2f-l), (II-A-2f-2), (II-A-2f-3), (II-A-2f-4), (ΪI-A- 2f-5), (II-A-2f-6), (II-A-2f-7), (II-A-2f-8), (H-A-2f-9), (D-A-2f-10), (II-B-1), (II-B-2), (II-B-
3), (II-B-la), (TT-B-2a), (II-B-2b), (II-B-3a), or (TI-B-3b), a compound selected from the compounds depicted in Table 1 or Table 2, or any one of compounds 1-329, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof In one aspect, the individual is a human. The individual, such as a human, may be in need of treatment, such as a human who has or is suspected of having a fibrotic disease. In one embodiment, a variation of the compounds includes any stereoisomer thereof.
[0212] In another aspect, provided is a method of delaying the onset and/or development of a fibrotic disease in an individual (such as a human) who is at risk for dev eloping a fibrotic disease. It is appreciated that delayed development may encompass prevention in the event 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-age or older adults), the presence of inflammation, having one or more genetic component associated with development of a fibrotic disease, medical history such as treatment with a drug or procedure believed to be associated with an enhanced 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 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, NS1P, PSC, PBC, or is an individual who has had or is suspected of having had a myocardial infarction
[0213] In some embodiments, the fibrotic disease is fibrosis of a tissue such as the lung (pulmonary fibrosis), the liver, the skin, the heart (cardiac fibrosis), the kidney (renal fibrosis), or the gastrointestinal tract (gastrointestinal fibrosis).
[0214] In some embodiments, the fibrotic disease is pulmonary fibrosis (such as IPF), liver fibrosis, skm fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or bibary fibrosis (such as PBC).
[0215] In some embodiments, the fibrotic disease is a pulmonary fibrosis, e.g., idiopathic pulmonary fibrosis (IPF), interstitial lung disease, systemic sclerosis-associated interstitial lung disease, or radiation-induced pulmonary fibrosis. In some embodiments, the individual at risk for developing a fibrotic disease is an individual who has or is suspected of having a history of viral lung infections
[0216] In some embodiments, the fibrotic disease is a primary sclerosing cholangitis, or biliary fibrosis.
[0217] In some embodiments, the fibrotic disease is fibrotic nonspecific interstitial pneumonia (NSIP)
[0218] 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 liver disease induced fibrosis, alcoholic steatosis induced liver fibrosis, nonalcoholic fatty liver disease, and cirrhosis.
[0219] In some embodiments, the fibrotic disease is biliary tract fibrosis
[0220] In some embodiments, the fibrotic disease is renal fibrosis, e.g. , diabetic kidney' disease, diabetic nephrosclerosis, hypertensive nephrosclerosis, diabetic nephropathy, focal segmental glomerulosclerosis (“FSGS”), Alport syndrome, chronic kidney disease, and acute kidney injury from contrast induced nephropathy.
[0221] In some embodiments, the fibrotic disease is systemic and local sclerosis or scleroderma, keloids and hypertrophic scars, or post surgical adhesions.
[Q222] In some embodiments, the fibrotic disease is atherosclerosis or restenosis.
[0223] In some embodiments, the fibrotic disease is a gastrointestinal fibrosis, e.g. ,
Crohn's disease.
[0224] In some embodiments, the fibrotic disease is cardiac fibrosis, e.g., post myocardial infarction induced fibrosis and inherited cardiomyopathy.
[0225] In one aspect, provided is a compound of formula (I), or any variation thereof, e.g. , a compound of formula (I), (Ha), (lib), (Ilia), (Illb), (IVa), (IVb), (Va), (Va-1), (Va-2), (Vb), (Vb-l ), or (Vb-2), a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a fibrotic disease .
[0226] Also provided is use of a compound of formula (I), or any variation thereof, e.g., a compound of formula (II), a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.
[0227] In another aspect, provided is a method of inhibiting anbό integrin in an individual comprising administering a compound of formula (I), or any variation thereof, e.g., a compound of formula (Ila), (Tib), (Ilia), (Tllb), (IVa), (IVb), (Va), (Va-I), (Va-2), (Vb), (Vb-l ), or (Vb-2), a stereoisomer thereof, or a compound selected from the compounds depicted in Table l, or a pharmaceutically acceptable salt thereof.
[0228] Also provided is a method of inhibiting TORb activation in a cell comprising administering to the cell a compound of formula (1), or any variation thereof, e.g., a compound of formula (Ila), (lib), (Ilia), ( I II b). (IVa), (IVb), (Va), (Va-1), (Va-2), (Vb), (Vb- 1 ), or (Vb-2), a compound selected from the compounds depicted in Table 1, or a
stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
[0229] Also provided is a method of inhibiting anb6 integrin in an individual in need thereof, comprising administering to the individual a compound of formula (I), or any variation thereof, e.g., a compound of formula (Ila), (lib), (Ilia), (Mb), (IVa), (IVb), (Va), (Va-1), (Va-2), (Vb), (Vb-1), or (Vb-2), a compound selected from the compounds depicted in Table 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one such method, the compound is a selective anb6 integral inhibitor. In another such method, the compound does not inhibit substantially a4b1, anb8 and/or a2b3 integrin. In yet another such method, the compound inhibits anb6 integrin but does not inhibit substantially a4b1 integrin. In still another such method, the compound inhibits anbό integrin but does not inhibit substantially anb8 integrin. In a further such method, the compound inhibits anbό integrin but does not inhibit substantially a2b3 integrin. In one embodiment is provided a method of inhibiting anb6 integrin and one or more of anbΐ, anb3, anb5, a2b1, a3b1, aόb1 integrin, «7bI and aΐ Ibΐϊh an individual in need thereof. In another embodiment is provided a method of inhibiting anbό integrin and anbΐ integrin. In another embodiment is provided a method of inhibiting anb6 integrin, anb3 integrin and anb5 integrin. In another embodiment is provided a method of inhibiting anb6 integrin and a2b1 integrin. In another embodiment is provided a method of inhibiting anb6 integrin, a2b1 integrin and a3b1 integrin. In another embodiment is provided a method of inhibiting anbό integrin and aόbΐ integrin. In another embodiment is provided a method of inhibiting anbd integrin and a7b1 integrin. In another embodiment is provided a method of inhibiting anbό integrin and a 11 b 1 integrin. In all such embodiments, in one aspect the method of inhibition is for an individual in need thereof, such as an individual who has or is suspected of hav ing a fibrotic disease, and wherein the method comprises administering to the individual a compound of formula (I), or any variation thereof, e.g., a compound of formula (Ila), (lib), (Ilia), (ITTb), (IVa), (IVb), (Va), (Va-1), (Va- 2), (Vb), (Vb-1), or (Vb-2), a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
[0230] Also provided is a method of modulating at least one integrin in a subject, the at least one integrin comprising an <xv subunit, the method comprising administering to the subject an effective amount of the compound of formula (I), or any variation thereof, e.g., a compound of formula (Ila), (lib), (Ilia), (Tllb), (IVa), (IVb), (Va), (Va-1), (Va-2), (Vb), (Vb- 1), or (Vb-2), a stereoisomer thereof, or a compound selected from the compounds depicted m Table 1, or a pharmaceutically acceptable salt thereof. In another aspect, the modulating comprising inhibiting the at least one integrin in the subject. In another aspect, the at least one integrin comprising at least one of anbi integrin and anbb integrin. In another aspect, the subject has or is at risk of a fibrotic disease selected from the group consisting of: idiopathic pulmonary' fibrosis (IFF), interstitial lung disease, radiation-induced pulmonary' fibrosis. nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease induced fibrosis, Alport syndrome, primary sclerosing cholangitis (PSC), primary biliary cholangitis, biliar ' atresia, systemic sclerosis associated interstitial lung disease, scleroderma, diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn’s Disease; and tire method comprises inhibiting one or both of anbi integrin and anbΰ integrin in the subject, thereby treating the fibrotic disease in the subject. In another aspect, the subject being in need of treatment for NASH, the effective amount administered to the subject being effective to inhibit at least anbi integrin, thereby treating the subject for NASH. In another aspect, the subject being in need of treatment for IPF, the effective amount administered to the subject being effective to inhibit at least anbd integrin, thereby treating the subject for IPF. In another aspect, the subject being in need of treatment for PSC, the effective amount administered to the subject being effective to inhibit at least one of anbi integrin and anbb integrin, thereby treating the subject for PSC.
[0231] Also provided is a method of modulating TGFp activation in a cell, comprising contacting the cell with the compound of formula (I), or any variation thereof, e.g., a compound of formula (Ila), (lib), (Ilia), (IKb), (IVa), (IVh), (Va), (Va-1), (Va-2), (Vb), (Vb- 1), or (Vb-2), a stereoisomer thereof, or a compound selected from the compounds depicted in Table 1, or a pharmaceutically acceptable salt thereof. In another aspect, the modulating comprising inhibiting TORb activation in the cell. In another aspect, the TORb activation being mediated in the cell by at least one of anbi integrin and anbd integrin.
[0232] Also provided is a method of treating a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of the compound of formula (1), or any variation thereof, e.g., a compound of formula (Ila), (Hb), (Ilia), (Illb), (IVa),
(i Vb). (Va), (Va-1), (Va-2), (Vb), (Vb-l), or (Vb-2), a stereoisomer thereof, or a compound selected from the compounds depicted in Table 1 , or a pharmaceutically acceptable salt thereof, wherein the subject has at least one tissue in need of therapy and the tissue has at least one elevated level of: TORb activation and/or expression; anbi integrin activity and/or expression; or anbό integrin activity and/or expression; wherein the at least one elevated level is elevated compared to a healthy state of the tissue. In some aspects, the method selectively inhibits anbi integrin compared to anbb integrin in the subject. In some aspects, the method selectively inhibits anbd integrin compared to anbi integrin in the subject. In some aspects, the method inhibits both of anbi integrin and anbd integrin in the subject. In some aspects, the method selectively inhibits both anbi integrin and anbb integrin compared to at least one other an-containing integrin in the subject. In some aspects, the anbi integrin is inhibited in one or more fibroblasts in the subject. In some aspects, the anbί. integrin is inhibited in one or more epithelial cells in the subject. In some aspects, the at least one tissue in the subject comprises one or more of: lung tissue, liver tissue, skin tissue, cardiac tissue, kidney tissue, gastrointestinal tissue, gall bladder tissue, and bile duet tissue.
[Q233] In one aspect, provided is a compound of formula (I), or any variation thereof, e.g. , a compound of formulae (I), (Ila), (lib), (Ilia), (I Ib), (IVa), (IVb), (Va), (Va-l), (Va-2), (Vb), (Vb-1 ), (Vb-2), (II-A-l), (P-A-2), (P-A-2Ϊ), (II~A~2ii), (II-A-la-1 ), flI-A-la-2), (P-A- la-3), (II-A-lb-l ), (II-A-lb-2), (II-A-lc-1), (II-A-lc-2), (II-A-ld-1), (II-A-ld-2), (H-A-ld- 3), (II-A-2a-l), (H-A-2a-2), (U-A-2a-3), (II-A-2a-4), (H-A-2b-l), (U-A-2b-2), (U-A-2c-l), (II-A-2c~2), (II-A-2c-3), (II~A~2c-4), (II-A-2d-l), (II-A-2d-2), (H-A-2d-3), (II-A-2d-4), (II-A- 2d-5), (II-A-2d-6), (H-A-2e~l), (II-A-2e-2), (II-A-2e-3), (II-A-2e~4), (II-A-2e-5), (II-A-2e-6), (II-A-2e-7), (II-A-2e-8), (H-A-2f-l), (II-A-2f-2), (II-A-2f-3), (II-A-2t-4), (II-A-2f-5), (II-A- 2f-6), (II-A-2f-7), (U-A-2f-8), (II-A-2f-9), (U-A-2f-10), (II-B-1), (H-B-2), (H-B-3), (H-B-la), (II-B-2a), (II-B-2b), (II-B-3a), or (II-B-3b), a compound selected from the compounds depicted in Table 1 or Table 2, or any one of compounds 1 -329, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a fibrotic disease.
[Q234] Also provided is use of a compound of formulae (I), (Ila), (lib), (Ilia), (IHb),
(IVa), (IVb), (Va), (Va-l), (Va-2), (Vb), (Vb-1 ), (Vb-2), (II-A-l), (II-A-2), (II-A-2Ϊ), (II-A- 2ii), (II-A-l a- 1), (H-A-la-2), (II-A-la-3), (H-A-lb-1), (H-A-lb-2), (II-A-lc-1), (H-A-lc-2), (II-A-ld-1 ), (II-A-ld-2), (II-A-l d-3), (II-A-2a-l), (II-A-2a-2), (II-A-2a-3), (II-A-2a-4), (II-A- 2b- 1), (II-A-2b-2), (II-A-2c-l ), (II-A-2c-2), (II-A-2c-3), (II-A-2c-4), (II-A-2d-l), (II-A-2d-2), (II- A-2d-3 ), (II-A-2d-4), (II-A-2d-5), (II-A-2d-6), (II-A-2e-l), (II-A-2e-2), (U-A-2e-3), (II-A- 2e-4), (II-A-2e-5), (II-A-2e-6), (H-A-2e-7), (H-A-2e-8), (H-A-2f-l), (II-A-2f-2), (H-A-2f-3), (II-A-2f-4), (II-A-2f-5), (II-A-2f-6), (II-A-2f-7), (II-A-2f-8), (Ii-A-2f-9), (II-A-2f-10), (P-B- 1), (II-B-2), (II-B-3), (P-B-la), (H-B-2a), (H-B-2b), (II-B-3a), or (II-B-3b), a compound selected from the compounds depicted in Table I or Table 2, or any one of compounds 1-329, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.
[023S] In another aspect, provided is a method of inhibiting anbό integrin in an individual comprising administering a compound of formulae (I), (Ila), (lib), (Ilia), (IHb), (IVa), (IVb), (Va), (Va-l), (Va-2), (Vb), (Vb-1 ), (Vb-2), (II-A-l), (II-A-2), (II-A-2Ϊ), (II-A- 2ii), (II-A-la-1), (ll-A-la-2), (II-A-la-3), (11-A-lb-l), (ll-A-lb-2), (U-A-lc-1), (II-A-lc-2), (II-A-ld-1), (II-A-ld-2), (II-A-ld-3), (II-A-2a-l), (II-A-2a-2), (II-A-2a-3), (II-A-2a-4), (II-A- 2b- 1), (IT-A-2b-2), (TT-A-2c-l), (II-A-2c-2), (IT-A-2c-3), (II-A-2c-4), (II-A-2d-l), (IT-A-2d-2), (II-A-2d-3), (II-A-2d-4), (II-A-2d-5), (II-A-2d-6), (II-A-2e-l), (II-A-2e-2), (II-A-2e-3), (II-A- 2e-4), (II-A-2e-5), (II-A-2e-6), (H-A-2e-7), (II-A-2e-8), (Il-A-2f-l), (ll-A-2f-2), (Il-A-2f-3), (II-A-2f-4), (II-A-2f-5), (H-A-2f-6), (II-A-2f-7), (II-A-2f-8), (H-A-2f-9), (B-A-2f-10), (II-B- 1), (P-B-2), (TT-B-3), (ΐΐ-B-la), (II-B-2a), (TI-B-2b), (II-B-3a), or (II-B-3b), a compound selected from the compounds depicted in Table I or Table 2, or any one of compounds 1-329, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
[0236] Also provided is a method of inhibiting TORb activation in a cell comprising administering to the cell a compound of formulae (I), (11a), (11b), (Ilia), (Ilib), (IV a), (IVb), (Va), (Va-l), (Va-2), (Vb), (Vb-1), (Vb-2), (P-A-1), (P-A-2), (P-A-2Ϊ), (II~A~2ri), (II-A-la- 1), (H-A-Ia-2), (II-A-la-3), (P-A-lb-l), (TI-A-lb-2), (P-A-lc-l), (II-A-lc-2), (P-A-ld-l ), (II-A-ld-2), (II-A-ld-3), (II-A-2a-l ), (II-A-2a-2), (II-A-2a-3), (lI-A-2a-4), (II-A-2b-l), (II-A- 2b-2), (U-A-2c-l), (II-A-2c-2), (II-A-2c-3), (II-A-2c-4), (Il-A-2d-l), (II-A-2d-2), (II-A-2d-3), (II-A-2d-4), (II-A-2d-5), (II-A-2d-6), (H~A~2e~l), (IT-A-2e-2), (II-A-2e-3), (II-A-2e~4), (P-A- 2e-5), (II-A-2e-6), (II-A-2e-7), (II-A-2e-8), (II-A-2f-l), (II-A-2f-2), (II-A-2f-3), (II-A-2†-4), (H-A-2f-5), (II-A-2f-6), (II-A-2f-7), (U-A-2f-8), (II-A-2f-9), (H-A-2f-10), (II-B-1), (II-B-2), (P-B-3), (II-B-la), (II-B-2a), (II-B-2b), (II-B-3a), or (II-B-3b), a compound selected from the compounds depicted hr Table 1 or Table 2, or any one of compounds 1-329, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
[0237] Also provided is a method of inhibiting anb6 integral in an individual in need thereof, comprising administering to the individual a compound of formulae (1), (Ha), (lib), (111a), (111b), (IV a), (IVb), (Va), (Va-l), (Va-2), (Vb), (Vb-1), (Vb-2), (II-A-1), (II-A-2), (II- A~2i), (H-A~2ii), (II-A-la-1), (II-A-la-2), (II-A-la-3), (II-A-lb-1), (II-A-lb-2), (II-A-lc-1), (II-A-Ic-2), (II-A-ld-1 ), (II-A-ld-2), (II-A-l d-3), (II-A-2a-l), (II-A-2a-2), (II-A-2a-3), (P-A- 2a-4), (II-A-2b-l), (II-A-2b-2), (ii-A-2c-l ), (II-A-2c-2), (II-A-2c-3), (II-A-2c-4), (II-A-2d-l), (II-A-2d-2), (II-A-2d-3), (II-A-2d-4), (Il-A-2d-5), (Il-A-2d-6), (H-A-2e-l), (II-A-2e-2), (II- A-2e-3), (II-A-2e-4), (II-A-2e-5), (II-A-2e-6), (II-A-2e-7), (II-A-2e-8), (H-A~2f-1), (II-A-2f- 2), (II-A-2f-3), (II-A-2f-4), (II-A-2f-5), (II-A-2f-6), (II-A-2f-7), (IT-A-2f-8), (IT-A-2f-9), (II- A-2f-lG), (Il-B-1), (Il-B-2), (P-B-3), (11-B-la), (II-B-2a), (Il-B-2b), (U-B-3a), or (II-B-3b), a compound selected from the compounds depicted in Table 1 or Table 2, or any one of compounds 1 -329, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one such method, the compound is a selective anbό integrin inhibitor. In another such method, the compound does not inhibit substantially a4b1, anb8 and/or a2b3 integrin. In yet another such method, the compound inhibits anb6 integrin but does not inhibit substantially a4b! integrin. In still another such method, the compound inhibits anbό integrin but does not inhibit substantially anb8 integrin. In a further such method, the compound inhibits anbό integrin but does not inhibit substantially a2b3 integrin. In one embodiment is provided a method of inhibiting anbό integrin and one or more of anbΐ, anb3, anb5, «2b1 , a3b1, aόbΐ integrin, a7b1 and a 11 b 1 in an individual in need thereof. In another embodiment is pro vided a method of inhibiting anb6 integrin and anbΐ integrin. In another embodiment is provided a method of inhibiting anb6 integrin, anb3 integrin and anb5 integrin. In another embodiment is provided a method of inhibiting anb6 integrin and a2b1 integrin. In another embodiment is provided a method of inhibiting anbό integrin, a2b1 integrin and a3b1 integrin. In another embodiment is provided a method of inhibiting anb6 integrin and aόbΐ integrin. In another embodiment is provided a method of inhibiting anbό integrin and a7b1 integrin. In another embodiment is provided a method of inhibiting anbό integrin and ori Ibΐ integrin. In all such embodiments, in one aspect the method of inhibition is for an individual in need thereof, such as an indi vidual who has or is suspected of having a fibrotic di sease, and wherein the method comprises administering to the individual a compound of formulae (I), (Ila), (lib), (Ilia), (lllb), (IV a), (IVb), (Va), (Va-1), (Va-2), (Vb), (Vb-1), (Vb-2), (P-A-1), (P-A-2), (P-A-2Ϊ), (II-A-2ii), (II-A-la-1), (II-A-la-2), (II-A-la-3), (II-A-lb-1), (D-A-lb-2), (II-A-lc-l), (P-A- lc-2), (II-A-ld-1), (II-A-ld-2), (II-A-ld-3), (II-A-2a-l), (II-A-2a-2), (II-A-2a-3), (II-A-2a-4), (II-A-2b-l), (II-A-2b-2), (II-A-2c-l ), (II-A-2c-2), (II-A-2c-3), (D-A-2c-4), (II-A-2d-l), (II-A- 2d-2), (II-A-2d-3), (II-A-2d-4), (II-A-2d-5), (II-A-2d-6), (II-A-2e-l), (II-A-2e-2), (H-A-2e- 3), (II-A-2e-4), (H-A-2e-5), (II-A-2e-6), (II-A-2e-7), (II-A~2e-8), (II-A-2f~l), (H-A-2f-2), (II- A-2f-3), (II-A-2f-4), (II-A-2f-5), (II-A-2f-6), (II-A-2f-7), ( I I--L--2 f- S ). (D-A-2f-9), (II-A-2f- 10), (IΪ-B-I), (II-B-2), (II-B-3), (II-B-la), (II-B-2a), (II-B-2b), (II-B-3a), or (II-B-3b), a compound selected from the compounds depicted in Table 1 or Table 2, or any one of compounds 1 -329, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
[Q238] Also provided is a method of modulating at least one integrin in a subject, the at least one integrin comprising an av subunit, the method comprising administering to the subject an effective amount of the compound of formulae (I), (Ila), (lib), (Ilia), (Illb), (IVa), (IVb), (Va), (Va-1), (Va-2), (Vb), (Vb-1), (Vb-2), (II-A-1 ), (II-A-2), (P-A-2Ϊ), (II-A-2n), (II- A-la-1), (II-A-la-2), (II-A-la-3), (II-A-!b-1), (D-A-lb-2), (II-A-ic-1), (H-A-le-2), (II-A-ld- 1), (Il-A-ld-2), (ll-A-ld-3), (ii-A-2a-I), (II-A-2a-2), (Il-A-2a-3), (H-A-2a-4), (H-A-2b-l), (II-A-2b-2), (II-A-2c-l), (II-A-2c-2), (D-A-2c-3), (II-A-2c-4), (H-A-2d-l), (II-A-2d-2), (P-A- 2d~3), (II-A-2d-4), (II-A-2d-5), (II-A-2d-6), (II~A~2e-l), (II-A-2e-2), (II-A-2e-3), (II-A-2e-4), (II-A-2e-5), (II-A-2e-6), (H-A-2e-7), (II-A-2e-8), (II-A-2f-l) (II-A-2f-2), (H-A-2f-3), (P-A- 2f-4), (II-A-2f-5), (II-A-2f-6), (II-A-2f-7), (H-A-2f-8), (ll-A-2f-9), (ll-A-2f-10), (II-B-1), (II- B-2), (P-B-3), (II-B-la), (II-B-2a), (II-B-2b), (II-B-3a), or (II-B-3b), a compound selected from the compounds depicted in Table 1 or Table 2, or any one of compounds 1-329, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the modulating comprising inhibiting the at least one integrin in the subject. In another aspect, the at least one integrin comprising at least one of anbi integrin and anbb integrin. In another aspect, the subject has or is at risk of a fibrotic disease selected from the group consisting of: idiopathic pulmonar fibrosis (IFF), interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease induced fibrosis, Alport syndrome, primary sclerosing cholangitis (PSC), primary biliary' cholangitis, biliary atresia, systemic sclerosis associated interstitial lung disease, scleroderma, diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn’s Disease; and the method comprises inhibiting one or both of anbi integrin and anbb integrin in the subject, thereby treating the fibrotic disease in the subject. In another aspect, the subject being in need of treatment for NASH, the effective amount administered to the subject being effective to inhibit at least anbi integrin, thereby treating the subject for NASH. In another aspect, the subject being in need of treatment for IPF, the effective amount administered to the subject being effective to inhibit at least anbb integrin, thereby treating the subject for IPF. In another aspect, the subject being in need of treatment for PSC, the effective amount administered to the subject being effective to inhibit at least one of anbi integrin and avpe integrin, thereby treating the subject for PSC.
[Q239] Also provided is a method of modulating TORb activation in a cell, comprising contacting the cell with the compound of formulae (I), (Ila), (lib), (Ilia), (Ilib), (IVa), (IVb), (Va), (Va-l), (V a-2), (Vb), (Vb-1), (Vb-2), (II-A-1), (II-A-2), (H-A-2Ϊ), (II-A-2u), (II-A-la- 1), (II-A-1 a-2), (II -A- la-3), (H-A-!b-i), (II-A-lb-2), (D-A-lc-1), (H-A-lc-2), (II-A-ld-1), (TI-A-ld-2), (II-A-l d-3), (II~A~2a-I), (II-A-2a-2), (II-A-2a-3), (II-A-2a-4), (II-A-2b-l ), (II-A- 2b-2), (II-A-2C-1), (II-A-2c-2), (II-A-2c-3), (D-A-2c-4), (H-A-2d-l), (II-A-2d-2), (II-A-2d-3), (II-A-2d-4), (II-A-2d-5), (II-A-2d-6), (H-A-2e-l), (II-A-2e-2), (H-A-2e-3), (II-A-2e-4), (P-A- 2e-5), (II-A-2e-6), (Il-A-2e-7), (II-A-2e-8), (II-A-2f-l), (Il-A-2f-2), (Il-A-2f-3), (II-A-2f-4), (II-A-2f-5), (II-A-2f-6), (II~A~2f-7), (II-A-2f-8), (II-A-2f-9), (P-A-2ί-10), (II-B-1), (P-B-2), (TI-B-3), (II-B-la), (II-B-2a), (II-B-2b), (II-B-3a), or (II-B-3b), a compound selected from the compounds depicted in Table 1 or Table 2, or any one of compounds 1-329, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the modulating comprising inhibiting 'TORb activation in the cell. In another aspect, the TORb activation being mediated in the cell by at least one of anbi integrin and anbd integrin.
[0240] Also provided is a method of treating a subject in need thereof, comprising:
administering to the subject a therapeutically effective amount of the compound of formula (I), or any variation thereof, e.g., a compound of formulae (I), (Ila), (lib), (Ilia), (IHb), (IVa), (IVb), (Va), (Va-1), (Va-2), (Vb), (Vb-1), (Vb-2), (P-A-1), (II-A-2), (ll-A-2i), (H-A-2ii), (II- A-la-1), (II-A-la-2), (II-A-la-3), (P-A-lb-l), (II-A-lb-2), (O-A-lc-1), (II-A-lc-2), (D-A-ld- 1), (IT-A-ld-2), (TI-A-ld-3), (II-A-2a-I), (II-A-2a-2), (II-A-2a-3), (II-A-2a-4), (II-A-2b-l), (II-A-2b-2), (II-A-2c-l), (II-A-2c-2), (II-A-2c-3), (II-A-2c-4), (II-A-2d-l), (II-A-2d-2), (II-A- 2d-3), (II-A-2d-4), (U-A-2d-5), (II-A-2d-6), (II-A-2e-l), (Il-A-2e-2), (II-A-2e-3), (II-A-2e-4), (P-A -2e-5), (II-A-2e-6), (II-A-2e-7), (II-A-2e-8), (II-A-2f-l), (II-A-2f-2), (II-A-2f-3), (P-A- 2f-4), (II-A-2f-5), (II-A-2f-6), (II-A-2f'-7), (Ii-A-2f-8), (D-A-2f-9), (II-A-2f-10), (II-B-1), (II- B-2), (Ii-B-3), (II-B-la), (II-B-2a), (II-B-2b), (ll-B-3a), or (U-B-3b), a compound selected from the compounds depicted in Table 1 or Table 2, or any one of compounds 1-329, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the subject has at least one tissue in need of therapy and the tissue has at least one elevated level of: TGFp activation and/or expression: anbi integrin activity and/or expression; or anbd integrin activity and/or expression; wherein the at least one elevated level is elevated compared to a healthy state of the tissue. In some aspects, the method selectively inhibits anbi integrin compared to anbd integrin in the subject. In some aspects, the method selectively inhibits anbd integrin compared to anbi integrin in the subject. In some aspects, the method inhibits both of anbi integrin and anbb integrin in the subject. In some aspects, the method selectively inhibits both anbi integrin and anbb integrin compared to at least one other av-containing integrin the subject. In some aspects, the anbi integrin is inhibited in one or more fibroblasts in the subject. In some aspects, the anb& integrin is inhibited in one or more epithelial cells in the subject. In some aspects, the at least one tissue the subject comprises one or more of: lung tissue, liver tissue, skin tissue, cardiac tissue, kidney tissue,
gastrointestinal tissue, gall bladder tissue, and bile duct tissue. [0241] In any of the described methods, in one aspect the individual is a human, such as a human in need of the method. The individual may be a human who has been diagnosed with or is suspected of having a fibrotic disease. The individual may be a human who does not have detectable disease but who has one or more risk factors for developing a fibrotic disease.
Kits
[0242] The invention further provides kits for carrying out the methods of the invention, which comprises 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
[0243] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can 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 within sterile packaging.
[0244] The kits may be in unit dosage forms, bulk packages (e.g. , multi-dose packages) 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 a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. 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).
[0245] The kits may optionally include a set of instractions, generally written
instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention. The instructions included with the kit generally include information as to the components and their administration to an individual. GENERAL PROCEDURES
[0246] Compounds provided herein may he prepared according to General Schemes, as exemplified by the General Procedures and Examples.
[0247] 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 performed on other specific stereoisomers, or an unspecified stereoisomer, or mixtures thereof. For example, a hydrolysis reaction of an L-homoserinate ester to an L-homoserine (i.e., free acid) can also be performed on a D-homoserinate ester to prepare a D-homoserine, or on a mixture of an L-homoserinate ester and a D-homoserinate ester to prepare a mixture of an L-homoserine and a D-homoserine. As another example, reactions of functional groups on a compound containing a trans-cyclobutyl group can also be performed on a compound containing a cis-cyclobutyl group, or on a mixture of a compound containing a cis-cyclobutyl group and a compound containing a trans-cyclobutyl group. As another example, reactions of functional groups on a compound containing a cycloalkyl Y group can also be performed on a compound lacking a Y group (i.e., where the linker is -Li- O-L2-L3- as defined in Formula (I)), or on a mixture of a compound containing a cycloalkyl group and a compound lacking a Y group.
[0248] Some of the following general procedures use specifi c 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 can be carried out on other specific compounds having the same functional group (e.g., a different compound having a protected amine where the Boc-protecting group can be removed using acid in the same manner) as long as 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 reacti on on those 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).
[0249] Where specific reagents or solvents are specified for reactions in the general procedures, the skilled artisan will recognize that other reagents or solvents can be substituted as desired. For example, acetylation is performed in the general examples with acetic anhydride, but an active ester of acetic acid can also be used. As another example, where hydrochloric acid is used to remove a Boc group, trifluoroacetic acid can be used instead. As another example, where HATIJ is used as a coupling reagent, BOP or PyBOP can be used instead.
General Procedure A
Detailed Procedures for General Scheme A and Scheme D-l
i BSCL i id
Figure imgf000137_0001
CH2CI2
[025Q] methyl (lr,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutane-l-carboxylate. To a solution of methyl (lr,3r)-3-hydroxycyclobutane-l -carboxylate (5.0 g, 38.42 mmol) in CH2Q2 (100 mL) was added imidazole (3.92 g, 57.63 mmol) then TBSQ (6.95 g, 46.10 mmol) at room temperature and the resulting heterogeneous mixture was vigorously stirred for 30 minutes. The reaction mixture was diluted with sat NaHCCh and water and stirred for 5 minutes. The layers were separated and the organic layer was washed with water (50 mL), dried over MgSOu filtered and concentrated in vacuo. The erode residue was purified by normal phase silica gel chromatography to give methyl (l r,3r)-3-((tert- butyldimethylsilyl)oxy)cyclobutane-l-carboxylate.
Dib !
Figure imgf000137_0002
[0251 ] ((lr,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)methanol. To a solution of methyl (lr,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutane-l-carboxylate (9.19 g, 37.60 mmol) at -78 °C in THF (92 mL) was added Dibal-H (1.0 M in heptane, 94 mL, 94.00 mmol) dropwise and the resulting solution was allowed to stir for 1 hr at -78 °C. The mixture was then wanned to 0 °C and then to this was slowly added EtOAc (100 mL) followed by a saturated aqueous solution of sodium potassium tartrate (250 mL) and water (100 mL) and the resulting mixture was then allowed to warm to room temperature and stirred vigorously for 4 hrs. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgS04, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give ((lr,3r)-3- ((tert-butyldimethylsilyl)oxy)cyelohuty!)metfaano!.
Figure imgf000137_0003
, 2 2
[0252] tert-butyl((lr,3r)-3-(iodomethyl)cyclobutoxy)dimethylsilane. To a solution of PPh3 (13.09 g, 49.91 mmol) and imidazole (4.53 g, 66.54 mmol) in CH2Q2 (78 mL) at 0 °C was slowly added b. (12.24 g, 48.24 mmol) and the mixture was stirred an additional 30 minutes and then allowed to warm to room temperature. A solution of ((l r,3r)-3-((tert- buty]dimethylsilyl)oxy)cyc]obutyl)rnethanol (7.2 g, 33.27 mmol) in CH2CI2 (20 mL) was then added to the reaction mixture and stirred for 6 hrs at room temperature. The reaction mixture was then diluted with sat. NaHCCh and stirred for 15 minutes. The layers were separated and the organic layer was washed with H2O, dried over MgSQr, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give tert-butyl(( lr,3r)-3-(iodomethyl)cyclobutoxy)dimethylsilane.
Figure imgf000138_0001
tM HCi, acetone
[0253| 4-((lr,3s)-3-hydroxycyclobutyl)butan-2-one. To a solution of acetone dimethyihydrazone (8.33 g, 83.13 mmol) at -78 °C in THF (83 mL) was slowly added «-BuLi (2.5 M in hexanes, 32.59 mL, 81.46 mmol) causing a pale yellow suspension to occur. Upon completion of the addition, the resulting suspension was stirred an additional 15 minutes, at which time, a solution of tert-butyl((lr,3r)-3-(iodomethyl)cyclobutoxy)dimethylsilane (10.85 g, 33.25 mmol) in THF (20 mL) was slowly added dropwise. The resulting mixture was warmed to 0 °C and stirred for 30 minutes and then carefully quenched with aq 1M HCI (250 mL) and acetone (50 mL). lire resulting mixture was allowed to stir at room temperature overnight and then was extracted with EtOAc. The combined organic extracts were dried over MgSOr, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography to give 4-(( lr,3s)-3-hydroxycyclobutyl)butan-2-one.
Figure imgf000138_0002
[0254| ( ls,3r)-3-(2-(l,8-naphthyridin-2- l)eth l)cyclobutan-l-ol . A sealed tube containing 4-((lr,3s)-3-hydroxycyclobutyl)butan-2-one (2.46 g, 17.30 mmol) was charged with L-proline (996 mg, 8.65 mmol) and 2-aminonicotinaldehyde (2.53 g, 20.76 mmol) and then diluted with 200 proof EtOH (50 mL) and then sealed and placed in an aluminum block and heated to 95 °C overnight. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by normal phase column chromatography to give (ls,3r)-3-(2~(l,8~naphthyridin~2-y!)ethyl)cyclobutan-l-ol.
Figure imgf000139_0001
[0255] 2-(2-((lr,3s)-3-(allyloxy)cyclobulyl)et yl)-l,8-nap lhyridine. To a solution of (ls,3r)-3-(2-(l,8-naphthyridin-2-yl)ethyl)cyclobutan-l-ol (3.36 g, 14.72 mmol) in 2: 1 THF/DMF (34 mL) at room temperature was slowly added NaH (60% dispersion in mineral oil, 883 mg, 22.08 mmol) and the resulting mixture was stirred for 30 minutes, at which time, ally! bromide (1.91 mL, 22.08 mmol) was added and the resulting mixture was warmed to 50 °C for 1 hr. The reaction mixture was cooled to room temperature and then carefully diluted with sat NaHCCh and H2O. The resulting mixture was extracted with 4: 1 DCM/VPrOH and the combined organic extracts were dried over MgSOy filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography to give 2-(2- (( 1 r,3 s)~3 -(allyloxy)cyclobutyl)ethyl)- 1 , 8-naphthyri dine .
Figure imgf000139_0002
[0256| 2-((ls,3r)-3-(2-(l,8-naphthyridin-2-yl)ethyl)cyclobutoxy)acetaldehyde. To a solution of 2-(2-((l r,3s)-3-(allyloxy)cyclobutyl)ethyl)-l,8-naphthyridine (1.38 g, 5.14 mmol) m 3: 1 Dioxane/HiO (14 mL) was added 2,6-!utidine (1.2 mL, 10.28 mmol), NalCfi (4.4Qg, 20.56 mmol), then OsCfi (2.5 wt% in /-BuOH, 1.05 mL, 0.10 mmol) and the resulting mixture was allowed to stir at room temperature for 4 hrs. The reaction mixture was diluted watli sat NaHCCb and H2O and stirred for 15 minutes and then filtered through a coarse fritted funnel and the filter cake was rinsed with 4: 1 DCM/'/PrOH. The layers were separated and the aqueous layer wras extracted with 4: 1 DCM/zPrOH and the combined organic extracts were dried over MgSOy filtered, and concentrated in vacuo to give 2~((!s,3r)-3-(2-(l,8- naphthyridin-2-yl)ethyl)cyclobutoxy)acetaldehyde.
Figure imgf000140_0001
buioxycarbonyl)amino)but-2-enoaie. To a solution of 2-((l s,3r)-3-(2-( l,8-naphthyridin-2- yl)ethyl)cyclobutoxy)acetaldehyde in CH2CI2 (14 mL) and to this was added methyl 2-((tert- butoxycarbonyl)amino)-2-(dimethoxyphosphoryl)acetate (2.29 g, 7.71 mmol) then DBU (1 .16 mL, 7.71 mmol) and the resulting mixture was allowed to stir at room temperature for 30 minutes and then concentrated in vacuo. Idle crude residue was purified by normal phase column chromatography to give methyl 4-((ls,3r)-3-(2-(l,8-naphthyridin-2- y!)ethy!)cyclobutoxy)-2~((tert-butoxycarbony!)amino)but-2-enoate.
Figure imgf000140_0002
[Q258] methyl N-(tert-butoxycarbonyl)-0-((ls,3r)-3-(2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl)cyclobut l)homoserinate. A flask containing methyl 4-((ls,3r)-3-(2- (l,8-naphthyridin-2-yl)ethyl)cyclobutoxy)-2-((tert-butoxycarbonyl)amino)but-2-enoate (2.27 g, 5.14 mmol) was charged with Pd(OH)2/'C (20 wt% on carbon, 454 mg) and then diluted with MeOH (23 ml,). The flask was then evacuated and backfilled with H2 for 3 cycles and then stirred under an Hi atmosphere overnight. The reaction mixture was then filtered through a pad of Celite and then concentrated in vacuo. The crude residue was purified by normal phase column chromatography to give methyl N-(tert-butoxycarbonyl)-0-((ls,3r)-3- (2-(5, 6,7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserinate.
[0259] After the synthesis of the racemic material as shown in the pre v ious step, a chiral separation can be performed to afford two single enantiomers using chiral SFC with the following method: Chiralpak AY-H, 250*25mm i.d. lOu 1 Mobile phase: A for C02 and B for Et0H((). l%NH3H20); Gradient: B%=45% 1 Flow rate:80 g/min 1 Wavelength:220 nm
1 Column temperature: 40 °C 1 System back pressure: 100 bar. General Procedure B
Detailed Procedures for General Scheme B and Scheme E-l
Figure imgf000141_0001
[0260] methyl ( ls,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutane-l-carboxylate . To a solution of methyl (ls,3s)-3-hydroxycyclobutane-l-carboxylate (5.0 g, 38.16 mmol) in CH2CI2 (100 mL) was added imidazole (3.92 g, 57.63 mmol) then TBSCI (6.95 g, 49.61 mmol) at room temperature and the resulting heterogeneous mixture was vigorously stirred for 30 minutes. The reaction mixture was diluted with sat. NaHCOs (50 mL) and water (50 mL) and stirred for 5 minutes. The layers were separated and the organic layer was washed with water (50 mL), dried over MgSQy filtered and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give methyl (ls,3s)-3-((tert- butyldimethylsilyl)oxy)cyclobutane-l-carboxylate.
Figure imgf000141_0002
[0261] ((ls,3s)-3-((tert-butyldimethylsilyl)oxy)cyclohutyl)methanol. To a solution of methyl ( ls,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutane- 1-carboxylate (9.20 g, 37.76 mmol) at -78 °C in THF (92 mL) was added Dibal-H (1.0 M in heptane, 113 mL, 113.00 mmol) dropwise and the resulting solution was allowed to stir for 1 hr at -78 °C. The mixture was then wanned to 0 °C and then to this was slowly added EtOAc (100 mL) followed by a saturated aqueous solution of sodium potassium tartrate (250 mL) and water (100 mL) and the resulting mixture was then allowed to warm to room temperature and stirred vigorously for 4 hrs. The layers were separated and the aqueous layer was extracted with EtOAc. Tire combined organic extracts were dried over MgS04, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give ((ls,3s)-3- ((tert-butyldimethylsilyl)oxy)cyclobutyl)methanol.
Figure imgf000141_0003
, 2 2
[Q262] tert-butyl((ls,3s)-3-(iodomethyl)cyclobutoxy)dimethylsilane. To a solution of PPI13 (12.80 g, 48.79 mmol) and imidazole (4.43 g, 65.05 mmol) in CH2CI2 (72 mL) at 0 °C was slowly added I2 (1 1.97 g, 47.16 mmol) and the mixture was stirred an additional 30 minutes and then allowed to warm to room temperature. A solution of ((ls,3s)-3-((tert- butyldimethylsilyl)oxy)cyclobutyl)methanol (7.04 g, 32.53 mmol) in CH2CI2 (20 mL) was then added to the reaction mixture and stirred for 6 hrs at room temperature. The reaction mixture was then diluted with sat. NaHCCb and stirred for 15 minutes. The layers were separated and the organic layer was washed with HiO, dried over MgSOy filtered, and concentrated in vacuo. Hie crude residue w'as purified by normal phase silica gel chromatography to give tert-butyl(( is,3s)-3-(iodomethyT)cyclobutoxy)dimethyTsiiane.
Figure imgf000142_0002
[Q263] 4-((ls,3r)-3-hydroxycyclobutyl)butan-2-one. To a solution of acetone dimethylhydrazone (8.15 g, 81.39 mmol) at -78 °C in THF (82 mL) was slowly added «-BuLi (2.5 M in hexanes, 31.25 ml,, 78.13 mmol) causing a pale yellow suspension to occur. Upon completion of the addition, the resulting suspension was stirred an additional 15 minutes, at which time, a solution oftert-butyl((ls,3s)-3-(iodomethyl)cyclobutoxy)dimethylsilane (10.62 g, 32.55 mmol) in THF (20 ml,) was slowly added dropwise. The resulting mixture was wanned to 0 °C and stirred for 30 minutes and then carefully quenched with aq 1M HC1 (250 mL) and acetone (50 mL). The resulting mixture was allowed to stir at room temperature overnight and then was extracted with EtOAc. The combined organic extracts were dried over MgSQy filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography to give 4-(( ls,3r)-3-hydroxycyclobutyl)butan-2-one.
Figure imgf000142_0001
,
[0264] (lr,3s)-3-(2-(l,8-naphthyridin-2-yl)ethyl)cyclobutan-l-ol. A sealed tube containing 4-((l s,3r)-3-hydroxycyclobutyl)butan-2-one (2.72 g, 19.18 mmol) was charged with L-proline (1.10 g, 9.59 mmol) and 2-aminonicotinaldehyde (3.51 g, 28.77 mmol) and then diluted with 200 proof EtOH (50 mL) and then sealed and placed in an aluminum block and heated to 95 °C overnight. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo. The crude residue was purified by normal phase column chromatography to give ( lr,3s)-3-(2-(l,8-naphthyridin-2-yl)ethyl)cyclobutan-l-ol.
Figure imgf000143_0001
[0265] 2-(2-((ls,3r)-3-(allyloxy)cyclobulyl)et yl)-l,8-nap thyridine. To a solution of (lr,3s)-3-(2-(l,8-naphthyridin-2-yl)ethyl)cyclobutan-l-ol (3.72 g, 16.30 mmol) in 2: 1 THF/DMF (37 mL) at room temperature was slowly added NaH (60% dispersion in mineral oil, 847 mg, 21 .18 mmol) and the resulting mixture was stirred for 30 minutes, at which time, allyl bromide (1.83 mL, 21.18 mmol) was added and the resulting mixture was wrarmed to 50 °C for 1 hr. The reaction mixture was cooled to room temperature and then carefully diluted with sat NaHCCh and H2O. The resulting mixture was extracted with 4: 1 DCM/VPrOH and the combined organic extracts were dried over MgSOr, filtered, and concentrated in vacuo. The crude residue w¾s purified by normal phase column chromatography to give 2-(2- (( 1 s,3r)-3-(allyloxy)cyclobutyl)ethyl)- 1 ,8-naphthyridine .
Figure imgf000143_0002
Dioxane/H O
[0266] 2-((lr,3s)-3-(2-(l,8-naphthyridin-2-yl)ethyl)cyclobutoxy)acetaldehyde. To a solution of 2-(2-((l s,3r)-3-(allyloxy)cyclobutyl)ethyl)-l,8-naphthyridine (946 mg, 3.53 mmol) 3: 1 Dioxane/KhO (10 mL) w¾s added 2,6-lutidine (0.82 mL, 7.05 mmol), NalOr
(3.02 g, 14.10 mmol), then 0s04 (2.5 wt% in /-BuQH, 0.88 mL, 0.07 mmol) and the resulting mixture was allowed to stir at room temperature for 4 hrs. The reaction mixture was diluted with sat NaHCO and H2O and stirred for 15 minutes and then filtered through a coarse fritted funnel and the filter cake was rinsed with 4: 1 DCM/VPrOH. The layers were separated and the aqueous layer was extracted with 4: 1 DCM/VPrOH and the combined organic extracts were dried over MgSOr, filtered, and concentrated in vacuo to give 2-((lr,3s)-3-(2-(l,8- naphtllyridin-2-\i)ethyl)cyclobutoxy)acetaidehyde.
Figure imgf000143_0003
[Q267] methyl 4-((lr,3s)-3-(2-(l,8-naphthyridin-2-yl)ethyl)cyclobutoxy)-2-((tert- butoxycarbonyl)amino)but-2-enoate. To a solution of 2-((lr,3s)-3-(2-(l ,8-naphthyridin-2- yl)ethyl)cyclobutoxy)acetaldehyde (953 mg, 3.53 mmol) in CH2CI2 (10 mL) and to tins was added methyl 2-((tert-butoxycarbonyl)amino)-2-(dimethoxyphosphor l)acetate (1.57 g, 5.29 mmol) then DBU (0.64 mL, 4.23 mmol) and the resulting mixture was allowed to stir at room temperature for 30 minutes and then concentrated in vacuo. The crude residue was purified by normal phase column chromatography to give methyl 4-((lr,3s)-3-(2-(l,8-naphthyridin-2- yl)ethyl)cyclobutoxy)-2-((tert-butoxycarbonyl)amino)but-2-enoate.
Figure imgf000144_0001
[Q268] methyl N-(tert-butox carbon l)-0-((Jr,3s)-3-(2-(5, 6,7, 8-tetrahyJro-l, 8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserinate. A flask containing methyl 4-((lr,3s)-3-(2- (l,8-naphthyridin-2-yl)etliyl)cyclobutoxy)-2-((teit-butoxycarbonyl)amino)but-2-enoate (846 mg, 1.92 mmol) was charged with Pd(OH)2/C (20 wt% on carbon, 169 mg) and then diluted with MeOH (9 mL). The flask was then evacuated and backfilled with H2 for 3 cycles and then stirred under an tb atmosphere overnight. The reaction mixture was then filtered through a pad of ( elite and then concentrated in vacuo. The crude residue was purified by normal phase column chromatography to give methyl N-(tert-butoxycarbonyl)-0-((lr,3s)-3- (2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserinate.
[0269] After the synthesis of the racemic material as shown in the previous step, a chiral separation can be performed to afford two single enantiomers using chiral SFC with the following method: Chiralpak AY-H 250*30mm i.d. 5u; mobile phase: A for C02 and B for EtOH (0.1% NH3H2O); gradient: B% = 50%; flow rate: 80g/min; wavelength: 220 nm; column temperature: 40 °C; system back pressure: 100 bar.
General Procedure C
Detailed Procedures for General Scheme C and Scheme F-l
Figure imgf000144_0002
[0270] 4-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)butan-l-ol. To a suspension of 4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butanoic acid hydrochloride (1.23 g, 4 79 mmol, 1.0 equiv) in THF was added LiAlHU (1.0M in THF, 10.6 mL, 10.6 mmol) dropwise and the resulting mixture w¾s refluxed overnight. The mixture w¾s then cooled in an ice bath and to this was slowly added H2O (400 pL), then aqueous 1.0 M NaOH (400 pL), then H2O (400 pL) again and stirred for 15 minutes and then a large excess of MgSOr was added and stirred for an additional 30 minutes. The resulting organic mixture was filtered and then concentrated in vacuo to provide 4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butan-l-ol.
Figure imgf000145_0001
[0271] 7-(4-(allyloxy)butyl)-l,2,3,4-tetrahydro-l,8-naphthyridine. To a stirring suspension ofNaH (60 wt% dispersion in mineral oil, 238 mg, 5.96 mmol) in THF (8.2 mL) at 0 °C was added a solution of 4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butan-l-ol (820 mg, 3.98 mmol) in THF (4.1 mL) dropwise. Upon completion of the addition, the ice bath was removed and the resulting mixture was stirred at room temperature for 30 minutes, at which time, ally! bromide (400 mΐ,, 4.62 mmol) was added dropwise. The suspension was stiixed for an additional 6 hrs at room temperature and then carefully diluted with H2O and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSOy filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography to provide 7-(4-(allyloxy)butyl)- 1 ,2,3 ,4-tetrahydro- 1 ,8-naphthyridine .
Figure imgf000145_0002
solution of 7-(4-(allyloxy)butyl)-l,2,3,4-tetrahydro-l,8-naphthyridine (582 mg, 2.36 mmol) in 3: 1 THF/H2O (6 mL) at room temperature was added NalCL (2.02 g, 9.44 mmol) followed by OsO (2.5 wt% in t-BuOH, 480 pL, 0.05 mmol). The resulting suspension was stirred at room temperature for 5 hrs and then diluted with 1 : 1 sat. aq. NaHCCb/sat. aq. Na SzCh and EtOAc and then stirred for 1 hr at room temperature. The biphasic mixture was filtered through a small pad of Celite and then the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts w¾re dried over MgSOy filtered. and concentrated in vacuo to provide 2-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butoxy)acetaldehyde that was used without further purification.
Figure imgf000146_0001
[0273] methyl 2-((tert-hutoxycarbonyl) amin o)~4~( 4-(5, 6, 7, 8-tetrahydro- 1, 8- naphthyridin-2-yl)butoxy)but-2-enoate. To a solution of 2-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butoxy)acetaldehyde (586 mg, 2 36 mmol) in CH2CI2 (6 mL) at room temperature was added methyl 2-(((benzyloxy)carbonyl)amino)-2-
(dimethoxyphosphoryl)acetate (860 mg, 2.60 mmol) followed by DBU (391 pL, 2.60 mmol) and stirred for 30 minutes at room temperature lire mixture was diluted with sat. aq. NH4CI and stirred for 5 minutes at room temperature. The layers were separated and the aqueous layer was extracted with EtOAc. Tire combined organic extracts were dried over MgSOr, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatogaphy to provide methyl 2-((tert-butoxycarbonyl)amino)-4-(4-(5,6,7,8-tetrahydro- 1 , 8 -naphthyridi n -2-yl )butoxy)but-2-enoate .
Figure imgf000146_0002
(20 wt% on Carbon)
MeOH
[Q274] methyl N-(tert-butox carbon l)-0-(4-(5, 6,7, 8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserinate . A flask containing methyl 2-((tert-butoxycarbonyl)amino)-4-(4-
(5,6,7,8-tetrahydro-L8-naphthyridin-2-yl)butoxy)but-2-enoate (497 mg, 1.10 mmol) and 20 wt% Pd(OH)2 on carbon (100 mg) was diluted with MeOH (5 ml) and then evacuated and backfilled with lh for 3 cycles and then stirred under an H2 atmosphere for 3 hrs. The resulting mixture was filtered through a pad of Celite and then concentrated m vacuo to give methyl N-(teit-butoxycarbonyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserinate (352 mg) that was used without further purification.
[Q275] After the synthesis of the racemic material as shown in tire previous step, a chiral separation can be performed to afford two single enantiomers using chiral SFC with the following method: Chiralpak AY-H 250*30mm i.d. 5u; mobile phase: A for C02 and B for 1PA (0.1%NH3H2O); gradient: B%= 0% 1 flow rate: 70 g/min 1 wavelength:220 nm 1 column temperature: 40 °C 1 system back pressure: 100 bar.
General Procedure D
Figure imgf000147_0001
[Q276] Methyl 0-(cis-3-(2~(5,6, 7 ,8-tetrahydro~l ,8~napkthyridin~2~
yl)ethyl)cyclobutyl)homoserinate. To a solution ofrnethyl N-(tert-butoxycarbonyl)-0-(cis-3- (2-(5,6,7,8-tetraliydro-l,8-naphtliyridin-2-yl)ethyi)cyc3obutyi)liomoserinate (2.26 g, 5.05 mmol) in DCM (13 mb) was added 4 N HC1 in 1 ,4-dioxane (10 mL, 40 mmol). The reaction was allowed to stir at rt overnight. LCMS then showed the consumption of starting material . The reaction was concentrated and used the next step without further purification.
General Procedure E
Figure imgf000147_0002
[0277] Methyl N~(quinazoUn~4-yl)-Q-(trans-3-(2~(5, 6, 7, 8-tetrahydro~J8~naphthyridm~
2~yl)ethyl)cydohutyl)homoserinate. To a solution of methyl 0-(trans-3~(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyi)cyclobutyi)homoserinate (14 rng, 0.040 mmol) in IPA (2 mL) was added 4-chloroquinazoiine (9.9 mg, 0.060 mmol) and DIPEA (0.035 mL, 0.20 mmol). The reaction was heated at 60 C for 18 h. The reaction mixture was then concentrated and used directly in the next step.
[0278] General Procedure E can be used in the coupling step of compound 14 A, or a similar compounds, with compound 15 A in General Scheme A, General Scheme B, General Scheme C, General Scheme D-2, General Scheme E-2, General Scheme F-2, General Scheme G-2, or General Scheme H.
Figure imgf000148_0001
[0279] methyl N-(isopropoxycarbonyl)-0-(trans-3-(2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserinate. Methyl 0-(trans-3-(2-(5,6,7,8-tetrahydro- l,8-naphihyridin-2-yl)ethyl)cyclobutyl)homoserinate (54 mg, 0.16 mmol) in CH2CI2 (2.0 mL) was added DIPEA (60 mg, 0.47 mmol) was added isopropyl carbonochloridate (23 mg, 0.19 mmol) and the resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The crude product was used without further purification.
[0280] General Procedure F can be used in the coupling step of compound 14A, or a similar compounds, with compound 16A in General Scheme A, General Scheme B, General Scheme C, General Scheme D-2, General Scheme E-2, General Scheme F-2, General Scheme G-2. or General Scheme H.
General Procedure G
Figure imgf000148_0002
[0281] methyl N-(tert-butylcarbamoyl)-0-(trans-3-(2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserinate. To a solution of methyl 0-(trans-3-(2- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserinate (71 mg, 0.20 mmol) in DCM (2.4 mL) was added imidazole (15 mg, 0.22 mmol) and GDI (36 mg, 0.22 mmol). This mixture was allowed to stir at rt for 30 min before adding tert-butylamine (22 mg, 0.31 mmol). The reaction was stirred at rt for 18 h. LCMS indicated that methyl 0-(trans-3-(2- (5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl)cyclobutyl)hornoserinate remained, and imidazole (15 mg, 0.22 mmol), GDI (36 mg, 0.22 mmol), and tert-butylamine (22 mg, 0.31 mmol) were added. After 5 h, tire reaction was concentrated in vacuo and the resulting crude residue was purified by normal phase silica gel chromatography to give methyl N-(tert- butylcarbamoyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserinate.
General Procedure H
Figure imgf000149_0001
[0282] methyl N-(diethylcarbamo l)-0-(trans-3-(2-(5, 6,7, 8-tetrahydro-l ,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserinate. To a mixture of methyl 0-(trans-3-(2- (5,6,7,8-tetraliydro-l,8-naphthyridin-2-yl)ethyl)cyciobutyl)homoserinate (57 mg, 0.16 mmol) in DCM (2.4 ml.) at rt was added DIPEA (0.23 mL, 1.3 mmol) then diethylcarbamoy! chloride (0.10 mL, 0 82 mmol) and the resulting reaction mixture was stirred at rt overnight. The mixture was concentrated in vacuo and the resulting crude residue was purified by preparative reverse phase HPLC to give methyl N-(diethy!carbamoyl)-0-(trans-3-(2-(5 ,6,7,8- tetrahydro- 1 ,8-naphthyridin-2-yl)ethyl)cyclobutyT)homoserinate .
[0283] General Procedure H can be used in the coupling step of compound 14A, or a similar compounds, with compound 16A in General Scheme A, General Scheme B, General Scheme C, General Scheme D-2, General Scheme E-2, General Scheme F-2, General Scheme G-2, or General Scheme H.
Genera! Procedure I
Figure imgf000149_0002
[0284] Methyl 0-(cis-3-(2-(5,6,7,8-tetrahydro- 1 ,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N- (4-(trifluoromethyl)tetrahydro-2H-pyran-4-carbonyl)homoserinate. To a solution of methyl 0-(cis-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserinate (1.62 g, 4.68 mmol) in DMF (10 ml.) was added DIPEA (5.7 mL, 32 mmol), HATU (2.0 g, 5.1 mmol), and 4-(trifluoromethyl)tetrahydro-2H-pyran-4-carboxylic acid (1.0 g, 5.1 mmol). The reaction was allowed to stir at rt for 18 h. LCMS showed product mass, and the reaction was concentrated, diluted with EtOAc and aqueous sat. sodium bicarbonate solution. The layers veere separated, and the aqueous layer was extracted two times. Combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford crude product, which was purified by silica gel chromatography to afford methyl 0-(cis-3-(2-(5,6,7,8-tetrahydro-l,8- naphtliyridin-2-yl)ethyl)cyc3obutyl)- N-(4-(trifluoromet3iyl)tetrahydro-2H-pyran-4- carbonyl)homoserinate.
[0285] General Procedure I can be used in the coupling step of compound 14A, or a similar compounds, with compound 16A in General Scheme A, General Scheme B, General Scheme C, General Scheme D-2, General Scheme E-2, General Scheme F-2, General Scheme G-2, or General Scheme H.
General Procedure J
[Q286] The following transformation:
R-OH
Figure imgf000150_0001
wherein R is R2t as defined for formula (I), or any applicable variations detailed herein, can be performed as exemplified below.
Figure imgf000150_0002
carboxylate. To a mixture of tert-butyl 3-hydroxy-3-methylazetidine-l-carboxylate ( 1.1 g,
5.8 mmol) and AyV-diisopropylethylamine (2.02 mL, 11.6 mmol) in acetonitrile (10 mL) was added disuceinimidyi carbonate (3.0 g, 11.6 mmol) and the resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with water and extracted with EtOAc. Tire combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to afford tert-butyl 3-((((((2,5-dioxopyrrolidin-l- yl)oxy)carbonyl)oxy)carbonyl)oxy)-3 -methyiazetidine- 1 -carboxylate .
[0288] General Procedure J can be used to make the appropriate reagent for use in General Procedure K
General Procedure K [0289] The following transformation:
Figure imgf000151_0001
wherein R2f is as defined for formula (I), or any applicable variations detailed herein, can be performed as exemplified below.
Figure imgf000151_0002
[0290] tert~but.yl 3-(((l -meth oxy- 1 -oxo-4-( trans-3-( 2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl)cyclobutoxy)butan-2-yl)carbamoyl)oxy)-3-methylaz tidine-l- carboxylate. To a solution of methyl Q-(trans-3-(2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserinate dihydrochloride (220.0 mg, 0.63 mmol) and N,N- diisopropylethylam e (0.4 mL, 2.5 mmol) in dichloromethane (2.0 mL) was added tert-butyl 3 -((((2,5 -dioxopyrrolidin- 1 -yl)oxy)carbonyl)oxy)-3 -methylazetidine- 1 -carboxylate (249.5 mg, 0.8 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture vcas concentrated in vacuo and purified by normal phase silica gel column chromatography to afford tert-butyl 3-(((l -methoxy-l-oxo-4-(trans-3-(2-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobutoxy)butan-2-yl)carbamoyl)oxy)-3-methylazetidine-l- carboxylate.
[0291] General Procedure K can be used in die coupling step of compound 14A, or a similar compounds, with compound 16A in General Scheme A, General Scheme B, General Scheme C, General Scheme D-2, General Scheme E-2, General Scheme F-2, General Scheme G-2, and General Scheme H.
Figure imgf000151_0003
[0292] The following transformation:
Figure imgf000152_0001
wherein 2. refers to that portion of the molecule which links the
-(0)nC(0)N(H)CH(C00CH3)L1- portion of the molecule with the remainder of the R2 moiety, wherein n is 0 or 1, L! and R2 are as defined for formula (I), or any applicable variations detailed herein, can be performed as exemplified below. In some variations, Z is an alkylene moiety and R is hydrogen. In some variations, Z is taken together with the adjacent “NR” group to fonn a heterocyclic ring.
Figure imgf000152_0002
[0293] methyl N-(((l-acetyl-3-methylaz tidin-3-yl)oxy)carbonyl)-0-(trans-3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserinate. To a solution of methyl N- (((3-methylazetidin-3-yl)oxy)carbonyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserinate bis(2,2,2-trifluoroacetate) (35.0 mg, 0.05 mmol) and N,N- diisopropylethylamme (52.9 mT, 0.304 mmol) in dichlorome thane (2.0 mL) at 0° C was added acetic anhydride (8.6 pL, 0.091 mmol). The reaction mixture was removed from the ice bath and allowed to warm to room temperature. After 20 minutes the reaction mixture was concentrated in vacuo and used without further purification.
General Procedure M
[0294] The following transformation:
Figure imgf000152_0003
wherein Z refers to that portion of the molecule which links the
(0)€(0)N(H)€H(€00€H3)ί-3- portion of the molecule with the remainder of the R2 moiety, wherein n is 0 or 1, L1 and R2 are as defined for formula (I), or any applicable variations detailed herein, can be performed as exemplified below. In some variations, Z is an alkyiene moiety and R is hydrogen. In some variations, Z is taken together with the adjacent “NR” group to form a heterocyclic ring.
Figure imgf000153_0001
[0295] methyl N-(((3-methyl-l -(methylsulfonyl)azetidin-3-yl)oxy)carbonyl)-0-(trans-3- (2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserinate. To a solution of methyl N-(((3-methylazetidin-3-yl)oxy)carbonyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8- naphtliyridin-2-yl)ethyl)cyciobutyl)homoserinate bis(2,2,2-trifluoroacetate) (28.0 mg, 0.04 mmol) and N,N~Diisopropylethylamine (42.4 pL, 0.24 mmol) in dichloromethane (2.0 mL) at 0° C was added methanesulfonyl chloride (5.6 pL, 0.073 mmol). Tire reaction mixture was removed from the ice bath and allowed to warm to room temperature. After 20 minutes the reaction mixture vas concentrated in vacuo and used without further purification.
General Procedure N
Figure imgf000153_0002
[0296] N-( 4-cyan o-2, 6-dimethylben zoyl)-0-( ds-3-(2-{5, 6, 7, 8-tetrahydro-l, 8~
naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. To a solution of methyl N-(4-cyano-2,6- dimethylbenzoyl)-0-(cis-3-(2-(5,6,7,8-tetraliydro-I,8-naphthyridm-2- yl)ethyl)cyclobutyl)homoserinate (427 mg, 0.846 mmol) in THF/MeOH/H20 3: 1 : 1 was added LiOH (81.0 mg, 3.38 mmol). The reaction w'as allowed to stir at rt for 4 h. LCMS showed conversion to product, and the reaction mixture was diluted with water and purified by reverse phase preparative HPLC to afford N-(4-cyano-2,6-dimethylbenzoyl)-0-(cis-3-(2- (5,6,7,8-tetraliydro-l,8-naphtiiyridin-2-yl)ethyl)cyciobutyl)homoserine as a TFA salt.
General Procedure Q
Synthesis of tert-buty! 7-(4~oxohutyT)~3,4~dihydro-l ,8-naphthyridine-l(2FI)~carboxyk?/e
Figure imgf000154_0001
[Q297] tert-butyl 7-(4-ethoxy-4-oxobutyl)-3,4-dihydro-l,8-naphthyridine-l(2H)- carboxylate. To a solution of ethyl 4~(5,6,7,8-tetrahydro~l,8~naphthyridin-2~y])butanoate (5.25g, 21.1 mmol) and di-tert-butyl dicarbonate (5.89 mb, 25.4 mmol in THF (70 mL) was added lithium bis(trimethylsilyl)amide (25.4 mL, 25.4 mmol) was added at 0 °C. After 2 hr, the reaction was diluted with EtO Ac (50 ml.) and was quenched with sat MtUC! (50 mL). After 30 min of stirring, the layers were separated and the organic layer was washed with brine (20 mL), dried over NarSOy and concentrated in vacuo. The resulting crude residue was purified by normal phase silica gel chromatography to give tert-butyl 7-(4-ethoxy-4- oxohutyi)-3 ,4-dihydro- 1 ,8-naphthyridine- 1 (2H)-carboxylate .
Boc Boc
Figure imgf000154_0002
[0298] tert-butyl 7-(4-hydroxybutyl)-3,4-dihydro-l, 8-naphthyridine-l (2H)-carboxylate.
To a solution of tert-butyl 7-(4-ethoxy-4-oxobutyl)-3,4-dihydro-l,8-naphthyridine-l(2H)- earboxylate (6.81 g, 19.5 mmol) in THF (50 mL) was added LiBH4 (1.0M in THF, 19.5 mL, 19.5 mmol) at rt. The mixture was stirred overnight and then quenched with sat. NHUCl and diluted with EtO Ac. The layers were separated and the aqueous layer was extracted with EtO Ac. The combined organic extracts were washed with H2O, dried over NazSO-», filtered, and concentrated in vacuo. The resulting erode residue was purified by normal phase silica gel chromatography to give tert-butyl 7-(4-hydroxybutyl)-3,4-dihydro-l,8-naphthyridine- 1 ( 2H)-carboxy late .
Figure imgf000155_0001
[0299] tert-butyl 7-(4-oxobutyl)-3,4-dihydro-l,8-naphthyridine-l (2H)-carboxylate. A solution of oxalyl chloride (2.57 mL, 29.3 mmol) in CH2CI2 (69 mL) was cooled to -78 °C for 5 minutes, 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-l,8- naphthyridine-l-carboxylate (6.9 g, 22.6 mmol) in CH2CI2 (10.5 mL) w¾s added and stirred at -78 °C for 1 hr. Triethylamine (10.5 mL, 75.1 mmol) was then added to the reaction mixture and stirred for 30 mins. The reaction was quenched with water and extracted with CH2Q2. The organic layer was collected and dried over sodium sulfate. The organic layer was concentrate to give tert-butyl 7-(4-oxobutyl)-3,4-dihydro-l,8-naphthyridine-l(2H)- carboxylate that was used without further purification.
General Procedure P
Synthesis of 3-(thiazol-5-yl)benzoic acid
Figure imgf000155_0002
[0300] methyl 3-(thiazol-5-yl) benzoate. A microwave vial was charged with (3- (methoxycarbonyl)phenyl)boronic acid (513 mg, 2.85 mmol), 5-bromothiazole (513 mg, 3.13 mmol), and Pd(PPh3)4 (132 mg, 0.11 mmol) and then diluted with dioxane (5 mL) and 2M aq. K2CO3 (4.25 mL). The mixture was degassed by bubbling N2 through the solution while vigorously stirring at rt and then sealed and heated to 100 °C for 30 min. The reaction mixture was cooled to rt and diluted with EtOAc and H2O. The layers were separated and the organic layer was dried over Na2S04, filtered and concentrated in vacuo. The erode residue was purified by normal phase silica gel chromatography to give methyl 3~(thiazo3-5-yl)benzoate.
Figure imgf000156_0001
[0301 ] 3-(thiazol-5-yl)benzoic add. To a mixture of methyl 3-(thiazol-5-yl)benzoate (600 mg, 2.74 mmol) in 4: 1 : 1 THF/MeOH/HiO (6 m l·} was added LiOH (98 mg, 4.10 mmol) and the resulting mixture was stirred at rt for 3 hr. The mixture was partially concentrated in vacuo to remove the volatile organics and then acidified with 1 M HC1 to pH = 1 causing a precipitate to form. The suspension was filtered and tire solid that was collected was washed with H2O and dried under high vacuum to give 3-(thiazol-5-yl)benzoic acid.
General Procedure O
Figure imgf000156_0002
[0302] trans~2-(3,5-dimethyl-lH-pyrazol-l-yl)cyclopentan-l-ol (racemic). To a solution of cyclopentene oxide (2.03 g, 24.1 mmol) in MeCN (10 mL) was added 3, 5 -dimethyl- 1/7- pyrazole (2.78 g, 28.96 mmol) then CS2CO3 (9.43 g, 28.96 mmol) and the resulting mixture was heated to reflux for 16 hours. The mixture was allowed to cool to room temperature and then filtered and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give irans-2-(3 ,5 -dimethyl- LFf-pyrazol- 1 -yl)cyclopentan- 1 -ol (racemic).
General Procedure K
Preparation oftert-butyl 3-hydroxy-3-(4-isopropylphenyl)azetidine-l-carboxylate
Figure imgf000156_0003
[0303] tert-butyl 3-hydroxy-3-(4-isopropylphenyl)az tidine-l-carboxylate. A solution of tert-butyl 3 -oxoazetidine- 1 -carboxylate (793 mg, 4.63 mmol) in THF (4 mL) at -78 °C was added (4-isopropylpheny])magnesium bromide (0.5 M in THF, 5 mL, 5.0 mmol) dropwise and the resulting mixture was stirred for 30 minutes at -78 °C. The mixture was diluted with sat. aq. NH4CI and extracted with EtOAc. The combined organic extracts were dried over Na2SQ4, filtered, and concentrated in vacuo. The crude residues was purified by normal phase silica gel chromatography to give tert-butyl 3-hydroxy-3-(4-isopropy]phenyl)azetidine-l- carboxylate.
Figure imgf000157_0001
[Q304] The chemical reactions 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 deemed to be within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully performed 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 other than those described, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention. In the following Examples, certain compounds are noted as racemic, as separated isomers, or with unassigned absolute stereochemistry at some stereocenters, and the like. For some compounds, further separation of isomers and/or assignment of absolute stereochemistry was performed. The assigned stereochemistry of such compounds is shown in the structures as depicted in FIG, 1 , Table 2.
Example 1, Compound l
Two Syntheses of N-(2-chloro-3-fluorobenzoyl)-0-(4-(5,6,7,8-tetrahydro-l,8- naphtbyridin-2-yl)butyl)homoserine
Example la B i oc
Figure imgf000158_0001
[0305] Compound la-a: To a solution of tert-butyi 7-(4-hydroxybutyl)-3,4-dihydro-2H- l,8-naphthyridine-l-carboxylate (11 g, 35.90 mmol) in DMF (150 mL) was added NaH (2.15 g, 53.85 mmol, 60% suspension in mineral oil) at 0 °C under N2. The mixture was stirred for 30 min at 0 °C, then 3-bromoprop-l-ene (5.21 g, 43.08 mmol, 1.2 eq) was added into the mixture at 0 °C. The mixture was stirred for 10 hrs at 20 °C. TLC (Petroleum ether/Ethyl acetate=3/l, Rf=0.1) indicated tert-butyl 7-(4-hydroxybutyl)-3,4-dihydro-2H-l,8- naphthyridine-l-carboxylate (11 g, 35.90 mmol) was consumed completely. LCMS indicated desired M+H+ was detected. The mixture was quenched by NH4CI solution and extracted by EtOAc (3 x 50ml·}. The organic layer was dried by brine and NaiSQy filtered and
concentrated under reduced pressure to give a residue. Hie crude product was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate:=:50/l to 5: 1 ) to give compound la-a (6 g, 16.64 mmol, 46.36% yield) as a colourless oil. LCMS (ESI+): m/z = 347.3(M+H)+, RT = 0.943 min.
[0306] 1 1 NMR (400 MHz, CDC13) d ppm 7.29 (s, 1 H i 6.82 (d, J= 7.50 Hz, 1 H) 5.92
(td, .7=11.19, 5.18 Hz, 1 H) 5.11 - 5.32 (m, 2 H) 3.96 (br d, ./=5.51 Hz, 2 H) 3 75 (t, .7=5.95 ITz, 2 H) 3 47 (t, .7=6.50 Hz, 2 H) 2.70 - 2 77 (m, 4 H) i .89 - 1 95 (m, 2 H) 1 .81 (br t, J= 7.83 Hz, 2 H) 1.64 - 1.72 (m, 2 H) 1.52 (s, 9 H).
[0307] Compound la-b: To a solution of compound la-a (3 g, 8.66 mmol) in MeOH (25 mL) and H2O (25 mL) at 20 °C was added NalCL (4.63 g, 21 .65 mmol, 1.2 mL) and OsCL (44.03 mg, 173.18 umol, 8.99 uL). The resulting suspension was stirred at 20 °C for 10 hrs. TLC (Petroleum ether/Ethyl acetate=l/l, Rf =0.6) indicated compound la-a was consumed completely and a new spot was detected. Tire mixture was quenched by NazSCL solution (150 mL) and extracted by EtOAc (3 x 60 ml,). The organic layer was dried by brine and NaiSOy filtered and concentrated under reduced pressure to give compound la-b (2.7 g, 7.75 mmol 89.5% yield) as a yellow oil. The crude product was used for next step without further purification.
[0308] 1 1 IN MR (400 MHz, ( DC 13) 6 ppm 9.73 (s, 1 H) 7.29 (br d, 7 7.7.2 Hz, 1 H) 6.80
- 6.83 (m, 1 H) 3.74 (br d, J= 5.95 Hz, 2 H) 3.57 (br t, 7=6.39 Hz, 2. H) 3 44 - 3.49 (m, 2 H) 2.72 (br t, .7=6.28 Hz, 4 H) 1.90 - 1 .94 (m, 2 H) 1.70 - 1 .84 (m, 4 H) 1.52 (s, 9 H)
[0309] Compound la-c: To a solution of compound la-b (2.7 g, 7.75 mmol) in DCM (30 mL) was added methyl 2-(benzyloxycarbonylamino)-2-dimethoxyphosphoryl-acetate (2.82. g, 8.52 mmol) followed by DBU (1.30 g, 8.52 mmol, 1.28 mL). Tire resulting suspension was stirred at 20 °C for 1 hr. TLC (Petroleum ether/Ethyl acetate=l/l, Rr =0.26) indicated compound la-b was consumed completely and one major new spot was detected. The mixture was quenched by NHsCl solution and extracted with EtOAc (3 x 40 mL). The organic layer was dried by brine and NaiSOy filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (SiC , Petroleum ether/Ethyl acetate=l 0/l to 1 : 1). The product compound la-c (3 g, 5 42 mmol, 94.40% yield) was obtained as a brown oil.
[0310] 1 1 IN MR (400 MHz, CDC13) 6 ppm 7.32 - 7.39 (m, 5 H) 6.80 (d, 7=7.50 Hz, 1 H)
6.68 (br s, 1 H) 6.57 (t, .7=5 62 Hz, 1 H) 5.14 (s, 2 H) 4 15 (d, 7=3.51 Hz, 2 H) 3.79 (s, 3 H) 3.74 (d, ,7=5.95 Hz, 2 H) 3.47 (t, 7=6.50 Hz, 2 H) 2.70 - 2.75 (m, 4 H) 1.92 (quin, 7=6.34 Hz, 2 H) 1.76 - 1.84 (m, 2 H) 1.63 - 1.68 (m, 2 H) 1.52 (s, 10 H).
[0311] Compound la-d: The solvent MeOH (30 mL) was added PdiOHfi/C (507.31 mg, 722.48 umol, 20% purity) and degassed under vacuum and purged with Hi several times. The mixture was stirred under H?. (50 psi) at 50 °C for 4 hrs. Then compound la-c (2 g, 3.61 mmol) was added into the mixture. The suspension was degassed under vacuum and purged with l-h for 3 rimes. The mixture was stirred under Hz (50psi) at 50 °C for 4 hrs LCMS indicated desired MS was detected. The mixture was filtered and concentrated under reduced pressure. The product compound la-d (1.4 g, crude) was obtained as a yellow oil, which was used for next step without further purification. LCMS (ESI+): m/z = 422 3 (M+H)+; RT= 0.752 min. [0312] Compound la-e: To a mixture of 2-chloro-3-fluoro-benzoic acid (807.50 mg, 4.63 mmol) in DMF (15 ml,) was added HOBt (721.25 mg, 5.34 mmol), EDCI (1.02 g, 5.34 mmol) and DIEA (1 .38 g, 10.68 mmol, 1.86 ml,). Then compound la-d (1 .5 g, 3.56 mmol) was added into the mixture. The mixture was stirred at 20 °C for 5 hrs. TLC (Petroleum ether/Ethyl acetate=0/l, Rf=0.2) indicated compound la-d was consumed completely. The mixture was extracted by H2O (40mL) and EtOAc (3 x 20mL). The organic layer was dried by brine and NaiSOr, filtered and concentrated under reduced pressure. The crude product was purified by prep-HPLC (neutral conditions) to give compound la-e (1.3 g, 2.2 mmol, 61.69% yield, 97.61 % purity) as a brown oil. HPLC purification conditions: column:
Phenomenex Gemini Cl 8 250 x 50mm x 10 um; mobile phase: [water (10 mM NH4HC03)- ACN]; B%: 40%-70%, 20mm. LCMS (ESI+): m/z = 578.4 (M+H)+; R i 1.038 mm.
[0313] Example la: To a mixture of compound la-e (500 mg, 864.94 umol) was added HC1 (4 M, 3.24 mL, 15 eq). Tie mixture was stirred at 70 °C for 10 hrs. LCMS indicated desired M+H+ was detected. The mixture was freeze-dried directly to give Example la (304.47 mg, 587.12 umol, 67.88% yield, 96.492% purity, HC1) which was delivered without any further purification. LCMS (ESI+): m/z=464.1(M+H)÷, RT= 2.450 min; HPLC purity : 96.492 %, RT-6.566 min; Chiral SEC purity: 52.72%, ee value: 0 %, RT-3.447 min.
[0314] !H NMR (400 MHz, MeOH-ώ) d ppm 7.57 (d, .7=7.28 Hz, 1 H) 7 32 - 7.47 (m, 3 H) 6 65 (d, 7=7 28 Hz, 1 H) 3.54 - 3.64 (m, 3 H) 3.43 - 3.50 (m, 3 H) 2 80 (t, 7=6.28 Hz, 2 H) 2.70 - 2.77 (m, 2 H) 2.29 (ddt, 7=14.08, 9.40, 4.80, 4.80 Hz, 1 H i 1.62 - 2.00 (m, 8 H).
Example lb
Figure imgf000160_0001
Figure imgf000161_0001
Example 1 b
[0315] Compound lb-a: To a suspension of 4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butanoic acid hydrochloride (1.23 g, 4.79 mmol, 1.0 equiv) in THF was added LiAlH4 (1 0M in THF, 10.6 mL, 10.6 mmol) dropwise and the resulting mixture was refluxed overnight. The mixture was then cooled in an ice bath and to this was slowly added H20 (400 pL), then aqueous 1.0 M NaOH (400 pL), then H20 (400 pL) again and stirred for 15 minutes and then a large excess of MgS04 was added and stirred for an additional 30 minutes. The resulting organic mixture was filtered and then concentrated in vacuo to provide compound lb-a.
[0316] Compound lb-b: To a stirring suspension of NaH (60 wt% dispersion in mineral oil, 238 mg, 5.96 mmol) in THF (8.2 mL) at 0 °C was added a solution of lb-a (820 mg, 3.98 mmol) THF (4.1 mL) dropwise. Upon completion of the addition, the ice bath was removed and the resulting mixture was stirred at room temperature for 30 minutes, at which time, allyl bromide (400 pL, 4.62 mmol) was added dropwise. The suspension was stirred for an additional 6 hrs at room temperature and then carefully diluted with H20 and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. Tie combined organic extracts were dried over MgSQ4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography to provide compound lb-b.
[0317] Compound lb-c: To a solution of lb-b (582 mg, 2.36 mmol) in 3: 1 THF/H20 (6 mL) at room temperature was added NaI04 (2.02 g, 9.44 mmol) followed by Os04 (2.5 wt% in t-BuOH, 480 pL, 0.05 mmol). Tie resulting suspension was stirred at room temperature for 5 hrs and then diluted with 1 : 1 sat. aq. NaHC03/sat. aq. Na2S203 and EtOAc and then stirred for 1 hr at room temperature. The biphasic mixture was filtered through a small pad of Celite and then the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried over MgS04, filtered, and concentrated in vacuo to provide a crude residue that was used without further purification.
[0318] To the crude residue obtained from the previous reaction (586 mg, 2.36 mmol) in CH2C12 (6 mL) at room temperature was added methyl 2-(((benzyloxy)carbonyl)amino)-2- (dimethoxyphosphoryl)acetate (860 mg, 2.60 mmol) followed by DBU (391 pL, 2.60 mmol) and stirred for 30 minutes at room temperature. The mixture was diluted with sat. aq. NH4C1 and stirred for 5 minutes at room temperature. Tire layers w ere separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgS04, filtered, and concentrated vacuo. The crude residue w¾s purified by silica gel
chromatogaphy to provide compound Ib-c.
[0319] Compound lb-d: A flask containing lb-c (497 mg, 1.10 mmol) and 20 wt% Pd(OH)2 on carbon (100 mg) was diluted with MeOH (5 ml) and then evacuated and backfilled with 1 13 for 3 cycles and then stirred under an H2 atmosphere for 3 hrs. The resulting mixture was filtered through a pad of Celite and then concentrated in vacuo to give compound lb-d (352 mg) that was used without further purification.
[Q320] Compound lb-e: A flask containing lb-d (50.0 mg, 0.15 mmol) was charged with 2-chloro-3-fluorobenzoic acid (40.7 mg, 0.23 mmol) and then diluted with 10: 1 THF/DMF (2.0 mL). To this was then added DIPEA (81 pL, 0.47 mmol) followed by HATU (89 mg, 0.23 mmol) and stirred for 30 minutes at room temperature and then concentrated in vacuo. The crude residue was purified by silica gel chromatography to provide compound lb-e.
[0321] Example lb: To a solution of lb-e (61 mg, 0.13 mmol) in 4: 1 : 1 THF/MeOH/H20 (2.0 mL) wus added Li OH (9 mg, 0.39 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was then neutralized with AcOH and then and purified by preparative reverse phase HPLC to give Example lb as the trifluoroacetate salt. LCMS theoretical m/z = 464.9 i \1 · 1 I I · . found: 464.9.
Example 2 Compound 8
2-(2-ethylbutanamido)-5-(3-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)propoxy)pentanoic add
Figure imgf000163_0001
[Q322] Compound 2a: two batches in parallel: To a mixture of ethyl 4-oxopentanoate (50 g, 346.82 mmol, 49.50 mL,) and 2-aminopyridine-3-carhaldehyde (42.35 g, 346.82 mmol) in EtOH (800 mL) was added L-proline (19.96 g, 173.41 mmol). The mixture was refluxed at 85°C for 12 hrs. LCMS indicated the reaction was completed. TLC (Petroleum ether/Ethyl acetate = 2: 1 , Rr = 0.31 ) was the spot of product. The mixture was combined and concentrated under reduced pressure. The mixture was extracted by H2O (1000 mL) and EtOAc (3 x 800 mL), washed with brine and dried with NarSOy filtered and concentrated under reduced pressure. The erode product was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate=10/l to 1 : 1) to give compound 2a (60 g, 240.85 mmol, 34.72% yield, 92.4 % purity) as a yellow solid. LCMS (ESI+): m/z = 23 l . l(M+H)+, RT = 0.68 min. ¾ NMR (400 MHz, CDC13) d ppm 9.08 (dd ./ 4. 19. 1.98 Hz, 1 H) 8 07 - 8.19 (m, 2 H) 7.42 - 7.48 (m, 2 H) 4.12 (q, J= 7.06 Hz, 2 H) 3.32 - 3.39 (m, 2 H) 3.06 (t, .7=7 28 Hz, 2 H) 1.23 (t, ,7=7.17 Hz, 3 H). [Q323] Compound 2b: two batches were processed in parallel: To a solution of compound 2a (26 g, 112.91 mmol) in EtOH (300 mL) was added Pd/C (3 g, 10%) under Nr. The suspension was degassed under vacuum and purged with Hr several times. The mixture was stilted under Hr (50psi) at 20°C forli) hrs. TLC (Petroleum ether/Ethyl acetate = 0: 1, Rr = 0.3) indicated the compound 5a was consumed completely and a new' spot was detected. LCMS indicated desired MS was detected. The mixture was filtered and concentrated under reduced pressure to give compound 2b (46 g, 196 33 mmol, 86.94% yield) as a white solid. The crude product was used for next step with further purification. LCMS (ESI ): m/z = 235.1(M+H)+, RT = 0.772 min
[0324] Compound 2c: A mixture of compound 2b (46 g, 196.33 mmol) and BocrO (100 mL) was stirred at 40°C for 15 hrs. TLC (Petroleum ether/Ethyl acetate= 2: 1, Rr = 0.11) indicated compound 2c was formed. The mixture was not worked up but evaporated and applied to a column of silica gel . The crude product was purified by column chromatography (Si(>2, Petroleum ether/Ethyl acetate=T00/l to 5: 1) to give compound 2c (32 g, 95.69 mmol, 48.74% yield) as a white solid. H NMR (400 MHz, CDCT3) d ppm 7.33 (d, ./ 7.72 Hz, 1 H) 6.88 (d, .7=7 72 Hz, 1 H) 4.17 (q, 7=7.06 Hz, 2 H) 3.76 - 3 81 (m, 2 H) 3.04 - 3 10 (m, 2 H) 2.81 - 2.86 (m, 2 H) 2.76 (t, .7=6.62 Hz, 2 H) 1.95 (quin, .7=6.34 Hz, 2 H) 1.51 (s, 9 H) 1.28 (t, ,7=7.06 Hz, 3 H).
[Q325] Compound 2d: To a solution of compound 2c (14 g, 41.86 mmol) in TOP (140 mL) was added LiBHs (1.82 g, 83.73 mmol) in several portions at 0°C under Nr. The reaction mixture was warmed to 15°C for 1 hr. The reaction mixture was stirred at 40°C for 12 hrs. TLC (Petroleum ether/Ethyl acetate = 1 : 1, Rf = 0.61) indicated compound 2c was consumed completely. The mixture was poured into the saturated NHrCl solution (500 mL) and was extracted by EtOAc (3 x 300 mL). The organic layer was dried by brine and NaiSOr, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiCfe, Petroleum ether/Ethyl acetate=0: 1 ) to give compound 2d (18 g, 61.57 mmol, 73.53% yield) as a white solid. TT NMR (400 MHz, CDC13) d ppm 7.31 (d, 7=7.72 Hz, 1 H) 6.83 (d, .7=7.72 Hz, 1 H) 3.74 - 3.78 (m, 2 H) 3.69 (hr t. 7=5.62 Hz, 2 H) 2.88 - 2.93 (m, 2 H) 2 73 (t, 7=6.50 Hz, 2 H) 1.89 - 1 96 (m, 4 H) 1.54 (s, 9 H).
[0326] Compound 2e: To a mixture of compound 2d (3 g, 10.26 mmol) in DMF (30 mL) was added NaH (2 46 g, 61.57 mmol, 60% purity) at 0°C. Then the mixture was stirred at 0°C for 0.5hr. Then 5-bromopent-l -ene (6.12 g, 41.04 mmol) was added into the mixture at 0°C. The mixture was warmed to 15°C for 12 hrs. LCMS indicated desired MS was detected. TLC (Petroleum ether/Ethyl acetate=3/l, Rr =0.18) indicated compound 2d was consumed. The mixture was poured into NH4Cl solution (50 ml,) and extracted by EtOAc (3 x 30 mL). The organic layer was dried by brine and NarSCri, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate== 100/1 to 10: 1) to give compound 2e (2.8 g, 7.77 mmol, 75.70% yield) as a yellow oil. LCMS (ESI+): m/z = 361.3 ( M i l) : R G 1.016 min. ¾ NMR (400 MHz, CDC13) 5 ppm 7.25 (d, J= 3.09 Hz, 1 H) 6.80 (d, J=7.72 Hz, 1 H) 5 80 (ddt, J=17 03, 10.31, 6.61, 6.61 Hz, 1 H) 4.92 - 5.02 (m, 2 H) 3.72 (d, J=5.95 Hz, 2 H) 3.40 - 3.44 (m, 4 H) 2.69 - 2.77 (m, 4 H) 2.08 - 2.13 (m, 2 H) 1.97 - 2.02 (m, 2 H) 1.88 - 1.92 (m, 2 H) 1 62 - 1.67 (m, 2 H) 1 .49 (s, 9 H).
[0327] Compound 2f: Ozone was bubbled into a solution of Compound 2e (2.8 g, 7.77 mmol) in DCM (20 mL) and Me OH (10 mL) at -78°C for 30 minutes. After excess O3 was purged by O2, Me2S (4.83 g, 77.67 mmol, 5.70 mL) was added at -78°C. Tire mixture was stirred for 12 hrs at 20°C. LCMS indicated desired MS was detected. TLC (Petroleum ether/Ethyl acetate=T : 1, Rf=0.6) indicated compound 2e was consumed completely. The mixture was concentrated under reduced pressure. Hie crude product was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=30: l to 8: 1 ) to give compound 2f (1.4 g, 3.86 mmol, 49.73% yield) as a brown oil. LCMS (ES1+): m/z = 363.3 (M+H)+; RT = 0.853 min
[0328] Compound 2g: To a solution of compound 2f (1.4 g, 3.86 mmol, 1 eq) in THF (10 mL) was added 2-methylpropane-2-sulfinamide (514.95 mg, 4.25 mmol) and
tetraethoxytitanium (2.64 g, 1 1.59 mmol, 2.40 mL). The mixture was stirred at 50°C for 12 hrs. LCMS indicated the desired MS. Hie mixture was concentrated under reduced pressure to give compound 2g (1.7 g, crude) as brown oil. Hie crude product was used directly for next step without purification. LCMS (ESI+): m/z= 466.3 (M+H)+, RT: 0.991 min.
[0329] Compound 2h: To a mixture of compound 2g (1.7 g, 3.65 mmol) in dried THF (20 mL) was added NaCN (536.75 mg, 10.95 mmol). The mixture was stirred at 40 °C for 12 hrs. NaCN (536.75 mg, 10.95 mmol) and i-PrOH (658.19 mg, 10.95 mmol, 838.46 uL) was added into the mixture with stirring for 16 hrs at 55°C, LCMS indicated desired M+H was detected . TLC (Petroleum ether/Ethyl acetate = 1 : 1 , Rf:=: 0.72) indicated compound 2g was consumed. The mixture was extracted by H2O (50 mL) and EtOAc (3 x 30 mL). The organic layer was dried by brine and NaiSOr, filtered and concentrated under reduced pressure. The H2O layer was quenched by NaCIO solution. The crude product was purified by column chromatography (SiC , Petroleum ether/Ethyl acetate=10: l to 1 : 1) to give compound 2h (450 mg, 850 45 umol, 23.29% yield) as yellow oil. LCMS (ESI+): m/z= 493.4 (M+H)+, RT= 0.958 min.
[033Q] Compound 2i: To a mixture of compound 2h (450 mg, 913.38 umol) in
HCl/MeOH (5 mL) was stirred at 50 °C for 16 hrs. LCMS indicated desired MS was detected. The mixture was concentrated under reduced pressure to give the crude compound 2i (360 mg, crude) as a brown oil, which was used directly for next step without further purification LCMS (ESI+): m/z = 322.3 (M+H)+, RT= 0.628 min.
[0331] Compound 2j : To a mixture of 2-ethylbutanoic acid (79.53 mg, 684.7 umol, 86.26 uL) in DMF (3 mL) was added HQBt (92.52 mg, 684.70 umol), EDC1 (131.26 mg, 684.7 umol) and DIEA (176.98 mg, 1.37 mmol, 2.38.52 uL). Then compound 2i (180 mg, 456 46 umol) was added into the mixture. The mixture was stirred at 15°C for 10 hrs. LCMS indicated desired MS was detected. The mixture was extracted by FbO (20 mL) and EtOAc (3 x 10 mL). The organic layer was dried by brine and NaiSOr, filtered and concentrated under reduced pressure. The crude produet was purified by prep-TLC (SiCh, Ethyl acetate/MeOH=10: l) to give compound 2j (65 mg, 154.93 umol, 33.94% yield) as a yellow oil. LCMS (ESH-): m/,·: 419.56 {.M Hr . RT 0.855 min.
[Q332] Example 2: To a mixture of compound 2j (65 mg, 154.92 umol) was added HO (4 M, 193.66 uL). The mixture was stirred at 70 °C for 12 hrs. LCMS indicated desired MS was detected. The mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC (TEA condition) to give Example 2 (40 mg, 76.13 umol, 49.14% yield, 98.887% purity, TEA) as a colourless oil.
[0333] HPLC purification conditions: column: Luna C 18 100 x 30 5u; mobile phase: [water (0.1%TFA)-ACN]; B%: l%-40%, 5mm.
[0334] 1 1 IN MR (400 MHz, MeGH-A) d ppm 7.59 (d, J=7.50 Hz, 1 H) 6.64 (d, .7=7.28
Hz, 1 H) 4.46 (dd, .7=9 26, 4 85 Hz, 1 H) 3.44 - 3.53 (m, 6 H) 2.78 - 2.85 (m, 4 H) 2 14 (it,
7= 9.59, 4.96 Hz, 1 H) 1.91 - 1.98 (m, 5 H) 1.44 - 1.75 (m, 7 H) 0.87 - 0.95 (m, 6 H) : LCMS (ESI+): m/z=406.2(M+H)+, RT= 2.336 min; HPLC purity: 98.887 %, RT=6.242 min: Chiral SFC purity: 52.72%, ee value: 5.44 %, RT=2.G13 min.
Example 3, Compound 9
2-(2-chloro-3-fluorobenzamido)-5-(3-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- y!)propoxy)pentanoic acid
Figure imgf000167_0001
[0335] Example 3 was prepared by the same procedure used to prepare Example 2 with the exception that the acid was replaced by 2-chloro-3-fluorobenzoic acid in the reaction with intermediate 2i.
[Q336] HPLC purification conditions: column: Phenomenex Synergi C18
100*21 2mm* 4um; mobile phase: [water (0.1 %TFA)-ACN] ;B%: 15%-45%,10min
[0337] Ή NMR (400 MHz, MeOH-rfi) d ppm 7.57 (d, ./ 7.50 Hz, 1 H) 7.30 - 7.43 (m, 3 H) 6.63 (d, 7=7.28 Hz, 1 H) 4.63 (dd, 7=9.26, 4.85 Hz, 1 H) 3.47 - 3.52 (m, 6 H) 2.78 - 2.83 (m, 4 H) 2.01 - 2.09 (m, 1 H) 1.92 - 1 .97 (m, 4 H) 1.71 - 1.87 (m, 3 H); HPLC purity:
99.041 %, RT: 6.480 min; LCMS (ESI+): m/z = 464.1 (M+H)+, RT=2.399 min; Chiral SFC purity: 52.42%, ee value: 4.84%, RT = 3.870 min
Example 4 Compound
Figure imgf000167_0002
[0338] N-(J-methyl-lH-indazole-4-carbonyl)-0-(4-(5,6, 7,8-tetrahydro-l,8- naphthyridm-2~yl)butyl)homoserine. Prepared according to General Scheme C using General Procedure 1 watli 1 -methyl- lH-indazole-4-carboxylic acid. LCMS theoretical m/z = 466.2. [M+H]+, found 466.2.
Example 5, Compound 3
Figure imgf000167_0003
Figure imgf000168_0001
yl)butyl)homoserine. Prepared according to General Scheme C using General Procedure Ϊ with 2-ethylbutanoic add. LCMS theoretical m/z = 406.3 [M+H]+, found: 406.3.
Example 6, Compound 4
Figure imgf000168_0002
[0340] N-benzoyl-0-(4-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)homoserine.
Prepared according to General Scheme C using General Procedure I with benzoic acid. LCMS theoretical m/z = 412.2 | \ M ! i · . found: 412.2.
Example 7 Compound 5
Figure imgf000168_0003
[0341 ] N-(4,4-difluorocyclohexane-l-carbonyl)-0-(4-(5,6, 7,8-tetrahydro-J,8- naphthyridin-2-yl)butyl)homoserine. Prepared according to General Scheme C using General Procedure I with 4,4-difluorocyclohexane-l -carboxylic acid. LCMS theoretical m/z = 454 3 | M · 1 1 ] . found: 454 3.
Example 8, Compound 6
Figure imgf000168_0004
[0342] N-pentanoyl-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)homoserine.
Prepared according to General Scheme C using General Procedure I with butanoic acid. LCMS theoretical m/z = 392.3 i M 1 1 ! . found: 392.3.
Example 9, Compound 7
Figure imgf000169_0001
[Q343] N-(3-fluoro-5-(trifluoromethyl)benzo l)-0-(4-(5,6, 7,8-tetrahydro-l,8- naphlhyruUn-2-yl)butyl)homoserme Prepared according to General Scheme C using General Procedure I with 3-fluoro-5-(trifluoromethyl)benzoic acid. LCMS theoretical m/z = 498.2 ! M 1 1 j . found: 498.2.
Example 10, Compound 15
Figure imgf000169_0002
[0344] N-(3-fluoro-5-(trifluoromethyl)benzoyl)-0-(3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme H using General Procedure 1 with 3-iluoro-5~(trifluoromethyl)benzoic acid. LCMS theoretical m/z = 524.2 | M · 1 l i . found 524 3.
Example 11 Compound 18
Figure imgf000169_0003
[0345] N-pentanoyl-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclohutyl)homoserine. Prepared according to General Scheme H using General Procedure I with pentanoic acid. LCMS theoretical m/z ::: 418.3 [M+H]+, found 418.3.
Example 12, Compound 19
Figure imgf000170_0001
[0346] N-(tert-butoxycarbonyl)-0-(3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme H through intermediate 13H, followed by General Procedure N. LCMS theoretical m/z = 434.3 i \i · ! I ] . found 434.3.
Example 12 A, Compound 19
Figure imgf000170_0002
[0347] N-(tert-butoxycarbonyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2 - yl)ethyl)cyclobuiyl)homoserine. Prepared according to General Scheme A through intermediate 13A, followed by General Procedure N. LCMS theoretical m/z ::: 434.3 | M H | . found 434.3.
Example 13, Compound 22
Figure imgf000170_0003
[0348] N-(tert-hutox carbonyl)-0-(4-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserine. Prepared according to General Scheme C through intermediate 7C, followed by General Procedure N. LCMS theoretical m/z ::: 408.2 [M+H]+, found: 408.2.
Example 14, Compound 14
Figure imgf000170_0004
[Q349] N-(2-chloro-3-fluorobenzoyl)-0-(cis-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin- 2-yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme B using General Procedure I with 2-chloro-3~fluorobenzoic acid. LCMS theoretical m/z = 490.2 [M+H]+, found 490.2.
Example 15, Compound 24
Figure imgf000171_0001
[Q350] N-(4-ftuorobenzoyl)-0-(cis-3-{2-(5,6,7,8-tetrahydro-l,8-napktkyridm-2- yl)ethyl)cyclohutyl)homoserine. Prepared according to General Scheme B using General Procedure I with 4-fluorobenzoic acid. LCMS theoretical m/z ::: 456.2 [M+H]+, found 456.
Example 16, Compound 24
Figure imgf000171_0002
[0351] N-(4-fluorobenzoyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with 4-fluorobenzoic acid. LCMS theoretical m/z = 456.2 [M+H]+, found 456.2.
Example 17, Compound 25
Figure imgf000171_0003
-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure 1 with 4-chlorobenzoic acid. LCMS theoretical m/z ::: 472.2 [M+H]+, found 472.2. Example 18, Compound 19
Figure imgf000172_0001
[0353] N-(tert-butoxycarbonyl)-0-(cis-3-(2-(5,6,7,8-tetrah dro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Isomer E2 was used in General Procedure N. LCMS theoretical m/z = 434 3 [M+H]+, found 434.3.
Example 19, Compound 26
Figure imgf000172_0002
[0354] N-(3-fluorobenzoyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with 3-fluorobenzoic acid. LCMS theoretical m/z ::: 456.2 [M+H]+, found 456.2.
Example 20, Compound 27
Figure imgf000172_0003
[0355] N-(3-chlorobenzoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyriditi-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with 3-chlorobenzoic acid. LCMS theoretical m/z = 472 2 [M+H]+, found 472.2.
Example 21, Compound 28
Figure imgf000173_0001
[0356] N-(2-chlorobenzoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyriditi-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure Ϊ with 2-chlorobenzoic acid. LCMS theoretical m/z = 472.2 [M+H]+, found 472.2.
Example 22, Compound 29
Figure imgf000173_0002
[0357] N-(2-fluorobenzoyl)-0-(trans-3-(2-(5,6,7,8-letrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure Ϊ with 2-fluorobemzoic acid. LCMS theoretical m/z = 456.2 [M+H]+, found 456.2
Example 23, Compound 30
Figure imgf000173_0003
[0358] N-(2,3-difluorobetizoyl)-0-(irans-3-(2-(5,6,7,8-ieirahydro-J,8-naphthyridift-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with 2,3-difluorobenzoic acid. LCMS theoretical m/z = 474.2 [M+H]+, found 474.2,
Example 24 Compound 31
Figure imgf000174_0001
[0359] N-(2,4-difluorobenzoyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2 - yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with 2,4-difluorobenzoic acid. LCMS theoretical rn/z ::: 474.2 [M+H]+, found 474.2.
Example 25, Compound 22
Figure imgf000174_0002
[0360] N-(2-chloro-4-fluorobenzoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)c clobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with 2-chloro-4-difluorobenzoic acid. LCMS theoretical m/z = 490.2 [M+H]+, found 490.2.
Example 26 Compound 33
Figure imgf000174_0003
[0361] N-(3-chloro-5-fluorobenzoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Prepared according to General Scheme A usmg General Procedure I with 3~chloro-5-fluorobenzoic acid. LCMS theoretical m/z = 490.2 [ M 1 11 · found 490.2.
Example 27, Compound 34
Figure imgf000175_0001
[0362] N-(3-chloro-2-fluorobenzoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with 3-chloro-2-fluorobenzoic acid. LCMS theoretical m/z = 490.2 ] M 1 11 . found 490.2.
Example 28, Compound 35
Figure imgf000175_0002
[Q363] N-(3,5-difluorobenzoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure 1 with 3,5-difluorobenzoic acid. LCMS theoretical m/z = 474.2 [M+HJ+, found 474.2
Example 29 Compound 36
Figure imgf000175_0003
[0364] N-(3,4-difluorobenzoyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure 1 with 3,4-difluorobenzoic acid. LCMS theoretical m/z = 474.2 [M+HJ+, found 474.2 Example 30, Compound 37
Figure imgf000176_0001
[Q365] N~(2,3~dichlorobenzoyl)~0~(irans~3~(2~(5,6,7,8~teirahydro~l,8~naphtkyridm~2~ yl}ethyi)cyclobutyl)homoserme. Prepared according to General Scheme A using General Procedure I with 2,3-dichlorobenzoic acid. LCMS theoretical m/z = 506.2 [M+H]+, found 506.2
Example 31, Compound 38
Figure imgf000176_0002
[0366] N-(2-chloro-6-fluorobenzoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure 1 with 2-chloro-5-fluorobenzoic acid. LCMS theoretical m/z ::: 490.2
I \ i H | . found 490.2.
Example 32, Compound 39
Figure imgf000176_0003
[0367] N~(2,6~difluorobenzoyl)-0~(trans-3-(2~(5,6,7,8-tetrakydro~J8~napkihyridin-2- yl)etkyl)cyclobutyl)komoserlne. Prepared according to General Scheme A using General Procedure 1 with 2,6-difluorobenzoic acid. LCMS theoretical m/z ::: 474.2 [M+H]+, found 474.2. Example 33, Compound 40
Figure imgf000177_0001
[0368] N-(2,5-difluorobetizoyl)-0-(trans-3-(2-(5,6,7,8-telrahydro-l,8-napht yriditi-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure Ϊ with 2,5-difluorobenzoic acid. LCMS theoretical m/z = 474.2 [M+H]+, found 474.2.
Example 34, Compound 41
Figure imgf000177_0002
[0369] N-(3,4-dichlorobetizoyl)-0-(lrans-3-(2-(5,6,7,8-telrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with 3,4-dichlorobenzoic acid. LCMS theoretical m/z = 506.2 [M+H]+, found 506.2.
Example 35, Compound 42
Figure imgf000177_0003
[0370] N-picolinoyl-0-(tram-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2 - yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure 1 with picolinic aad. LCMS theoretical m/z = 439.2 [M+H]+, found 439.2.
Example 36, Compound 43
Figure imgf000178_0001
[0371] N-nicotinoyl-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobuiyl)homoserine. Prepared according to General Scheme A using General Procedure I with nicotinic acid. LCMS theoretical m/z = 439.2 [M+HJ-h found 439.3.
Example 37, Compound 44
Figure imgf000178_0002
[Q372] N-isonicotinoyl-0-(tram-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure 1 with isomcotimc acid. LCMS theoretical m/z ::: 439.2 [M+H]+, found 439.3.
Example 38, Compound 45
Figure imgf000178_0003
[0373] N-(J-methyl-lH-indazole-4-carbonyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-J,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with ! -methyl- lH-indazole-4-carboxylie acid. LCMS theoretical m/z = 492 3 [M+H]+, found 492.3.
Example 39, Compound 46
17
Figure imgf000179_0001
[Q374] N-(2-methyl-2H-indazole-6-carbon l)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyI)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with 2-methyl-2H-indazole-6-carboxylic acid. LCMS theoretical m/z = 492.3 [ M i l l· found 492 3.
Example 40, Compound 47
Figure imgf000179_0002
[0375] N-(2-methyl-2H-indazole-5-carbon l)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A us g General Procedure I with 2-methyl-2H-indazole-5-carboxylic acid. LCMS theoretical m/z = 492.3 [M+H]+, found 492 3.
Example 41 Compound 48
Figure imgf000179_0003
[0376] N-( l -methyl-lH-pyrrolo[2, 3-b Jpyridin e-4-carbonyl)-0-( trans-3-( 2-(5, 6, 7, 8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with l-methyl-lH-pyrrolo[2,3-b]pyridine-4- carboxylic acid. LCMS theoretical m/z ::: 492 3 [M+H]+, found 492.3.
Example 42, Compound 49
Figure imgf000180_0001
[Q377] N-((R)-3-hydroxy-2-phenylpropanoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyI)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with (R)-3-hydroxy-2-phenylpropanoic acid and General
Procedure N followed by preparative HPLC to afford the first eluting of two diastereomers as a single stereoisomer. The amino acid stereochemistry was unassigned. LCMS theoretical m/z = 482.3 | \ M l j · . found 482.3.
Figure imgf000180_0002
[0378] N-((R)-3-hydroxy-2-phenylpropanoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)eth l)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with (R)-3-hydroxy-2-phenylpropanoic acid and General
Procedure N followed by preparative HPLC to afford the second eluting of two diastereomers as a single stereoisomer. The amino acid stereochemistry was unassigned. LCMS theoretical m/z = 482.3 [M+H]+, found 482.3.
Example 44, Compound 50
Figure imgf000180_0003
[Q379] N-(2-ethylbutanoyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with 2-ethyl butanoic acid. LCMS theoretical m/z = 432.3 [M+H]+, found 432.3
Example 45, Compound 5
Figure imgf000181_0001
yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with 3-ethylpentanoic acid. LCMS theoretical m/z = 446 3 [M+H]+, found 446.3.
Example 46, Compound 49
Figure imgf000181_0002
[0381] N-((S)-3-hydrox -2-phenylpropanoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with (S)-3-hydroxy-2-phenylpropanoic acid and General
Procedure N followed by preparative HPLC to afford the first eluting of two diastereomers as a single stereoisomer. The amino acid stereochemistr ' was unassigned. LCMS theoretical m/z = 482.3 | M 1 11 · found 482 3.
Example 47, Compound 49
Figure imgf000182_0001
[Q382] N-((S)-3-hydrox -2-phenylpropanoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyI)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with (S)-3-hydroxy-2-phenylpropanoic acid and General
Procedure N followed by preparative HPLC to afford the second eluting of two diastereomers as a single stereoisomer. The amino acid stereochemistry was unassigned. LCMS theoretical m/z = 482.3 | \ M l j · . found 482.3.
Example 48, Compound 52
Figure imgf000182_0002
[0383] N-(l-methyl-lH-pyrroIo[2,3-b]pyridine-5-carbonyl)-0-(trans-3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yI)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with 1 -methyl- IH-pyrrolo [2,3 -b]pyridine-5- carhoxylic acid. LCMS theoretical m/z = 492.3 [M+H]+, found 492.3.
Example 49, Compound 53
Figure imgf000182_0003
[Q384] 0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-(3- (thiazol-5-yl)benzoyl)homoserine. Prepared according to General Scheme A using General Procedure I with 3-(thiazol-5-yl)benzoic acid. LCMS theoretical m/z = 521 .2 [M+H]+, found
521.2.
Example 50, Compound 54
Figure imgf000183_0001
[0385] N-(3-(hydroxymethyl)benzoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with 3 -(hydroxy methyl)benzoic acid. LCMS theoretical m/z =
468.2. [M+H]+, found 468.3.
Figure imgf000183_0002
[0386] N-(quinoline-5-carbonyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with quinoline-5-carboxylic acid. LCMS theoretical m/z = 489.2. [M+H]+, found
489.3.
Figure imgf000183_0003
[Q387] N-(2-cyclopropylbenzoyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with 2-cyclopropylbenzoic acid. LCMS theoretical m/z = 478.3. [M+H]+, found
478.3.
Figure imgf000184_0001
[0388] N-(quinoline-7-carbonyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with quinoline -7-carboxylic acid. LCMS theoretical m/z = 489.2. [M+H]+, found
489.3.
Figure imgf000184_0002
[0389] N-(quinoline-6-carbonyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with quinoline-6-carboxy!ic acid. LCMS theoretical m/z = 489.2. [M+H]+, found
489.3.
Figure imgf000184_0003
[Q390] N-(quinoline-8-carbonyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with quinoline-8-carboxylic acid LCMS theoretical m/z = 489.2 [M+H]+, found
489.3.
Figure imgf000185_0001
[0391] N-(3-cyclopropylbenzoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure Ϊ with 3 -cyclop ropy Ibenzoic acid LCMS theoretical m/z = 478.3. [M+H]+, found
478.3.
Figure imgf000185_0002
[0392] N-(4-cyclopropylbenzoyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with 4-cyclopropylbenzoic acid. LCMS theoretical m/z = 478.3. [M+H]+, found
478.3.
Figure imgf000185_0003
[Q393] N-isonicotinoyl-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)-D-homoserine. Isomer D1 was employed in General Scheme D-2 using General Procedure I with isonicotinic acid LCMS theoretical m/z = 439.2. [M+H]+, found 439.3.
Example 59, Compound 51
Figure imgf000186_0001
[Q394] N-(3-ethylpentanoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-J,8-naphthyridin-2- yl)ethyl)cyclobutyl)-D-homoserine. Isomer D1 was employed in General Scheme D-2 using General Procedure 1 with 3-ethylpentanoic acid. LCMS theoretical m/z = 446.3. [M+H]+, found 446.3
Example 60, Compound 14
Figure imgf000186_0002
[0395] N-(2-chloro-3-fluorobenzoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. isomer Dl was employed m General Scheme D-2 using General Procedure 1 with 2-chloro-3-fluorobenzoic acid. LCMS theoretical m/z = 490.2. | M · 1 I I · . found 490.2.
Example 61, Compound 53
Figure imgf000186_0003
[Q396] 0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-(3- (thiazol-5-yl)benzoyl)homoserine. isomer Dl was employed in General Scheme D-2 using General Procedure I with 3-(thiazol-5-yi)benzoic acid. LCMS theoretical m/z = 521 2.
] M I I I· found 521.2
Figure imgf000187_0001
[0397] N-isonicotinoyl-0-(tram-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with isonicotinic acid. LCMS theoretical m/z = 439.2. [M+H]+, found 439.3.
Example 63 Compound 51
Figure imgf000187_0002
[0398] N-(3-ethylpentanoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 3-ethylpentanoic acid. LCMS theoretical m/z = 446.3. [M+H]+, found 446.3.
Example 64, Compound 14
Figure imgf000187_0003
ahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. isomer D2 was employed in General Scheme D-2 using General Procedure I with 2-chloro-3-fluorobenzoic acid. LCMS theoretical m/z = 490 2. | M · 1 l i . found 490 2.
Example 65 Compound 53
Figure imgf000188_0001
[0400] 0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-(3- (thiazol-5-yl)benzoyl)homoserine. isomer D2 was employed in General Scheme D-2 using General Procedure I with 3-(thiazol-5-yi)benzoic acid. LCMS theoretical m/z = 521 2.
| M 1 11 · found 521.2.
Example 66, Compound 36
Figure imgf000188_0002
[0401] N-(3,4-difluorobenzoyl)-0-(cis-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme B using General Procedure I with 3,4-difluorobenzoic acid. LCMS theoretical m/z = 474.2. [M+H]+; found 474.2.
Figure imgf000188_0003
[Q402] N-(3-ethylpentano l)-0-(cis-3-(2-(5,6,7,8-tetrah dro-l,8-naphth ridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme B using General Procedure I with 3-ethy!pentanoic acid. LCMS theoretical m/z = 446.3. [M+H]+, found 446.3.
Figure imgf000189_0001
[0403] N-isonicotinoyl-0-(cis-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme B using General Procedure I with isonicotinic acid LCMS theoretical m/z = 439.2. [M+H]+, found 439.2.
Example 69, Compound 53
Figure imgf000189_0002
[0404] 0-(cis-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-(3- (thiazol-5-yl)benzoyl)homoserine. Prepared according to General Scheme B using General Procedure I with 3-(thiazol-5-yl)benzoic acid. LCMS theoretical m/z = 521.2. [M+H]+; found
521.2.
Figure imgf000189_0003
[Q405] N-((R)-3-hydroxy-2-phenylpropanoyl)-0-(cis-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Prepared according to General Scheme B usmg General Procedure I with (R)-3-hydroxy-2-phenylpropanoic acid, and General Procedure N to afford the title compound as the first eluting isomer. LCMS theoretical rn/z = 482.3. [M+HJ+, found 482.3.
Figure imgf000190_0001
[0406] N-((R)-3-hydroxy-2-phenylpropanoyl)-0-(cis-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)c clobutyl)homoserine. Prepared according to General Scheme B using General Procedure I with (R)-3-hydroxy-2-phenylpropanoic acid, and General Procedure N to afford the title compound as the second eluting isomer. LCMS theoretical m/z = 482.3. ] M 1 ! ] . found 482.3.
Figure imgf000190_0002
[0407] N-(3-(l-methyl-lH-pyrazol-4-yl)benzoyl)-0-(trans-3-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with 3-(l -methyl- lH-pyrazoi-4-yl)benzoic acid. LCMS theoretical m/z == 518.2. I M I t ] . found 518.2.
Example 73, Compound 63
Figure imgf000191_0001
[Q408] N-(3-(l-methyl-lH-pyrazol-4-yl)benzo l)-0-(4-(5,6, 7,8-tetrahydro-l,8- naphlhyruUn-2-yl)butyl)homoserme. Prepared according to General Scheme C using General Procedure I with 3 -( 1 -methyl- 1 H-pyrazol-4-yl)benzoic acid. LCMS theoretical m/z = 492.3 [M+H]+, found 492.3
Figure imgf000191_0002
[0409] N-((S)-2-hydroxy-2-phenylacetyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserine. Prepared according to General Scheme C using General Procedure I with (S)-2 -hydroxy-2 -phenylacetic acid, and General Procedure N to afford the title compound as the first eluting isomer. LCMS theoretical m/z = 442.2. [M+H]+, found 442.2.
Figure imgf000191_0003
[0410] N-( (S)-2~hydroxy~2~phenylaceiyl}~0~{ 4~( 5, 6, 7 , 8-tetrahydro-l, 8~n aphthyridin -2- yl)butyl)homoserine. Prepared according to General Scheme C using General Procedure I with (S)-2 hydroxy-2 -phenylacetic acid, and General Procedure N to afford the title compound as the second eluting isomer. LCMS theoretical m/z = 442.2. [M+H]+, found 442.2
Example 76, Compound 64
Figure imgf000192_0001
[0411] N-((R)-2-hydroxy-2-phenylacetyl)-0-(4-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2 - yl)butyl)homoserine . Prepared according to General Scheme C using General Procedure I with (R)-2-hydroxy-2-phenyiacetic acid, and General Procedure N to afford the title compound as the first eluting isomer. LCMS theoretical m/z ~ 442.2. [M+HJ+, found 442.2.
Figure imgf000192_0002
[0412] N-((R)-2-hydroxy-2-phenylacetyl)-0-(4-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)hutyl)~D~homa$erine . Prepared according to General Scheme C using General Procedure I with (R)-2 -hydroxy-2 -phenyiacetic acid, and General Procedure N to afford the title compound as the second eluting isomer. LCMS theoretical m/z = 442.2. [M+H]+, found 442.2.
Figure imgf000192_0003
[0413] N-((S)-2-hydroxy-2-phenylacetyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A us g General Procedure 1 with (S)-2-hydroxy-2-phenylacetic acid and General Procedure N to afford the title compound as the first eluting isomer. LCMS theoretical m/z = 468.3.
! M 1 1 j . found 468 3. Example 79, Compound 65
Figure imgf000193_0001
[0414] N-((S)-2-hydroxy-2-phenylacetyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with (S)-2-hydroxy-2-phenylacetic acid, and General Procedure N to afford the title compound as the second eluting isomer. LCMS theoretical m/z = 468.3.
[ M H I · found 468.3.
Example 80, Compound 65
Figure imgf000193_0002
[0415] N-((R)-2-hydroxy-2-phenylacetyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure I with (R)-2-hydroxy-2-phenylacetic acid, and General Procedure N to afford the title compound as the first eluting isomer. LCMS theoretical m/z = 468.3.
! M 1 1 j . found 468 3.
Figure imgf000193_0003
[0416] N-((R)-2-hydroxy-2-phenylaceiyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Prepared according to General Scheme A usmg General Procedure I with (R)-2-hydroxy-2-phenylacetic acid, and General Procedure N to afford the title compound as the second eluting isomer. LCMS theoretical m/z = 468.3. j \ i i l l· . found 468.3.
Figure imgf000194_0001
[0417] N-(l-phenylcychpropane-l-carbonyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)c clobutyl)homoserine. Isomer Gl was employed in General Scheme G-2 using General Procedure I with 1 -phenylcyclopropane- 1 -carboxylic acid. LCMS theoretical m/z ::: 478.3. | M l 1 | . found 478.3.
Figure imgf000194_0002
[0418] N-(2-methyl-2-phenylpropanoyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Isomer Gl was employed in General Scheme G-2 using General Procedure I with 2-methyl-2-phenylpropanoic acid. LCMS theoretical m/z = 480.3. | \ ! I l l · . found 480.1.
Example 84, Compound 68
Figure imgf000194_0003
[0419] N-(J-phenylc clobutane-l-carbon l)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine Isomer Gl was employed in General Scheme G-2 using General Procedure I with 1-phenyicyclobutane-l -carboxylic acid. LCMS theoretical m/z = 492.3. [M+H]+, found 492.2.
Figure imgf000195_0001
[0420] N-(2,2-dimethyl-3-phenylpropanoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8 - naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. isomer Gl was employed in General Scheme G-2 using General Procedure I with 2,2-dimethyl-3-phenylpropanoic acid. LCMS theoretical m/z = 494.3. [M+H]+, found 494.2.
Example 86, Compound 19
Figure imgf000195_0002
[0421] N-(tert-butoxycarbonyl)-0-(trans-3-{2-(5,6,7,8-telrahydro-l,8-napktkyridw-2- yl)etkyl)cyclobutyi)komoserine. Prepared using Scheme G-l to afford Isomer Gl, then using di-tert-butyl dicarbonate and triethylamine in DCM afforded methyl N-(tert-butoxycarbonyl)- 0-(trans-3-(2-(5,6,7,8-tetrahydro-I,8-naphthyridin-2-yl)etliyl)cyciobiityi)homosermate, which was subjected to General Procedure N. LCMS theoretical m/z = 434.3. [M+H]+, found
434.3.
Figure imgf000195_0003
[0422] N-(2-(4-fluorophenyl)-2-methylpropanoyl)-0-(tram-3-(2-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer Gl was employed in General Scheme G-2 using General Procedure I with 2-(4-fluorophenyl)-2-methylpropanoic acid. LCMS theoretical m/z = 498.3. [M+H]+, found 498.3.
Example 88, Compound 71
Figure imgf000196_0001
[0423] N-(3-methyloxetane-3-carbonyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Isomer G! was employed in General Scheme G-2 using General Procedure I with 3-methyloxetane-3-carboxylic acid. LCMS theoretical m/z = 432.2. [M+H]+, found 432.2.
Figure imgf000196_0002
[0424] N-(3-hydroxy-2,2-dimethylpropanoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)c clobutyl)homoserine. Isomer G1 was employed in General Scheme G-2 using General Procedure I with 3-hydroxy-2,2-dimethylpropanoic acid. LCMS theoretical m/z ::: 434.3. [M+H]+, found 434.2.
Figure imgf000196_0003
[Q425] N-(3-methoxy-2,2-dimethylpropanoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Isomer G! was employed in General Scheme G-2 using General Procedure I with 3~methoxy~2,2~dimethylpropanoic acid. LCMS theoretical m/z = 448.3. [M+H]+, found 448.3.
Figure imgf000196_0004
[Q426] N-(2-methyl-2-(pyridin-3-yl)propanoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Isomer G! was employed in General Scheme G-2 using General Procedure I with 2-methyl-2-(pyridin-3-yl)propanoic acid. LCMS tlieoretical m/z = 481.3. | \ ! I l l · . found 481.3.
Figure imgf000197_0001
[0427] N-(2,3-dihydro-lH-indene-2-carbonyl)-0-(lrans-3-(2-(5,6, 7,8-telrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Isomer Gl was employed in General Scheme G-2 using General Procedure I with 2,3-dihydro- lH-indene-2 -carboxylic acid. LCMS theoretical m/z = 478.3. | M 1 11 · found 478.1.
Figure imgf000197_0002
[0428] N-(3-cycmo-2,2-dimethylpropanoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-J,8- naphthyridin-2-yl)ethyl)c clobutyl)homoserine. Isomer Gl was employed in General Scheme G-2 using General Procedure I with 3-cyano~2,2~dimethylpropanoic acid LCMS theoretical m/z ::: 443.3. [M+H]+, found 443.1.
Figure imgf000197_0003
[0429] N-pivaloyl-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Isomer Gl was employed in General Scheme G-2 using General Procedure I with pivalic acid. LCMS theoretical m/z = 418.3. [M+H]+, found 418.4.
Figure imgf000198_0001
[0430] N-(2,3-dihydro-lH-indene-l-carbonyl)-0-(lrans-3-(2-(5,6, 7,8-telrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Isomer G! was employed in General Scheme G-2 using General Procedure I with 2,3-dihydro-lH-indene-l -carboxylic acid, and General Procedure N followed by separation of the diastereomers by chiral SFC to afford title compound as the first eluting isomer as a single enantiomer. LCMS theoretical m/z = 478.3. i M l l l · . found 478.2.
Figure imgf000198_0002
[0431] N-(2,3-dihydro-lH-indene-l-carbonyl)-0-(lrans-3-(2-(5,6, 7,8-telrahydro-l,8- naphthyridin-2-yl)ethyI)cyclobutyl)homoserine. Isomer G1 was employed in General Scheme G-2 using General Procedure I with 2, 3 -dihydro- lH-indene-l -carboxylic acid, and General Procedure N followed by separation of the diastereomers by chiral SFC to afford title compound as the second eluting isomer as a single enantiomer. LCMS theoretical m/z = 478.3. | .% 1 1 11 found 478.2.
Figure imgf000198_0003
, 7, 8-tetrahydro-l, 8~
Figure imgf000198_0004
Isomer D2 was employed in General Scheme D-2 using General Procedure I with 1-phenyicyclopropane-I -carboxylic acid. LCMS theoretical m/z = 478.3. | M · 1 l i . found 478 3.
Figure imgf000199_0001
[0433] N-(2~methyl~2~phenylpropanoyl)~0~(trans~3~(2-(5,6, 7,8~tetrahydro-i,8- naphthyrMin~2~yl)ethyl)cyclohutyl)homoserine. isomer D2 was employed in General Scheme D-2 using General Procedure I with 2~methyl~2-phenylpropanoic acid. LCMS theoretical m/z = 480.3. | M 1 11 · . found 480.3.
Figure imgf000199_0002
[0434] N~(l -pkenylcyclohutan e-l -carhonyl)~0~(trans~3-{2-(5, 6, 7, 8-tetrahydro- 1, 8- naphthyridm~2~yl)ethyl}cyc!obutyl)komoserme. Isomer D2 was employed in General Scheme D-2 using General Procedure 1 with 1-phenylcyclobutane-l -carboxylic acid. LCMS theoretical m/z = 492.3. [M+H]+, found 492.3.
Figure imgf000199_0003
[0435] N~(2,2~dimeihyl~3~phenylprapanoyl)~()~(ircms~3~(2~(5,6, 7,8~tetrahydra~l,8~ naphikyrldin-2~yl)etkyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2,2-dimethyi-3-phenyipiOpanoic acid. LCMS theoretical m/z = 494.3. | M · 1 1 . found 494.4. Example 101, Compound 19
Figure imgf000200_0001
[0436] N-(tert-butoxycarbonyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)c clobutyl)homoserine. Isomer D2 was used in General Procedure N. LCMS theoretical m/z = 434.3. [M+H]+, found 434.2.
Figure imgf000200_0002
[0437] N-(2-(4-fluorophenyl)-2-methylpropanoyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2-(4-fluorophenyl)-2-methylpropanoic add. LCMS theoretical m/z = 498.3. | NM I j . found 498.3.
Example 103, Compound 71
Figure imgf000200_0003
[0438] N-(3-methyloxetane-3-carbonyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 3-methyloxetane-3-carboxylic acid. LCMS theoretical m/z ~ 432.2. [M+HJ+, found 432.2.
Example 104, Compound 72
Figure imgf000201_0001
naphthyriditi-2-yl)ethyl)cyclobulyl)homoserine. Isomer D2 was employed in General
Scheme D-2 using General Procedure I with 3-hydroxy-2,2-dimethylpropanoic acid. LCMS theoretical m/z = 434.3. | M · 1 l i . found 434.4.
Figure imgf000201_0002
[0440] N-(3-methoxy-2,2-dimethylpropanoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure 1 with 3-methoxy-2,2-dimethylpropanoic acid. LCMS theoretical m/z = 448.3. | \1 · 1 l i · . found 448.4.
Figure imgf000201_0003
[0441 ] N-( 2-methyl-2-(pyridin-3-yl)propan oyl)~()~( trans-3-(2-(5 , 6, 7, 8-tetrahydro- 1, 8~ naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General
Scheme D-2 using General Procedure I with 2-methyl-2-(pyridin-3-yi)propanoic acid. LCMS theoretical m/z = 481.3. | M · 1 l i . found 481.4.
Example 107. Compound 75
Figure imgf000202_0001
[0442] N-(2,3-dihydro-lH-indene-2-carbonyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2,3-dihydro- lH-indene-2 -carboxylic acid.
\ .( MS theoretical m/z = 478.3. | .M H I · found 478.4.
Figure imgf000202_0002
[0443] N-(3-cyano-2,2-dimethylpropanoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8 - naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 3-cyano-2,2-dimethylpropanoic acid. LCMS theoretical m/z ~ 443.3. [M+HJ+, found 443.3.
Figure imgf000202_0003
[0444] N-pivaloyl-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared using General Scheme D-2 beginning with Isomer D2 using General Procedure 1 with pivalic acid. LCMS theoretical m/z === 418.3. [M+H]+, found 418.3.
Example 110, Compound 78
Figure imgf000203_0001
6, 7,8-tetrahydro-l,8-
Figure imgf000203_0002
Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2, 3 -dihydro- lH-indene-1 -carboxylic acid, and General Procedure N to afford the title compound as the first eluting isomer as a single enantiomer. LCMS theoretical m/z = 478.3. i M 1 11 . found 478.3.
Figure imgf000203_0003
[0446] N-(2,3-dihydro-lH-indene-l-carbonyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)c clobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2,3-dihydro-lH-indene-l-carboxylic acid, and General Procedure N to afford the title compound as the second eluting isomer as a single enantiomer. LCMS theoretical m/z = 478.3. [M+H]+, found 478.2.
Example 112, Compound 79
Figure imgf000203_0004
[Q447] N-( (neopentyloxy)carbonyl)-0-(trans-3-(2-( 5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-
Figure imgf000203_0005
Isomer D2 was employed in General Scheme D-2 using
General Procedure F with neopentyl chloroformate. LCMS theoretical m/z = 448.3. [M+H]+, found 448.3.
Example 113, Compound 80
Figure imgf000204_0001
[0448] N~((l -methylcyclopropoxy)carbonyl)-0-( trans-3-( 2-(5, 6, 7, 8-tetrahydro- 1, 8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure J with l-meihyicyclopropan-I-ol, General Procedure K, and General Procedure N. LCMS theoretical m/z = 432.3. [M+H]+, found 432.2.
Example 114, Compound 81
Figure imgf000204_0002
[0449] N-( ( 1 -methylcyclobutoxy)carbonyl)-0-(trans-3-(2-(5,6, 7, 8-tetrahydro- 1, 8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure J with !-methylcyclobutan-i -ol, General Procedure K, and General Procedure N. LCMS theoretical m/z ::: 446.3. [M+H]+, found 446.3.
Example 115, Compound 82
Figure imgf000204_0003
[045Q] 0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N- (((l,l,l-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)homoserine. Isorner D2 was employed in General Scheme D-2 using General Procedure J with l, l, l-trifluoro-2-methylpropan-2-ol, General Procedure K, and General Procedure N. LCMS theoretical m/z = 488.2. [M+H]+, found 488.2.
Example 116, Compound 83
Figure imgf000205_0001
[0451] N-(isopropoxycarbonyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure F with isopropyl chloroformate. LCMS theoretical m/z = 420.3 [M+H]+, found 420.2.
Example 11 7. Compound 84
Figure imgf000205_0002
[0452] N-(diethylcarbamoyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure H with diethylcarbamoyl chloride. LCMS theoretical m/z = 433.3.
| M H | . found 433.3.
Example 118, Compound 85
Figure imgf000205_0003
[0453] N-(tert-butylcarbamoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. isomer D2 was sequentially used in General Procedure D, General Procedure G with tert-butylamine, and General Procedure N. LCMS theoretical m/z = 433.3. | M 1 11 · found 433.3.
Example 119, Compound 86
Figure imgf000206_0001
-tetrahydro-l,8-
Figure imgf000206_0002
Isomer D2 was sequentially used in General Procedure D, General Procedure G with N,2-dimethylpropan-2-amine, and General
Procedure N LCMS theoretical m/z = 447.3 [M+H]+, found 447.3.
Figure imgf000206_0003
[0455] N-(isopropyl(methyl)carbamoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure G with N-methylpropan-2-amine, and General Procedure N. LCMS theoretical m/z = 433.3. [M+H]+, found 433.3.
Figure imgf000206_0004
dro-l,8-naphthyridin-2- yl)ethyi)cyclobutyl}homoserme. Isomer D2 was sequentially used in General Procedure D, General Procedure G with diisopropylamine, and General Procedure N. LCMS theoretical m/z = 461 .3. | M · 1 1 ] . found 461.3.
Example 122. Compound 89
Figure imgf000207_0001
[Q457] N-(3,3-dimethylbutanoyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 3,3-dimethylbutanoic acid. LCMS theoretical m/z = 432.3.
! M 1 1 j . found 432 3.
Figure imgf000207_0002
[0458] N-(3-methylbutanoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 3-methylbutanoic acid. LCMS theoretical m/z = 418.3. [M+H]+, found 418.3.
Figure imgf000207_0003
[0459] N-(2-cyclobutylacetyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2-cyclobutylacetic acid. LCMS theoretical m/z = 430.3. [M+H]+, found 430.3.
Example 125. Compound 92
Figure imgf000208_0001
[0460] N-(2-(l-methylcyclopropyl)acetyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphihyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2-(l-methylcyclopropyl)aeetic acid. LCMS theoretical m/z = 430.3. | \ M l j · . found 430.3.
Figure imgf000208_0002
[0461] N-(2-cyclopropylacetyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobut l)homoserine. isomer D2 was employed in General Scheme D-2 using General Procedure I with 2-cyclopropylacetic acid. LCMS theoretical m/z = 416.3. [M+H]+, found 416.3.
Example 127, Compound 94
Figure imgf000208_0003
[0462] N-(((l-(tert-butoxycarbonyl)-3-methylazetidin-3-yl)oxy)carbonyl)-0-(trans-3-(2- (5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-butyl 3-((((2,5- dioxopyrrolidin- 1 -yl)oxy)carbonyl)oxy)-3 -methylazetidine- 1 -carboxylate (prepared using General Procedure J with tert-butyi 3-hydroxy-3-methylazetidine-l-carboxylate), and General Procedure N LCMS theoretical m/z = 547.31. [M+H]+, found 547.3.
Figure imgf000209_0001
[0463] N-(((3-methyl-l-(methylsulfonyl)azetidin-3-yl)oxy)carbonyl)-0-(trans-3-(2- (5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-butyi 3 -((((2, 5- dioxopyrrolidin- 1 -yl)oxy)carbonyl)oxy)-3-methylazetidine- 1 -carboxylate (prepared using General Procedure J with tert-butyi 3-hydroxy-3 -methylazetidine- 1 -carboxylate), General Procedure D, General Procedure M, then General Procedure N. LCMS theoretical m/z = 525.24. j \ M 11 · . found 525 2.
Figure imgf000209_0002
[0464] N-(((l-acetyl-3-meth lazetidin-3-yl)oxy)carbonyl)-0-(trans-3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-butyi 3-((((2,5-dioxopyrrolidin- l-yl)oxy)carbonyl)oxy)-3-methylazetidine-l-carboxylate (prepared using General Procedure J with tert-butyi 3 -hydroxy -3 -methylazetidine- i -carboxylate), General Procedure D, General Procedure L, then General Procedure N. LCMS theoretical m/z = 489.27. [M+H]+, found
489.3
Example 130. Compound 9/
Figure imgf000210_0001
[0465] N-(((3-meth lazetidin-3-yl)oxy)carbonyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-butyl 3-((((2,5-dioxopyrrolidin-l- yl)oxy)carbony})oxy}~3~methylazetidine-l~earboxylate (prepared using General Procedure J with tert-butyl 3-hydroxy-3-methylazetidine-l-carboxylate), General Procedure D, then General Procedure N. LCMS theoretical m/z = 447.26. [M+H]+, found 447.3.
Figure imgf000210_0002
[Q466] N-((cyclohexyloxy)carbonyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure F with cyclohexyl chlorofomiate. LCMS theoretical m/z ::: 460.28. [M+Ή|+, found 460.3.
Figure imgf000210_0003
[0467] N-(isobutoxycarbonyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)c clobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure F with isobutyl chloroformate. LCMS theoretical m/z = 434.27. [M+H]+, found 434.3.
Figure imgf000211_0001
[0468] N-((((S)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)carbonyl)-0-(trans-3-(2- (5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-butyl (S)-3-((((2,5- dioxopyrrolidin- 1 -yl)oxy)carbonyl)oxy)pyrrolidine- 1 -carboxylate (prepared using General Procedure I with tert-butyl (S)-3-hydroxypyrrolidine- 1 -carboxylate), then General Procedure N. LCMS theoretical m/z ::: 547.31. [M+H]+, found 547.3.
Example 134, Compound 101
Figure imgf000211_0002
[0469] N-((((S)-pyrrolidin-3-yl)oxy)carbonyl)-0-(tram-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)c clobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-butyl (S)-3-((((2,5-dioxopyrrolidin-l - yl)oxy)carbonyl)oxy)pyrrolidine-l -carboxylate (prepared using General Procedure J with tert-butyl (S)-3-hydroxypyrrolidine-l-carboxylate), General Procedure D, then General Procedure N. LCMS theoretical m/z = 447.26. [M+H]+, found 447.3.
Example 135, Compound 102
Figure imgf000211_0003
[0470] N-(4-(methylsulfonyl)butanoyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)homoserine. isomer D2 was employed in General Scheme D-2 using General Procedure I with 4-(methylsulfonyl)butanoic acid. LCMS theoretical m/z = 482.23. [M+H]+; found 482.2.
Example 136, Compound 103
Figure imgf000212_0001
-0-(trans-3-(2- «(53,06, 7,8· tetrahydro-l,8-naphthyridm-2-yI)ethyl)cyclohutyf)homoserme. Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-buty! (S)-3-((((2,5- dioxopyrrolidin- 1 -yl)oxy)carbonyl)oxy)pyrrolidine- 1 -carboxylate (prepared using General Procedure J with tert-butyl (S)-3-hydroxypyrro3idme-l -carboxylate). General Procedure D, General Procedure M, then General Procedure N. LCMS theoretical m/z = 525.2/4. [M+H]+, found 525.2.
Example 13/, Compound 104
Figure imgf000212_0002
[0472] N-((((S)-l-acetylpyrrolidin-3-yl)oxy)carbonyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-butyl (S)-3-((((2,5-dioxopyrrolidin-l- yl)oxy)carbonyl)oxy)pyrrolidine-l-carboxylate (prepared using General Procedure J with tert-butyl (S)-3-hydroxypyrro]idine-I -carboxylate), General Procedure D, General Procedure L, then General Procedure N. LCMS theoretical m/z = 489.27. [M+H]+, found 489.3.
Figure imgf000213_0001
[0473] N-((((R)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)carbonyl)-0-(trans-3-(2- (5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-butyl (R)-3-((((2,5- dioxopyrrolidin- 1 -yl)oxy)carbonyl)oxy)pyrrolidine- 1 -carboxylate (prepared using General Procedure J with tert-butyl (R)-3-hydroxypyrrolidine-l-carboxylate), then General Procedure N. LCMS theoretical m/z ::: 547.31. [M+H]+, found 547.3.
Example 139, Compound 104
Figure imgf000213_0002
[0474] N-((((R)-l-acetylpyrrolidin-3-yl)oxy)carbonyl)-0-(trans-3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-butyl (R)-3-((((2,5- dioxopyrrolidin-1 -yl)oxy)carbonyl)oxy)pyrrolidine-l-carboxylate (prepared using General Procedure J with tert-butyl (R)-3-hydroxypyrrolidine-l-carboxylate), General Procedure D, General Procedure L, then General Procedure N. LCMS theoretical m/z = 489.27. [M+H]+, found 489.3.
Example 140, Compound 105
Figure imgf000214_0001
[0475] N-(((R)-l-phenylethoxy)carbonyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)c clobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure K with (R)-2,5-dioxopyrrolidin-l-yl (1-phenylethyl) carbonate (prepared using General Procedure J with (R)-l-phenylethan-l -ol). LCMS theoretical m/z = 482 27.
Figure imgf000214_0002
found 482.3.
Figure imgf000214_0003
[0476] N-(((S)-l-phenylethoxy)carbonyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure K with (S)-2,5-dioxopyrrolidin- 1 -yl (1-phenylethyl) carbonate (prepared using General Procedure J with (S)~ 1 -phenyl ethan-i -ol). LCMS theoretical m/z ::: 482.27. [M+H]+, found 482.3.
Figure imgf000214_0004
[0477] N-((2-phenylcyclobutoxy)carbonyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyI)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure K with 2,5 -dioxopyrrolidin- 1 -yl (2-phenyleyclobutyl) carbonate (prepared using General Procedure J with 2-phenylcyclobutan-l-oi). LCMS theoretical m/z = 508.28. [M+H]+, found 508.3.
Figure imgf000215_0001
[Q478] N-((cis-3-phenylcyclobutoxy)carbonyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure K with 2,5-dioxopyrrolidin-l-yl ((ls,3s)-3- phenylcyclobutyl) carbonate (prepared using General Procedure J with (ls,3s)-3- phenylcyclobutan-l-ol). LCMS theoretical m/z ::: 508.28. [M+H]+, found 508.3.
Figure imgf000215_0002
[0479] N-((((lR,2S)-2-phenylcyclohexyl)oxy)carbonyl)-0-(trans-3-(2-(5, 6,7,8- tetrahydro~l,8-naphthyridin~2-yl)ethyl)cyclohutyl)hommerine. Isomer D2 was employed in General Scheme D-2 using General Procedure K with 2,5-dioxopyrrolidin-l-yl ((l R,2S)-2- phenylcyclohexyl) carbonate (prepared using General Procedure J with ( lR,2S)-2- phenyicyciohexan-l-oi). LCMS tlieoretical m/z = 536.31. [M+H]+, found 536.3.
Example 145, Compound 109
Synthesis oftrans-2-((tert-butoxycarbonyl)amino)-3-methyl-4-(trans-3-(2-(5,6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutoxy)butanoic acid and cis~2~((tert- butoxycarbonyl)amino)-3-methyl-4-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutoxy)butanoic acid (racemate)
Figure imgf000216_0001
[0480] 2-(2~((lr,3s)-3~((2-methylallyl)oxy)cyclobutyl)ethyl)~l,8~naphthyridine. To a suspension of sodium hydride (60 wt% dispersion in mineral oil, 64 mg, 1.59 mmol) in DMF (3 mL) at 0 °C was added (ls,3r)-3-(2-(l,8-naphthyridin-2-yl)ethyl)cyclobutan-l-ol (302 mg, 1.32 mmol) DMF (2 mL) and the resulting mixture was allowed to wann to room temperature and stirred for an additional 30 minutes. To this was then added 3-bromo-2- methylprop-i-ene (357 mg, 2.65 mmol) and the reaction mixture was stirred for 4 hours at room temperature and then diluted with sat. aq. NaHCOii and extracted with EtOAc. The combined organic extracts were dried over NaiSOr, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give 2-(2-((lr,3s)-3- ((2-methylaiiyi)oxy)cyclobutyi)ethyl)-i,8-naphthyridme.
Figure imgf000216_0002
[0481] l-((is,3r)-3-(2-(l,8-naphthyridin-2-yl)ethyl)cyclobutoxy)propan-2-one. To a mixture of 2-(2-((lr,3s)-3-((2-methylallyl)oxy)cyclobutyl)ethyl)-l,8-naphthyridine (174 mg, 0.62 mmol) in 3: 1 Dioxane/HiQ (3 mL) was added 2,6-lutidme (132 mg, 1.23 mmol), NalOr
(527 mg, 2.46 mmol), then K20s04»2H20 (1 1 mg, 0.03 mmol) and the resulting mixture was allowed to stir at room temperature for 3 hours. The mixture was filtered and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give 1-
((ls,3r)-3-(2-(l,8-naphthyridin-2-yl)ethyl)cyclobutoxy)propan-2-one.
Figure imgf000216_0003
[Q482] methyl 4-((ls,3r)-3-(2-(J8-naphthyridin-2-y!)ethyl)cyclobutoxy)-2-((tert- hutoxycarbonyl)amino)-3~methylbut-2-enoate To a solution of 1 -(( 1 s,3r)-3-(2-( 1,8- naphthyridin-2-yl)ethy!)cyclobutoxy)propan~2-one (175 mg, 0.62 mmol) in CH2CI2 (2 mL) was added methyl 2-((tert-butoxycarbonyl)amino)-2-(dimethoxyphosphoryl)acetate (366 mg. 1.23 mmol) then 1, 1,3,3-tetramethylguanidine (142 mg, 1.23 mmol) and the resulting mixture was heated to 40 °C for 2 days. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The crude residue was purified by norma] phase silica gel chromatography to give methyl 4-((ls,3r)-3-(2-(l,8-naphthyridin-2-yl)ethyl)cyclobutoxy)-2- ((tert-biitoxycarbony3)amino)-3-methylbut-2-enoate.
Figure imgf000217_0001
[0483] methyl 2-((tert-butoxycarbonyl)amino)-3-methyl-4-(( Is.3r)-3-(2-(5, 6, 7, 8- tetrahydro-l,8-naphthyndin-2-yl)ethyl)cyclobutoxy)hutanoate. To a flask containing methyl 4-((ls,3r)-3-(2-(l,8-naphthyridin-2-y])ethyl)cyclobutoxy)-2-((tert-butoxycarbonyl)amino)-3- methylbut-2-enoate ( 148 mg, 0.32 mmol) was charged Pd(OH)2/C (20 wt% on carbon, 30 mg) and the mixture was evacuated and backfilled with H?. gas for 3 cycles and then stirred under an Tk atmosphere overnight. The mixture was filtered through a pad of Celite and then concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give methyl 2-((tert-butoxycarbonyl)amino)-3-methyl-4-((ls,3r)-3-(2- (5 ,6, 7, 8-tetrahydro- 1 , 8-naphthyridin-2-yl)ethyl)cyclobutoxy)butanoate .
Figure imgf000217_0002
[0484] 2-((tert-butoxycarbonyl)amino)-3-methyl-4-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutoxy)butanoic acid. Prepared beginning with methyl 2-((tert- butoxycarbonyl)amino)-3-methyl-4 -(trans-3-(2 -(5,6, 7, 8-tetrahydro- l,8-naphthyridin-2- yl)ethyl)cyclobutoxy)butanoate then using General Procedure N whereby a racemic mixture of the title compound was isolated as the second eluting isomer by reverse phase preparative HPLC. LCMS theoretical m/z = 448.28. [M+H]+, found 448.3. The absolute stereochemistry of the product of Example 145a was subsequently assigned as (2S,3S)-2-((tert- butoxycarhonyl)amino)-3-methyi~4-((ls,3S)~3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutoxy)butanoic acid.
Example 145b, Compound 109
Figure imgf000218_0001
[Q485] 2-((tert-butox carbonyl)amino)-3-methyl-4-(trans-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutoxy)butanoic acid. Prepared beginning with methyl 2-((tert- butoxycarbonyl)amino)-3-methyl-4-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutoxy)butanoate then using General Procedure N whereby a racemic mixture of the title compound was isolated as the first eluting pealk by reverse phase preparative HPLC. LCMS theoretical m/z = 448.28. [M+H]+. found 448.3. The absolute stereochemistry of the product of Example 145b was subsequently assigned as (2S,3R)-2-((tert- butoxycarbonyl)amino)-3-methyl-4-((l s,3R)-3-(2 -(5,6,7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl)cyclobutoxy)butanoic acid (see structure in FIG. 1, Table 2).
Figure imgf000218_0002
[Q486] N-((((lS,2R)-2-phenylcyclohexyl)oxy)carbonyl)-0-(trans-3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure K with 2,5-dioxopyrrolidin-l-yl ((lS,2R)-2- phenylcyclohexyl) carbonate (prepared using General Procedure J with ( 1 S,2R)-2- phenylcyclohexan-l-ol). LCMS theoretical m/z = 536.31. [M+H]+, found 536.3.
Example 147, Compound 110
Figure imgf000219_0001
[0487] N-(((l-(tert-butoxycarbonyl)az/etidin-3-yl)oxy)carbonyl)-0-(trans-3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-butyl 3-((((2,5-dioxopyrrolidin- l-yl)oxy)carbonyl)oxy)azetidine-l-carboxylate (prepared using General Procedure J with tert-butyl 3-hydroxyazetidine- 1 -carboxy!ate), then General Procedure N LCMS theoretical m/z = 533.30. | M · P | . found 533.3.
Example 148, Compound ill
Figure imgf000219_0002
[0488] N-(((trans-4-phenylcyclohexyl)oxy)carbonyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed General Scheme D-2 using General Procedure K with 2,5 -dioxopyrrolidin- 1 -yl (trans-4- phenylcyclohexyl) carbonate (prepared using General Procedure J with trans-4- phenylcyclohexan-l-ol). LCMS theoretical m/z = 536.31. [M+H]+, found 536.3.
Example 149, Compound 111
Figure imgf000220_0001
[0489] N-(((cis-4-phenylcyclohexyl)ox )carbon l)-0-(tram-3-(2-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure K with 2,5 -dioxopyrrolidin- 1 -yl (cis-4- phenylcyclohexyl) carbonate (prepared using General Procedure J with cis-4- phenylcyclohexan-l-ol). LCMS theoretical m/z = 536.31. [M+H]+, found 536.3.
Example 150, Compound 112
Figure imgf000220_0002
[0490] N-(((l-acetylazetidin-3-yl)oxy)carbonyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-butyl 3~((((2,5-dioxopyrrohdin-I~
yl)oxy)earbonyl)oxy)azetidine-l-carboxylate (prepared using General Procedure J with tert- butyl 3 -hydroxyazetidine- 1 -carboxylate), General Procedure D, General Procedure L, then General Procedure N. LCMS theoretical m/z = 475.26. [M+H]+, found 475.3.
Example 151, Compound 113
Figure imgf000221_0001
[0491 ] N-((((S)-l-acetamidopropan-2-yl)oxy)carbonyl)-0-(trans-3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-butyi (S)-(2-((((2,5- dioxopyrrolidin- 1 -yl)oxy)carbonyl)oxy)propyl)carbamate (prepared using General Procedure I with tert-butyi (S)-(2-hydroxypropyl)carbamate), General Procedure D, General Procedure L, then General Procedure N. LCMS theoretical m/z = 477.27. [M+H]+, found 477.3.
Figure imgf000221_0002
[0492] N-( ( ((S)-l-((tert-butoxycarbonyl)amino)propan-2-yl)oxy)carbonyl)-0-(trans-3-
(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with test-butyl (S)-(2-((((2,5- dioxopyrrolidm-i~yl)oxy)carbony!)oxy)propy!)carbamate (prepared using General Procedure J with tert-butyi (S)-(2-hydroxypropyl)carbamate), then General Procedure N. LCMS theoretical m/z = 535.31. [M+H]+. found 535.3.
Example 153
Figure imgf000222_0001
[0493] N-((((R)-l-((tert-butoxycarbonyl)amino)propan-2-yl)oxy)carbonyl)-0-(trans-3-
{ 2-(5,6, 7,8~ietrahydro-l,8-napkthyruiin~2~ l)ethyl}c clohutyl)homoserine . Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-butyl (R)-(2-((((2,5- dioxopyrrolidin-l -yl)oxy)carbonyl)oxy)propyl)carbamate (prepared using General Procedure I with tert-butyl (R)-(2-hydroxypropyl)carbamate), then General Procedure N. LCMS theoretical m/z = 535.31. [M+H]+, found 535.3.
Figure imgf000222_0002
[0494] N-( ( ((R)-l-acetamidopropan-2-yl)oxy)carbonyl)-0-(trcms-3-(2-(5,6, 7, 8- tetrahydro-l,8-naphthyridin-2-yI)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-butyl (R)~(2-((((2,5- dioxopyrrolidin-l-yl)oxy)carbonyl)oxy)propyl)carbamate (prepared using General Procedure J with tert-butyl (R)-(2-hydroxypropyl)carbamate), General Procedure D, General Procedure L, then General Procedure N. LCMS theoretical ni/z = 477.27. [M+H]+, found 447.3.
Example 155a, Compound 115
Figure imgf000223_0001
[0495] N-((((trans)-2-(3,5-dimethyl-lH-pyrazpl-l-yl)cyclopentyl)oxy)carbonyl)-0- (trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with trans-2-{3,5~ dimethyl- lH-pyrazol- l-yl)cyclopentyi (2,5-dioxopyrrolidin-l -yl) carbonate (racemic, prepared using General Procedure J with trans-2-(3,5-dimethyl-lH-pyrazol-l-yl)cyclopentan- l-ol), then General Procedure N followed by preparative HPLC to afford the title compound as the first eluting isomer of unknown absolute stereochemistry at the cyclopentane. LCMS theoretical m/z ::: 540.32. [M+H]+; found 540.3. The absolute stereochemistr of the product of Example 155a was subsequently assigned as N-((((lR,2R)-2-(3,5-dimethyl-lH-pyrazol-l- yl)cyclopentyl)oxy) carbonyl)-0-((ls,3S)-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)-L-homoserine (see structure in FIG. 1, Table 2).
Figure imgf000223_0002
[0496] N-((((trans)-2-(3,5-dimethyl-lH-pyrazol-l-yl)cyclopentyl)oxy)carbonyl)-0- (trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with trans-2-(3,5- dimethy 1- lH-pyrazol- 1 -y l)cy dopentyi (2, 5 -dioxopyrrolidm- 1 -yl) carbonate (racemic, prepared using General Procedure J with trans-2-(3,5-dimethyl-lH-pyrazol-l-yl)cyclopentan- l-ol), then General Procedure N followed by preparative HPLC to afford the title compound as the second eluting isomer of unknown absolute stereochemistry at the cyclopentane. LCMS theoretical m/z = 540.32. [M+H]+, found 540.3. The absolute stereochemistry' of the product of Example 155b was subsequently assigned as N-((((l S,2S)-2-(3,5-dimethy]-lH-pyrazol-l- yl)cyclopentyl)oxy) carbonyl)-0-((ls,3S)-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2· yl)ethyl)cyclobutyl)-L-homoseiine (see structure in FIG. 1 , Table 2).
Figure imgf000224_0001
[0497] N-((((trans)-2-(3,5-dimethyl-IH-pyrazol- l -yl)cyclohexyl)oxy)carbonyl)-0-(trans- 3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with trans-2-(3,5-dimethyl- lH~pyrazo!~l-yl)eyclohexyl (2,5-dioxopyrrolidin-l-yl) carbonate (racemic, prepared using General Procedure I with trans-2-(3,5-dimethy]-lH-pyrazo]-l-yl)cyclohexan-l-ol), then General Procedure N followed by preparative HPLC to afford the title compound as the first eluting isomer of unknown absolute stereochemistry at the cyclohexane. LCMS theoretical m/z = 554.33. [M+H]+, found 554.4. The absolute stereochemistry of the product of Example 156a was subsequently assigned as N-((((l R,2R)-2-(3,5-dimethyl-lH-pyrazol-l- yl)cyclohexyl)oxy)carbonyl)-0-((ls,3S)-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)-L-homoserine (see structure in FIG. 1, Table 2).
Figure imgf000224_0002
[0498] N-((((trans)-2-(3,5-dimethyl-lH-pyrazol-l-yl)cyclohexyl)oxy)carbonyl)-0- (trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer
D2 was sequentially used in General Procedure D, General Procedure K with trans-2-(3,5- dimethyl- 1 H-pyrazol- 1 -yi)cyclohexyi (2,5-dioxopyrrolidin- 1 ~yl) carbonate (racemic, prepared using General Procedure J with trans-2-(3,5-dimethyl-lH-pyrazol-l -yl)cyclohexan- l-ol), then General Procedure N followed by preparative HPLC to afford the title compound as the second eluting isomer of unknown absolute stereochemistry at tire cyclohexane. LCMS theoretical m/z = 554.33. [M+H]+, found 554.4. The absolute stereochemistry of the product of Example 156b was subsequently assigned as N-((((l S,2S)-2-(3,5-dimethyl-lH-pyrazol-l- yl)cyelohexyl)oxy)carbonyl)-0-((ls,3S)-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)-L-homoserine (see structure in FIG. 1, Table 2).
Figure imgf000225_0001
[0499] N-(((l-(tert-butoxycarbonyl)-3-(3-chlorophenyl)azetidin-3-yl)oxy)carbonyl)-0- (trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobuiyl)homoserme. Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-butyl 3-(3~ chloropheny l)-3 -((((2,5 -dioxopyrrolidin- 1 -yl)oxy)carbonyl)oxy)azetidine- 1 -carhoxylate
(prepared using General Procedure J with tert-butyl 3-(3-chlorophenyl)-3-hydroxyazetidine-
1 -carhoxylate), then General Procedure N. LCMS theoretical m/z = 643.29. [M+H]+, found 643.3
Figure imgf000225_0002
[0500] N-(((l-(tert-butox carbon l)-3-(4-isopropylphenyl)azetidin-3-yl)oxy)carbonyl)- 0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine.
Isomer D2 w¾s sequentially used in General Procedure D, General Procedure K with tert- butyl 3 -((((2,5 -dioxopyrrolidin- 1 -yl)oxy)carbony l)oxy )-3 -(4-isopropy lphenyl)azetidine- 1 - carboxyiate (prepared using General Procedure J with tert-butyl 3-hydroxy-3-(4- isopropylphenyl)azetidine~l -carboxyiate), then General Procedure N. LCMS theoretical m/z = 651 .38. [M+H]+, found 651.4.
Figure imgf000226_0001
[0501] N-(((l-(tert-butox carbonyl)-3-(phenylethynyl)azetidin-3-yl)oxy)carbonyl)-0- (trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with tert-butyl 3- ((((2,5-dioxopyrrolidin~l -yi)oxy)carbonyl)oxy)-3-(pheny!ethynyl)azetidine-l -carboxyiate (prepared using General Procedure J with tert-butyl 3-hydroxy-3-(phenylethynyl)azetidine-l- carboxylate), then General Procedure N. LCMS theoretical m/z = 633.33. [M+HJ+, found 633.4.
Example 160, Compound 120
Figure imgf000226_0002
[0502] N-(l-(tert-butoxycarbonyl)piperidine-4-carbonyl)-0-(trans-3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 w as employed in General Scheme D-2 using General Procedure I with l-(tert-butoxycarbonyl)piperidine-4- carboxylic acid. LCMS theoretical m/z = 545.33. [M+H]+, found 545.3.
Example 161, Compound 121
Figure imgf000227_0001
[Q503] N-(3,3-difluoroc clohexane-l-carbon l)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 3,3-difluorocyclohexane-l-caiboxylic acid. LCMS theoretical m/z = 480 27. [M+H]+, found 480.3.
Example 162a. Compound 122
Figure imgf000227_0002
[0504] N-(-2-ethyl-4,4-difluorobutanoyl)-0-(tram-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)c clobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2 -ethyl-4, 4-difluorobutanoic acid, then General Procedure N followed by preparative HPLC to afford the title compound as the first eluting isomer of unknown absolute stereochemistry at the 2-ethy 1-4, 4-difluorobutanoic amide. LCMS theoretical m/z = 468.27. [M+H]+, found 468.3. The absolute stereochemistry of the product of Example 162a was subsequently assigned as N-((S)-2-ethyl-4,4-difluorobutanoyl)- 0-((ls,3S)-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine (see structure in FIG. 1, Table 2).
Example 162b, Compound 122
Figure imgf000227_0003
[Q505] N-(-2-ethyl-4,4-difluorobutano l)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2-ethyl-4,4-difluorobutanoic acid, then General Procedure N followed by preparative HPLC to afford the title compound as the second eluting isomer of unknown absolute stereochemistry at the 2-ethyl-4,4-difluorobutanoic amide. LCMS theoretical m/z = 468.27. [M+H]+, found 468.3. The absolute stereochemistry of the product of Example 162a was subsequen tly assigned as N-((R)-2-ethyl-4,4- difluorobutanoyl)-0-((ls,3S)-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)-L -homoserine (see structure in FIG. 1 , Table 2).
Figure imgf000228_0001
[0506] N-(((trans-2-(phenylethynyl)cyclohexyl)oxy)carbonyl)-0-(trans-3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 w as sequentially used in General Procedure D, General Procedure K with 2,5-dioxopyrrolidm-l-yl trans-2- (phenylethynyl)cyclohexyl) carbonate (prepared using General Procedure J with trans-2- (phenylethynyl)cyclohexan-l-ol), and General Procedure N followed by preparative HPLC to afford the title compound as the first eluting isomer of unknown absolute stereochemistry at the cyclohexane. LCMS theoretical m/z = 560.31. [M+H]+, found 560.3. The absolute stereochemistry' of the product of Example 163a was subsequently assigned as N-((((1R,2S)- 2-(phenylethynyl)cyclohexyl)oxy)carbonyl)-0-((ls,3S)-3-(2-(5,6,7,8-tetrahydro-l,8- naphtliyridin-2-yi)ethyl)cyclobutyl)-L-homoserme (see structure in FIG. 1, Table 2).
Figure imgf000228_0002
[Q507] N-(((trans-2-(phenylethynyl)cyclohexyl)oxy)carbonyl)-0-(trans-3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was sequentially used in General Procedure D, General Procedure K with 2,5-dioxopyrrolidin-l-yl trans-2- (phenyletliynyl)cyclohexyl) carbonate (prepared using General Procedure J with trans-2- (phenylethynyl)cyclohexan-l-ol), then General Procedure N followed by preparative HPLC to afford the title compound as the second eluting isomer of unknown absolute
stereochemistr ' at the cyclohexane LCMS theoretical m/z = 560.31. [M+H]+, found 560.3. The absolute stereochemistry of the product of Example 163b was subsequently assigned as
N-((((l S,2R)-2-(phenylethynyl)cyclohexyl)oxy)carbonyl)-0-((ls, 3S)-3-(2-(5, 6,7,8- tetrahydro- 1 ,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine (see structure in FIG 1 , Table 2).
Figure imgf000229_0001
[0508] N-(4-methyltetrahydro-2H-pyran-4-carbonyl)-0-(trans-3-(2-(5, 6, 7, 8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure 1 with 4-methyltetrahydro-2H-pyran-4-carboxylic acid. LCMS theoretical m/z = 460.28. [M+H]+, found 460.3.
Figure imgf000229_0002
[Q509] N-( 2-cycloh exyl-2-methylpropan oyl)-0-(trans-3-(2-(5, 6, 7, 8-tetrahydro- 1, 8~ naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2-cyclohexyl-2-methylpropanoic acid. LCMS theoretical m/z = 486 33
Figure imgf000229_0003
found 486.3
Example 166, Compound 126
Figure imgf000230_0001
[0510] N-(2-(pyridin-2-yl)benzoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin· 2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2-(pyridin-2-yl)benzoic acid. LCMS theoretical m/z ::: 515.27.
| M H | . found 515 3.
Example 167, Compound 127
Figure imgf000230_0002
[0511] N-(2-ethyl-4,4,4-trifluorobutanoyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2-ethyl-4,4,4-trifluorobutanoic acid. LCMS theoretical m/z = 486.26. [M+H]+, found 486.3.
Figure imgf000230_0003
Figure imgf000230_0004
Isomer D2 was employed in General Scheme D-2 using
General Procedure I with 2-morpholinobenzoic acid. LCMS theoretical m/z = 523.29.
I M 1 1 j . found 523 3.
Example 169, Compound 129
Figure imgf000231_0001
[0513] N-(2-ethyl-2-phenylbutanoyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)c clobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2-ethyl-2-phenylbutanoic acid. LCMS theoretical m/z = 508.32. [M+H]+, found 508.3.
Figure imgf000231_0002
[0514] N-(lH-pyrrolo[3,2-b]pyridine-7-carbonyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid. LCMS theoretical m/z = 478.25. [M+H]+, found 478.4.
Example 171, Compound 131
Figure imgf000231_0003
[0515] N-(4-cyanotetrahydro-2H-pyran-4-carbonyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)c clobut l)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 4-cyanotetrahydro-2H-pyran-4-carboxylic acid. LCMS theoretical m/z ::: 471.26. [M+H]+, found 471.3.
Example 172, Compound 132
Figure imgf000232_0001
[0516] N-(l-(tert-butoxycarbonyl)-3-methylazetidine-3-carbonyl)-0-(trans-3-(2- (5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with l-(tert-butoxycarbonyl)-3- methylazetidine-3 -carboxylic acid LCMS theoretical m/z = 531.32. [M+H]+, found 531.3.
Figure imgf000232_0002
[0517] N-(l-(tert-butoxycarbonyl)azetidine-3-carbonyl)-0-(trans-3-(2-(5,6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with i~(tert-hutoxycarbony])azetidine-3- carboxylic acid. LCMS theoretical m/z = 517.30. [M+H]+, found 517.3.
Example 174, Compound 134
Figure imgf000232_0003
[0518] 0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-(4- (trifluoromethyl)tetrahydro-2H-pyran-4-carbonyl)homoserine. isomer D2 was employed in General Scheme D-2 using General Procedure I with 4-(trif!uoromethyl)tetrahydro-2H-pyran- 4-carboxylic acid, then General Procedure N. LCMS theoretical m/z ~ 514.25. [M+H]+, found 514.3.
Figure imgf000233_0001
[0519] N-(J-(meth lsulfonyl)piperidine-3-carbonyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure 1 with l-(methylsulfonyl)piperidine-3 -carboxylic acid, then General Procedure N followed by preparative HPLC to afford the title compound as the first eluting isomer of unknown absolute stereochemistry at the piperidine LCMS theoretical m/z = 523.26. [M+H]+, found 523.3. The absolute stereochemistry of the product of Example 175a was subsequently assigned as N-((R)-l-(methylsulfonyl)piperidine-3-carbonyl)-0- ((ls,3S)-3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridm-2-yl)ethyl)cyclobutyl)-L-homoserine (see structure in FIG. 1, Table 2).
Figure imgf000233_0002
[0520] N-(l-(methylsulfonyl)piperidine-3-carbonyl)-0-(tram-3-(2-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. isomer D2 was employed in General Scheme D-2 using General Procedure I with i -(methy!sulfonyl)piperidine~3-carboxylic acid, then General Procedure N followed by preparative HPLC to afford the title compound as the second eluting isomer of unknown absolute stereochemistry at the piperidine. LCMS theoretical m/z = 523.26. [M+H]+, found 523.3. The absolute stereochemistry of the product of Example 175b was subsequently assigned as N-((S)-l-(methylsulfonyl)piperidine-3- carbonyl)-0-(( 1 s,3 S)-3 -(2-(5 ,6,7,8-tetrahydro- 1 , 8-naphthyridin-2-y l)ethyl)cyclobutyl)-L- homoserine (see structure in FIG. 1, Table 2).
Example 176a, Compound 136
Til
Figure imgf000234_0001
[0521] 0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N -
(4,5,6, 7-tetrahydro-lH-indazole-6-carbonyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure 1 with 4,5,6,7-tetrahydro-lH-indazole-6- carboxylic acid, then General Procedure N followed by preparative HPLC to afford the title compound as the first eluting isomer of unknown absolute stereochemistry at the cyclohexylpyrazole. LCMS theoretical m/z = 482.28. [M+H]+, found 482.3. Tire absolute stereochemistry' of the product of Example 176a was subsequently assigned as 0-((ls,3S)-3- (2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-((R)-4,5,6,7-tetrahydro-lH- indazole-6-carbonyl)-L-homoserine (see structure in FIG. 1, Table 2).
Figure imgf000234_0002
[0522] 0-(trans-3-(2-( 5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-
(4,5,6, 7-tetrahydro-lH-indazole-6-carbonyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 4,5,6,7-tetrahydro-lH-indazole-6- carboxylic acid, then General Procedure N followed by preparative HPLC to separate the diastereomers as the second eluting isomer of unknown absolute stereochemistry at the cyclohexylpyrazole. LCMS theoretical m/z = 482.28. [M+H]+, found 482.3. The absolute stereochemistry' of the product of Example 176b was subsequently assigned as 0-((l s,3S)-3- (2 -(5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-((S)-4, 5, 6,7-tetrahydro-lH- rndazoie-6-carbonyl)-L-homoserine (see structure in FIG. 1, Table 2).
Example 177, Compound 137
Figure imgf000235_0001
[0523] 0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N- (4,S,6,7-tetrahydro-lH-indazole-7-carbonyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 4,5,6,7-tetrahydro-lH-indazole-7- carboxylic acid. LCMS theoretical m/z = 482.28. [M+H]+, found 482.3.
Example 178, Compound 124
Figure imgf000235_0002
[0524] N-(4-methyltetrahydro-2H-pyran-4-carbon l)-0-(cLs-3-(2-(5,6, 7,8-tetrah dro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme B using General Procedure 1 w ith 4-methyltetrahydro-2H-pyran-4-carboxylic acid. LCMS theoretical m/z = 460.28. [M+H]+, found 460.3.
Example 179, Compound 124
Figure imgf000235_0003
[0525] N-(4-methyltetrahydro-2H-pyran-4-carbonyl)-0-(cis-3-(2-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl) homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 4-methyltetrahydro-2H-pyran-4-carboxylic acid. LCMS theoretical m/z = 460.3 i \I 1 1 | . found 460.3.
Example 180a, Compound 138
Figure imgf000236_0001
[Q526] N-((R)-l-methyl-4,5,6, 7-tetrahyJro-lH-indazole-6-carbonyl)-0-(trans-3-(2- (5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 1 -methyl-4, 5, 6, 7- tetrahydro-lH-indazole-6-carboxylic acid, then General Procedure N followed by preparative HPLC to afford the first eluting of two diastereomers as a single stereoisomer. LCMS theoretical m/z = 496.29. [M+H]+, found 496.3. The absolute stereochemistry of the product of Example 180a was subsequently assigned as N-((R)~ 1 -methyl-4,5 ,6,7-tetrahydro- 1H- indazole-6-carbonyl)-0-((l s,3S)-3-(2 -(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2- yl)ethyl)cyclobutyl)-L-homoserine (see structure in FIG. I, Table 2).
Figure imgf000236_0002
[0527] N-((S)-l-methyl-4,5,6,7-tetrahydro-lH-indazole-6-carbonyl)-0-(trans-3-(2- (5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 1 -methyl-4, 5,6,7- tetrahydro-lH-indazole-6-carboxylic acid, then General Procedure N followed by preparative HPLC to afford the second eluting of two diastereomers as a single stereoisomer LCMS theoretical m/z ::: 496.29. [M+H]+, found 496.3. The absolute stereochemistry of the product of Example 180b was subsequently assigned as N-((S)-l-methyl-4,5,6,7-tetrahydro-lH- indazole-6-carbonyl)-0-((ls, 3S)-3-(2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2~
yl)ethyl)cyclobuty])-L-homoserine (see structure in FIG. 1 , Table 2).
Example 181, Compound 139
Figure imgf000237_0001
[Q528] N-(l-ethyl-4,4-difl orocyclohexane-l-carbonyl)-0-(trans-3-(2-(5, 6, 7,8- tetrahydro-l,H-naphihyridin-2-yl)ethyl)cyclohutyl}homo erine. Isomer D2 was employed in General Scheme D-2 using General Procedure 1 with 1 -ethyl-4, 4-difluorocyclohexane- 1 - carboxylic acid. LCMS theoretical m/z = 508 3. [M+H]+, found 508.3.
Example 182, Compound 140
Figure imgf000237_0002
[0529] N-(l-(6-methylindoline-l-carbonyl)cyclopropane-l-carbonyl)-0-(trans-3-(2- (5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with l-(6-methylindoline-l- carbonyl)cyclopropane-l -carboxylic acid. LCMS theoretical m/z = 561.3. [M+H]+, found 561.3
Example 183, Compound 134
Figure imgf000237_0003
[0530] 0-(cis-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-(4- (trifluoromethyl)tetrahydro-2H-pyran-4-carbonyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 4-trifiuoromethyltetrahydro-2H-pyran- 4-carboxylic acid. LCMS theoretical m/z = 514.2 [M+H]+, found 514.2.
Example 184, Compound 141
Figure imgf000238_0001
[0531] N-(4-(((tert-butoxycarbonyl)amino)methyl)tetrahydro-2H-pyran-4-carbonyl)-0- (cis-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 4-(((tert- butoxycarbonyl)amino)methyl)tetrahydro-2H-pyran-4-carboxylic acid. LCMS theoretical m/z = 575 3 I M I ! | . found 575.3.
Example 185, Compound 142
Figure imgf000238_0002
[0532] N-(l-(pyridin-3-ylmethyl)cyclopropane-l-carbonyl)-0-(trans-3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yI)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with l-(pyridin-3-ylmethyl)cyclopropane-l- carboxylic acid. LCMS theoretical m/z = 493 3. [M+H]+, found 493.2.
Example 186, Compound 143
Figure imgf000238_0003
[0533] N-(3-ch Ioro-5-methylisonicotin oyl)-0-( 4-(5, 6, 7.8-tetrahydro- E 8-n aphthyridin-
2-yl)butyl)homoserine. Prepared according to General Scheme C using General Procedure I with 3~chloro-5-methylisonicotinic acid. LCMS theoretical m/z = 461.2 | M · 1 11 · . found 461.2
Example 187, Compound 144
Figure imgf000239_0001
[0534] N-(4-methyltetrahydro-2H-pyran-4-carbonyl)-0-(4-(5,6,7,8-letrahydro-l,8- naphthyridin-2-yl)butyl)homoserine. Prepared according to General Scheme C using General Procedure I with 4-methyltetrahydro-2H-pyran-4-carboxylic acid LCMS theoretical m/z = 434.3 | \ S I I I · . found 434 3.
Example i 88, Compound i 45
Figure imgf000239_0002
[0535] N-(2,6-dichlorobenzoyl)-0-(4-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserine. Prepared according to General Scheme C using General Procedure I with 2,6-dichiorobenzoic acid. LCMS theoretical m/z = 480.1 [M+H]+, found 480.2.
Example 189, Compound 146
Figure imgf000239_0003
[0536] N-(3,5-dichloroisonicotinoyl)-0-(4-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserine. Prepared according to General Scheme C using General Procedure I with 3,5-dichloroisonicotinic acid. LCMS theoretical m/z = 481.1 I R | . found 481.2.
Example 190, Compound 147
Figure imgf000239_0004
[Q537] N-(l-(4-(tert-butyl)phenyl)cyclobutane-l-carbonyl)-0-(trans-3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with l -(4-(tert-buty])phenyl)cyclobutane-l- carhoxylic acid. LCMS theoretical m/z = 548.3. [M+H]+, found 548.3.
Example 191, Compound 124
Figure imgf000240_0001
[Q538] N-(4-methyltetrah dro-2H-pyran-4-carbonyl)-0-(cis-3-(2-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer El was employed in General
Scheme E-2 using General Procedure 1 with 4-methyltetrahydro-2H-pyran-4-carboxylic acid. LCMS theoretical m/z = 460.3. [M+H]+, found 460.3.
Example 192, Compound 134
Figure imgf000240_0002
[0539] 0-(cis-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-(4- (trifluoromethyl)tetrahydro-2H-pyran-4-carbonyl)homoserine. Isomer El w as employed in General Scheme E-2 using General Procedure I with 4-(trifluoromethyl)tetrahydro-2H-pyran- 4-carboxylic acid. LCMS theoretical m/z = 514.3. [M+H]+, found 514.3.
Example 193, Compound 148
Figure imgf000240_0003
[Q540] N-(3,5-dimeth lisonicotinoyl)-0-(cis-3-(2-(5,6,7,8-tetrahydro-l,8-naphth ridin-
Figure imgf000241_0001
Isomer El was employed in General Scheme E-2 using General Procedure I with 3.5-dimethylisonicotinic acid. LCMS theoretical m/z = 467 3.
M 1 11 · found 467.3.
Example 194, Compound 149
Figure imgf000241_0002
[0541] N-(3-chloro-5-methylisonicotinoyl)-0-(cis-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer El was employed in General Scheme E-2 using General Procedure I with 3-chloro-5-methylisonicotinic acid. LCMS theoretical m/z = 487.2 [M+H]+, found 487.2.
Example 195, Compound 150
Figure imgf000241_0003
[0542] N-(3,5-dichloroisonicotinoyl)-0-(cis-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin·
2~yl)ethyl)cyclobutyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 3,5-dichloroisonicotinic acid. LCMS theoretical m/z = 507.1 [M+H]+, found 507.1.
Example 196, Compound 151
Figure imgf000241_0004
[Q543] N-(bicyclo[2.2.2Joctane-2-carbonyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with bicyclo[2.2.2]octane-2 -carboxylic acid. LCMS theoretical m/z = 470.3. [M+H]+, found 470.3.
Example 197, Compound 152
Figure imgf000242_0001
[Q544] N-(2-methyl-l, 2,3, 4-tetrahydronaphthalene-2-carbon l)-0-(trans-3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2-methyl- 1, 2,3,4- tetrahydronaphthalene-2-carboxy!ic acid. LCMS theoretical m/z = 430.27 [M+H]+, found 430.3.
Example 198, Compound 153
Figure imgf000242_0002
[0545] N-((meth lsulfonyl)prolyl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-
2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with (methylsulfonyl)proline. LCMS theoretical m/z = 509.2. [M+H]+, found 509.3.
Example 199, Compound 149
Figure imgf000242_0003
[Q546] N-(3-chloro-5-meth lisonicotinoyl)-0-(cis-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 3-chloro-5-methylisonicotinic acid. LCMS theoretical m/z = 487.2 | M 1 11 · found 487.2.
Example 200, Compound 154
Figure imgf000243_0001
[Q547] N-(2,4-dimethylnicotinoyl)-0-(cis-3-(2-(5,6, 7,8-tetrah dro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 2,4-dimethylnicotinic acid. LCMS theoretical m/z = 467.3 [M+HJ+, found 467.3
Example 201, Compound 155
Figure imgf000243_0002
[0548] N-(4-phenyltetrahydro-2H-pyran-4-carbonyl)-0-(trans-3-(2-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobut l)homoserine. Isomer 5)2 was employed in General Scheme D-2 using General Procedure I with 4-phenyltetrahydro-2H-pyran-4-carboxylic acid. LCMS theoretical m/z = 522.3. [M+H]+, found 522.2.
Example 202, Compound 156
Figure imgf000243_0003
[Q549] N-( 4-cyan o-2, 6-dimethylbenzoyl)-0-( cis-3-( 2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 4-cyano~2,6~dimethylbenzoic acid. LCMS theoretical m/z = 491.3 | M i i J . found 491.3.
Example 203, Compound 157
Figure imgf000244_0001
[Q550] 0-(cis-3-(2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-(2, 4, 6- trimethylpyrimidine-5-carbonyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 2,4,6-trimethylpyrimidine-5-carboxylic acid. LCMS theoretical m/z = 482.3 [M+HJ +, found 482.2.
Example 204, Compound 158
Figure imgf000244_0002
[0551] 0-(cis-3-(2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-(2, 4,6- trimethylnicotinoyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 2,4,6-trimethylnicotinic acid. LCMS theoretical m/z = 481.3 ! M 1 1 j . found 481 2.
Example 205, Compound 159
Figure imgf000244_0003
[Q552] N-(3-ch loro- 5-flu oroison icotin oyl)-0-(cis-3-(2-( 5, 6, 7, 8-tetrahydro-l , 8- naphthyrMin~2-yl)ethyl)cyclohutyl)homo$erine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 3-chloro-5-fluoroisonicotimc acid LCMS theoretical m/z = 491.2 | M i i J . found 491.1
Example 206, Compound i 60
Figure imgf000245_0001
[Q553] N-(l-(isoquinolin-l-yl)cyclopropane-l-carbonyl)-0-(trans-3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with l-(isoquinolin-l-yl)cyclopropane-l- carboxylic acid. LCMS theoretical m/z = 529 3. [M+H]+, found 529.3
Example 207, Compound 161
Figure imgf000245_0002
[0554] N-(2-(pyridin-2-yl)spiro[3.3 ]heptane-2-carbonyl)-0-(trans-3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2-(pyridin-2-yl)spiro[3.3]heptane-2- carboxylic acid. LCMS theoretical m/z = 533.3. [M+H]+, found 533.3.
Example 208, Compound 162
Figure imgf000245_0003
[Q555] N-(2-(l-methyl-lH-p razol-4- l)tetrahydrofuran-2-carbon l)-0-(trans-3-(2- (5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2-(i -methyl- 1 H-pyrazol-4- yl)tetrahydrofuran-2 -carboxylic acid, then General Procedure N followed by preparative HPLC to afford the title compound as the first eluting isomer. LCMS theoretical m/z = 512.3. [M+H]+, found 512.3.
Example 209, Compound 162
Figure imgf000246_0001
[0556] N-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydrofuran-2-carbonyl)-0-(trans-3-(2- (5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2-(l -methyl- l H-pyrazol-4- yl)tetraliydrofuran-2 -carboxylic acid, then General Procedure N followed by preparative HPLC to afford the title compound as the second eluting isomer. LCMS theoretical m/z = 512.3. [M+H]+, found 512.3.
Example 210, Compound 163
Figure imgf000246_0002
[0557] N-(2,4-dimethyl-6-oxo-l,6-dihydropyridine-3-carbonyl)-0-(cis-3-(2-(5,6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 2,4-dimethyl-6-oxo-l,6-dihydropyiidine- 3 -carboxylic acid. LCMS theoretical m/z = 491.2 [M+H]+, found 491.1.
Example 211, Compound 164
Figure imgf000247_0001
[0558] N-(4,6-dimethylpyrimidine-5-carbonyl)-0-(cis-3-(2-(5,6,7,8-tetrahydro-l,8- naphihyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 4,6-dimethylpyrimidine-5-carboxylic acid. LCMS theoretical m/z = 468.3 i \! ! ! | . found 468.2.
Example 212, Compound 165
Figure imgf000247_0002
[0559] N-(2,6-dichloro-4-(trifluorometh l)benzp l)-0-(cis-3-(2-(5,6,7,8-tetrah dro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 2,6-dichloro-4-(trifluoromethyl)benzoic acid. LCMS theoretical m/z ::: 574.1 [M+H]+, found 574.1.
Example 213, Compound 166
Figure imgf000247_0003
[0560] N-(l-(2-fluorophenyl)cyclopropane-l-carbonyl)-0-(trans-3-(2-(5,6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)eyelobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with l-(2-fluorophenyl)cyclopropane-l - carboxylic acid. LCMS theoretical m/z = 512.3. [M+H]+, found 512.3.
Example 214, Compound 167
Figure imgf000248_0001
[Q561 ] N-(l-(ben zo[d][l,3 Jdioxol-5-yl ) cycloh exane~l~carbonyl}~()~(tmns~3~( 2- (5, 6, 7, 8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure 1 with l-(benzo[d][l,3]dioxol-5- yl)cyclopropane- 1 -carboxylic acid. LCMS theoretical m/z = 564.3. [M+H]+, found 564.3
Example 215, Compound 168
Figure imgf000248_0002
[0562] N-(2,2-difluoro-l -( m-tolyi ) cyclopropan c-1 -carbonyl)-0-(trans-3-(2-(5, 6, 7, 8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2,2-dif!uoro-l -(m-tolyi)cyclopropane-l - carboxylic acid. LCMS theoretical m/z = 528.3. [M+H]+, found 528.3.
Figure imgf000248_0003
[Q563] 0-(trans-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclob tyl)-N-(l- (tetrahydro-2H-pyran-2-yl)cyclopropane-l-carbonyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with l-(tetrahydro-2H-pyran-2- yl)cyclopropane-i -carboxylic acid. LCMS theoretical m/z = 486.3. [M+H]+, found 486.3.
Example 217 Compound 170
Figure imgf000249_0001
[0564] N-( 4-meth oxy-2, 6-dimethylben zoyl)-0-( ds-3-(2~( 5, 6, 7, 8-tetrahydro- 1, 8- naphthyridm-2-yl)ethyl)cyclobutyl)homoserme. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 4-methoxy-2,6-dimetiiylbenzoic acid LCMS theoretical m/z = 496 3 [M+H]+, found 496.2.
Example 218, Compound 171
Figure imgf000249_0002
[0565] N-(l-acetyl-4-(trifluoromethyl)piperidine-4-carbonyl)-0-(cis-3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yI)ethyl)cyclobutyl)homoserine. Isomer E2 was sequentially used in General Procedure D, General Procedure I with l-(tert-butoxycarbonyl)-4- (trifluoromethyl)piperidine-4-carboxylic acid, General Procedure D, General Procedure L, and General Procedure N. LCMS theoretical m/z = 496.3 [M+H]+, found 496.2.
Example 219, Compound 172
Figure imgf000249_0003
3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 2,3-dihydrobenzo[b][l,4]dioxine-2- carboxylic acid. LCMS theoretical m/z = 496.2. [M-ί-Hj t, found 496.2. Example 220, Compound 173
Figure imgf000250_0001
[0567] N-(l-(3-chlorobenzyl)cyclopentane-l-carbonyl)-0-(trans-3-(2-(5,6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with l-(3-chlorobenzyl)cyclopentane-l- carboxylic acid. LCMS theoretical m/z = 554.3. [M+H]+, found 554.3.
Example 221, Compound 174
Figure imgf000250_0002
[0568] 0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-(l-
(3~(trifluoromethoxy)phenyl)cyclopropane~l~carbonyi)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with l-(3- (trifluoromethoxy)phenyl) cyclopropane- 1 -carboxylic acid. LCMS theoretical m/z = 562 2. [M+H]+, found 562.2.
Example 222, Compound 175
Figure imgf000250_0003
[0569] N-( 4~fluoro~2, 6-dimethylbenzoyl)-0-( cis-3-( 2-( 5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 4-fiuoro-2,6-dimethylbenzoic acid. LCMS theoretical m/z = 484.3 [ M i l ] . found 484.2.
Example 223, Compound 148
Figure imgf000251_0001
[0570] N-(3,5-dimethylisonicotinoyl)-0-(cis-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin- 2-yl)ethyl)cyclobutyl)homoserme. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 3,5-dimethylisonicotinic acid. LCMS theoretical m/z = 467 3 ! M 1 1 j . found 467 2.
Example 224, Compound 178
Figure imgf000251_0002
[0571] N-(quinazolin-4-yl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Prepared according to General Scheme A using General Procedure E with 4-chloroquinazoline . LCMS theoretical m/z ~ 462.3. [M+HJ+, found 462.3.
Figure imgf000251_0003
[0572] N-( 2-{ tert-butyl)pyrimidin- 4-yl)-0-(trans-3-( 2-(5, 6, 7, 8-tetrahydro- 1, 8~ naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General
Scheme D-2 using General Procedure E with 2-tert-butyl-4-chloro-pyrimidine. LCMS theoretical m/z = 468.3 I \ i · ! f j . found 468.3.
Example 226, Compound 188
Figure imgf000252_0001
[0573] N-(4-(tert-butyl)pyrimidin-2-yl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure E with 4-(tert-butyl)-2-chloropyrimidine. LCMS theoretical m/z = 468.3 [M+H]+, found 468 3.
Example 227 Compound 178
Figure imgf000252_0002
[Q574] 0-(trans-3-(2-(l,8-naphthyridm-2-yl)ethyl)cyclobutyl)-N-(quinazolin-4- yl)homoserine. Isomer D1 was employed in General Scheme D-2 following General Procedure E with 4-chloroquinazoline. LCMS theoretical m/z = 462.3 [M+H]+, found 462.3.
Example 228, Compound 178
Figure imgf000252_0003
[0575] 0-(trans-3-(2-(l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-(quinazolin-4- ylihom serine. Isomer D2 was employed in General Scheme D-2 following General Procedure E with 4-chloroquinazoline. LCMS theoretical m/z ::: 462.3 [M+H]+, found 462.3.
Example 229, Compound 186
Figure imgf000253_0001
[0576] N-(6-(tert-butyl)pyrimidin-4-yl)-0-(trans-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure E with 4-(tert-butyl)-6-chloropyrimidine. LCMS theoretical m/z = 468.3 [M+H]+, found 468 3.
Example 230, Compound 210
Figure imgf000253_0002
[0577] N-(4-amino-2,6-dichlorobenzoyl)-0-((lr,3R)-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 4-amino-2,6-dichlorobenzoic acid. LCMS theoretical m/z = 520.2. [M+H]+, found 521.1.
Example 231, Compound 211
Figure imgf000253_0003
[0578] N-(4-chloro-2,6-dimethylnicotinoyl)-0-((lr,3B)-3-(2-(5,6, 7,8-tetra ydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 4-chloro-2,6-dimethylnicotinic acid LCMS theoretical m/z = 500 2. [M+H]+, found 501 2.
Example 232, Compound 212
Figure imgf000254_0001
[Q579] N~(3~ch loro-6-methylpicolin oyl)-0-( ( I r,3R)-3-( 2-(5, 6, 7, 8-tetrahydro- 1, 8- naphthyridin-2-yl)ethyI)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 3-ch3oro~6-methyIpieolinie acid. LCMS theoretical m/z = 486.2. [M+H]+, found 487 2.
Example 233, Compound 213
Figure imgf000254_0002
[0580] N-((2R, 6S)-2,6-dimethylpiperidine-l-carbonyl)-0-((lr,3R)-3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure G with (2R,6S)-2,6-dimethylpiperidine . LCMS theoretical m/z ::: 472.3. [M+H]+, found 473.3.
Example 234, Compound 214
Figure imgf000254_0003
[0581 ] N-( f 2R, 5S)-2, 5-dimethylpyrrolidin e-1 -carbonyl)-0-( ( 1 r,3R)-3-(2-( 5, 6, 7, 8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure G with (2R,5S)-2,5-dimethylpyrrolidine. LCMS theoretical m/z = 458.3. [M+H]+, found 459.3.
Example 235, Compound 215
Figure imgf000255_0001
[0582] N-((2R,5R)-2,5-dimethylpyrrolidine-l-carbonyl)-0-((lr,3R)-3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure G with (2R,5R)-2,5-dimethylpyrrolidine. LCMS theoretical m/z ::: 458.3. | M · 1 1 | . found 459.3.
Example 236, Compound 216
Figure imgf000255_0002
[0583] N-(2,6-dichloro-4-cyanobenzoyl)-0-((lr,3R)-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobuiyl)-L~homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 2,6-dichloro-4-cyanobenzoic acid. LCMS theoretical m/z ~ 530.1. [M+HJ+, found 531.1.
Example 237, Compound 217
Figure imgf000255_0003
[0584] N-(2,6-dichloro-3-nitrobenzoyl)-0-((lr,3R)-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 -was employed in General Scheme El-2 using General Procedure I with 2,6-dichloro-3-nitrobenzoic acid. LCMS theoretical m/z = 550.2. [M+H]+, found 551 .2.
Example 238, Compound 218
Figure imgf000256_0001
[Q585] 0-((lr,3R)-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N- ( l,2,4-trimethyl-6-oxo-l,6-dihydropyridine-3-carbonyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure 1 with l,2,4-trimethyl-6-oxo-L6- dihydropyridine-3 -carboxylic acid. LCMS theoretical m/z = 496.3. [M+H]+, found 497.3.
Example 239, Compound 219
Figure imgf000256_0002
[0586] N-(2-chloro-4-cyano-6-methylbenzoyl)-0-((lr,3R)-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 2-chloro-4-cyano-6-methylbenzoic acid. LCMS theoretical m/z =:: 510.2. [ M i l l . found 511 2
Example 240, Compound 220
Figure imgf000256_0003
[0587] N-(3-bromo-5-chloro-2-fluoroisonicotinoyl)-0-((Jr,3R)-3-(2-(5,6, 7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 3-bromo-5-chloro-2-fluoroisonicotinic acid. LCMS theoretical m/z = 568.1. | \ 1 · 1 11 · . found 569.1.
Example 241, Compound 221
Figure imgf000257_0001
[0588] 0-((lr,3R)-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N- (5,6,7,8-tetrahydronaphthalene-l-carhonyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 5,6,7,8-tetrahydronaphthalene-l - carboxylic acid. LCMS theoretical m/z = 491.3. [M+H]+; found 492.3.
Example 242, Compound 222
Figure imgf000257_0002
[0589] N-(3-bromo-2,6-dimethylbenzoyl)-0-((lr,3R)-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyI)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 3-bromo-2,6-dimethylbenzoic acid. LCMS theoretical m/z = 543.2. [M+H]+, found 544.2.
Example 243, Compound 223
Figure imgf000257_0003
[0590] N-(3-chloro-5-methoxyisonicotinoyl)-0-((lr,3R)-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2~yl}ethyl)cyclobutyl}~L~homoserine Isomer E2 was employed in General Scheme E-2 using General Procedure I with 3-chloro-5-methoxyisonicotinic acid. LCMS theoretical m/z = 502.2. | M · 1 l i . found 503.2.
Example 244, Compound 224
Figure imgf000258_0001
[Q591 ] N-( 2, 6-dich loro-4- flu orobenzoyl)-0-( ( I r,3R)-3-( 2-(5, 6, 7, 8-tetrahydro- 1, 8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure 1 with 2,6-dichloro-4-fluorobenzoic acid. LCMS theoretical m/z = 523.1. | M · 1 l i . found 524.1.
Example 245, Compound 225
Figure imgf000258_0002
[0592] N-(2-ch loro-6-fluorobenzoyl)-0-( ( l r,3R)-3 - (2-(5, 6, 7, 8-lelrahydro-l, 8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme El-2 using General Procedure 1 with 2-chloro-6-fluorobenzoic acid. LCMS theoretical m/z = 489.2. [M+H]+, found 489.9.
Example 246, Compound 226
Figure imgf000258_0003
[Q593] N-(3-bromo-2-chloro-6-fluorobenzoyl)-0-((lr,3R)-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyrMin~2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 3-bromo-2-chloro-6-fluorobenzoic acid. LCMS theoretical m/z = 567.1. [M+H]+, found 568.1.
Example 247, Compound 227
Figure imgf000259_0001
[Q594] N-(2,4-dimethyl-6-oxo-J-phenyl-l,6-dihydropyridine-3-carbonyl)-0-((Jr,3R)-3- (2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine Isomer E2 was employed in General Scheme E-2 using General Procedure I with 2,4-dimethyl-6-oxo-l- phenyl~l,6~dihydropyridine~3-carbox\iie acid. LCMS theoretical m/z = 558.3. [M+H]+, found 559.3
Example 248, Compound 228
Figure imgf000259_0002
[0595] N-( 5-bromo-2-hydroxyison icotinoyl)-0-( ( l r,3R)-3-( 2-( 5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 -was employed in General Scheme E-2 using General Procedure I with 5-bromo-2-hydroxyisonicotinic acid LCMS theoretical m/z = 532.1. [M+H]+, found 533.1.
Example 249, Compound 229
Figure imgf000259_0003
naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General
Scheme E-2 using General Procedure I with 3-chloro-5-cyclopropylisonicotinic acid. LCMS theoretical m/z = 512.2. [M+H]+, found 513.2.
Example 250, Compound 230
Figure imgf000260_0001
[0597] N-(3-chloro-5-ethyUsonicotinoyl)-0-((lr,3R)-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 3-chloro-5-ethylisonicotinic acid. LCMS theoretical m/z = 500.2. [M+H]+, found 501.2.
Example 251, Compound 231
Figure imgf000260_0002
[0598] N-(3-chloro-5-ethyUsonicotinoyl)-0-((lr,3R)-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyI)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 3-cyano-2,6-dimethylbenzoic acid. LCMS theoretical m/z = 490.2. [M+H]+, found 491.2.
Example 252, Compound 232
Figure imgf000260_0003
[0599] N-(3-bromo-5-fluoroisonicotinoyl)-0-( ( 1 r,3R)-3-(2-(5, 6, 7, 8-tetrah dro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure 1 with 3-bromo-5-fluoroisonicotinic acid. LCMS theoretical m/z = 534.1. | M · 1 l i . found 535.1.
Example 253, Compound 233
Figure imgf000261_0001
[0600] J5-(2~meihoxy-3,5~dimethylisonicotinoyl)~()~((ir,3R)~3-(2-(5,6,7,8~ietrah dro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 2-methoxy-3,5-dimethylisonicotimc acid. LCMS theoretical m/z = 496.2. [M+H]+, found 497.2.
Example 254, Compound 234
Figure imgf000261_0002
[0601] N-(3-chloro-5-(trifluoromethyl)isonieotinoyl)-0-((lr,3R)-3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 3-chloro-5- (trifluoromethyl)isonicotinic acid. LCMS theoretical m/z = 540.2. [M+H]+, found 541.2.
Example 255, Compound 235
Figure imgf000261_0003
[0602] N-(3-bromo-5-chloroisonicotinoyl)-0-((lr,3R)-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure 1 with 3-bromo-5-chloroisonicotinic acid. LCMS theoretical m/z = 550.1. | M · 1 l i . found 551.1.
Example 256, Compound 236
Figure imgf000262_0001
[0603] N-(5-chloro-2-(dimethylamino)-3-methylisonicotinoyl)-0-((lr,3R)-3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 5-cli3oro~2-(dimethylaniino)~3- methylisonicotinic acid. LCMS theoretical m/z = 509.3. [M+H]+, found 510.2.
Example 257, Compound 237
Figure imgf000262_0002
[0604] N~(3~chloro~5~fluoro~2~metky $onicotmoyl)~0~((lr,3R}~3~(2~(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer 1:2 was employed in General Scheme Pi-2 using General Procedure Ϊ with 3-chloro-5-fluoro-2- methylisonicotinic acid. LCMS theoretical m/z = 504.2. [M+H]+, found 505.1
Example 258, Compound 238
Figure imgf000262_0003
[Q605] N-(2,6-dichloro-3-cyanobenzoyl)-0-((lr,3R)-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin~2~yl)ethyl)cyclobutyl)~L~homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 2,6-dichloro-3-cyanobenzoic acid. LCMS theoretical m/z = 530.1. | \ M l j · . found 531.1.
Example 259, Compound 239
Figure imgf000263_0001
[Q606] N-(3-methyl-5-(trifluoromethyl)isonicotinoyl)-0-((lr, 3R)-3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure 1 with 3-methyl-5- (triiluoromethyl)isonicotinic acid. LCMS theoretical m/z = 520.2. [M+H]+, found 521.2.
Example 260, Compound 240
Figure imgf000263_0002
[0607] N-(2-hydroxy-3,5-dimethylisonicotinoyl)-0-((lr,3R)-3-(2-(5,6, 7,8-tetrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General
Scheme E-2 using General Procedure I with 2-hydroxy-3,5-dimethylisonicotinic acid. LCMS theoretical m/z = 488.2. | \1 · 1 I I · . found 483.2.
Example 261, Compound 241
Figure imgf000263_0003
[0608] N-(3-cyano~2~h drox ~6-metkylisonicaimo l)-0-((lr,3R)-3~(2-{5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 3-cyano-2-hydroxy-6- methylisonicotinic acid. LCMS theoretical m/z = 493.2. [M+H]+, found 494.2.
Example 262, Compound 242
Figure imgf000264_0001
[0609] N-(5-chloro-3-fluoro-2-methylisonicotinoyl)-0-((lr,3R)-3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure 1 with 5-chloro-3-fluoro-2- methylisonicotinic acid. LCMS theoretical m/z = 504.2. [M+H]+, found 505.2.
Example 263, Compound 243
Figure imgf000264_0002
[061Q] N-(6-methoxy-2,4-dimethylnicotinoyl)-0-((lr,3R)-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 6-methoxy-2,4-dimethylnicotinic acid. LCMS theoretical m/z = 496.2. [ M i l ! . found 497.2.
Example 264, Compound 244
Figure imgf000264_0003
[0611] N-(2,6-dimethyl-4-((4-methylpiperaz n-l-yl)methyl)benzoyl)-0-((lr,3R)-3-(2- (5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserme. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 2,6-dimethyl-4-((4~ methylpiperazin- 1 - l)methyl)benzoic acid. LCMS theoretical m/z = 577.3. [M+H]+, found 578.3.
Example 265, Compound 245
Figure imgf000265_0001
[0612] N-( (ph enylsu lfonyl)-L-prolyl)-0-( ( l r,3R)-3- (2-( 5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyI)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with (pheny!sulfonyl)-L-proline. LCMS theoretical m/z = 570.2. [M+H]+, found 571.2.
Example 266, Compound 246
Figure imgf000265_0002
[0613] N-((3R, 5S)-3, 5-dimethylmorpholme-4-carbonyl)-0-((l r, 3R)-3-(2-(5, 6, 7, 8- tetrahydro-1, 8-naphthcyridin-2-yl)etkyl)cyclohutyl)-L-homoserme . isomer E2 was employed in General Scheme E-2 using General Procedure G with (3R,5S)-3,5-dimethylmorpholme. LCMS theoretical m/z ::: 474.3. | M · 1 1 | . found 475.3.
Example 267, Compound 247
Figure imgf000265_0003
[0614] N-(5-chbro-3-fluoro-2-((4-methylpiperazin-l-yl)methyl)isonicotinoyl)-0- (( 1 r,3R)-3-(2-(5, 6, 7, 8-tetrahydro-l, 8-n aph thy ridm-2-yl) ethyl) cyclobutyl)-L-h omoserin e . Isomer E2 was employed in General Scheme E-2 using General Procedure I with 5-chloro-3- fluoro-2-((4-methylpiperazin-l-y])methyl)isoiiicotiiiic acid. LCMS theoretical m/z = 602.3. [ M i l l . found 603.3. Example 268, Compound 248
Figure imgf000266_0001
[0615] N-(7-chloro-5-oxo-l,2,3,5-tetrahydroindolizine-8-carbonyl)-0-((Jr,3JR)-3-(2- (5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 7-chloro-5-oxo-l, 2,3,5- tetrahydroindolizine-8-carboxylic acid. LCMS theoretical m/z = 528 2. [M+H]+, found 529.2.
Example 269, Compound 249
Figure imgf000266_0002
[0616] N-(2,6-difluoro-4-hydroxyhenzoyl)-0-((lr,3R)-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure 1 with 2,6-difluoro-4-hydroxybenzoic acid. LCMS theoretical m/z = 489.2. | M · 1 l i . found 490.2.
Example 270, Compound 250
Figure imgf000266_0003
[0617] N-(4-ch loro- 1 -methyl- lH-pyrazole-5-carbonyl)-0-( ( 1 r,3R)~3~(2~( 5, 6, 7, 8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 4-chloro-l -methyl-lH-pyrazole-5- carboxylic acid. LCMS theoretical m/z = 475.2. [M+H]+, found 476.2. Example 271, Compound 251
Figure imgf000267_0001
[0618] N-(l -methyl-lH-pyrazole-5-carbonyl)-0-( { 1 r,3R)-3-( 2-(5, 6, 7, 8-tetrahydro- 1, 8- naphthyridin-2-yl)ethyI)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 1 -methyl -lH-pyrazole-5 -carboxylic acid. LCMS theoretical m/z = 441.2. [M+H]+, found 442 2.
Example 272, Compound 252
Figure imgf000267_0002
[0619] N-(3-chloro-5-fluoroisonicotinoyl)-0-((lr,3S)-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)-D-homoserine. Isomer El was employed in General Scheme E-2 using General Procedure I with 3-chloro-5-fluoroisonicotinic acid. LCMS theoretical m/z = 490.2. | M 1 1 | . found 491.2.
Example 273, Compound 253
Figure imgf000267_0003
[0620] N-((S)-l-(phenyls lfonyl)piperidine-2-carbonyl)-0-((lr,3R)-3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer 1:2 was employed in General Scheme E-2 using General Procedure Ϊ with (S)-l-(phenylsulfonyl)piperidine-2- carboxyiic acid. LCMS theoretical m/z = 584.3. [M+H]+, found 585.2.
Example 274, Compound 254
Figure imgf000268_0001
[0621] N-(3-chloro-5-fluoro-2-((4-methylpiperazin-l-yl)methyl)isonicotinoyl)-0-
((lr,3R)-3-(2~(5,6,7,8-tetrahydro~l,8~naphihyridm-2-yl)ethyi)cyclobutyl)-L~homoserme. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 3-chloro-5- fluoro-2-((4-methyipiperazin-l-yl)methyl)isonicotmic acid. LCMS theoretical m/z = 602.3.
| M H | . found 603 3.
Example 275, Compound 255
Figure imgf000268_0002
[0622] N-(3,3-dimethylbutanoyl)-0-((lr,3R)-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin -
2-yl)ethyl)cyclobutyl)-L-homoserine Isomer E2 was employed in General Scheme E-2 using General Procedure I with 3,3-dimethylbutanoic acid. LCMS theoretical m/z ~ 431.3.
i M · 1 1 | · . found 432.3.
Example 276, Compound 256
Figure imgf000268_0003
[0623] N-(2-phenylacetyl)-0-((lr,3R)-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 2-phenylacetic acid. LCMS theoretical m/z = 451.3. [M+H]+, found 452.3.
Example 277, Compound 257
Figure imgf000269_0001
[0624] 0-((lr,3R)-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-
(4,4,4~trifhioro~3,3~dimethylhutano l)-L~homo$erine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 4,4,4-trifluoro-3,3-dimethylbutanoic acid. LCMS theoretical m/z ::: 485.3. [M+H]+, found 486.3.
Example 278, Compound 258
Figure imgf000269_0002
[Q625] N-(4,4-difluoro-3,3-dimethylbutanoyl)-0-((lr,3R)-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyrldin-2~yl)ethyl)cyclobutyl)~L~komoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 4,4-difluoro-3,3-dimethylbutanoic acid. LCMS theoretical m/z = 467.3. [M+H]+, found 468 3.
Example 279, Compound 259
Figure imgf000269_0003
[0626] N-((S)-2-phenylpropanoyl)-0-((lr,3R)-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with (S)-2-phenylpropanoic acid. LCMS theoretical m/z ::: 465.3. | \I · 1 I j . found 466.3.
Example 280, Compound 260
Figure imgf000269_0004
[Q627] N-(2-(3,5-difluorophenyl)acetyl)-0-((lr,3R)-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure I with 2-(3,5-difluorophenyl)acetic acid. LCMS theoretical m/z = 487.2. [M+H]+, found 488.2.
Example 281, Compound 261
Figure imgf000270_0001
[0628] N-( ( ( (S)-l-((tert-butoxycarbonyl)amino)propan-2-yl)oxy)carbonyl)-0-(( ls,3S)~
3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with (S)-i~((tert- butoxycarbonyl)amino)propan-2-yl hydrogen carbonate. LCMS tlieoretical m/z = 534.3.
| M H | . found 535.3.
Example 282, Compound 262
Figure imgf000270_0002
[0629] N-(3, 6-dimethylpicolin oyl)-0-( { 1 r,3R)-3-(2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridm-2~yl)ethyl)cyclohiiiyl)~L~homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 3,6-dimethylpicolinic acid. LCMS theoretical m/z = 466.3. | .M H I · found 467.3.
Example 283, Compound 263
Figure imgf000270_0003
[Q630] N-( 6-fluorochroman e-2-carbonyl)-0-( ( 1 s,3S)-3-( 2-f 5, 6, 7, 8-tetrahydro-l , 8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 6-fluorochromane-2 -carboxylic acid LCMS theoretical m/z == 511.3. [M+H]+, found 512.3.
Example 284, Compound 264
Figure imgf000271_0001
[0631] 0-((ls,3S)-3-(2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl)cyclobutyl)-N-
(2-(3-(trifluoromethyl)phenyl)butanoyl)-L-homoserine. Isomer 1)2 was employed in General Scheme D-2 using General Procedure I with 2-{3-(tnfluoromethyl)plienyl)butanoic acid. LCMS theoretical m/z = 547.3. [M+H]+, found 548.3.
Example 285, Compound 265
Figure imgf000271_0002
[0632] N-(3-chloro-5-methylisonicotinoyl)-0-((ls,3S)-3-(2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl)cyclob tyl)-L-homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 3-chloro-5-methylisonicotinic acid. LCMS theoretical m/z ==: 486.2. [ M i l ] . found 487.2.
Example 286, Compound 266
Figure imgf000271_0003
[0633] N-(3-chloro-5-fluoroisonicotinoyl)-0-((ls,3S)-3-(2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 3-chloro-5-fluoroisonicotinic acid. LCMS theoretical m/z = 490.2. | M · 1 l i . found 491.2.
Example 287, Compound 267
Figure imgf000272_0001
[0634] N-(4-cyano-2,6-dimeth lbenzoyl)-0-((Js,3S)-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer D2 was employed in General
Scheme D-2 using General Procedure I with 4-cyano-2,6-dimethylbenzoic acid. LCMS theoretical m/z = 490.3. | M · 1 l i . found 491.3.
Example 288, Compound 268
Figure imgf000272_0002
[Q635] N-(4-(2-chlorophenyl)tetrahydro-2H-pyran-4-carbonyl)-0-((ls,3S)-3-(2- (5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserme. Isomer D2 was employed in General Scheme D-2 using General Procedure 1 with 4-(2- chlorophenyl)tetrahydro-2H-pyran-4-carboxylic acid. LCMS theoretical m/z = 555.3.
! M 1 1 j . found 556 3.
Example 289, Compound 269
Figure imgf000272_0003
[0636] N-(2-hydroxy-2,3-dihydro-lH-itidene-2-carbonyl)-0-((Js,3S)-3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer D2 n as employed in General Scheme D-2 using General Procedure 1 with 2 -hydroxy-2, 3-dihydro-lH-indene-2- carboxylic acid. LCMS theoretical m/z = 493.3. [M+H]+, found 494.2.
Example 290, Compound 270
Figure imgf000273_0001
[Q637] N-([ 1, 1 - bifcyclopropane )]-l -carbonyl)-0-(( 1 s,3S)-3-(2-( 5, 6, 7, 8-tetrahydro-l , 8- naphthyridin-2-yl)ethyl)cyclobut l)-L-homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with [l,r-bi(cyclopropane)]-l -carboxylic acid. LCMS theoretical m/z = 441.3. | .M H I · found 442.3.
Example 291, Compound 271
Figure imgf000273_0002
[0638] N-((S)-3-(difluoromethyl)-5,6, 7,8-tetrahydro-[l,2,4]triaz/olo[4,3-a]pyridine-6- carbonyl)-0-((ls>3S)-3-(2-(5,6,7>8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L- homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 3-(difluoromethyl)-5,6,7,8-tetrahydro-[ 1 ,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid LCMS theoretical m/z = 532 3. [M+H]+, found 533.3.
Example 292, Compound 272
Figure imgf000274_0001
[0639] N-((R)-3-(difluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyridine-6- carhonyl)-0-((ls,3S)-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cycloh tyl)-L- homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 3-(difluoromethyl)-5,6,7,8-tetrahydro-[ 1 ,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid LCMS theoretical m/z = 532 3. [M+H]+, found 533.3.
Example 293, Compound 273
Figure imgf000274_0002
[0640] N-(l-cyclopropylcyclobutane-l-carbotiyl)-0-((ls,3S)-3-(2-(5,6, 7,8-letrahydro- l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 1 -cyclopropyl cyclobutane ~1 -carboxylic acid. LCMS theoretical m/z = 455 3. | M ! 1 j . found 456.3.
Example 294, Compound 274
Figure imgf000274_0003
[0641] N-( l -( 4-isopropylphen l)cyclopentane-l-carbon l)-0-( ( l s,3S)-3-(2-( 5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with l-(4-isopropylphenyl)cyclopentane- 1 -carboxylic acid. LCMS theoretical m/z = 547.3. [M+H]+, found 548.3. Example 295, Compound 275
Figure imgf000275_0001
[Q642] N-(bicyclo[2.2, 2 Joctan e-1 -car bony l)-0-( ( 1 s,3S)-3-(2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl)cyclobut l)-L-homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with bicyclo[2.2.2]octane-l-carboxylic acid. LCMS theoretical m/z = 469.3. | \ M l j · . found 470.3.
Example 296, Compound 276
Figure imgf000275_0002
[0643] N-(octahydrobenzofuran-3a-carbonyl)-0-((ls,3S)-3-(2-(5,6, 7,8-tetrahydro-J,8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with octahydrobenzofuran-4-carboxylic acid. LCMS theoretical m/z = 485.3. [M+H]+, found 486.3.
Example 297, Compound 277
Figure imgf000275_0003
[0644] N-(l-phenethylcyclopropane-l-carbonyl)-0-((ls,3S)-3-(2-(5,6,7,8-tetrahydro- J,8-naphthyridin-2-yl)ethyl)c clob tyl)-L-homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 1-phenethyicyclopropane-l -carboxylic acid. LCMS theoretical m/z = 505.3. | \1 · 1 1 | . found 506.3.
Example 298, Compound 278
Figure imgf000276_0001
[Q645] N-(4-(3-methylisoxazol-5-yl)tetrahydro-2H-pyran-4-carbonyl)-0-((ls,3S)-3-(2- (5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 4-(3-methylisoxazol-5- yl)tetraliydro-2H-pyran-4-carboxylic acid. LCMS theoretical m/z = 526.3. [M+H]+, found 527.1.
Example 299, Compound 279
Figure imgf000276_0002
[0646] N-( l -(phenylsulfonyl)cyclopropane-l-carbonyl)-0-( ( ls,3S)-3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with l-(phenylsulfonyl)cyclopropane-l- carboxylic acid. LCMS theoretical m/z = 541.2. [M+Hj t, found 542.2.
Example 300, Compound 280
Figure imgf000276_0003
[0647] N-(l-phenylcyclo eptane-l-carbotiyl)-0-((ls,3S)-3-(2-(5,6, 7,8-letrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 1-phenylcycloheptane-l -carboxylic acid. LCMS theoretical m/z = 533.3. [M+H]+, found 534.3.
Example 301, Compound 281
Figure imgf000277_0001
[Q648] N-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-carbonyl)-0-((ls,3S)-3-(2-(5, 6,7,8- teirakydro~l,8~naphtkyridin-2~yi)etkyl)cyclohutyi}~L~homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with 4-(methylsulfonyl)tetrahydro-2H- pyran-4-carboxylic acid. LCMS theoretical m/z = 523.2. [M+HJ+, found 524.2.
Example 302, Compound 282
Figure imgf000277_0002
[0649] N-( 1 -( 4-sulfamoylphenyl)cyclopropane-l-carbonyl)-0-( ( Is,3S)-3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with l~(4-sulfamoylphenyl)cyclopropane- 1 -carboxylic acid. LCMS theoretical m/z = 556.2. [M+H]+, found 557.2.
Example 303, Compound 283
Figure imgf000277_0003
[0650] N-((phenyIsuIfonyI)-L-prolyl)-0-((ls,3S)-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure I with (pheny!sulfony!)-L-proline LCMS theoretical m/z = 570.2. [ M i l ! found 571.2.
Example 304, Compound 284
Figure imgf000278_0001
[0651] N-(5-chloro-3-fl oro-2-((4-methylpiperazin-l-yl)methyl)isonicotinoyl)-0- ((ls,3S)-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine.
Isomer D2 was employed in General Scheme D-2 using General Procedure 1 with 5-chloro-3- fluoro-2-((4-methylpiperazin-l-yl)methyl)isonicotinic acid. LCMS theoretical m/z = 602.3. [M+H]+, found 603 3.
Example 305, Compound 285
Figure imgf000278_0002
[0652] N-(3-chloro-5-fluoro-2-((4-methylpiperazin-l-yl)methyl)isotiicotinoyl)-0- ((ls,3S)-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine.
Isomer D2 was employed in General Scheme D-2 using General Procedure I with 3-chloro-5- fluoro-2-((4-methylpiperazin-l-yl)methyl)isonicotinic acid. LCMS theoretical m/z ::: 602.3.
| M H | . found 603.3.
Example 306, Compound 286
Figure imgf000278_0003
[0653] (i S)-2-(pyrimidm~4~ylamino)-5-(3~(5,0,7,8-ietrahydro~J8~naphtkyridm~2- yl)propoxy)pentanoic acid. Prepared by modifying the reaction with intermediate 2i in Example 2 to replace 2-ethylbutanoic acid with 4-chloropyrimidine and sodium bicarbonate. LCMS theoretical m/z = 385.2. | M I I I· . found 386.2.
Example 307, Compound 287
27
Figure imgf000279_0001
[0654] N-(3,5-dichloroisonicotinoyl)-0-(4-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)-L-homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure I with 3,5-dichloroisonicotinic acid LCMS theoretical m/z = 480.1 i M · 1 11 · . found 481.1 .
Example 308, Compound 288
Figure imgf000279_0002
[0655] N-(3-chloro-5-methylisonicotinoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl)butyl)-L-homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure 1 with 3-chloro-5-methylisonicotmic acid. LCMS theoretical m/z = 460.2.
I \ i H | . found 461 .2.
Example 309, Compound 289
Figure imgf000279_0003
yl)butyl)-L-homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure I with 2,4-dimethylmcotimc acid. LCMS theoretical m/z = 440.2. [M+H]+, found 441.2.
Example 310, Compound 290
Figure imgf000280_0001
[0657] N-(4-cyano-2,6-dimethylbenzoyl)-0-(4-(5,6, 7,8-tetrahydro-l,8-naphth ridin-2- yl)butyl)-L-homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure I with 4-cyano~2,6~dimetliy3benzoic acid. LCMS theoretical m/z = 464.2. [M+H]+, found 465.3.
Example 311, Compound 291
Figure imgf000280_0002
[0658] N-(3,5-dichhroisonicotinoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2 - yl)butyl)-D-homoserine. Isomer FI was employed in General Scheme F-2 using General Procedure 1 with 3,5-dichloroisonicotinic acid. LCMS theoretical m/z = 480.1. [M+HJ+, found 481.1.
Example 312, Compound 292
Figure imgf000280_0003
[Q659] N-(3-chloro-5-fluoroisonicotinoyl)-0-(4-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)but l)-L-homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure I with 3-chloro-5-fluoroisonicotinic acid. LCMS theoretical m/z = 464.2. [M+H]+; found 465.1.
Example 313, Compound 293
Figure imgf000281_0001
[Q660] N-((3R,5S)-3,5-dimethylmorpholine-4-carbonyl)-0-(4-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-L-homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure G with (3R,5S)-3,5-dimethylmorpholine. LCMS theoretical m/z = 448.3 [M+H]+, found 449.3
Example 314, Compound 294
Figure imgf000281_0002
[0661] N-(2,6-dichlorobenzoyl)-0-(4-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)- D-homoserine. Isomer FI was employed in General Scheme F-2 using General Procedure I with 2,6-dichlorobenzoic acid. LCMS theoretical m/z = 479.1. [M+H]+, found 480.1.
Example 315, Compound 295
Figure imgf000281_0003
[0662] N-(2,6-dichlorobenzoyl)-0-(4-(5,6,7,8-tetrahydro-J,8-naphthyridin-2-yl)butyl)- L-homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure I with 2,6-dichlorobenzoic acid. LCMS theoretical m/z = 479.1 [M+H]+, found 480.1
Example 316, Compound 296
Figure imgf000281_0004
[Q663] N-(3,5-dimethylisonicotinoyl)-0-(4-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)-D-homoserine . Isomer FI was employed in General Scheme F-2 using General Procedure I with 3,5-dimethylisonicotinic add. LCMS theoretical m/z = 440.2. [M+H]+, found 441.2.
Example 317, Compound 297
Figure imgf000282_0001
[Q664] N-(3,5-dimethylisonicotinoyl)-0-(4-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)-L-homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure I with 3,5-dimethylisonicotinic acid. LCMS theoretical m/z = 440.2. [M+H]+, found 441.2.
Example 318, Compound 298
Figure imgf000282_0002
[0665] N-(2,4-dich loro-6-fluoroben zoyl) -0-( 4~(5, 6, 7, 8-tetrahydro-l, 8~n aph thyridin-2- yl)hutyl)~L~homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure I with 2,4-dichloro-6-fluorobenzoic add. LCMS theoretical m/z = 497.1 [M+H]+, found 498.1.
Example 319, Compound 299
Figure imgf000282_0003
[0666] N-(2,4-dimethyl-6-oxo-l,6-dihydropyridine-3-carbonyl)-0-(4-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)-L-homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure I with 2,4-dimethyl-6-oxo-l,6-dihydropyridine-3- carboxylic acid. LCMS theoretical m/z = 456.2. [M+H]+, found 457.2.
Example 320, Compound 300
Figure imgf000283_0001
[Q667] N-(3-chloro-5-methoxyisonicotinoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-
2~yl)hut l)-L~homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure I with 3-chloro-5-methoxyisonicotinic acid. LCMS theoretical m/z = 476.2.
1 M H I · found 477.1.
Example 321, Compound 301
Figure imgf000283_0002
[0668] N-(2-chloro-6-fluorobenzpyl)-0-(4-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)-L-homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure Ϊ with 2-cli3oro~6-fluorobenzoic acid. LCMS theoretical m/z = 463.2 [M+H]+, found 464.2.
Example 322, Compound 302
Figure imgf000283_0003
[0669] N-(tert-butoxycarbonyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)-
L-homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure N. LCMS theoretical m/z = 421 .2. [M+H]+, found 422.2.
Example 323, Compound 303
Figure imgf000284_0001
[Q670] N-(tert-butoxycarbonyl)-0-(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)~ D-homoserine. Isomer FI was employed in General Scheme F-2 using General Procedure N. LCMS theoretical m/z = 421.2. | M I I I· . found 422.2.
Example 324, Compound 304
Figure imgf000284_0002
[0671 ] N-(5-bromo-2-hydroxyison icotinoyl)-0-( 4-(5, 6, 7, 8-tetrahydro-l , 8-n aphthyridin -
2-yl)butyl)-L-homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure I with 5-bromo-2-hydroxyisonicotinic acid. LCMS theoretical m/z ::: 506.1.
| M H | . found 507.1.
Example 325, Compound 305
Figure imgf000284_0003
[0672] N-(3-bromo-5-chloro-2-fluoroisonicotinoyI)-0-(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)-L-homoserine. Isomer F2 was employed in General Scheme F-2 us g General Procedure I with 3-bromo-5-chloro-2-fluoroisomcotmic acid. LCMS theoretical m/z = 542.1. [M+H]+, found 543.1.
Example 326, Compound 306
Figure imgf000284_0004
[Q673] N-(2, 4-dimethyl-6-oxo-l-phenyl-l,6-dihydropyridine-3-carbonyl)-0-(4-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)but l)-L-homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure I with 2, 4-dimethyl-6-oxo-l -phenyl-1, 6- dihydropyridine-3-carboxylic acid. LCMS theoretical m/z = 532.3. [M+H]+, found 533.3.
Example 327, Compound 307
Figure imgf000285_0001
[Q674] 0-(4-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)-N-(5,6, 7,8~
tetrahydronaphthalene-l-carbonyl)-L-homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure I with 5,6,7,8-tetrahydronaphthalene-l-carboxylic acid. LCMS theoretical m/z = 465.3. [M+H]+, found 466.2.
Example 328, Compound 308
Figure imgf000285_0002
[067S] N-(3-bromo-2,6-dimethylbenzoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- l)butyl)-L-homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure I with 3-bromo-2,6-dimethylbenzoic acid. LCMS theoretical m/z ::: 517.2.
| M H ] . found 518.2.
Example 329, Compound 309
Figure imgf000285_0003
[0676] N-(3-chloro-5-fluoroisonicotinoyl)-0-(4-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)-D-homoserine. Isomer FI was employed in General Scheme F-2 using General Procedure I with 3-chloro-5-fluoroisonicotinic acid. LCMS theoretical m/z = 464.1. | M · 1 l i . found 465.1 Example 330, Compound 310
Figure imgf000286_0001
[0677] N-(3-bromo-2-chloro-6-fluorobenzoyl)-0-(4-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-L-homoserine. Isomer F2 was employed in General Scheme F-2 using General Procedure I with 3-bromo-2-chloro-6-f!uorobenzoic acid LCMS theoretical m/z = 541.1. | M I I I· . found 542.1.
General Scheme Ϊ
Figure imgf000286_0002
isomer !1
Figure imgf000287_0001
Isomer 14
[0678] tert-butyl 7-(4-hydroxy-3-methylbutyl)-3,4-dihydro-l,8-naphthyridine-l(2H)- carhoxylate (21 in Scheme I). To a solution of tert-butyl 7-(4-ethoxy-4-oxobutyl)-3,4- dihydro-l ,8-naphthyridine-l(2H)-carboxylate (I I in Scheme I, 20 g, 57.40 mmol) and Mel (8.15 g, 57.40 mmol) in THF (200 mL) was added KHMDS (1 M, 57.40 mL) dropwise under N2 at -78 °C and the resulting mixture was allowed to stir for 1 h at -78 °C. The mixture was then warmed to 0 °C and then to this was slowly added EtOAc ( 100 mL) followed by a saturated aqueous solution of ammonium chloride (600 mL). The layers were separated and the aqueous layer -was extracted with EtOAc. The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The erode residue was purified by normal phase silica gel chromatography to give the title compound. Starting from the title compound, the remainder of the reactions in Scheme I were conducted analogousl y to the corresponding reactions in Scheme C/General Procedure C to provide the following five compounds.
Example 331, Compound 311
Figure imgf000287_0002
[0679] N-(3-ch loro-5-fluoroison icotin oy !)-()-{ 2-methyl-4-(5, 6, 7, 8-tetrahydro- 1, 8~ naphthyridin-2-yl)hutyl)homoserine. Prepared according to General Scheme I using General Procedure N with 3-chloro-5-fluoroisonicotinic acid whereby the title compound was isolated a racemic mixture. LCMS theoretical m/z = 478.1. I \ i · ! f j . found 479.1.
Example 332, Compound 312
Figure imgf000288_0001
[0680] N-(3-chloro-5-fluoroisonicotinoyl)-0-((R)-2-methyl-4-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-D-homoserine. Prepared according to General Scheme I using General Procedure N with 3-chloro-5-fluoroisonicotinic acid to provide a racemic mixture. The title compound was isolated from the racemic mixture as the fourth eluting isomer by SFC LCMS theoretical m/z = 478.1. [M+H]+, found 479.1.
Example 333, Compound 313
Figure imgf000288_0002
[0681] N-(3-chloro-5-fluoroisonicotinoyl)-0-((S)-2-methyl-4-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to General Scheme Ϊ using General Procedure N with 3~chloro-5-fluoroisonicotinic acid to provide a racemic mixture. The title compound was isolated from the racemic mixture as the first eluting isomer by SFC. LCMS theoretical m/z ::: 478.1. | \I · 1 1 | . found 479.1.
Example 334, Compound 314
Figure imgf000288_0003
[0682] N~(3~ch loro- 5-flu oroison icotin oyl)-0-( (R)-2-methyl-4- (5, 6, 7, 8-tetrahydro - 1, 8- naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to General Scheme I using General Procedure N with 3-chloro-5-fluoroisonicotinic acid to provide a racemic mixture. The title compound was isolated from the racemic mixture as the second eluting isomer by SFC. LCMS theoretical m/z = 478.1. [ M i l l· found 479 1.
Example 335, Compound 315
Figure imgf000289_0001
[0683] N-(3-chloro-5-fluoroisonicotinoyl)-0-((S)-2-methyl-4-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-D-homoserine. Prepared according to General Scheme I using General Procedure N with 3-chloro-5-fluoroisonicotinic acid to provide a racemic mixture. The title compound was isolated from the racemic mixture as the third eluting isomer by SFC LCMS theoretical m/z = 478.1. [M+H]+, found 479.1.
Example 336, Compound 316
Figure imgf000289_0002
[0684] N-(3-chloro-5-methoxyisonicotinoyl)-0-(2-methyl-4-(5,6, 7,8-tetrahydro-l,8 - naphthyridm-2-yl)hutyl)homoserine. Prepared according to General Scheme I using General Procedure N with 3-chloro-5-rnethoxyisonicotinic acid to provide a racemic mixture. The title compound was isolated from the racemic mixture by preparative reverse phase HPLC. LCMS theoretical m/z = 490.2. [M+H]+, found 490 9.
Example 337, Compound 317
Figure imgf000289_0003
[0685] N~(2, 6-dich lorobenzoyl)-0-( (S)-2-methyl-4-(5, 6, 7, 8-tetrahydro- 1, 8- naphthyridin~2~yl)butyl)~L~homoserine. Prepared according to General Scheme I using General Procedure N with 2,6-dichlorobenzoic acid. The title compound was isolated as the first eluting isomer by SFC. LCMS theoretical m/z = 493.2. [M+H]+, found 494.2.
Example 338, Compound 318
Figure imgf000290_0001
[0686] N-(2,6-dichlorobenzoyl)-0-((R)-2-methyl-4-(5,6, 7,8-telrahydro-l,8- naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to General Scheme 1 using General Procedure N with 2,6-dichlorobenzoic acid. The title compound was isolated as the second eluting isomer by SFC. LCMS theoretical m/z = 493.2. [M+H]+, found 494.2.
Example 339, Compound 319
Figure imgf000290_0002
[0687] N~( 2, 6-dick lorobenzoyl)-0-( (S)-2-methyl-4-( 5, 6, 7, 8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-D-homoserine. Prepared according to General Scheme I using General Procedure N with 2,6-dichlorobenzoic acid. The title compound was isolated as the third eluting isomer by SFC. LCMS theoretical m/z = 493.2 [M+H]+, found 494.2.
Example 340, Compound 320
Figure imgf000290_0003
[Q688] N-(2,6-dichlorobenzoyl)-0-((R)-2-methyl-4-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-D-homoserine. Prepared according to General Scheme I using General Procedure N with 2,6-dichlorobenzoic acid. The title compound was isolated as the fourth eluting isomer by SFC. LCMS theoretical m/z = 493.2. [M+H]+. found 494.2.
Example 341, Compound 321
Figure imgf000291_0001
[0689] N-(2-chloro-6-fluorobenzoyl)-0-((S)-2-methyl-4-(5,6, 7,8-tetrahydro-l,8- naphthyridin~2~yl)butyl)~L~homoserine. Prepared according to General Scheme I using General Procedure N with 2-chloro-6-fluorobenzoic acid. The title compound was isolated as the first eluting isomer by SFC. LCMS theoretical m/z = 477.2 [M+H]+, found 478.1.
Example 342, Compound 322
Figure imgf000291_0002
[069Q] N-(2-chloro-6-fluorobenzoyl)-0-((R)-2-methyl-4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to General Scheme 1 using General Procedure N with 2~ehioro-6-fluorobenzoic acid. The title compound was isolated as the second eluting isomer by SFC. LCMS theoretical m/z = 477.2 [M+H]+, found 478.1 .
Example 343, Compound 323
Figure imgf000291_0003
[0691] N-(2-chloro-6-fluorobenzoyl)-0-((S)-2-methyl-4-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-D-homoserine. Prepared according to General Scheme I using General Procedure N with 2~ch!oro-6-fluorobenzoic acid. The title compound was isolated as the third eluting isomer by SFC. LCMS theoretical m/z = 477.2 [M+H]+, found 478.1.
Example 344, Compound 324
Figure imgf000292_0001
[0692] N-(2-chloro-6-fluorobenzoyl)-0-((R)-2-methyl-4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)but l)-D-homoserine. Prepared according to General Scheme I using General Procedure N with 2-chloro-6-fluorobenzoic acid. The title compound was isolated as the fourth eluting isomer by SFC. LCMS theoretical m/z = 477.2 [M+H]+, found 478.1.
Example 345, Compound 325
Figure imgf000292_0002
[0693] N-(4-fluoro-2-methylnicotinoyl)-0-((S)-2-methyl-4-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to General Scheme 1 using General Procedure N with 4-fluoro-2-methylnicotinic acid. The title compound was isolated as the first eluting isomer by SFC. LCMS theoretical m/z = 458.2 [M+H]+, found 459.2
Example 346, Compound 326
Figure imgf000292_0003
[0694] N-(4-fluoro-2-met ylnicotinoyl)-0-((R)-2-methyl-4-(5,6, 7,8-tetrahydro-J,8- naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to General Scheme I using General Procedure N with 4~fluoro-2-methylnicotinic acid. Tire title compound was isolated as the second eluting isomer by SFC. LCMS theoretical m/z = 458.2. [M+H]+; found 459.2.
Example 347, Compound 327
Figure imgf000293_0001
[0695] N-( 4-fluoro-2-methyln icotinoyl)-0-( (S)-2-methyl-4-(5, 6, 7, 8-tetrahydro- 1, 8- naphthyridin-2-yl)but l)-D-homoserine. Prepared according to General Scheme I using General Procedure N with 4-fluoro-2-methylnicotinic acid. The title compound was isolated as the third eluting isomer by SFC. LCMS theoretical m/z = 458.2. [M+H]+, found 459.2.
Example 348, Compound 328
Figure imgf000293_0002
[0696] N-(4-fluoro-2-methylnicotinoyl)-0-((R)-2-methyl-4-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)-D-homoserine. Prepared according to General Scheme I using General Procedure N with 4-fluoro-2-methylnicotinic acid. The title compound was isolated as the fourth eluting isomer by SFC. LCMS theoretical m/z = 458.2. [M+H]+, found 459.2.
General Scheme J
Figure imgf000293_0003
Figure imgf000294_0001
[0697] 2-(but-3-en-l-yl)-2-methyl-J 3-dioxolane . To a solution of hex-5 -en-2 -one (18 mL, 155 mmol) in toluene (155 mL) was added ethylene glycol (1 1.3 mL, 202 mmol) and p~ toluenesulfonic acid monohydrate (2.96 g, 15.5 mmol) ), and the resulting mixture was stirred at 110° C overnight and was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over NaiSOy filtered, and concentrated in vacuo to give the title compound, which w¾s used without further purification
[0698] 2-methyl-2-(2-(oxiran-2-yl)ethyl)-JS-dioxolane. To a solution of 2-(but-3-en-l- yl)-2 -methyl-1 , 3-dioxolane (15.8 g, 1 1 1 mmol) hi DCM (200 mL) was added m- chloroperoxybenzoic acid (23 g, 134 mmol), and the resulting mixture was stirred at rt overnight was diluted with water and DCM. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with water and brine, dried over NaiSOi, filtered, and concentrated in vacuo to give the title compound, which was used without further purification.
[0699] (S)-4~(2-methyl~J 3-dioxolan-2-yl)butane-J 2-diol. To a solution of 2-methyl-2-(2-
(oxiran-2-yl)ethyl)-l , 3-dioxolane (5.3 g, 33 mmol) in toluene (67 mL) was added (R,R)-(-)- A(iV"-bis(3,5-di-tertbutylsalicylidene)-l,2-cyclohexanediaminocobalt(II) (40.55 mg, 0.07 mmol), acetic acid (0.04 mL, 0.67 mmol), and water (0.33 mL, 18.5 mmol) and the resulting mixture was allowed to stir at rt overnight rt overnight and then was concentrated in vacuo. The crude residue was purified by silica gel chromatography to give the title compound. [Q700] (S)-l~(allyloxy)-4-(2-methyl-J3-dioxolan-2-yl)butan~2-ol. To a solution of (S)-4- (2-methyl-l,3-dioxolan-2-yl)butane-l,2-diol (1 8 g, 10.2 mmol) in THF (34 mL) was added NaH (410 mg, 10.2 mmol) at 0 °C and the resulting mixture was stirred at rt. After 1 h, allyl bromide (0.9 mL, 10.2 mmol) was added and the resulting mixture was allowed to stir at rt overnight and was concentrated in vacuo. The erode residue was purified by normal phase silica gel chromatography to give the title compound.
[0701] ( S)-((l-(aUyloxy)-4-(2-rneihyl-l, 3-dioxolan-2-yl)buian-2-yl)oxy)(teri - butyl)dimethyi 'silane. To a solution of (S)-l-(allyloxy)-4-(2-methyl-l,3-dioxolan-2-yl)butan- 2-ol (1.00 g, 4 6 mmol) in CH2CI2 (9 mL) was added imidazole (1.1 g, 16 mmol) and TBSC1 (1.8 mL, 6.9 mmol) and the resulting mixture was allowed to stir at rt for 10 min. The reaction mixture was diluted with saturated sodium bicarbonate and CH2CI2. The combined organic layers were washed with water and brine, dried over NaiSOy filtered, and concentrated in vacuo. The erode residue was purified by normal phase silica gel chromatography to give the title compound.
[0702] (S)-2-(2-((tert-butyldimethylsilyl)oxy)-4-(2-methyl-J3-dioxolan-2- yi)butoxy)ace (aldehyde. To a solution of (S)-((l-(allyloxy)-4-(2-methyl-l,3-dioxolan-2- yl)butan-2-yl)oxy)(tert-butyl)dimethylsilane ( 1.1 g, 2.4 mmol) in 3: 1 THF/H2O (15 mL) was added NalCfi (2.1 g, 9.7 mmol) and QsCfi (0.04 mL, 0.121 mmol) and the resulting mixture was allowed to stir at rt for 3 h and was diluted with saturated sodium bicarbonate, saturated sodium thiosulfate, and EtOAe. The layers were separated and the aqueous layer was extracted EtOAc. The combined organic layers were washed with water and brine, dried over NacSQu filtered, and concentrated in vacuo to give the title compound which veas used without further purification.
[0703] methyl (S,E)-2-((tert-butoxycarbonyl)amino)-4-(2-((tert-butyldimethylsilyl)oxy)-4-
(2-methyl-], 3-dioxolan-2-yl)butoxy)but-2-enoate. To a solution of (S)-2-(2-((tert- butyldimethylsilyl)oxy)-4-(2 -methyl-1, 3-dioxolan-2-yl)butoxy)acetaldehyde (1.1 mg, 2.4 mmol) in CH2CI2 (6 mL) was added methyl 2-((tert-butoxycarbonyl)amino)-2- (dimethoxyphosphoiyl)acetate (718 mg, 5.3 mmol) and DBU (0.53 mL, 3.50 mmol) and the resulting mixture was allowed to stir at rt for 2 h and then concentrated in vacuo. The crude residue was purified by normal phase column chromatography to give the title compound.
[0704] methyl (S,E)~2-((tert-butoxycarbonyl)amino)~4-((2~((tert~butyldimethylsilyl)oxy)~
5-oxohexyl)oxy)but-2-enoa(e . To a solution of methyl (S,E)-2-((tert-butoxycarbonyl)amino)- 4-(2-((tert-butyldimethylsilyl)oxy)-4-(2 -methyl- 1 ,3 -dioxolan-2-yl)butoxy)but-2-enoate (12.4 mg, 0.02 mmol) in CH3CN/H2O 4: 1 (0.5 mL) was added DDQ (0.9 mg, 0.004 mmol) and the resulting mixture was allowed to stir at rt for 2 h and then concentrated in vacuo. The crude residue was purified by normal phase column chromatography to give the title compound.
[0705] methyl N-(tert-butoxycarbonyl)-0-((S)-2-((tert-butyldimeihylsilyl)oxy)-5- oxohexyljhomoserinate. To a solution of methyl methyl (S,E)-2-((tert- butoxycarbonyl)amino)-4-((2-((tert-butyldimethylsilyl)oxy)-5-oxohexyl)oxy)but-2-enoate (195 mg, 0.334 mmol) in MeOH (2 ml.) was added Pd(OH)2/C (20 wt% on carbon, 20 mg) and the resulting mixture was stirred under an H2 atmosphere overnight and was filtered through Celite then concentrated in vacuo to give the title compound which was without further purification.
[Q706] methyl N-(tert-butoxycarbonyl)-0-((S)-2-( ( tert-hutyldimethylsilyl)oxy)-4-(l .8- naphthyridin-2-yl)bu(yl)homoserinate. To a solution of methyl N-(tert-butoxycarbonyl)-0- ((S)-2-((tert-butyldimethylsilyl)oxy)-5-oxohexyl)homoserinate (200 mg, 0.341 mmol) in EtOH (1 mL) was added L-proline (27.5 mg, 0.239 mmol) and 2-ammonicotinaidehyde (83.4 mg, 0.683 mmol) and the resulting mixture was stirred at 75° C overnight and was then concentrated m vacuo. The crude residue was purified by normal phase column
chromatography to give the title compound.
[0707] methyl N-(tert-butoxycarbonyl)-0-((S)-2-((tert-bu(yldimethylsilyl)oxy)-4-(l,8- naphtkyridin-2-yl)butyl)homoserinate. To a solution of methyl N-(tert-butoxycarbonyl)-0- ((S)-2~((tert-hutyidimethylsily])oxy)-4-(l,8-naphthyridin-2-yi)buty])homosermate (67.1 mg, 0.10 mmol) in MeOH (2 mL) was added Pd(OH)2/C (20 wt% on carbon, 20 mg) and the resulting mixture was stirred under an H2 atmosphere overnight and was filtered through Celite then concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to the title compound.
[Q708] methyl 0-((S)~2-((tert-butyldimethylsilyl)oxy)-4-(J8-naphthyridin-2- yl)butyl)homoserinate . To a solution of methyl N~(tert-butoxycarbonyl)-0-((S)~2-((tert~ buty!dimethyisiiyl)oxy)-4-(l,8-naphthyridm-2-yl)butyl)homoserinate (35 0 mg, 0.052 mmol) in DCM (0.1 mL) was added 4 N HC1 in 1,4-dioxane (0.06 mL, 0.207 mmol) and the resulting mixture was allowed to stir at rt overnight then was concentrated in vacuo to give the title compound which was used without further purification. [Q709] methyl N-(3-chloro-5-fluoroisomcotinoyl)-0-((S)-2-hydroxy-4-(J8-naphthyridin- 2-yl)butyl)homoserinate . To a solution of methyl 4-[(2S)-2-[tert-butyl(diphenyl)silyl]oxy-4~ (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butoxy]-2-[(3-chloro-5-fluoro-pyridine-4- carbonyl)amino]butanoate (38.0 mg, 0.0518 mmol) in TΉR (0.1 mL) was
added tetrabutylammonium fluoride (0.06 mL, 0.0622 mmol) and the resulting mixture was allowed to stir at rt for 2 h and was diluted with saturated NLUCl. The layers were separated and the aqueous layer was extracted CH2CI2. The combined organic layers were washed with water and brine, dried over hteSQy filtered, and concentrated in vacuo to give tire title compound which was used without further purification.
Example 349, Compound 329
Figure imgf000297_0001
[0710] N-(3-chloro-5-fluoroisonicotinoyl)-0-((S)-2-hydroxy-4-(l,8-naphthyridin-2- yl)butyl)homoserine. To a solution of methyl N-(3-chloro-5-fluoroisonicotinoyl)-0-((S)-2- hydroxy-4-(l,8-naphthyridin-2-yl)butyl)homoserinate (25.6 mg, 0.0518 mmol) in
THF/MeOH/H20 3: 1 : 1 was added LiOH (9.9 mg, 0.41 mmol) and the resulting mixture was allowed to stir at rt for 4 h. LCMS showed conversion to product, and the reaction mixture was diluted with water and purified by reverse phase preparative HPLC to afford N-(3- chloro-5-fluoroisonicotinoyl)-0-((S)-2 -hydroxy-4 -(l,8-naphthyridin-2-yl)butyl)homoserine as a TFA salt.
[0711] N-(3-chloro-5-fluoroisonicotinoyl)-0-((S)-2-hydroxy-4-(5,6,7,8-tetrahydro-l,8- naphthyridin~2~yl)butyl)homoserme (Compound 329, alternate preparation) Prepared according to General Scheme J using General Procedure I with 3-chloro-5-fluoroisonicotinic acid and General Procedure N. The mixture was neutralized with AcOH and then purified by preparative reverse phase HPLC to the title compound as a trifluoroacetic acid salt. LCMS theoretical m/z = 480.2. [M+H]+, found 481 .1.
Example 350, Compound 10
Figure imgf000298_0001
naphthyridin-2-yl)propoxy)pentanoic acid. Prepared according to Example 2 with the exception that the acid was replaced by 1 -methyl- lH-indazole-4-carboxylic acid in the reaction with intermediate 2i. LCMS theoretical m/z = 465.2. [M+H]+, found 466.1.
Example 351. Compound 11
Figure imgf000298_0002
[0713] (S)-2-(3-(l-methyl-lH-pyrazol-4-yl)benzamido)-5-(3-(5,6, 7,8-tetrah dro-l,8- naphthyridin-2-yl)propoxy)pentanoic acid. Prepared according to Example 2 with tire exception that the acid was replaced by 3-(l-methyl-lH-pyrazol-4-yl)benzoic acid in the reaction with intermediate 2i. LCMS theoretical m/z = 491.2. [M+H]+, found 492 2.
Example 352, Compound 12
Figure imgf000298_0003
[0714] (S)-2-(2-chloro-3-fluorobenzamido)-6-(2-(5, 6, 7, 8-tetrahydro-J 8-naphthyridin-2- yl)ethoxy)hexanoic acid. Prepared according to Example 2 with the exception that the bromide was replaced with 6-bromohex-l-ene in the reaction with intermediate 2d and the acid was replaced by 2-chloro-3-fluorobenzoic acid in the reaction with intermediate 2i. LCMS theoretical m/z = 463.2. [M+H]+, found 464.1. Example 353, Compound 13
Figure imgf000299_0001
[0715] (S)-2-(3-( 1 -methyl-lH-pyrazol-4-yl) benzamido)-6-( 2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethoxy)hexanoic acid. Prepared according to Example 2 with the exception that the bromide was replaced with 6-bromohex-l-ene in the reaction with intermediate 2d and the acid was replaced by 3-( 1-methyl- lH-pyrazol-4-yl)benzoic acid in the reaction with intermediate 2i. LCMS theoretical m/z = 491.2. [M+H]+, found 492 2.
Example 354. Compound 16
Figure imgf000299_0002
[0716] (S)-2-(2-ethylbutanamido)-6-(2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethoxy)hexanoic acid. Prepared according to Example 2 with the exception that the bromide was replaced with 6-bromohex-l-ene in the reaction with intermediate 2d and the acid was replaced by 2-ethylbutanoic acid in die reaction with intermediate 2i. LCMS theoretical m/z ::: 405.2. | M · 1 1 | . found 406.2.
Example 355. Compound 17
Figure imgf000299_0003
[0717] (S)-2-(l-methyl-lH-indazole-4-carboxamido)-6-(2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yI)ethoxy)hexanoic acid. Prepared according to Example 2 with the exception that the bromide was replaced with 6-bromohex-l-ene the reaction with intermediate 2d and the acid was replaced by 1 -methyl- lH-indazole-4-carboxylic acid in the reaction with intermediate 2i. LCMS theoretical m/z = 465.2 [M+H]+, found 466.2.
Example 356. Compound 20
Figure imgf000300_0001
[0718] ( 'S)-2-((tert-butoxycarbonyl)amino)-5-(3-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)propoxy)pentanoic acid. Prepared according to Example 2 with the exception that the acid was replaced by di-fert-butyl dicarbonate in the reaction with intermediate 2i. LCMS theoretical m/z = 407.2. | \M I I · . found 408.2.
Example 357, Compound 21
Figure imgf000300_0002
[0719] N-benzoyl-0-((ls,3r)-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Isomer D2 was employed in General Scheme D-2 using General Procedure 1 with benzoic acid. LCMS theoretical m/z = 437.2. [M+HJ+, found 438.8.
Example 358, Compound 178
Figure imgf000300_0003
[0720] N-(quinazolin-4-yl)-0-((lr,3s)-3-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure E with 4-chloroquinazoline. LCMS theoretical m/z = 461.2. [M+H]+, found 462.3.
Example 359, Compound 179
Figure imgf000301_0001
[0721] N-(8-fluoroquinazoUn-4-yl)-0-((ls,3r)-3-(2-(5,6, 7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure E with 4-chloro-8-fluoroquinazoline. LCMS theoretical m/z = 479.2. | M 1 11 · found 480.2.
Example 360, Compound 180
Figure imgf000301_0002
[Q722] N-(7-fluoroquinazolin-4-yl)-0-((ls,3r)-3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobut l)homoserine. isomer E2 was employed in General Scheme E-2 using General Procedure E with 4-chloro-7-fluoroquinazoline. LCMS theoretical m/z ::: 479.2. | \I · 1 1 | . found 480.2.
Example 361, Compound 181
Figure imgf000301_0003
[0723] N-(7-methylquinazolin-4-yl)-0-((ls,3r)-3-(2-(5,6, 7,8-tetrahydro-l,8 - naphthyridin-2-yl)ethyl)c clobutyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure E with 4-chloro-7-methylquinazoline. LCMS theoretical m/z = 475.3. [M+HJ+, found 476.3.
Example 362, Compound 182
Figure imgf000302_0001
[0724] N~( 6-fluoroquinazolin-4-yl)-0-( ( ls,3r)-3-( 2-(5,6, 7, 8-tetrahydro-l, 8~
naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure E with 4-chloro-6-fluoroquinazoline. LCMS theoretical m/z = 479.2. | .M H I · found 480.2.
Example 363, Compound 183
Figure imgf000302_0002
[0725] N-(5-fluoroquinazolin-4-yl)-0-((ls,3r)-3-(2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure E with 4-chloro-5-fluoroquinazoline. LCMS theoretical m/z = 479.2. | M · 1 1 . found 480.2.
Example 364, Compound 184
Figure imgf000302_0003
[0726] N-( 6-metkylqum azolin-4-yl)-0-(( ls,3r)-3-( 2- (5, 6, 7, 8-tetrahydro- 1, 8~
naphthyridin-2-yl)ethyI)cyclobutyl)homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure E with 4~eh!oro-6-methylquinazoline. LCMS theoretical m/z = 475.3. [M+H]+, found 476 3.
Example 365, Compound 185
Figure imgf000303_0001
[0727] N-(6-(tert-buiyl)-2-phenylpyrimidin-4-yl)-0-((ls,3S)-3-(2-(5,6, 7,8-tetrahydro - l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-L-homoserine. Isomer E2 was employed in General Scheme E-2 using General Procedure E with 4-(tert-hutyl)-6-chioro-2-phenylpyrimidine. LCMS theoretical m/z = 543.3. | .M H I · found 544.3
Example 366, Compound 23
Figure imgf000303_0002
[0728] (S)-2-((tert-butoxycarbonyl)amino)-6-(2-(5,6, 7,8-tetrahydro-l,8-naphthyridin-2- yl)ethoxy)hexanoic add. Was prepared by the same procedure used to prepare Example 2 with the exception that the bromide was replaced with 6-bromohex-l-ene in the reaction with intermediate 2d and the acid was replaced by di~/e/7-butyl di carbonate in the reaction with intermediate 2i. LCMS theoretical m/z ::: 407.2. [M+HJ-t, found 408.2.
BIOLOGICAL EXAMPLES
Example Bl- Proximity-Based Integrin Receptor Binding Assay for Determining Inhibitor Potency
[Q729] The biochemical potency of compounds was determined using a proximity-based assay (ALPHASCREEN®, Perkin Elmer, Waltham, MA) as described previously (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 gauge the potency of inhibitors of binding to human integrin anbb, inhibitor compounds and integrin were incubated together with TGF-bl LAP and biotinylated anti- LAP antibody plus acceptor and donor beads, following the manufacture’s recommendations. The donor beads were coated with streptavidin. Tire acceptor beads had a nitrilotriacetic acid Ni chelator, for binding to a 6xHis Tag on human integrin a,nbΰ. All incubations occurred at room temperatures in 50 mM Tris-HCl, pH 7.5, 0.1% BSA supplemented with 1 mM each CaCk and MgCk.
[0730] The order of reagent addition was as follows:
[0731] 1. Alpha-v-beta-6 integrin, test inhibitor compound, LAP, biotinylated anti-LAP antibody and acceptor beads were all added together.
[0732] 2. After 2 hours, donor beads were added. After another 30 minute incubation, samples were then read.
[0733] Integrin binding was evaluated by exciting donor beads at 680 urn, and measuring the fluorescent signal produced, between 520-620 nni, using a Biotek Instruments (Winooski, VT, USA) SynergyNeo2 multimode plate reader. Compound potency was assessed by determining inhibitor concentrations required to reduce fluorescent light output by 50%. Data analysis for ICso determinations was carried out by nonlinear four parameter logistic regression analysis using Dotmatics ELN Software (Core Informatics Inc , Branford, Ct).
ICso values for the compounds in the Examples are provided below Table B-I in ranges: below 50 nM; from above 50 nM to 250 nM; from above 250 nM to 1000 nM; and above 1000 nM. TABLE B-l
Figure imgf000305_0001
Figure imgf000305_0002
Figure imgf000306_0002
Figure imgf000306_0001
Figure imgf000307_0002
Figure imgf000307_0001
Figure imgf000308_0002
Figure imgf000308_0001
Figure imgf000309_0002
Figure imgf000309_0001
* first eluting compound from general synthetic scheme referenced was assayed
* * second eluting compound from general synthetic scheme referenced was assayed
† first eluting compound from last chromatography step described in example was assayed †† second eluting compound from last chromatography step described in example was assayed Fs amnlp
Figure imgf000310_0001
[0734] The biochemical potency of compounds for inhibiting anbd integrin was determined for a second series of compounds using a proximity-based assay
(ALPHASCREEN®, Perkin Elmer, Waltham, MA) as described previously (Ullman EF et al., Luminescent oxygen channeling immunoassay: Measurement of particle binding kinetics by chemiluminescence. Proc. Natl. Acad. Sci. USA, Voi. 91, pp. 5426-5430, June 1994). To gauge the potency of inhibi tors of binding to human integrin anb>6, inhibitor compounds and integrin were incubated together with TGF-hi LAP and biotinylated anti-LAP antibody plus acceptor and donor beads, following the manufacture’s recommendations. The donor beads were coated with streptavidin. Tire acceptor beads had a nitrhotriacetic acid Ni chelator, for binding to a 6xHis Tag on human integrin anbb All incubations occurred at room
temperatures in 50 mM Tris-HCl, pH 7 5, 0.1% BSA supplemented with 1 mM each CaCk and MgCk.
[0735] The order of reagent addition was as follow's:
[Q736] 1. Alpha-v-beta-6 integrin, test inhibitor compound, LAP, biotinylated anti-LAP antibody and acceptor beads were all added together.
[0737] 2. After 2 hours, donor beads were added. After another 30 minute incubation, samples were then read.
[0738] Integrin binding was evaluated by exciting donor beads at 680 nm, and measuring the fluorescent signal produced, between 520-620 nm, using a Biotek Instruments (Winooski, VT, USA) SynergyNeo2 multimode plate reader. Compound potency was assessed by determining inhibitor concentrations required to reduce fluorescent light output by 50%. Data analysis for ICso determinations was carried out by nonlinear four parameter logistic regression analysis using Dotmatics ELN Software (Core Informatics Inc , Branford, Ct)
[0739] Example B3— The Compounds Potently Inhibit anbi in a Proximity-Based
Assay The biochemical potency of compounds for inhibiting anbi integrin was determined using a proximity-based assay (ALPHASCREEN®, Perkin Elmer, Waltham, MA) as described previously (Ullman EF et ah, Luminescent oxygen channeling immunoassay: Measurement of particle binding kinetics by chemiluminescence. Proc. Natl. Acad. Sci. USA, Vol. 91, pp. 5426-5430, June 1994). To gauge the potency of inhibitors of binding to human integrin anbi, inhibitor compounds and integrin were incubated together with TGF-bl LAP and biotinylated anti-LAP antibody plus acceptor and donor beads, following the manufacture’s recommendations. The donor beads were coated with streptavidim. The acceptor beads had a nitrilotriacetic acid Ni chelator, for binding to a 6x1 lis Tag on human integrin anbi. All incubations occurred at room temperatures in 50 mM Tris-HCl, pH 7.5, 0.1 % BSA supplemented with 1 mM each CaCk and MgC .
[0740] The order of reagent addition was as follows:
[0741] 1. Alpha-v-beta- 1 integrin, test inhibitor compound, LAP, biotinylated anti-LAP antibody and acceptor beads were all added together.
[0742] 2. After 2 hours, donor beads were added. After another 30 minute incubation, samples were then read.
[Q743] Integrin binding was evaluated by exciting donor beads at 680 nm, and measuring the fluorescent signal produced, between 520-620 nm, using a Biotek Instruments (Winooski, VT, USA) SynergyNeo2 multimode plate reader. Compound potency was assessed by determining inhibitor concentrations required to reduce fluorescent light output by 50%. Data analysis for ICso determinations was carried out by nonlinear four parameter logistic regression analysis using Dotmatics ELM Software (Core Informatics Inc., Branford, Ct).
ICso values for the compounds in the Examples are provided in FIG. 2, Table B-2 in ranges: 50 nM and below; from above 50 nM to 250 nM; from above 250 nM to 1000 nM; and above 1000 nM.
Combined Inhibition Results of Examples Bl, B2, and B3
[0744] Table B-2, FIG. 2, show's ICso data from Examples Bl, B2, and B3 for inhibition of anbi and anb& integrin in the solid phase assays and inhibition of human anbi and anbb mtegrin in the proximity-based ALPHASCREEN® assays. The ICso data is shown in four ranges: 50 nM and below ; from 50 nM to below 250 nM; from above 250 nM to below 1000 nM; and 1000 nM and above.

Claims

What is claimed is:
1 A compound of formula (I):
Figure imgf000312_0001
or a salt thereof, wherein:
R’! is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by R4, 1,2, 3,4- tetrahydro-L8-naphthyridin-2-yl optionally substituted by R4, 6-aminopyridin-2-yl optionally substituted by R4, or (pyndin-2-yl)ammo optionally substituted by R4:
G is -C(0)R2 or R3:
R2 is Ci-Ce alkyl optionally substituted by R23, Cn-Cs cycloalkyl optionally substituted by R2b, 3- to 12-membered heterocyclyl optionally substituted by R2c, C&-Ci4 aryl optionally substituted by R2d, 5- to 10-membered heteroaryl optionally substituted by R2e, -QR2f, or -NR2gR2h;
R3 is Ci-Ce alkyl optionally substituted by R3a, C3-C8 cycloalkyl optionally substituted by R3b, 3- to 12-rnernbered heterocyclyl optionally substituted by R3c, Ce-Cw aryl optionally substituted by R3d, or 5- to lO-membered heteroaryl optionally substituted by R3e;
L1 is C2-C4 alkylene optionally substituted by R4;
L2 is a bend or C1-C3 alkylene optionally substituted by R4;
L3 is C2-C4 alkylene optionally substituted by R4;
Y is a bond or C3-C5 cycloalkylene optionally substituted by Y3;
R21 is Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, Cs-Cir aryl, or 5- to 10-membered heteroaryd, wherein the Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cir aryl, and 5- to 10-membered heteroaryl of R2f are independently optionally substituted by R21;
R2g and R2h are each independently hydrogen, deuterium, Ci-Ce alkyl,
C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, Cs-Cw aryl, or 5- to 10-membered heteroaryl, wherein the CI-CG alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl,
C6-C14 aryl, and 5- to 10-membered heteroaiy d of R2g and R2h are independently optionally substituted by R2·';
each R2a, R2b, R2c, R2d, R2e, R2i, R¾, R3a, R3b, R3c, R3d, R3e and Ya is independently oxo or R4;
each R4 is independently deuterium, halogen, Ci-Ce alkyl, CI-CG alkenyl, C2- CG alkynyl, Cs-Cs cycloalkyl, 3- to 12-membered heterocyclyl, CG-CM and, 5- to 10- membered heteroaryl, -CN, -OR5, -SR5, -NR6R7, -NO2, -C=NH(OR5), -C(0)R5, -0C(0)R5, -C(0)0R5, ~C(0)NR6R7, ~NR5C(0)R6, ~NR3C(0)0R6, -NR5C(0)NR6R7, -S(0)R5, -S(0)2R5, -NR5S(0)R6, -NR5S(0)2R6, -S(0)NR6R7, -S(0)2NR6R7, or -P(0)(0R5)(0R6), wherein the CI-
CG alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg cycloalkyl, 3- to 12-membered heterocyclyl, CG-CI4 aryl, and 5- to 10-membered heteroaryl of R4 are independently optionally substituted by R4a; each R4a is independently deuterium, halogen, oxo, -OR8, -NR8R9,
-C(0)R8, -C(0)0R8, -NR8C(O)OR:0, -CN, -S(0)R8, -S(0)2R8, -P(0)(0R8)(0R9), Ci-Cs cycloalkyl, 3- to 12-membered heterocyclyl, 5- to lO-membered heteroaryl, Ce-Cir aiyl, or C -Cfi alkyl, wherein the 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Ce- Ci4 aryl, and Ci-Ce alkyl of R4a are independently optionally substituted by R4b; each R4b is independently deuterium, oxo, -OH, -G(2H), halogen, or Ci-Ce alkyl optionally substituted by deuterium, halogen, -OH, -0(2H), or oxo; each R5 is independently hydrogen, deuterium, CI-CG alkyl, CI-CG alkenyl, Cr-Ce alkynyl, CG-CG cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the CI-CG alkyl, C?.-CG alkenyl, Ci-Ce alkynyl, CI-CG cycloalkyl, CG-CI4 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl of R3 are each independently optionally substituted by R33; each R3a is independently halogen, deuterium, oxo, -CN, -OR10, -NRnR12,
-P(0)(0Rn)(0R12), 3- to 12-membered heterocyclyl, or CI-CG alkyl optionally substituted by deuterium, halogen, -OH, -0(2H), or oxo; each R6 is independently hydrogen, deuterium, CI-CG alkyl, CI-CG alkenyl, CZ-CG alkynyl, CI-CG cycloalkyl, CG-CM aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the CI-CG alkyl, C2-C6 alkenyl, CC-CG alkynyl, CG-CG cycloalkyl, CG-CM aryl, 5- to iO-membered heteroaryl, and 3- to 6-membered heterocyclyl of R6 are independently optionally substituted by deuterium, halogen, oxo, -CN, -OR10, -NR!1Ri2, or Ci-Ce alkyl optionally substituted by deuterium, halogen, -OH, ~0(2H), or oxo; each R7 is independently hydrogen, deuterium, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyi, Ce-Ce cycloalkyl, ( V.-C : aryl, 5- to I Q-membered heteroaryd, or 3- to 6-membered heterocyclyl, wherein the Ci-Ce alkyl, C?.-CG alkenyl, C2-G5 alkynyi, Ci-Ce cycloalkyl, Ce-Cir aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R7 are independently optionally substituted by deuterium, halogen, oxo, -CN, -OR10, -NRnR12, or Ci-Ce alkyl optionally substituted by deuterium, halogen, -OH, -0(2H), or oxo; or R6 and R7 are taken together with the atom to which they are attached to form a 3 - to 10-membered heterocyclyl optionally substituted by deuterium, halogen, oxo, -OR10, ~NR!!R12, or Ci-Ce alkyl optionally substituted by deuterium, halogen, oxo, -OH, or - 0(2H); each R8 is independently hydrogen, deuterium, CI-CG alkyl optionally substituted by deuterium, halogen, or oxo, Cr-Ce alkenyl optionally substituted by deuterium, halogen, or oxo, or CJ-CG alkynyi optionally substituted by deuterium, halogen, or oxo; each R9 is independently hydrogen, deuterium, Ci-Ce alkyl optionally substituted by- deuterium, halogen, or oxo, Ci-Ce alkenyl optionally substituted by deuterium, halogen, or oxo, or Cr-Ce alkynyi optionally substituted by deuterium, halogen, or oxo; each R10 is independently hydrogen, deuterium, Ci-Ce alkyl optionally substituted by deuterium, halogen, or oxo, C2-C6 alkenyl optionally substituted by deuterium, halogen, or oxo, or C2-C6 alkynyi optionally substituted by deuterium, halogen, or oxo; each R11 is independently hydrogen, deuterium, Ci-Ce alkyl optionally substituted by deuterium, halogen, or oxo, Cr-Ce alkenyl optionally substituted by deuterium, halogen, or oxo, or C2-C6 alkynyi optionally substituted by deuterium, halogen, or oxo: and each R!2 is independently hydrogen, deuterium, Ci-Ce alkyl optionally substituted by deuterium, halogen, or oxo, Cr-Ce alkenyl optionally substituted by deuterium, halogen, or oxo, or C2-C6 alkynyi optionally substituted by deuterium, halogen, or oxo; or Rn and Ri2 are taken together with the atom to which they are attached to form a 3- 6 membered heterocyelyi optionally substituted by deuterium, halogen, oxo or Ci-Ce alkyl optionally substituted by deuterium, oxo, or halogen
2. The compound of claim 1, or a salt thereof, wherein 1/ is C2 aikylene optionally
substituted by R!0
3. The compound of claim 2, or a salt thereof, wherein L! is -CH2CH2-.
4. The compound of claim 1, or a salt thereof, wherein at least one of R R2h, R23, R2b,
R2C o2d 1) 2 e R2 R2j R3a Rib R3C Rid t> 3e ya R4a R 4b RJ R.¾ R6 R7 R8 R9 R! O
R11, or R12 is deuterium.
5. The compound of claim 1, or a salt thereof, wherein -L!-0-L2-Y-L3- are taken
together to form a moiety selected from the group consisting of:
|— C2-C4 aikylene— O-C2-C7 aikylene— I
Figure imgf000315_0001
wherein
Figure imgf000315_0002
a C3-C5 cycloalkylene optionally substituted by Ya, and
Figure imgf000315_0003
wherein YY is a C3-C5 cycloalkylene optionally substituted by Y3.
Idle compound of claim 5, or a salt thereof, wherein -L!~Q-L2-Y-L·3- are taken together to form a moiety selected from the group consisting of:
Figure imgf000315_0004
The compound of claim 5, or a salt thereof, wherein -l/-0-L2~Y~L3- are taken together to form a moiety selected from the group consisting of:
Figure imgf000316_0001
8 The compound of claim 5, or a salt thereof, wherein -Tί-O-I U-IA are taken
together to form a moiety selected from the group consisting of:
Figure imgf000316_0002
9. The compound of any one of claims 1-8, or a salt thereof, wherein G is -C(Q)R2.
10 The compound of claim 9, or a salt thereof, wherein R2 is Ci-Ce alkyl substituted by 0-5 R-'3 groups.
11 The compound of claim 9, or a salt thereof, wherein R2 is unsubstituted Ci-Ce alkyl.
12 The compound of claim 9, or a salt thereof, wherein R2 is unsubstituted CVCe alkyl
13. The compound of claim 9, or a salt thereof, wherein R2 is C1-C5 alkyl substituted by 1-5 R2a groups, wherein each R2a is independently selected from halogen, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C14 aryl, 5- to 10-membered heteroaryl, -CN, -OR3, ~NR6R7, -NR5C(0)0R6, and -S(0)2R5, wherein the Ci- Ce alkyl, Cs-Cs cycloalkyl, 3- to 12-membered heterocyclyi, Cb-Ci4 aryd, and 5- to 10- membered heteroaryl of R2a are independently optionally substituted by R4a.
14. The compound of claim 12, or a salt thereof, wherein R2 is C2-C5 alkyl substituted by 1-5 R2a groups, wherein at least one of the R2a groups is halogen.
15. The compound of claim 12, or a salt thereof, wherein R2 is C1-C5 alkyl substituted by 1-5 R2a groups, wherein at least one of the R2a groups is C3-C& cycloalkyl.
16. The compound of claim 12, or a salt thereof, wherein R2 is C1-C3 alkyl substituted by Ci-Ce cycloalkyl, wherein the CT-Ce cycloalkyl is substituted by 0-5 groups selected from the group consisting of halogen, Ci-Ce alkyl, and -OR5.
The compound of claim 12, or a salt thereof, wherein R2 is C1-C3 alkyl substituted by C3-C6 cycloalkyl, wherein the Cs-Ce cycloalkyl unsubstituted.
18. The compound of claim 12, or a salt thereof, wherein R2 is C1-C5 alkyl substituted by 1-5 R2a groups, wherein at least one of the R2a groups is 3- to 12-membered heterocyclyi.
19 The compound of claim 12, or a salt thereof, wherein R2 is Ci alkyl substituted by 6- membered heterocyclyi.
20. The compound of claim 12, or a salt thereof, wherein R2 is C1-C5 alkyl substituted by 1-5 R2a groups, wherein at least one of the R2a groups is C&-Ci4 aryl, wherein the G>~ Ci4 aryl is independently optionally substituted by halogen or Ci-Ce alkyl substituted by 0-5 halogen.
21. Hie compound of claim 19, or a salt thereof, wherein R2a is unsubstituted phenyl or phenyl substituted by 1-5 halogen.
22. The compound of claim 12, or a salt thereof, wherein R2 is C2-C5 alkyl substituted by 1-5 R2a groups, wherein at least one of the R2a groups is 5- to IG-membered heteroaryl substituted by 0-5 R4a groups.
23. The compound of claim 21 , or a salt thereof, wherein R23 is unsubstituted pyridinyl.
24. The compound of claim 12, or a salt thereof, wherein R2 is C1-C5 alkyl substituted by
1-5 Ria groups, wherein at least one of the R2a groups is -OR5, wherein each R5 is independently selected from hydrogen, CI-CG alkyl, and CG~CI4 aryl.
25. The compound of claim 23, or a salt thereof, wherein R5 is Ce-Cir aryl substituted by 0-5 halogen.
26. The compound of claim 12, or a salt thereof, wherein R2 is C1-C5 alkyl substituted by
1-5 R2a groups, wherein at least one of the R2a groups is -CN, ~NR6R', -NR5C(0)0R6, or -S(0)2R5.
27. The compound of claim 12, or a salt thereof, wherein R2 is C 1-C5 alkyl substituted by
2-5 R2a groups, wherein each R2a is independently selected from halogen, Ci-Ce alkyl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, Ce-Ci and, -CN, -OR5,
and -NR5C(0)0R6.
28. The compound of claim 26, or a salt thereof, wherein R2 is C1-C5 alkyl substituted by 2-5 R2a groups, wherein at least one R2a group is phenyl substituted by 0-5 halogen and at least one R2a group is OR3, wherein each R5 is independently selected from hydrogen and CI-CG alkyl.
29. The compound of claim 9, or a salt thereof, wherein R2 is C3-C« cycloalkyl substituted by 0-5 R2b groups.
30. The compound of claim 28, or a salt thereof, wherein R2 unsubstituted Ci-Cs
cycloalkyl.
31. The compound of claim 28, or a salt thereof, wherein R2 is Ci-Cs cycloalkyl
substituted by 1-5 R2b groups, wherein each R2b is independently selected from halogen, Ci-Ce alkyl, 3- to 13-mem he fed heterocyclyl, Ce-Chr aryl, 5- to 10- me inhered heteroaryl, and -OR3.
32. The compound of claim 30, or a salt thereof, wherein R2 is Ce-Ce cycloalkyl
substituted by 1-5 R2b groups, wherein at least one of the R2b groups is halogen.
33. The compound of claim 30, or a salt thereof, wherein R2 is C.3-Ce cycloalkyl
substituted by 1-5 R2b groups, wherein at least one of the R2b groups is Ci-Ce alkyl, wherein the Ci-Ce alkyl of R2b is substituted by 0-5 R4a groups.
34. The compound of claim 30, or a salt thereof, wherein R2b is C1-C2 alkyl substituted by 1-5 R4a groups, wherein each R4a groups is independently selected from phenyl substituted by 0-5 halogen and 6-membered heteroaryl substituted by 0-5 halogen.
35. The compound of claim 30, or a salt thereof, wherein R2 is Ch-Ce cycloalkyl
substituted by 1-5 R2b groups, wherein at least one of the R2b groups is 3- to 12- membered heterocyclyl.
36. The compound of claim 34, or a salt thereof, wherein R2b is tetrahydro~2/7~pyranyl or benzodioxolyl.
37. The compound of claim 30, or a salt thereof, wherein R2 is C3-C4 cy cloalkyl
substituted by 1-5 R2b groups, wherein at least one of the R2b groups is Ce-Cir aryl substituted by 0-5 R4a groups, wherein each R4a is independently selected from halogen, Ci-Ce alkyl, and -OR8.
38. The compound of claim 30, or a salt thereof, wherein R2 is C3-C7 cycloalkyl
substituted by 1-5 R2b groups, wherein at least one of the R2b groups is 5 - to 10- membered heteroaryl.
39. The compound of claim 37, or a salt thereof, wherein R2b is pyridinyl or isoquinolinyl.
40. The compound of claim 30, or a salt thereof, wherein R2 is C3-C6 cycloalkyl
substituted by 2-5 R2b groups, wherein each R2b is independently selected from halogen, Ci-Ce alkyl, Ce-Cu aryl, and -OR5.
41. The compound of claim 39, or a salt thereof, wherein R2 is C.7-Ce cycloalkyl
substituted by 2-5 R2b groups, wherein at least one R2b group is halogen and at least one R2D group is phenyl substituted by 0-5 Ci-Ce alkyl.
42. The compound of claim 9, or a salt thereof, wherein R2 is 3- to 12-membered
heterocyclyl substituted by 0-5 R2c groups.
43. The compound of claim 41 , or a salt thereof, wherein R2 unsubstituted 4- to 10- membered heterocyclyl.
44. The compound of claim 41, or a salt thereof, wherein R2 is 3- to 12-membered heterocyclyl substituted by 1-5 R2c groups, wherein each R2c is independently selected from oxo, halogen, Ci-Ce alkyl, Ce-Cir aryl, 5- to lO-membered heteroaryl, -CN, -OR5, -C(0)R5, -C(0)0R5, and -S(0)2Rs.
45. The compound of claim 43, or a salt thereof, wherein R2 is 4- to 6-membered
heterocyclyl substituted by 1-5 R2c groups, wherein at least one of the R2c groups is Ci-Ce alkyl, wherein the Ci-Ce alkyl of R2c is substituted by 0-5 R43 groups
46. The compound of claim 44, or a salt thereof, wherein R2c is C1-C2 alkyl substituted by 1-5 R4a groups, wherein each R4a groups is independently selected from halogen; phenyl substituted by 0-5 halogen; 6-membered heteroaryl substituted by 0-5 halogen; and -NR8C(0)OR10.
47. The compound of claim 43, or a salt thereof, wherein R2 is 4- to 6-membered
heterocyclyl substituted by 1-5 R2c groups, wherein at least one of the R2c groups is unsubstituted Ce-Cir aryl
48. The compound of claim 43, or a salt thereof, wherein R2 is 5-membered heterocyclyl substituted by 1-5 R2c groups, wherein at least one of the R2c groups is 5- to lO- membered heteroaryl substituted by 0-5 Ci-Ce alkyl.
49. The compound of claim 41, or a salt thereof, wherein R2 is 4- to 6-membered
heterocyclyl substituted by 1-5 Ric groups, wlierein at least one R2c group is -C(0)R3, ~C(Q)QR5, or -S(0)2R5, wherein each R5 is independently Ci-C& alkyl.
50. The compound of claim 41, or a salt thereof, wherein R2 is 4- to 6-membered
heterocyclyl substituted by 1-5 R2c groups, wherein at least one R2c group is oxo.
51. The compound of claim 41, or a salt thereof, wherein R2 is 4- to 6-membered
heterocyclyl substituted by 2-5 R2c groups, wherein each R2c is independently selected from halogen, Ci-Ce alkyl, -C(0)R5, and -C(0)0R5.
52. The compound of claim 49, or a salt thereof, wherein R2 is 4- to 6-membered
heterocyclyl substituted by 2-5 R2c groups, wherein at least one R2c group is Ci~
Ce alkyl substituted by 0-5 halogen and at least one R2c group is -C(0)R5
or -C(0)0R5.
53. The compound of claim 41, or a salt thereof, wherein R2 is azetidinyl, pyrrohdinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxabicyclohexanyl, oxabicyclooctanyl, tetrahydro-2H-thiopyranyl, morpholinyl, or benzodioxanyl, each of which is substituted by 0-5 R2c groups.
54. The compound of claim 9, or a salt thereof, wherein R2 is C6-C14 aryl substituted by 0- 5 R2d groups.
55. The compound of claim 54, or a salt thereof, wherein R2 is unsubstituted Ce-Cio aryl.
56. The compound of claim 54, or a salt thereof, wherein R2 is Ce-Cio aryl substituted by 1-5 Rid groups, wherein each R2d is independently selected from halogen, Ci-Ce alkyl, CB-CS cycloalkyl, 3- to 12-membered heterocydyl, 5- to lO-membered heteroaryl, -CN, and -OR3, wherein the Ci-Ce alkyl, Cs-Cs cycloalkyl, 3- to 12-membered heterocydyl and 5- to lO-membered heteroaryl of R2d are each independently substituted by 0-5 halogen, Ci-C& alkyl or OR8.
57. The compound of claim 56, or a salt thereof, wherein R2 is Ce-Cio aryl substituted by 1-5 R-'a groups, wherein at least one of die R2d groups is halogen
58. The compound of claim 56, or a salt thereof, wherein R2 is Ce-Cio aryl substituted by 1-5 R2d groups, wherein at least one of the R2d groups is Ci-Ce alkyl, wherein the Ci- Ce alkyl of R2d is substituted by 0-5 R4a groups.
59. The compound of claim 58, or a salt thereof, wherein R2d is C1-C2 alkyl substituted by 1-5 R4a groups, wherein each R4a groups is independently selected from halogen and OR8.
60. The compound of claim 56, or a salt thereof, wherein R2 is phenyl substituted by 1-5 R2d groups, where at least one of the R2d groups is C3-C6 cycloalkyl.
61. The compound of claim 56, or a salt thereof, wherein R2 is phenyl substituted by 1-5 R2d groups, wherein at least one of the R2d groups is 6-membered heterocydyl
62. The compound of claim 56, or a salt thereof, wherein R2 is phenyl substituted by 1-5 R2d groups, wherein at least one of the R2d groups is 5- to 6-membered heteroaryl, wherein the heteroaryi of R2d is substituted by 0-5 Ci-Ce alkyl groups.
63. The compound of claim 56, or a salt thereof, wherein R2 is phenyl substituted by 1-5 R2d groups, wherein at least one of the R2d groups is -OR5, wherein each R5 is independently selected from C1-C2 alkyl substituted by 0-5 groups selected from halogen and -OR10.
64. The compound of claim 56, or a salt thereof, wherein R2 is phenyl substituted by 2-5 R2d groups, wherein each R2d is independently selected from halogen, Ci-Ce alkyl, - CN, and -OR3.
65. The compound of claim 64, or a salt thereof, wherein R2 is phenyl substituted by 2-5 R2a groups, wherein at least two of the R2d groups are halogen.
66. The compound of claim 64, or a salt thereof, wherein R2 is phenyl substituted by 2-5 R2d groups, wherein at least one of the R2d groups is Ci-C& alkyl and at least one of the R2d groups is selected from the group consisting of halogen, -CN, and -OR5.
67. The compound of claim 54, or a salt thereof, wherein R2 is phenyl, indanyl, or 1, 2,3,4- tetrahydronaphthalenyi, each of which is substituted by 0-5 R2d groups.
68. The compound of claim 9, or a salt thereof, wherein R2 is 5- to 10-membered
heteroaryl substituted by 0-5 R2e groups.
69. The compound of claim 68, or a salt thereof, wherein R2 is unsubstituted 5- to 10- membered heteroaryl.
70. The compound of claim 68, or a salt thereof, wherein R2 is 5- to 10-membered
heteroaryl substituted by 1-5 R2e groups, wherein each R2e is independently selected from halogen, Ci-Ce alkyl, and -OR5.
71. The compound of claim 70, or a salt thereof, wherein R2 is 5- to 10-membered
heteroaryl substituted by 1-5 R2e groups, wherein at least one of the R2e groups is halogen.
72. The compound of claim 70, or a salt thereof, wherein R2 is 5- to 10-membered
heteroaryl substituted by 1-5 R2e groups, wherein at least one of the R2e groups is Ci- Cr alkyl, wherein the C1-C4 alkyl of R2e is substituted by 0-5 halogen groups.
73. The compound of claim 70, or a salt thereof, wherein R2 is 5- to 10-membered
heteroaryl substituted by 2-5 R2e groups, wherein each R2e is independently selected from halogen, Ci-Ce alkyl, and -CN.
74. The compound of claim 73, or a salt thereof, wherein R2 is 5- to 10-membered
heteroaryl substituted by 2-5 R2e groups, wherein at least two of the R2e groups are halogen.
75. The compound of claim 73, or a salt thereof, w'herein R2 is 5- to 10-membered
heteroaryl substituted by 2-5 R2e groups, w'herein at least two of the R2e groups are Ci~C& alkyl.
76. The compound of claim 73, or a salt thereof, wherein R2 is 5- to 10-membered
heteroaryl substituted by 3-5 R2e groups, wherein each R2e is independently selected from halogen, Ci-Ce alkyl, and -CN.
77. The compound of claim 68, or a salt thereof, wherein R2 is pyrazolyl, pyridyl,
pyrimidinyl, indazolyl, pyrrolopyridinyl, quinolinyl, or 4,5,6,7-tetrahydro-indazolyl, each of which is substituted by 0-5 R2e groups.
78. The compound of claim 9, or a salt thereof, wherein R2 is -OR21.
79. The compound of claim 78, or a salt thereof, wherein R2 is -OR21, wherein R2f is selected from the group consisting of Ci-Ce alkyl, Cs-Cs cycloalkyl, 3- to 12- membered heterocyclyl, Ce-Cw aryl, and 5- to 10-membered heteroaryl.
80. Idle compound of claim 79, or a salt thereof, wherein R2t is Ci-Ce alkyl substituted by 0-5 R2! groups.
81. The compound of claim 80, or a salt thereof, wherein R21 is unsubstituted Ci-Ce alkyl.
82. The compound of claim 80, or a salt thereof, wherein R2f is Ci-Ce alkyl substituted by
1-5 R21 groups, wherein each R21 is independently selected from the group consisting of halogen, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, Ce-
C14 aryl, 5- to 10-membered heteroaryl, -OR5, -NR5C(0)R6 and -NR5C(0)0R6, wherein the Ci -Ce alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, Ce- C14 aryl, and 5- to 10-membered heteroaryl of R21 is substituted by 0-5 groups selected from the group consisting of halogen, -CN, -QRS, and Ci-Ce alkyl optionally substituted by halogen.
83. The compound of claim 82, or a salt thereof, wherein R2f is Ci-Ce alkyl substituted by 1-5 R21 groups, wherein at least one of the R21 groups is halogen.
84. The compound of claim 82, or a salt thereof, wherein R2t is Ci-Ce alkyl substituted by 1-5 R21 groups, wherein at least one of the R2i groups is phenyl.
85. The compound of claim 82, or a salt thereof, wherein R2f is Ci-Ce alkyl substituted by 1-5 R2! groups, wherein at least one of the R2i groups is -NR5C(0)0R6, wherein R5 is hydrogen and R6 is Ci-Ce alkyl.
86. The compound of claim 79, or a salt thereof, wherein R2f is CVCs cycloalkyl
substituted by 0-5 R2* groups.
87. The compound of claim 86, or a salt thereof, wherein R2t is unsubstituted
Ci-Cs cycloalkyl.
88. The compound of claim 86, or a salt thereof, wherein R2f is C3-Cs cycloalkyl
substituted by 1 -5 R2i groups, wherein each R21 is independently selected from the group consisting of halogen, Ci-Ce alkyl, Ci-Ce alkynyl, Ce-Cir aryl, and 5- to 10- membered heteroaryl, wherein the Ci-Ce alkyl, Ci-Ce alkynyl, Ce-Cw aryl, and 5- to 10-membered heteroaryl of R21 are substituted by 0-5 groups selected from the group consisting of Ci-Ce alkyl and Ce-C aryl .
89. The compound of claim 88, or a salt thereof, wherein R2f is CVCe cycloalkyl substituted by 1-5 R21 groups, wherein at least one R21 group is Ci alkyl.
90. The compound of claim 88, or a salt thereof, wherein R2f is C3-C6 cycloalkyl
substituted by 1-5 R2s groups, wherein at least one R·' group is C2 alkynyl substituted by 0-1 phenyl group.
91. The compound of claim 88, or a salt thereof, wherein R2f is Cii-Ce cycloalkyl
substituted by 1-5 R2i groups, wherein at least one R2 group is phenyl substituted by 0-3 Ci-Cfi alkyl groups or is pyrazolyl substituted by 0-3 Ci-Ce alkyl groups, which Ci-Ce alkyl groups on phenyl or pyrazolyl of R2‘ may be the same or different.
92. The compound of claim 79, or a salt thereof, wherein R2f is 3- to 12-membered
heterocyclyl substituted by 0-5 R2' groups.
93. The compound of claim 92, or a salt thereof, wherein R2t is unsubstituted 3- to 12- membered heterocyclyl.
94. The compound of claim 92, or a salt thereof, wherein R2f is 3- to 12-membered
heterocyclyl substituted by 1-5 R21 groups, wherein each R2i is independently selected from the group consisting of Ci-Ce alkyl, C -Ce alkynyl, Ce-Cir aryl, -C(0)R3, -C(Q)QR3, and -S(0).'R\
95. The compound of claim 94, or a salt thereof, wherein R2t is 3- to 12-membered
heterocyclyl substituted by 1-5 R21 groups, wherein at least one R2i group is Ci- Ce alkyl or Ci-Ce alkynyl, each of which is substituted by 0-1 phenyl group.
96. The compound of claim 94, or a salt thereof, wherein R2f is 3- to 12-membered
heterocyclyl substituted by 1-5 R21 groups, wherein at least one R21 group is Ce- Ci4 aryl substituted by 0-5 R4a groups, wherein each R4a is independently selected from the group consi sting of halogen and Ci-Ce alkyl.
97. The compound of claim 94, or a salt thereof, wherein R2t is 3- to 12-membered
heterocyclyl substituted by 1-5 R21 groups, wherein at least one R2i group is -C(Q)R5, wherein R3 is Ci-Ce alkyl.
98. The compound of claim 94, or a salt thereof, wherein R2f is 3- to 12-membered
heterocyclyl substituted by 1-5 R2 groups, wherein at least one R2’ group is
-C(Q)QR5, wherein R3 is Ci-Ce alkyl.
99. The compound of claim 94, or a salt thereof, wherein R2f is 3- to l2-membered
heterocyclyl substituted by 1-5 R2' groups, wherein at least one R2i group is -S(O) ·K3. wherein R3 is Ci-Ce alkyl. 100 The compound of claim 94, or a salt thereof, wherein R2f is 3- to l2-membered heterocyclyl substituted by 2-5 R21 groups, wherein at least one R21 group is
-C(Q)R5, -C(0)0R5, or -S(0)2R5, wherein R5 is Ci-Ce alkyl .
101 The compound of claim 92, or a salt thereof, wherein R2t is azetidinyi, pyrrolidinyl, or tetrahydropyranyl, each of which is optionally substituted by 0-5 R2i.
102 The compound of claim 79, or a salt thereof, wherein R2f is Ce-Cu aryl substituted by 0-5 R2 groups.
103. The compound of claim 102, or a salt thereof, wherein R2f is unsubstituted
Ce-Ci4 aryl .
104. The compound of claim 9, or a salt thereof, wherein R2 is -NR2gR2h.
105. The compound of claim 104, or a salt thereof, wherein R2g is hydrogen and R2h is Ci-Ce alkyl substituted by 0-5 halogen.
106. The compound of claim 104, or a salt thereof, wherein R2g is Ci-Ce alkyl substituted by 0-5 halogen and R2li is C1-C6 alkyl substituted by 0-5 halogen.
107. The compound of any one of claims 1-106, or a salt thereof, wherein G is -C(Q)R2
and R2 is selected from the group consisting of:
Figure imgf000324_0001
Figure imgf000324_0002
Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
326
Figure imgf000328_0001
Figure imgf000329_0001
Figure imgf000330_0001
29
Figure imgf000331_0001
108. Tlie compound of any one of claims 1-106, or a salt thereof, wherein G is -C(Q)R2 and R2 is selected from the group consisting of:
Figure imgf000331_0002
Figure imgf000332_0001
109. The compound of any one of claims 1-106, or a salt thereof, wherein G is -C(0)R2 and R2 is selected from the group consisting of:
Figure imgf000333_0001
Figure imgf000333_0002
Figure imgf000334_0001
Figure imgf000335_0001
110. The compound of any one of claims 1-8, or a salt thereof, wherein G is R3.
111. The compound of claim 110, or a salt thereof, wherein R3 is 5 - to 10-me inhered heteroaryl substituted by 0-5 R3e groups, wherein each R3e group is independently selected from halogen; Ci-Ce alky] optionally substituted by halogen; 5- to 10- membered heteroaryl optionally substituted by halogen or Ci-Ce alkyl; and Ci-Ce a!koxy.
112. The compound of claim 110, or a salt thereof, wherein R3 is unsubstituted 5- to 10- membered heteroaryl.
113. The compound of claim 110, or a salt thereof, wherein R3 is pyrimidinyl or
quinazolinyl .
1 14. The compound of claim 1 10, or a salt thereof, wherein R3 is 5- to lO-membered
heteroaryl substituted by 1-5 R3e groups, wherein each R3e group is independently selected from halogen, CI-CG alkyl, and CG-CU aryl.
115. The compound of claim 110, or a salt thereof, wherein R3 is 5- to 10-membered
heteroaryl substituted by 1-5 R3e groups, wherein at least one R3e group is halogen.
116. The compound of claim 110, or a salt thereof, wherein R3 is 5- to 10-membered
heteroaryl substituted by 1-5 R3e groups, wherein at least one R3e group is C1-C4 alkyl.117. The compound of claim 110, or a salt thereof, wherein R3 is 5- to lO-membered
heteroaryl substituted by 1-5 R3e groups, wherein at least one R3s group is phenyl.
118. The compound of claim 110, or a salt thereof, wherein RJ is 5- to 10-membered
heteroaryl substituted by 2-5 R3e groups, wherein at least one R3e group is CI-CG alkyl, and wherein at least one R3e group is CG~CI4 aryl.
119. The compound of claim 110, or a salt thereof, wherein G is R3 and R3 is selected from
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000337_0002
, wherein each R3e is independently R4.
The compound of claim 110, or a salt thereof, wherein G is R3 and R3 is selected from
Figure imgf000337_0003
Figure imgf000338_0001
121 The compound of claim 110, or a salt thereof, wherein G is R3 and R3 is selected from
Figure imgf000338_0004
The compound of any one of claims 1-121, or a salt thereof, wherein R2 is 5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl optionally substituted by R4.
The compound of claim 1, or a salt thereof wherein the compound is selected from
Figure imgf000338_0002
124. The compound of claim 1, or a salt thereof, wherein the compound is selected from
H H the group consisting of:
Figure imgf000338_0003
Figure imgf000339_0001
125. A compound selected from one of:
Compound Nos. 1-209 in Table 1, or a salt thereof;
Compound Nos. 210-329 in Table 2, or a salt thereof; or
Compound Nos 1-329 in Tables 1 and 2
126. A compound selected from the group consisting of:
N-(2-chloro-3-fluorobenzoyl)-0-(4-(5,6,7,8-tetraliydro-l,8-naphthyridin-2- yl)butyi)homoserine; N-(l-methyl-lH-indazole-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro-l,8- naph†hyridin-2-yl)butyl)homoserine; N-(4,4~dif!uorocyclohexane~l -carbonyl)-0-(4-(5, 6,7,8- tetrahydro-L8-naphthyridin-2-yl)butyl)homoserine; N-pentanoyl-0-(4-(5,6,7,8-tetrahydro- l,8-naphtliyridin-2-yl)butyl)homoserine; N-(3-fluoro~5~(trifluoromethyi)benzoyi)-Q-(4-
(5 ,6,7, 8-tetrahydro- 1 , 8-naphthyridin -2-y] )butyl)homoserine ; N-(3 -fluoro-5 - (trifluoromethyl)benzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-pentanoyl-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl)ethyl)cyclobutyl)homoserine; N-(tert-butoxycarbonyl)-0-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)homoserine; N-(4-fluorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(4-chlorobenzoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(3-fluorobenzoyl)-0-(3-(2- (5,6,7,8-tetrahydro-l ,8-naphthyridin-2-y])ethyi)cyclobutyl)homoserine; N-(3-chlorobenzoyl)- 0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphthyridin-2-yi)ethyl)cyclobutyl)homoserine; N-(2- chlorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethy3)cyclobutyl)homoserine; N~(2-fluorobenzoyi)-0-(3-(2~(5,6,7,8-tetrahydro~l,8~ naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(2,3-difluorobenzoyl)-0-(3-(2-(5,6,7,8- tetrahydro-L8-naphthyridin-2-yl)ethyi)cyclobutyi)homoserine; N-(2,4-difluorobenzoyl)-0- (3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yi)ethyl)cyclobiityl)homoserme; N-(2-chloro-4- fluorobenzoyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphtliyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(3-chloro-5-fluorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro- L8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(3-chloro-2-fluorobenzoyl)-0-(3-(2- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(3,5- difluorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydrol,8-naphthyridin-2- yl)ethyl)cyclobuty])hornoserine; N-(2,3-dichlorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)eihyl)cyclobutyl)homoserine; N-(2-chloro-6-fluorobenzoyl)-0-(3-(2- (5 ,6, 7, 8-tetraliydro- 1 , 8-naphtliyridin-2-yl)eihy l)cycIobui l)homoserine ; N -(2,6- difluorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyl)cyc!obutyl)homoserine; N-(2,5-difluorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(3 ,4-dichlorobenzoyl)-0-(3-(2-(5, 6,7,8- tetrahydro~l,8-naphthyridin-2~y3)ethyi)cyclobutyi)homoserine; N-picolinoyl-0-(3-(2- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)hornoserine; N-nicotinoyl-0-(3- (2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(l-methyl-lH- indazole-4-carbonyl)-0-(3-(2-(5,6,7,8-tetra3iydro-l,8-naphtiiyndin-2- yl)ethyl)cyclobutyl)homoserine; N-(2 -methyl-2H-indazole-6-carbonyl)-0-(3-(2-(5, 6,7,8- tetrahydro- 1 ,8-n¾)hthyridm-2-yl)ethyl)cyclobutyl)homoserine; N-(2-methyl-2H-indazole-5- carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N- (l-metliyl-lH-pyiTolo[2,3-b]pyridine-4-carbonyI)-0-(3-(2-(5,6,7,8-ietrahydiO-l,8- naphthyridin-2-yl)ethyI)cyclobutyl)homoserine; N-(2 -ethylbutanoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-L8-naphthyridin-2-y3)ethyl)cyclobutyl)homoserine; N-( l-methyl-lH-pyrrolo[2,3- b]pyridine-5-carbonyi)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethy3)cyc3obuty!)homoserine; N-(3-(hydroxymethyl)benzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-
1.8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserme; N-(quinoline-5-carbonyl)-0-(3-(2- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobut>'l)homoserine; N-(2- cycIopropylbenzoyl)-0-(3-(2-(5,6,7,8-tetra3iydro-l,8-naphtliyridin-2- yl)ethy3)cyc3obutyl)homoserine; N-(quinoline-7-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)eihy3)cyclobuly3)homoserine; N-(quinoline-6-carbonyl)-0-(3-(2-(5, 6,7,8- tetrahydro-L8-naphthyridin-2-yl)etiiyl)cyciobiityl)homoserme; N-(quinoline-8-carbonyl)-0- (3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridm-2-yl)ethyl)cyclobutyl)homoserine; N-(3- cyclopropylbenzoyl)-0-(3-(2 -(5,6,7, 8-tetraJhydro-l, 8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(4-cyclopropylbenzo}d)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyciobutyl)homoserine; N-isonicotinoyl-0-(3-(2-(5,6,7,8-tetrahydro-
1.8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserine; N-(3-ethylpentanoyl)-0-(3~(2-(5,6,7,8- tetrahydro-l ,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserine; N-(2~chloro-3~
fluorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(3,4-difluorobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethy!)cyclobuty!)homoserine; N-(3-ethylpentanoyl)-0-(3~(2-(5, 6,7,8- tetrahydro-l ,8-naphthyridin-2-yl)ethyl)cyclobut\l)homoserine; N-isonicotinoyl-0-(3-(2- (5,6,7, 8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; 0-(3-(2-(5, 6,7,8- tetrahydro-L8-naphthyridin-2-yl)etliyl)cyciobutyl)-N~(3-(thiazol-5-yl)benzoyl)homoserine; N-(3-hydroxy-2-phenylpropanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyc!obutyl)homoserine; N-(3-( l-methyl-lH-pyrazol-4-yl)benzoyl)-0-(3-(4-(5, 6,7,8- tetraliydro-l,8-naphtiiyridin~2-yl)butyl)cyclobutyl)homoserme; N-(3-(l-methyl-lH-pyrazoi- 4-yl)benzoyl)-0-(4-(5,6,7,8-tetraliydro-l,8-naphtliyridin-2-yl)butyl)homoserine; N~(2- hydroxy-2-phenylacetyl)-0-(4~(5,6,7,8-tetrahydro~l ,8~naphthyridin~2~y!)butyl)hornoserine; N-(2-hydroxy-2-phenylacetyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)- homoserine; N~(2diydroxy-2-phenyiacetyl)-Q-(3~(2-(5,6,7,8-tetrahydro-L8-naphthyridin-2- yl)ethyl)cyelobuty!)homoserine; N-(l-phenylcyclopropane-l-carbonyl)-0-(3-(2-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(2-methyl-2- phenylpropanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-L8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(l-phenylcyciobutane-l-carbonyl)-0-(3-(2-(5,6,7,8- tetrahydro~l,8-naphthyridin-2~y3)ethyi)cyelobutyi)homoserine; N-(2,2-dimethyl-3- phenylpropanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(tert-butoxycarbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(2-(4-fluorophenyl)-2-methylpropanoyl)- 0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyc]obutyl)homoserine; N-(3- methyloxetane-3-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(3-hydroxy-2, 2-dimethylpropanoyl)-0-(3-(2-(5, 6,7,8- tetrahydro- 1 ,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoseiine; N-(3-methoxy~2,2~ dimethylpropanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yi)eiliyl)cyc3obutyl)homoserine; N-(2-meth}d-2-(pyridin-3-yl)propanoyl)-0-(3-(2-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(2,3-dihydro-lH-indene-2- carbony!)~0~(3-(2-(3,0 ,8-tetrahydro~l,8~naphthyridin-2~yl)ethyl)cyc!obutyl)hornoserine; N- (3-cyano-2,2-dirnethylpropanoyl)-0-(3-(2-(5,6,7,8-ietrahydro-L8-naphthyridm-2- yl)ethyl)cyclobutyl)homoserine; N-pivaloyl-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphtliyridin~2~ yl)ethyl)cyclobutyl)homoserine; N-(2, 3 -dihydro- lH-indene- 1 -carbonyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l ,8-naphthyridin-2-y!)ethyi)cyclobutyi)homoserine; N-((neopentyloxy)carbonyl)- 0-(3-(2-(5,0,7,8-tetrahydro-l ,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-((l- methylcyclopropoxy)carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphthyridm-2- yl)ethyl)cyclobutyl)homoserine; N-(( l-methylcyclobutoxy)carbonyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l ,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; 0-(3-(2-(5,6,7,8-tetraJhydro-
1.8-naphthyridin-2-yl)ethyl)cyclobuty l)-N-((( 1 , 1,1 -trifluoro-2-methylpropan-2- yi)oxy)carbonyl)homoserine; N-(isopropoxycarbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(dietliylcarbamoy3)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridm-2-yl)ethyl)cyclobutyl)homoserine; N-(tert-butylcarbamoyl)-0- (3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(tert- butyl(methyl)carbamoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobuty])homoserine; N-(isopropyl(methyl)carbamoyl)-0-(3-(2-(5,6,7,8- tetrahydro-L8-naphthyridin-2-y3)ethyl)cyclobutyl)homoserine; N-(diisopropylcarbamoyl)-0- (3-(2-(5,6,7,8-tetrahydiO-l,8-naphthyridin-2-yl)ethyl)cyclobiityl)homoserme; N-(3,3- dimethylbutanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyc!obutyl)homoserine; N-(3-methylbutanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyc3obutyl)honioserine; N-(2-cyclobuty3acetyl)-0-(3-(2-(5, 6,7,8- tetrahydro- 1 ,8-naphthyridm~2-y3)ethyl)cyclobutyl)homoserine: N-(2-( 1 - methylcyclopropyl)acetyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridm-2- yl)ethyl)cyclobutyl)homoserine; N-(2-wclopropylacet> )-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphtliyridin-2-yl)eihyl)cyc3obutyl)homoserine; N-(((l-(tert-butoxycarbonyl)-3- methylazetidin-3-yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyc!obutyl)homoserine; N-(((3-methyl-l -(methylsulfonyl)azetidin-3- yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyi)cyclobutyl)homoserine; N-(((l-acetyl-3-methyiazetidin-3-yl)oxy)carbonyl)-0-(3-(2- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(((3- methylazetidin-3-yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-((cyclohexyloxy)carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro-
1.8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(isobutoxycarbonyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridm-2-yl)ethyl)cyclobutyl)homoserine; N-(((pyrro]idin-3- yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(4-(methylsulfonyl)butanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-
1.8-naplithyridin-2-yl)ethyl)cyclobutyl)homoserine; N-((( 1 -(methylsulfonyl)pyrrolidm-3- yl)oxy)carbonyl)-0-(3-(2 -(5,6,7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(((l-(tert-biitoxycarbonyl)pyrrolidin-3-yl)oxy)carbonyl)- 0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyi)homoserine; N-(((l- acetylpyrrolidin-3-yl)oxy)carbonyl)-0-(3-(2-(5,6, 7, 8-tetrahydro- l,8-naphthyridin-2- yl)ethyl)cyclobuty])hornoserine; N-((l -phenylethoxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro- 8-naphthyridin-2-yl)etliyl)cyclobutyl)homoserine; N-((2-phenylcyclobutoxy)carbonyl)-0- (3-(2-(5,6,7,8-tetxahydro-l,8-naphthyridin-2-yl)ethyl)cyclobiityl)homoserine; N-((3- phenylcyclobutoxy)carbonyl)-0-(3-(2-(5,6,7,8-†etrahydro-l ,8-naphthyridin-2- yl)ethyl)cyc!obutyl)homoserine; 2-((tert-butoxycarbony])amino)-3-methyl-4-(3-(2-(5, 6,7,8- tetraliydro-l,8-naphthyridm-2-yl)ethyl)cyclobutoxy)butanoic acid; N-(((2- phenylcyclohexyl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobuty])hornoserine; N-(((l -(tert-butoxycarbonyl)azetidin-3-yl)oxy)carbonyl)-0- (3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethy )cyclobuty )homoserine; N-(((4- phenyicyclohexyl)oxy )carbonyl)-0-(3-(2-(5, 6,7, 8-tetrahydro- l,8-naphthyridin-2- yl)ethyl)cyclobuty!)homoserine; N-(((l-acetylazetidin-3-yl)oxy)carbonyl)-0-(3-(2-(5, 6,7,8- tetrahydro- 1 ,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-((( 1 -((tert- butoxycarbonyl)amino)propan-2-yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydrc -l,8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(((l-acetamidopropan-2-yl)oxy)carbonyl)- 0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(((2-(3,5- dimethyl-l H-pyrazol-l-yl)cyclopentyl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphtliyiidin-2-yl)eihyl)cyclobutyl)-homoserine: N-(((2-(3,5-dimethyl-lH-pyrazol-l- yl)cyciohexyl)oxy)earbonyl)-Q-(3 -(2-(5 ,6, 7, 8-tetrahydro- 1 , 8-naphthyridin-2- yl)ethyl)cyclobutyl)-homoserine; N-(((l-(tert-butoxycarbonyl)-3-(3-ch]orophenyl)azetidin-3- yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(((l-(tert-butoxycarbonyl)-3-(4-isopropylphenyl)azetidin- 3-yl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(((l-(tert-butoxycarbonyl)-3-(phenylethynyl)azetidin-3- yi)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphthyridin-2- yl)ethyl)cyc3obuty!)homoserine; N-(l-(tert-butoxycarbonyl)piperidine-4-carbonyl)-0-(3-(2- (5,6,7,8-tetrahydro-l ,8-naphthyridin-2-y])ethyl)cyclobutyl)homoserine; N-(3,3- difluorocyclohexane-l-carbonyl)-0-(3-(2-(5, 6, 7, 8-tetrahydro- l ,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(2-ethyl-4,4-difluorobutanoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridm-2~y3)ethy3)cyclobutyi)-homoserine; N-(((2- (phenylethynyl)cyclohexyl)oxy)carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)-homoserine; N-(2-cyclohexyl-2-methylprc panoyl)-0-(3-(2-(5,6,7,8- teiraIiydfQ-l,8-naphthyridm-2-yl)eihyi)cyclobutyi)homosefine: N-(2-(pyridin-2-yl)benzoyl)- 0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(2~ethy3- 4,4,4-trifluorobutanoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(2-morpholinobenzoyl)-0-(3-(2 -(5, 6, 7, 8-tetrahydro-l, 8- naptithyridin-2-yl)eihyl)cyc3obutyl)homoserine; N-(2-ethyl-2-phenylbutanoyl)-0-(3-(2- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(lH-pyrrolo[3,2- b]pyridine-7-carbonyl)-0-(3-(2 -(5,6,7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyi)cyclobutyl)homoserine; N-(4-cyanotetrahydro-2H-pyran-4-carbonyl)-0-(3-(2- (5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(l-(tert- butoxycarbonyl)-3-methylazetidine-3-carbonyl)-0-(3-(2-(5, 6,7, 8-tetrahydro-l, 8- naphthyridin-2-yl)eihyl)cyclobutyl)homoserine; N-(l-(tert-butoxycarbonyl)azetidine-3- carbonjd)-0-(3-(2-(5, 6,7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N- (l-(methylsulfonyl)piperidine-3-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)-homoserine; 0-(3-(2 -(5,6, 7, 8-tetrahydro-l , 8-naphthyridin-2 - yl)e1hyl)cyc3obutyl)-N-(4,5,6,7-tetrahydro-lH-indazo3e-6-carbonyl)-homoserine; 0-(3-(2- (5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl)cyciobutyl)-N-(4, 5,6, 7-tetrahydro-lH- indazole-7-carbonyl)homoserine; N-(4-methyltetrahydro-2H-pyran-4-carbonyl)-0-(3-(2- (5,6,7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethy3)cyclobuty3) homoserine; N-(l-methyl-4,5,6,7- tetrahydro-lH-indazole-6-carbonyl)-0-(3-(2-(5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl)cyelobuty!)-homoserine; N-(l-ethyl-4,4-difluorocyclohexane-l-carbonyl)-0-(3-(2- (5,6,7,8-tetrahydro-l ,8-naphthyridin-2-y])ethyl)cyclobutyl)homoserine; N-(l-(6- methylindoline-l-carbonyl)cyclopropane-l-carbonyl)-0-(3-(2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(4-(((tert- butoxycarbonyl)ainino)methyl)tetrahydro-2H-pyran-4-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-
1.8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(l-(pyridin-3-ylmethyl)cyclopropane- l-carbonyl)-Q-(3-(2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridm-2-y3)ethyi)cyclobutyi)homosefine: N-(3-chloro-5-methylisonicotinoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)homoserine; N-(4-methyltetrahydro-2H-pyran-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro-
1.8-naphthyridin-2-yl)butyl)homoserine; N-(2,6-dichlorobenzoyl)-0-(4-(5,6,7,8-tetrahydro-
1.8-nap3iihyridin-2-yl)butyi)homoserine: N-(3,5-dichloroisonicotinoyl)-0-(4-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)homoserine; N-(l-(4-(tert-butyl)phenyl)cyclobutane- l-carbony!)-0-(3-(2-(5, 6,7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(4-methyltetrahydro-2H-pyran-4-carbonyl)-0-(3-(2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin- 2-yl)ethyI)cyciobutyI)homosenne; 0-(3-(2~(5,6,7,8-tetraliydro-l,8~naphtliyridin-2- yl)ethy3)cyclobutyl)-N-(4~(trifluoroniethyi)tetrahydro-2H-pyran~4-carbonyl)homoserine; N- (3~chloro-5-methy]isonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridm-2~ yl)etliyl)cyclobutyl)homoserine; N-(3,5-dichloroisonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro- l,8~naphtliyridin-2-yl)eihyl)cyclobutyl)homoserine; N-(bicycio 2.2.2]octane-2-carbonyl)-0- (3-(2-(5;,6,7,8~tetraliydro-i;,8-naphthyndin-2-yi)ethyl)cyclobiit5'l)hoiTiosenne; N-(2-methy3~ l,2,3,4-tetrahydronaphAalene-2-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-((methylsulfonyl)profyl)-0-(3-(2-(5,6,7,8-tetrahydrc)-l,8- naphthyridm-2-yl)ethy!)cyclobuty!)homoserine; N-(2,4-dimethylnicotinoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l ,8-naplithyridin-2-y!)ethyi)cyclobutyi)homoserine; N-(4-phenyltetrahydro-2H- pyran-4-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yi)eiliyl)cyc3obutyl)3iomoserine; N-(4-cyano-2, 6-dimetliyIbenzoyI)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; 0-(3-(2-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-y])ethyl)cyclobuty'l)-N-(2,4,6-trimethylpyrimidine-5- carbonyl)homoserine; 0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)wclobutyl)-N- (2,4,6-trimethy lnicotinoy l)homoserine; N -( 3 -chloro-5 -fluoroisonicotinoyl)-0-(3 -(2-(5 ,6,7, 8- tetrahydro- 1 ,8-naphthyridin-2~y3)ethyi)cyclobutyi)homoserine; N~( 1 -(isoquinolin- 1 - yl)cyclopropane- 1 -carbonyl)-0-(3-(2-(5,6,7,8-tetrah} ro- 1 ,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(2-(pyridin-2-yl)spiro[3.3]heptane-2-carbonyl)-0-(3-(2- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethy3)cyclobuty3)homoserine; N-(2-(l-methyl-lH- pyrazol-4-y])tetrahydrofuran-2-carbony])-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyc3obutyl)homoserine; N-(2,4-dimethyl-6-oxo-l,6-dihydropyridine-3-carbonyl)-0- (3-(2-(5,6,7,8-tetraliydro-l,8-naphiliyridm-2-yI)ethyi)cyclobutyi)homoserine: N~(4,6~ dimethylpyrimidine-5-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethy l)cyclobutyl)homoserine ; N -(2 ,6-dichloro-4-(trif!uoromethyl)benzoyl)-0-( 3 -(2 - (5 ,6,7, 8-tetraliydro- 1 , 8-naphthyridin-2-yl)eihy l)cycIobuty l)homoserine ; N-(l-(2- fluorophenyl)cyclopropane-l-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyc!obutyl)homoserine; N-(l-(benzo[d][l,3]dioxol-5-yl)cyclohexane-l-carbonyl)-0- (3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(2,2- difluoro- 1 -(m-tolyl)cyclopropane- 1 -carbony l)-0-(3 -(2-(5 ,6,7, 8-tetrahydro- 1 ,8-naphthy ridin- 2-yl)ethyl)cyclobutyl)homoserine; 0~(3-(2-(5,6,7,8-tetraliydro-l,8-naphthyridin-2- yl)ethy!)cyclobuty])-N-( ! -(tetraliydro-2H-pyran-2-yl)cyclopropane- 1 -carbonyl)homoserine; N-(4-methoxy-2,6-dimethylbenzoyl)-0-(3-(2-(5,6, 7, 8-tetrahydro- l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(l-acetyl-4-(trifluoromethyl)piperidine-4-carbonyl)-0-(3- (2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(2,3- dihydrobenzo[b] [l,4]dioxine-2-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(l-(3-chlorobenzyl)cyclopentane-l-carbonyl)-0-(3-(2- (5,6,7,8-tetraliydro-l,8-naphthyridin-2-yl)elliyl)cycIobutyl)homoserine; 0-(3-(2-(5, 6,7,8- tetrahydro- 1 ,8-naphthyridin-2-yl)ethyl)cyciobutyl)-N-( 1 -(3- (trifluoromethoxy)pheny])cyclopropane-l-carbonyl)homoserine; N-(4-fluoro-2,6- dimethylbenzoyl)-0-(3-(2-(5,6,7,8-tetfahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)homoserine; N-(3,5-dimethylisonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-
1.8-naphth\Tidin-2-yl)ethyl)cyclobuty])homoserine; N-(2-(tert-butyl)pyrimidin-4-y])-0-(3-(2- (5,6,7, 8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)homoserine; N-(4-(tert- butyl)pyrimidin~2-yl)-0-(3-(2-(5,6,7,8~tetrahydro-L8-naphthyridin-2- yl)ethy3)cyc3obuty!)homoserine; 0-(3-(2-(l ,8-naphthyridin-2-yl)ethyl)cyclobutyl)-N- (quinazolin-4-yl)homoserine; N-(6-(tert-butyl)pyrirnidin-4-yl)-0-(3-(2 -(5,6,7, 8-tetrahydro-
1.8-naphihyridin-2-yl)ethyl)cyclobutyl)honioserine; 2-[(4-amino-2,6-dichloro- benzoyl)amino]-4-[3-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; N-(4-chloro-2,6-dimethylnicotinoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserme; 2-[(3-chloro-6-methyl- pyridine-2-carbonyl)ammoJ-4-[3~j2-(5,6,7,8-tetraliydro-l,8-naphiliyridm-2- yl)ethyl]cyclobutoxy]butanoic acid; N-(2,6-dimethylpiperidine-l-carbonyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserine; N-(2,5-dimethylpyrrolidine- l-carbonyl)-0-(3-(2-(5,6,7,8-ietrahydro-L8-naphthyridin-2-y3)ethyl)cyclobutyl)-homoserine; N-(2,6-<HcMoro-4-cyanobenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethy!)cyclobutyl)-homoserine; N-(2,6-dichloro-3-nitrobenzoyl)-0-(3-(2-(5 ,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserme; 4-[3-[2-(5,6,7,8-tetrahydro- l,8~napht3iyridin-2-yl)eiliyl]cyc3obutoxy]-2-[(l,2,4-trimethyl-6-oxo-pyridine-3- carbonyl)aniino]butanoic acid; N-(2-chloro-4-cyano-6-methylbenzoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserine; N-(3-bromo-5-chloro-2- fluoroisonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)- homoserine; 0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobiityl)-N-(5,6,7,8- tetrahydronaphtha3ene-l-carbonyl)-homoserine; N-(3-bromo-2,6-dimethylbenzoyl)-0-(3-(2- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobuty])-homoserine; 2-[(3-chloro-5- methoxy-pyridine-4-carbonyl)amino]-4-[3-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl]cyclobutoxy |butanoic acid: 2-[(2,6-dichloro-4-fluoro-benzoyl)amino]-4-[3-[2- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl]cyclobutoxy]butanoic acid; 2-[(2-chloro-6- fluoro-benzoyl)amino]-4-[3-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; N-(3-bromo-2-chloro-6-fluorobenzoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-L8-naphthyridin-2-yl)et3iy3)cyclobuty3)-homoserme; N-(2,4-dimethyl-6-oxo-l- phenyl-l,6-dihydropyridine-3-carbonyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)-homoserine; N-(5-bromo-2-hydroxyisonicotinoyl)-0-(3-(2-(5, 6,7,8- teiraIiydfG-l,8-naphthyridin-2-y3)e!hyl)cydobuiyl)-homoserine; N-(3-chloro-5- cyclopropylisonicotinoyl)-0-(3-(2-(5,6,7,8-†etrahydro-l ,8-naphthyridin-2- yl)ethyl)cyclobuty])-homoserine; N-(3-chloro-5-ethylisonicotinoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserine; N-(3-cyano-2,6- dimethylbenzoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)e1hyl)cyciobutyl)- homoserine; N-(3-bromo-5-fluoroisonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydio-l,8- naphthyridin-2-y])ethyl)cyclobut 'l)-homoserine; N-(2-methoxy-3,5-dimethylisonicotinoyl)- 0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserine; N-(3- chloro-5-(trifluoromethyl)isonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)-homoserine; N-(3-bromo-5-chloroisonicotinoyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserine; N-(2-(dimethylamino)-3,5- dimethylisonicotinoyi)-0-(3-(2-(5,6,7,8-tetraliydiO-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)- homoserine; N-(3-chloro-5-fluoro-2-methylisonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethyl)cyclobu1yl)-homoserine; N-(2,6-dichloro-3-cyanobenzoyl)-0-(3-(2- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserine; N-(3-methyl-5- (trifluoromethyl)isonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl)cyclobutyl)-homoserine; N-(2 -hydroxy-3, 5-dimethylisonicotinoyl)-0-(3-(2-(5, 6, 7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserine; N-(3-cyano-2-hydroxy-6- methylisonicotinoyl)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphthyridin-2-y3)ethyl)cyclobutyl)- homoserine; N-(5-chloro-3-fluoro-2-methylisonicotinoyl)-0-(3-(2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-y])ethyl)cyclobutyl)-homoserine; 2-[(6-methoxy-2,4-dimethyl-pyridine-3- carbonyi)aminoj-4-| 3-[2-(5,6,7 8-teirahydro-l,8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; 2 [2,6~dimetIiyl-4~[(4-metiiyIpiperazm-I- yl)methyl]benzoyl]amino]-4-[3-[2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; N-(3,5-dimethy]morpholine-4-carbonyl)-0-(3-(2- (5,6,7, 8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserine; 2-ff5-chloro-3- fluoro-2-[(4-methylpiperazin-l-yl)methyl]pyridine-4-carbonyl]amino]-4-[3-[2-(5,6,7,8- tetrahydro- l,8-naphthyridin-2-yl)ethyl]cyclobutoxy]butanoic acid; methyl 2-[(7-chloro-5- oxo-2, 3-dihydro- lH-indo]izine-8-carbonyl)amino]-4-[3-[2-(5, 6,7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl]cyclobutoxy]butanoate; 2-[(2,6-difluoro-4-hydroxy-benzoyl)aminol- 4-[3-[2-(5,6,7,8-tetrahydfo-l,8-naphthyridin-2-yl)ethyl]cyclobutoxyJbutanoic acid; 2-j(4- chloro-2-methyl-pyiazole-3-carbonyi)amino]-4-[3-[2-(5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; 2-[(2-methylpyrazole-3-carbonyl)amino]-4-[3-[2- (5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl]cyclobutoxy]biitanoic acid; N-(l- (phenylsulfonyl)piperidine-2-carbonyl)-0-(3-(2-(5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl)cyclobut>4)-homoserine; 2-(3,3-dimethylbutanoylamino)-4-[3-[2-(5,6,7,8-tetrahydro- L8-naphthyridin-2-yl)ethyi|cyclobutoxy]butanoic acid; 2-[(2-phenylacetyl)amino]-4-[3-[2- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl]cyclobutoxy]butanoic acid; 4-[3-[2-(5,6,7,8- tetrahydro-L8-naphthyridin-2-yl)etliy3]cyciobutoxy]-2-[(4, 4, 4-trifluoro-3, 3-dimethyl- butanoyl)amino]butanoic acid; 2-[(4,4-difluoro-3,3-dimethyl-butanoyl)amino]-4-[3-[2- (5 ,6,7, 8-tetrahydro- 1 , 8-naphthyridin-2-yl)ethyl] cyclobutoxyjbutanoic acid; 2- [ [2 - phenylpropanoyl]amino]-4-[3-[2-(5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethy3]cyc3obutoxy]butanoic acid; 2-[[2-(3, 5-difluorophenyl)acety!]amino]~4-[3-[2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-y3)ethyi]cyclobutoxy]butanoic acid; 2-[[2-(tert- butoxycarbonylamino)-l-methyl-ethoxy]carbonylamino]-4-[3-[2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl]cyclobutoxy]butanoic acid; 2-[(3,6-dimethylpyridine-2- carbonyl)amino]-4-[3-[2-(5,6,7,8-tetraliydro-l,8-naphthyridin-2- yl)ethyl]cyc3obutoxy]butanoic acid; 2-f(6-fluorochromane-2-carbonyl)amino]-4-[3-f2- (5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)etliyl]cyclobutoxy]biitanoic acid; 4-[3-| 2-(5, 6,7,8- tetrahy dro- 1 , 8 -naphthy ridin -2-yl )ethyl] cyclobutoxy] -2- [2- [3 -
(trifluoromethyl)phenyl]butanoylamino]butanoic acid; 2-[(3-chloro-5-methyl-pyridine-4- carbonyl)amino]-4-[3-[2-(5, 6,7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; 2-[(3-chloro-5-fluoro-pyridine-4-carbonyl)amino]-4-[3- [2 -(5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethy]]cyclobutoxy]butanoic acid; 2-[(4-cyano- 2,6-dimethyl-benzoyl)amino]-4-[3-|2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethy3]cyclobutoxy]butanoic acid; 2-[[4-(2-chlorophenyl)tetrahydropyran-4- carbonyl]amino]-4-[3-[2-(5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; 2-[(2-hydroxyindane-2-carbonyl)amino]-4-[3-[2- (5 ,6,7, 8-tetrahydro- 1 , 8-naphthyridin-2-yl)ethy 3 ] cyclobutoxy jbutanoic acid; 2 -[( 1 - cyclopropylcyclopropanecarbonyl)amino]-4-[3-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; 2-[[3-(difluoromethyl)-5,6,7,8-tetrahydro- [1, 2, 4]triazo]o[4,3-a]pyridine-6-carbony]]aminoj-4-[3-[2 -(5, 6,7, 8-tetrahydro-l, 8- naphthyridin-2-yl)eihyi|cyclobutoxy jbutanoic acid; 2-[(l- cyclopropylcyclobutanecarbonyl)amino]-4-[3-[2~(5,6,7,8-tetrahydro-l,8~naphtliyridin-2- yl)ethyl]cyclobutoxy]butanoic acid; 2-[[ 1 -(4-isopropylphenyl)cyclopentanecarbonyl]amino] - 4-[3-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-y])ethyl]cyclobutoxy]butanoic acid; 2- (bicyclo[2.2.2]octane-4-carbonylamino)-4-[3-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethyIjcyclobutoxyjbutanoic acid; 2-(3,4,5,6,7,7a-hexahydro-2H-benzofuran~3a- carbonylamino)-4-[3-[2 -(5,6,7, 8-tetrahydro-l , 8-naphthyridin-2- yl)ethyl]cyclobutoxy jbutanoic acid; 2-j [ 1 -(2-phenylethyl)cyclopropanecarbonyl]amino]-4-f3- [2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyl]cyclobutoxy jbutanoic acid; 2-[[4-(3- metiiylisoxazol-5-yl)tetrahydropyran-4-caibonyl]amino]-4-[3-[2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-y])ethyl]cyclobutoxy]butanoic acid; 2-[[l - (benzenesulfonyl)cyclopropanecarbonyl]amino]-4-[3-[2-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)ethyl]cyclobutoxy]biitanoic acid; 2-[(l- phenylcycloheptanecarbonyl)amino]-4-[3-[2-(5, 6,7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethyl]cyclobutoxy jbutanoic acid; 2-[(4-methylsulfonyltetrah} ropyran-4-carbonyl)aminoj- 4-[3-[2-(5, 6,7, 8-tetrahydro-l, 8-naphthyridin-2-yl)ethyljcyclobutoxyJbutanoic acid; 2-[[l-(4- sulfanioylphenyl)cyclopropanecarbonyl]amino]-4-[3-[2-(5,6,7,8-tetraliydro-l,8-naphtliyridin- 2-yl)ethyl]cyclobutoxy]butanoic acid; N-((phenylsulfonyl)prolyl)-0-(3-(2-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserinc; N-(5-chloro-3-fluoro-2-((4- methylpiperazin-l-yl)methyl)isonicotinoyl)-0-(3-(2-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)ethy!)cyclobutyl)-homoserine; N-(3-chloro-5-fluoro-2-((4-metiiylpiperazin-l- yl)methyl)isonicotmoyl)-0-(3-(2-(5,6,7,8-ietrahydiO-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)- homoserine; 2-(pyrimidin-4-}damino)-5-(3-(5,6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)propoxy)pentanoic acid; 2-[(3-chloro-5-methyl-pyridine-4-carbonyl)amino]-4-[4-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butoxyjbutanoic acid; 2-[(2,4-dimethylpyridine-3- carbonyl)aminoj-4-[4-(5, 6,7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butoxy]butanoic acid; 2-[(4- cyano-2,6-dimethyi-benzoyi)aminoj-4-[4-(5, 6,7, 8-tetrahydro-l, 8-naphthyridm-2- yl)butoxy]butanoic acid; 2-[(3, 5-dichloropyridine-4-carbonyl)amino]-4-[4-(5, 6,7,8- tetrahydro- 1 ,8-naphthyridin-2-yl)butoxy]butanoic acid; 2-[(3-chloro-5-fluoro-pyridine-4- carbomd)amino]-4-[4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butoxy]butanoic acid; N- (3,5-dimethylmorpholine-4-carbonyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)but>'l)- homoserine; N-(2,6-dichlorobenzoyl)-0-(4-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)butyl)- homoserine; N-(3,5-dimethylisonicotinoy])-0-(4-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)butyl)-homoserine; 2-[(2,4-dichloro-6-fluoro-benzoyl)amino]-4-[4-(5,6,7,8-tetrahydro-l ,8- naphtliyridin-2-yi)biitoxy]butanoic acid; 2-[(2,4-dimethyl-6-oxo-lH-pyridine-3- carbonyl)amino]-4-[4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butoxy]butanoic acid; N-(3- ch!oro-5-methoxyisonicotinoyl)~0~(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-y!)butyl)- homoserine; 2-[(2-chlofo-6-fluoro-benzoyl)aminoJ-4-[4-(5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl)butoxy]butanoic acid; N-(tert-butoxycarbonyl)-0-(4-(5,6,7,8-tetrahydro- 1,8- naphthyridin-2-yl)butyi)-homoserine; N-(5-bromo-2-hydroxyisonicotinoyl)-0-(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)-homoserine; N-(3-bromo-5-chloro-2- fluoroisonicotinoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)-homoserine; N- (2, 4-dimethyl -6-oxo- 1 -phenyl- 1 ,6-dihydropyridine-3-carbonyl)-0-(4-(5 ,6,7,8-tetrahydro- 1,8- naphthyridin-2-y])butyl)-homoserine; 0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridm-2-yl)butyl)- N-(5,6,7,8-tetrahydronaphthalene-l-carbonyl)-homoserine; N-(3-bromo-2,6- dimethylbenzoyl)-0-(4-(5,6,7,8-tetrahydro-L8-naphthyridin-2-yl)but\4)-homoserine; N-(3- chloro-5-fluoroisonicotinoyl)-0-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)- homoserine; N-(3-bromo-2-chloro-6-fluorobenzoyl)-0-(4-(5,6,7,8-tetrahydro-i,8- naphtliyridin-2-yl)biityl)-homoserme; 2-[(3-chloro-5-methoxy-pyridine-4-carbonyl)aminoJ-4- [2-methyl-4-(5,6,7,8-tetraliydro-l,8-naphtliyridin-2-yl)butoxy]butanoic acid; 2-[(3-chloro-5- fluoro-pyridine-4-carbonyl)amino]-4-[2-methyl-4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butoxy]butanoie acid; N-(3-chloro-5-fluoroisonicotinoyl)-0-(2-methyl-4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)-homoserine; N-(2,6-dichlorobenzoyl)-0-(2-methyl- 4-(5,6,7,8-tetraliydro-l,8-naphtliyridin-2-yl)butyl)-homoserine; N-(2-chloro-6- fluorobenzoyl)-0-(2-methyl-4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)biit>d)-homoserine; N-(4-fluoro-2-methylnicotinoyl)-0-(2-methyl-4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)-homoserine; 2-[(3-chloro-5-fluoro-pyridine-4-carbonyl)amino]~4-[2-hydroxy-4- (5,6,7,8-tetrahydro-l ,8-naphthyridin-2-y])butoxy]butanoic acid; 2-(l-methyl-lH-mdazole-4- carboxamido)-5-(3-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yd)propoxy)pentanoic acid; 2-(3- (l-metliyl-lH-pyrazol-4-yl)benzamido)-5-(3-(5,6,7,8-tetrahydiO-l,8-naphthyridin-2- yl)propoxy)pentanoic acid; 2-(2-chloro-3-f!uorobenzamido)-6-(2-(5,6,7,8-tetraliydro-l,8- naphthyridin-2-yl)ethoxy)hexanoic acid; 2-(3-( 1 -methyl- 1 H-pyrazol-4-yl)benzamido)-6-(2- (5,6,7, 8-tetrahydro-l,8-naphthyridin-2-yl)ethoxy)hexanoic acid; 2-(2-ethylbutanamido)-6-(2- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethoxy)hexanoic acid; 2-( 1 -methyl- lH-indazole-4- carboxamido)-6-(2-(5,6,7,8-tetrahydro-I,8-naplithyridin-2-yl)ethoxy)hexanoic acid; 2-({tert~ butoxycarbonyl)ammo)-5~(3-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)propoxy)pentanoic acid; Nhenzoyl-i)-(3-(2-(5, 6,7,8 Aetrahydro-1, 8-naphthyridin-2- yl)ethyl)cydobutyl)homoserine; N-(qidnazolin-4-yi)-0-(3-(2-(5,6,7,8-tetraliydro-i,8- naphthyridin-2-yl)ethyl)cyc3obutyl)homoserine; N-(8-fluoroquinazoiin-4-y3)-0-(3-(2- (5,6,7,8-tetrahydro-l ,8-naphthyridin~2-y])ethyi)cyclobutyl)homoserine; N-(7- fluoroquinazoiin-4-yl)-Q-(3-(2-(5,6,7,8-tetraliydr0-i,8-naphthyridm-2- yl)ethy3)eyclobutyl)homoserine; N~(7-methylquinazolin-4-yl)-0-(3-(2-(5,6,7,8-tetrahydro~
1.8-naphthyridin-2-yl)ethyl)cyc3obuty])homoserine; N-(6-fluoroquinazolin-4-yl)-0-(3-(2- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethy3)cyclobuty3)hornoserine; N-(5- fluoroqumazoim-4-yl)~0-(3-(2-(5,6,7,8-tetrahydiO-i,8-naphthyridin-2- yl)ethyl)cyc3obuty!)homoserine; N-(6-methylquinazoiin-4~y3)-0-(3~(2-(5,6,7,8-tetrahydro-
1.8-naphthyridin~2-yl)ethyl)cyclobutyl)homoserine; and N-(6-(tert-butyl)-2-phenylpyriniidin- 4-y3)-0-(3-(2-(5,6,7,8-tetraliydro-l,8-naphthyridin-2-yl)ethyl)cyclobutyl)-homoserine;
or a salt thereof.
127. The compound of claim 1 , wherein the compound is represented by any one of the following:
Figure imgf000351_0001
wherein j and k are respectively 2 and 4, 3 and 3, or 4 and 2,
or a salt thereof.
128. The compound of claim 127, wherein the compound is represented by any one of:
Figure imgf000352_0001
(n-A-la-3)
or a salt thereof
129. The compound of claim 127, wherein the compound is represented by any one of:
Figure imgf000352_0002
or a salt thereof.
130. The compound of claim 127, wherein the compound is represented by any one of:
Figure imgf000352_0003
or a salt thereof.
131. The compound of claim 127, wherein the compound is represented by any one of:
Figure imgf000353_0001
or a salt thereof.
132. Tlie compound of claim 127, wherein tire compound is represented by any one of:
Figure imgf000353_0002
or a salt thereof.
133. The compound of claim 127, wherein the compound is represented by any one of:
Figure imgf000353_0003
or a salt thereof
134. The compound of claim 127, wherein the compound is represented by any one of:
Figure imgf000354_0001
or a salt thereof
135 The compound of claim 127, wherein the compound is represented by any one of:
Figure imgf000354_0002
or a salt thereof.
136. The compound of claim 127, wherein the compound is represented by any one of:
Figure imgf000354_0003
Figure imgf000355_0001
or a salt thereof.
137. The compound of claim 12.7, wherein the compound is represented by any one of:
Figure imgf000355_0002
Figure imgf000356_0001
or a salt thereof.
138. The compound of claim 1 , wherein the compound is represented by any one of:
Figure imgf000356_0002
wherein j and k are respectively 2 and 4, 3 and 3, or 4 and 2,
or a salt thereof.
139. The compound of claim 138, wherein the compound is represented by:
Figure imgf000356_0003
140. The compound of claim 138, wherein tire compound is represented by any one of:
Figure imgf000357_0001
or a salt tliereof.
141. A pharmaceutical composition comprising a compound of any one of claim s 1 to 140, or a salt thereof, and a pharmaceutically acceptable carrier or excipient.
142. A method of treating a fibrotic disease in an individual in need thereof comprising administering a compound of any one of cl aims 1 to 140 or a pharmaceutically acceptable salt thereof.
143. The method of claim 142, wherein the fibrotic disease is pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, kidney fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis.
144. A kit comprising a compound of any one of claims 1 to 140, or a pharmaceutically acceptable salt thereof.
145. The kit of claim 144, further comprising instructions for the treatment of a fibrotic disease.
146. A method of inhibiting anbb tegrin in an individual comprising administering a compound of any one of claims 1 to 140 or a pharmaceutically acceptable salt thereof.
147. A method of inhibiting TGFp activation in a cell comprising administering to the cell a compound of any one of claims 1 to 140 or a pharmaceutically acceptable salt thereof.
148. Use of a compound of any one of claims 1 to 140 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a fibrotic disease.
149. A method of modulating at least one mtegrin in a subject, the at least one integrm comprising an av subunit, the method comprising administering to the subject an effective amount of: the compound of any one of claims 1-140, or a pharmaceutically acceptable salt thereof.
150. The method of claim 149, the modulating comprising inhibiting the at least one
integrin in the subject.
151. The method of claim 149, the at least one integrin comprising at least one of anbi integrin and anbb integrin.
152. The method of claim 149, wherein:
the subject has or is at risk of a fibrotic disease selected from the group consisting of: idiopathic pulmonary fibrosis (IFF), interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty li ver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease induced fibrosis, Alport syndrome, primary' sclerosing cholangitis (PSC), primary' biliary cholangitis, biliary atresia, systemic sclerosis associated interstitial lung disease, scleroderma, diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn’s Disease; and
the method comprises inhibiting one or both of anbi integrin and anbb integrin in the subject, thereby treating the fibrotic disease in the subject.
153. The method of any of claims 149 to 152, the subject being in need of treatment for NASH, the effective amount administered to the subject being effective to inhibit at least anbi integrin, thereby treating the subject for NASH.
154. The method of any of claims 149 to 152, the subject being in need of treatment for IFF, the effective amount administered to the subject being effective to inhibit at least anbb integrin, thereby treating the subject for IFF
155. The method of any of claims 149 to 152, the subject being in need of treatment for PSC, the effective amount administered to the subject being effective to inhibit at least one of anbi integrin and anbd integrin, thereby treating the subject for PSC.
156. A method of modulating TGFp activation in a cell, comprising contacting the cell with: the compound of any one of claims 1-140, or a pharmaceutically acceptable salt thereof; or
the pharmaceutical composition of claim 141.
157. The method of claim 156, the modulating comprising inhibiting TGFfi acti vation in the cell .
158. The method of claim 156, the TORb activation being mediated in the cell by at least one of anbi integrin and anbό integrin.
159. A method of treating a subject in need thereof, comprising:
administering to the subject a therapeutically effective amount of the compound of any one of claims 1-140, or a pharmaceutically acceptable sal t thereof, wherein the subject has at least one tissue in need of therapy and the tissue has at least one elevated level of:
TGFp activation and/or expression;
anbi integrin activity and/or expression; or
anbd integrin activity and/or expression;
wherein the at least one elevated level is elevated compared to a healthy state of the tissue
160. The method of claim 159, wherein the method selectively inhibits anbi integrin
compared to anbb integrin in the subject.
161. The method of claim 159, wherein the method selectively inhibits anbb integrin
compared to anbi integrin in the subject.
162. lire method of claim 159, wherein the method inhibits both of anbi integrin and anbb integrin in the subject.
163. The method of claim 159, wherein the method selectively inhibits both anbi integrin and avpe integrin compared to at least one other an-containing integrin in the subject.
164. The method of claim 159, wherein the anbi integrin is inhibited in one or more
fibroblasts in the subject.
165. The method of claim 159, wherein the anbb integrin is inhibited in one or more
epithelial cells in the subject.
166. The method of claim 159, wherein the at least one tissue in the subject comprises one or more of: lung tissue, liver tissue, skin tissue, cardiac tissue, kidney tissue, gastrointestinal tissue, gall bladder tissue, and bile duct tissue.
PCT/US2019/055252 2018-10-08 2019-10-08 Amino acid compounds and methods of use WO2020076862A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
SG11202103283RA SG11202103283RA (en) 2018-10-08 2019-10-08 Amino acid compounds and methods of use
JOP/2021/0056A JOP20210056A1 (en) 2018-10-08 2019-10-08 Amino acid compounds and methods of use
MX2021004015A MX2021004015A (en) 2018-10-08 2019-10-08 Amino acid compounds and methods of use.
KR1020217013781A KR20210101205A (en) 2018-10-08 2019-10-08 Amino Acid Compounds and Methods of Use
EP19870448.8A EP3863711A4 (en) 2018-10-08 2019-10-08 Amino acid compounds and methods of use
EA202190967A EA202190967A1 (en) 2018-10-08 2019-10-08 AMINO ACID COMPOUNDS AND METHODS OF APPLICATION
PE2021000461A PE20211463A1 (en) 2018-10-08 2019-10-08 AMINO ACID COMPOUNDS AND METHODS OF USE
CR20210224A CR20210224A (en) 2018-10-08 2019-10-08 Amino acid compounds and methods of use
JP2021544112A JP7523450B2 (en) 2018-10-08 2019-10-08 Amino acid compounds and methods of use thereof
CN201980066146.7A CN113195053B (en) 2018-10-08 2019-10-08 Amino acid compounds and methods of use
CU2021000027A CU24690B1 (en) 2018-10-08 2019-10-08 USEFUL AMINO ACIDS COMPOUNDS AS AVß6 INTEGRIN INHIBITORS
AU2019358041A AU2019358041A1 (en) 2018-10-08 2019-10-08 Amino acid compounds and methods of use
BR112021006620A BR112021006620A2 (en) 2018-10-08 2019-10-08 amino acid compounds and methods of use
CA3115643A CA3115643A1 (en) 2018-10-08 2019-10-08 Amino acid compounds and methods of use
DO2021000054A DOP2021000054A (en) 2018-10-08 2021-03-30 AMINO ACID COMPOUNDS AND METHODS OF USE / AMINO ACID COMPOUNDS AND METHODS OF USE
IL282026A IL282026A (en) 2018-10-08 2021-04-04 Amino acid compounds and methods of use
CONC2021/0004279A CO2021004279A2 (en) 2018-10-08 2021-04-07 Amino acid compounds and methods of use
PH12021550784A PH12021550784A1 (en) 2018-10-08 2021-04-08 Amino acid compounds and methods of use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862742901P 2018-10-08 2018-10-08
US62/742,901 2018-10-08

Publications (1)

Publication Number Publication Date
WO2020076862A1 true WO2020076862A1 (en) 2020-04-16

Family

ID=70051340

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/055252 WO2020076862A1 (en) 2018-10-08 2019-10-08 Amino acid compounds and methods of use

Country Status (23)

Country Link
US (3) US11180494B2 (en)
EP (1) EP3863711A4 (en)
JP (1) JP7523450B2 (en)
KR (1) KR20210101205A (en)
CN (1) CN113195053B (en)
AU (1) AU2019358041A1 (en)
BR (1) BR112021006620A2 (en)
CA (1) CA3115643A1 (en)
CL (2) CL2021000863A1 (en)
CO (1) CO2021004279A2 (en)
CR (1) CR20210224A (en)
CU (1) CU24690B1 (en)
DO (1) DOP2021000054A (en)
EA (1) EA202190967A1 (en)
EC (1) ECSP21032717A (en)
IL (1) IL282026A (en)
JO (1) JOP20210056A1 (en)
MX (1) MX2021004015A (en)
PE (1) PE20211463A1 (en)
PH (1) PH12021550784A1 (en)
SG (1) SG11202103283RA (en)
TW (1) TW202028179A (en)
WO (1) WO2020076862A1 (en)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11021480B2 (en) 2018-08-29 2021-06-01 Morphic Therapeutic, Inc. Inhibiting (α-V)(β-6) integrin
US11040955B2 (en) 2017-02-28 2021-06-22 Morphic Therapeutic, Inc. Inhibitors of (alpha-v)(beta-6) integrin
US11046685B2 (en) 2017-02-28 2021-06-29 Morphic Therapeutic, Inc. Inhibitors of (α-v)(β-6) integrin
US11180494B2 (en) * 2018-10-08 2021-11-23 Pliant Therapeutics, Inc. Substituted amino acids as integrin inhibitors
WO2022008918A1 (en) * 2020-07-10 2022-01-13 University Of Nottingham Azetidine derivatives for the treatment of integrin associated diseases
US11396506B2 (en) 2018-06-27 2022-07-26 Pliant Therapeutics, Inc. Amino acid compounds with unbranched linkers and methods of use
US11419869B2 (en) 2019-04-08 2022-08-23 Pliant Therapeutics, Inc. Dosage forms and regimens for amino acid compounds
US11560376B2 (en) 2018-03-07 2023-01-24 Pliant Therapeutics, Inc. Amino acid compounds and methods of use
US11634418B2 (en) 2016-12-23 2023-04-25 Pliant Therapeutics, Inc. Amino acid compounds and methods of use
US11673887B2 (en) 2016-09-07 2023-06-13 Pliant Therapeutics, Inc. N-acyl amino acid compounds and methods of use
US12018025B2 (en) 2020-11-19 2024-06-25 Pliant Therapeutics, Inc. Integrin inhibitor and uses thereof
WO2024165831A1 (en) * 2023-01-24 2024-08-15 University Of Bradford Imidazolidone and succinimide derivatives for use as alpha v beta 3 integrin inhibitors for the treatment of cancer

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024145245A2 (en) * 2022-12-27 2024-07-04 Pliant Therapeutics, Inc. Alpha-v-beta-8 integrin inhibitors and uses thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6048861A (en) 1997-12-17 2000-04-11 Merck & Co., Inc. Integrin receptor antagonists
WO2008157162A1 (en) * 2007-06-13 2008-12-24 Bristol-Myers Squibb Company Dipeptide analogs as coagulation factor inhibitors
US20120289481A1 (en) * 2011-05-13 2012-11-15 O'neil Jennifer Compositions and methods for treating cancer
WO2016046226A1 (en) * 2014-09-26 2016-03-31 Glaxosmithkline Intellectual Property Development Limited Novel compounds
US20180008583A1 (en) * 2015-03-25 2018-01-11 Fujifilm Corporation Method for manufacturing novel nitrogen-containing compound or salt thereof and manufacturing intermediate of novel nitrogen-containing compound or salt thereof
WO2018049068A1 (en) 2016-09-07 2018-03-15 Pliant Therapeutics, Inc. N-acyl amino acid compounds and methods of use
WO2018119087A1 (en) 2016-12-23 2018-06-28 Pliant Therapeutics, Inc. Amino acid compounds and methods of use
WO2018160522A1 (en) 2017-02-28 2018-09-07 Lazuli, Inc. Inhibitors of (alpha-v)(beta-6) integrin

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015048819A1 (en) 2013-09-30 2015-04-02 The Regents Of The University Of California Anti-alphavbeta1 integrin compounds and methods
CA2981371A1 (en) 2015-03-10 2016-09-15 The Regents Of The University Of California Anti-alphavbeta1 integrin inhibitors and methods of use
KR20190026001A (en) * 2016-07-05 2019-03-12 더 락커펠러 유니버시티 Tetrahydronaphthyridine pentanamide integrin antagonist
MA46744A (en) * 2016-11-08 2019-09-18 Bristol Myers Squibb Co MONO AND SPIROCYCLIC COMPOUNDS CONTAINING CYCLOBUTANE AND AZETIDINE AS INHIBITORS OF INTEGRIN ALPHA V
RU2769702C2 (en) 2017-02-28 2022-04-05 Морфик Терапьютик, Инк. Avb6 integrin inhibitors
TW201938158A (en) 2018-03-07 2019-10-01 美商普萊恩醫療公司 Amino acid compounds and methods of use
TWI741268B (en) 2018-03-15 2021-10-01 美商輝瑞股份有限公司 Cyclopentane-based modulators of sting (stimulator of interferon genes)
TWI841573B (en) 2018-06-27 2024-05-11 美商普萊恩醫療公司 Amino acid compounds with unbranched linkers and methods of use
EP3617206A1 (en) 2018-08-29 2020-03-04 Morphic Therapeutic, Inc. Integrin inhibitors
WO2020047207A1 (en) 2018-08-29 2020-03-05 Morphic Therapeutics, Inc. Inhibitors of (alpha-v)(beta-6) integrin
WO2020047208A1 (en) 2018-08-29 2020-03-05 Morphic Therapeutic, Inc. Inhibitors of (alpha-v)(beta-6) integrin
TW202028179A (en) 2018-10-08 2020-08-01 美商普萊恩醫療公司 Amino acid compounds and methods of use
EP3952902A4 (en) 2019-04-08 2022-12-21 Pliant Therapeutics, Inc. Dosage forms and regimens for amino acid compounds
JP2023524970A (en) 2020-05-07 2023-06-14 プライアント・セラピューティクス・インコーポレイテッド Treatment of respiratory diseases with amino acid compounds

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6048861A (en) 1997-12-17 2000-04-11 Merck & Co., Inc. Integrin receptor antagonists
US20020010176A1 (en) * 1997-12-17 2002-01-24 Askew Ben C. Integrin receptor antagonists
WO2008157162A1 (en) * 2007-06-13 2008-12-24 Bristol-Myers Squibb Company Dipeptide analogs as coagulation factor inhibitors
US20120289481A1 (en) * 2011-05-13 2012-11-15 O'neil Jennifer Compositions and methods for treating cancer
US20140349968A1 (en) * 2011-05-13 2014-11-27 Ariad Pharmaceuticals, Inc. Compositions and Methods for Treating Cancer
WO2016046226A1 (en) * 2014-09-26 2016-03-31 Glaxosmithkline Intellectual Property Development Limited Novel compounds
US20180008583A1 (en) * 2015-03-25 2018-01-11 Fujifilm Corporation Method for manufacturing novel nitrogen-containing compound or salt thereof and manufacturing intermediate of novel nitrogen-containing compound or salt thereof
WO2018049068A1 (en) 2016-09-07 2018-03-15 Pliant Therapeutics, Inc. N-acyl amino acid compounds and methods of use
US20180093984A1 (en) * 2016-09-07 2018-04-05 Pliant Therapeutics, Inc. N-acyl amino acid compounds and methods of use
WO2018119087A1 (en) 2016-12-23 2018-06-28 Pliant Therapeutics, Inc. Amino acid compounds and methods of use
WO2018160522A1 (en) 2017-02-28 2018-09-07 Lazuli, Inc. Inhibitors of (alpha-v)(beta-6) integrin

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3863711A4

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11673887B2 (en) 2016-09-07 2023-06-13 Pliant Therapeutics, Inc. N-acyl amino acid compounds and methods of use
US11634418B2 (en) 2016-12-23 2023-04-25 Pliant Therapeutics, Inc. Amino acid compounds and methods of use
US11040955B2 (en) 2017-02-28 2021-06-22 Morphic Therapeutic, Inc. Inhibitors of (alpha-v)(beta-6) integrin
US11046669B2 (en) 2017-02-28 2021-06-29 Morphic Therapeutic, Inc. Inhibitors of (α-v)(β-6) integrin
US11046685B2 (en) 2017-02-28 2021-06-29 Morphic Therapeutic, Inc. Inhibitors of (α-v)(β-6) integrin
US11827621B2 (en) 2017-02-28 2023-11-28 Morphic Therapeutic, Inc. Inhibitors of (α-v)(β-6) integrin
US11795167B2 (en) 2017-02-28 2023-10-24 Morphic Therapeutic, Inc. Inhibitors of (α-v)(β-6) integrin
US11560376B2 (en) 2018-03-07 2023-01-24 Pliant Therapeutics, Inc. Amino acid compounds and methods of use
US11858931B2 (en) 2018-06-27 2024-01-02 Pliant Therapeutics, Inc. Amino acid compounds with unbranched linkers and methods of use
US11396506B2 (en) 2018-06-27 2022-07-26 Pliant Therapeutics, Inc. Amino acid compounds with unbranched linkers and methods of use
US11739087B2 (en) 2018-08-29 2023-08-29 Morphic Therapeutic, Inc. Inhibiting (α-v)(β-6) integrin
US11021480B2 (en) 2018-08-29 2021-06-01 Morphic Therapeutic, Inc. Inhibiting (α-V)(β-6) integrin
US11180494B2 (en) * 2018-10-08 2021-11-23 Pliant Therapeutics, Inc. Substituted amino acids as integrin inhibitors
US20220144829A1 (en) * 2018-10-08 2022-05-12 Pliant Therapeutics, Inc. Amino acid compounds and methods of use
US11952376B2 (en) * 2018-10-08 2024-04-09 Pliant Therapeutics, Inc. Substituted amino acids as integrin inhibitors
US11419869B2 (en) 2019-04-08 2022-08-23 Pliant Therapeutics, Inc. Dosage forms and regimens for amino acid compounds
WO2022008918A1 (en) * 2020-07-10 2022-01-13 University Of Nottingham Azetidine derivatives for the treatment of integrin associated diseases
US12018025B2 (en) 2020-11-19 2024-06-25 Pliant Therapeutics, Inc. Integrin inhibitor and uses thereof
WO2024165831A1 (en) * 2023-01-24 2024-08-15 University Of Bradford Imidazolidone and succinimide derivatives for use as alpha v beta 3 integrin inhibitors for the treatment of cancer

Also Published As

Publication number Publication date
CN113195053A (en) 2021-07-30
US11180494B2 (en) 2021-11-23
CU20210027A7 (en) 2021-11-04
IL282026A (en) 2021-05-31
EP3863711A4 (en) 2022-07-06
MX2021004015A (en) 2021-06-23
PH12021550784A1 (en) 2021-10-25
CL2023001331A1 (en) 2023-10-20
AU2019358041A1 (en) 2021-05-20
CL2021000863A1 (en) 2021-09-10
KR20210101205A (en) 2021-08-18
CN113195053B (en) 2024-08-30
TW202028179A (en) 2020-08-01
DOP2021000054A (en) 2021-08-31
JP2022508657A (en) 2022-01-19
SG11202103283RA (en) 2021-04-29
US20200109141A1 (en) 2020-04-09
JOP20210056A1 (en) 2021-03-24
CU24690B1 (en) 2023-12-07
US20240270742A1 (en) 2024-08-15
CR20210224A (en) 2021-06-08
ECSP21032717A (en) 2021-06-30
CA3115643A1 (en) 2020-04-16
EP3863711A1 (en) 2021-08-18
BR112021006620A2 (en) 2021-07-06
US11952376B2 (en) 2024-04-09
EA202190967A1 (en) 2021-09-17
CO2021004279A2 (en) 2021-04-30
US20220144829A1 (en) 2022-05-12
PE20211463A1 (en) 2021-08-05
JP7523450B2 (en) 2024-07-26

Similar Documents

Publication Publication Date Title
WO2020076862A1 (en) Amino acid compounds and methods of use
AU2019295769B2 (en) Amino acid compounds with unbranched linkers and methods of use
AU2019230209B2 (en) Amino acid compounds and methods of use
AU2020273158A1 (en) Dosage forms and regimens for amino acid compounds
CA3173761A1 (en) Treatment of respiratory diseases with amino acid compounds
JP2005519907A (en) Hydroxynaphthyridinone carboxamides useful as HIV integrase inhibitors
CA2938186C (en) Azaindole derivative
BR122023025996A2 (en) AMINO ACID COMPOUNDS, PHARMACEUTICAL COMPOSITION AND KIT COMPRISING THE SAME, THEIR USES, AND THEIR PRODUCTION METHOD
OA20261A (en) Amino acid compounds and methods of use.
OA18254A (en) Methyl-and trifluoromethyl-substituted pyrrolopyridine modulators of rorc2 and methods of use thereof.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19870448

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3115643

Country of ref document: CA

Ref document number: 2021544112

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2101002034

Country of ref document: TH

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112021006620

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2019870448

Country of ref document: EP

Effective date: 20210510

ENP Entry into the national phase

Ref document number: 2019358041

Country of ref document: AU

Date of ref document: 20191008

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 112021006620

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20210407

WWE Wipo information: entry into national phase

Ref document number: 521421669

Country of ref document: SA