US20240043421A1 - Amino acid compounds and methods of use - Google Patents

Amino acid compounds and methods of use Download PDF

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Publication number
US20240043421A1
US20240043421A1 US18/114,979 US202318114979A US2024043421A1 US 20240043421 A1 US20240043421 A1 US 20240043421A1 US 202318114979 A US202318114979 A US 202318114979A US 2024043421 A1 US2024043421 A1 US 2024043421A1
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tetrahydro
naphthyridin
butanoic acid
ethyl
pyrrolidin
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US18/114,979
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David John Morgans, Jr.
Randall L. Halcomb
Gustave Bergnes
Hui Li
Lan Jiang
Jacob CHA
Timothy HOM
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Pliant Therapeutics Inc
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Pliant Therapeutics Inc
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Priority to US18/114,979 priority Critical patent/US20240043421A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • 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

Definitions

  • This invention relates to amino acid compounds, pharmaceutical compositions comprising the amino acid compounds, and methods of use of the compounds and compositions in treating diseases, such as fibrotic diseases.
  • 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 fatty liver disease
  • fibrosis While liver fibrosis is reversible in its initial stages, progressive liver fibrosis can lead to cirrhosis.
  • 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 limited 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 the 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 Idiopathic pulmonary fibrosis
  • the lung tissue becomes thickened, stiff, and scarred.
  • HT 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.
  • 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.
  • NSIP Nonspecific interstitial pneumonia
  • the cellular form is defined mainly by inflammation of the cells of the interstitium.
  • the 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.
  • the ⁇ v ⁇ 6 integrin is expressed in epithelial cells, and binds to the latency-associated peptide of transforming growth factor- ⁇ 1 (TGF ⁇ 1) and mediates TGF ⁇ 1 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 IPF and NSIP patients.
  • TGF ⁇ 1 transforming growth factor- ⁇ 1
  • PSC Primary sclerosing cholangitis
  • 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 ⁇ v ⁇ 6 is elevated in liver and bile duct of PSC patients.
  • the present disclosure provides for ⁇ v ⁇ 36 integrin inhibitors that may be useful for tissue-specific treatment of fibrosis.
  • amino acid compounds that are ⁇ v ⁇ 6 integrin inhibitors, compositions containing these compounds and methods for treating diseases mediated by ⁇ v ⁇ 6 integrin such as a fibrotic disease.
  • a pharmaceutical composition comprising a compound of formula (I), or any variation thereof detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising a compound of formula (I-A), or any variation thereof detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient.
  • a method of treating a fibrotic disease in an individual 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 fibrotic disease is pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, kidney fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis.
  • a compound of formula (I-A), or any variation thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), as detailed herein may also be used in any of the methods detailed herein, such as in 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 developing a fibrotic disease.
  • 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 developing a fibrotic disease is provided.
  • a compound of formula (I), 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.
  • a compound of formula (I-A), 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.
  • kits comprising a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof.
  • a kit comprising a compound of formula (I-A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt 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.
  • a method of making a compound of formula (I) or any variation thereof is also provided. Also provided is a method of making a compound of formula (I-A) or any variation thereof. Also provided are compound intermediates useful in synthesis of a compound of formula (I) or (I-A), or any variation thereof.
  • 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. Also provided are compounds of formula (I-A), and variations thereof, pharmaceutical compositions comprising compounds of formula (I-A), and methods of using such compounds and compositions in treating fibrotic diseases.
  • references 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”.
  • 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., C 1 -C 10 means one to ten carbon atoms).
  • Particular alkyl groups are those having 1 to 20 carbon atoms (a “C 1 -C 20 alkyl”), having 1 to carbon atoms (a “C 1 -C 10 alkyl”), having 6 to 10 carbon atoms (a “C 6 -C 10 alkyl”), having 1 to 6 carbon atoms (a “C 1 -C 6 alkyl”), having 2 to 6 carbon atoms (a “C 2 -C 6 alkyl”), or having 1 to 4 carbon atoms (a “C 1 -C 4 alkyl”).
  • alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
  • Alkylene refers to the same residues as alkyl, but having bivalency. Particular alkylene groups are those having 1 to 20 carbon atoms (a “C 1 -C 20 alkylene”), having 1 to 10 carbon atoms (a “C 1 -C 10 alkylene”), having 6 to 10 carbon atoms (a “C 6 -C 10 alkylene”), having 1 to 6 carbon atoms (a “C 1 -C 6 alkylene”), 1 to 5 carbon atoms (a “C 1 -C 5 alkylene”), 1 to 4 carbon atoms (a “C 1 -C 4 alkylene”) or 1 to 3 carbon atoms (a “C 1 -C 3 alkylene”).
  • alkylene examples include, but are not limited to, groups such as methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), propylene (—CH 2 CH 2 CH 2 —), isopropylene (—CH 2 CH(CH 3 )—), butylene (—CH 2 (CH 2 ) 2 CH 2 —), isobutylene (—CH 2 CH(CH 3 )CH 2 —), pentylene (—CH 2 (CH 2 ) 3 CH 2 —), hex (—CH 2 (CH 2 ) 4 CH 2 —), heptylene (—CH 2 (CH 2 ) 5 CH 2 —), octylene (—CH 2 (CH 2 ) 6 CH 2 —), and the like.
  • groups such as methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), propylene (—CH 2 CH 2 CH 2 —), isopropylene (—CH 2 CH(CH 3 )—), butylene (—CH 2 (CH 2
  • Alkenyl 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 olefinic unsaturation (i.e., having at least one moiety of the formula C ⁇ C) and having the number of carbon atoms designated (i.e., C 2 -C 10 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 carbon atoms (a “C 2 -C 20 alkenyl”), having 6 to 10 carbon atoms (a “C 6 -C 10 alkenyl”), having 2 to 8 carbon atoms (a “C 2 -C 8 alkenyl”), having 2 to 6 carbon atoms (a “C 2 -C 6 alkenyl”), or having 2 to 4 carbon atoms (a “C 2 -C 4 alkenyl”).
  • alkenyl group examples include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, beta-1,3-dienyl, 2-methylbuta-1,3-dienyl, homologs and isomers thereof, for example, 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-1-enyl, prop-2-enyl (or 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, beta-1,3-dienyl, 2-methylbuta-1,3-dienyl, homologs and isomers thereof, for example, pent-1-en
  • Alkenylene refers to the same residues as alkenyl, but having bivalency. Particular alkylene groups are those having 2 to 20 carbon atoms (a “C 2 -C 20 alkenylene”), having 2 to 10 carbon atoms (a “C 2 -C 10 alkenylene”), having 6 to 10 carbon atoms (a “C 6 -C 10 alkenylene”), having 2 to 6 carbon atoms (a “C 2 -C 6 alkenylene”), 2 to 4 carbon atoms (a “C 2 -C 4 alkenylene”) or 2 to 3 carbon atoms (a “C 2 -C 2 alkenylene”).
  • alkenylene examples include, but are not limited to, groups such as ethenylene (or vinylene) (—CH ⁇ CH—), propenylene (—CH ⁇ CHCH 2 —), 1,4-but-1-enylene (—CH ⁇ CH—CH 2 CH 2 —), 1,4-but-2-enylene (—CH 2 CH ⁇ CHCH 2 —), 1,6-hex-1-enylene (—CH ⁇ CH—(CH 2 ) 3 CH 2 —), and the like.
  • groups such as ethenylene (or vinylene) (—CH ⁇ CH—), propenylene (—CH ⁇ CHCH 2 —), 1,4-but-1-enylene (—CH ⁇ CH—CH 2 CH 2 —), 1,4-but-2-enylene (—CH 2 CH ⁇ CHCH 2 —), 1,6-hex-1-enylene (—CH ⁇ CH—(CH 2 ) 3 CH 2 —), and the like.
  • Alkynyl 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 acetylenic unsaturation (i.e., having at least one moiety of the formula C ⁇ C) and having the number of carbon atoms designated (i.e., C 2 -C 10 means two to ten carbon atoms).
  • Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C 2 -C 20 alkynyl”), having 6 to 10 carbon atoms (a “C 6 -C 10 alkynyl”), having 2 to 8 carbon atoms (a “C 2 -C 5 alkynyl”), having 2 to 6 carbon atoms (a “C 2 -C 6 alkynyl”), or having 2 to 4 carbon atoms (a “C 2 -C 4 alkynyl”).
  • alkynyl group examples include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-2-vinyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.
  • Alkynylene refers to the same residues as alkynyl, but having bivalency. Particular alkylene groups are those having 2 to 20 carbon atoms (a “C 2 -C 20 alkynylene”), having 2 to 10 carbon atoms (a “C 2 -C 10 alkynylene”), having 6 to 10 carbon atoms (a “C 6 -C 10 is alkynylen.e”), having 2 to 6 carbon atoms (a “C 2 -C 6 alkynylene”), 2 to 4 carbon atoms (a “C 2 -C 4 alkynylene”) or 2 to 3 carbon atoms (a “C 2 -C 3 alkynylene”). Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetyl enylene) (—C ⁇ C—), propynylene (—C ⁇ CCH 2 —), 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., C 3 -C 10 means three to ten carbon atoms). Cycloalkyl can consist of one ring, such as cyciohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms.
  • a preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C 3 -C 8 cycloalkyl”), having 3 to 6 carbon atoms (a “C 3 -C 6 cycloalkyl”), or having from 3 to 4 annular carbon atoms (a “C 3 -C 4 cycloalkyl”).
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbomyl, and the like.
  • Cycloalkylene refers to the same residues as cycloalkyl, but having bivalency. Cycloalkylene can consist of one ring or multiple rings which may be fused, spino or bridged, or combinations thereof. Particular cycloalkylene groups are those having from 3 to 12 annular carbon atoms.
  • a preferred cycloalkylene is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C 3 -C 8 cycloalkylene”), having 3 to 6 carbon atoms (a “C 3 -C 6 cycloalkylene”), or having from 3 to 4 annular carbon atoms (a “C 3 -C 4 cycloalkylene”).
  • cycloalkylene examples include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbomylene, and the like.
  • a cycloalkylene may attach to the remaining structures via the same ring carbon atom or different ring carbon atoms. When a cycloalkylene attaches to the remaining structures via two different ring carbon atoms, the connecting bonds may be cis- or trans- to each other.
  • cyclopropylene may include 1,1-cyclopropylene and 1,2-cyclopropylene (e.g., cis-1,2-cyclopropylene or trans-1,2-cyclopropylene), or a mixture thereof.
  • Cycloalkenyl refers to and includes, unless otherwise stated, an unsaturated cyclic non-aromatic univalent hydrocarbon structure, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C ⁇ C) and having the number of carbon atoms designated (i.e., C 2 -C 10 means two to ten carbon atoms).
  • Cycloalkenyl can consist of one ring, such as cyclohexyl, or multiple rings, such as norbomenyl.
  • a preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C 3 -C 8 cycloalkenyl”). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbomenyl, and the like.
  • Cycloalkenylene refers to the same residues as cycloalkenyl, but having bivalency.
  • Aryl or “Ar” as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic.
  • Particular aryl groups are those having from 6 to 14 annular carbon atoms (a “C 6 -C 14 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 “C 6 -C 14 arylene”).
  • Iieteroaryl 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 or may not be aromatic.
  • Particular heteroaryl groups are 5 to 14-membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 5 to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5, 6 or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • particular heteroaryl groups are monocvclic 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 al 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
  • Heterocycle refers to a saturated or an unsaturated non-aromatic cyclic group having a single ring or multiple condensed rings, and having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like.
  • a heterocycle comprising more than one ring may be fused, bridged or spiro, or any combination thereof.
  • fused ring systems one or more of the fused rings can be cycloalkyl, aryl or heteroaryl.
  • 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 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • Heterocyclylene refers to the same residues as heterocyclyl, but having bivalency.
  • 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 more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl trihaloaryl etc. refer to aryl 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 perhaloalkyl group is trifluoroalkyl (—CF 3 ).
  • 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 trifluoroniethoxy (—OCF 3 ).
  • Carbonyl refers to the group C ⁇ O.
  • Thiocarbonyl refers to the group C ⁇ S.
  • Oxo refers to the moiety ⁇ O.
  • 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, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents.
  • 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 the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, delaying the occurrence or recurrence of the disease, delay or slowing the progression.
  • 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 he 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 forms 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, i.e., 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 route of delivery e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, 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, hydrobrotnic 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 ethanolamine, diethanolamine, triethanolamine and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodi urn hydroxide, and the like.
  • compositions can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic 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.
  • a drug or pharmaceutical such as a tablet containing a compound of the invention as an active ingredient.
  • Various substances may be 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.
  • the compound of the formula (I) is a derivative of (5)-2-acylaminobutanoic acid, having the formula (Ia):
  • R 1 , R 5 , R 7 , R 8 , X, m, n, p and q are as defined for formula (I).
  • the compound of the formula (I) is a derivative of (R)-2-acylaminobutanoic acid, having the formula (Ib):
  • R 1 , R 5 , R 7 , R 8 , X, m, n, p and q are as defined for formula (I).
  • n is 1. In some embodiments, n is 2. In some of these embodiments, m is 0. In some these embodiments, m is 1. In some these embodiments, m is 2. In some these embodiments, m is 3. In some these embodiments, m is 4. In some these embodiments, m is 5. In some these embodiments, m is 6. In some embodiments, m is 1 or 2.
  • each R 5 where present, is independently C 1 -C 5 alkyl optionally substituted by R 10 , C 3 -C 6 cycloalkyl optionally substituted by R 10 , halogen, —CN, —OR 5a , —C(O)OR 5a , —NR 5a C(O)R 5b ; —NR 5c R 5d , —C(O)NR 5c R 5d , —SO 2 R 5e , or —SO 2 NR 5c R 5d .
  • each R 5a and R 5b is independently hydrogen, C 1 -C 6 alkyl optionally substituted by R 10 ; C 3 C 8 cycloalkyl optionally substituted by R 10 ; C 6 -C 14 aryl optionally substituted by R 10 ; 5- to 10-membered heteroaryl optionally substituted by R 10 ; or 3- to 12-membered heterocyclyl optionally substituted by R 10 .
  • each R 5c and R 5d is independently hydrogen, C 1 -C 6 alkyl optionally substituted by R 10 ; C 3 -C 8 cycloalkyl optionally substituted by R 10 ; C 6 -C 14 aryl optionally substituted by R 10 ; 5- to 10-membered heteroaryl optionally substituted by R 10 ; or 3- to 12-membered heterocyclyl optionally substituted by R 10 ; or R 5c and R 5d are taken together with the nitrogen to which they are attached to form a 4- to 8-membered heterocyclyl optionally substituted by R 10 .
  • R 5c is C 1 -C 6 alkyl optionally substituted by R 10 ; C 3 -C 8 cycloalkyl optionally substituted by R 10 ; C 6 -C 14 aryl optionally substituted by R 10 ; 5- to 10-membered heteroaryl optionally substituted by e; or 3- to 12-membered heterocyclyl optionally substituted by R 10 .
  • the compound is of the formula (II):
  • R 1 , R 7 , R 8 , X, p and q are as defined for formula (I).
  • the compound of the formula (H) is a derivative of (S)-2-acylaminobutanoic acid, having the formula (IIa):
  • R 1 , R 7 , R 8 , X, p and q are as defined for formula (I) or (II).
  • the compound of the formula (II) is a derivative of (R)-2-acylaminobutanoic acid, having the formula (IIb):
  • R 1 , R 7 , R 8 , X, p and q are as defined for formula (I) or (II).
  • the compound is of the formula (III):
  • R 1 , R 7 , R 8 , X, p and q are as defined for formula (I).
  • the compound of the formula (III) is a derivative of (8)-2-acylaminobutanoic acid, having the formula (IIIa):
  • R 1 , R 7 , R 8 , X, p and q are as defined for formula (I) or (III).
  • the compound of the formula (III) is a derivative of (R)-2-acylaminobutanoic acid, having the formula (IIIb):
  • R 1 , R 7 , R 8 , p and q are as defined for formula (I) or (III).
  • X is C 1 -C 3 alkylene optionally substituted by R 10 .
  • X is C 1 -C 2 alkylene optionally substituted by e.
  • X is methylene optionally substituted by 1 or 2 groups selected from R 10 .
  • X is ethylene optionally substituted by 1 to 4 groups selected from R 10 .
  • X is propylene optionally substituted by 1 or 5 groups selected from R 10 .
  • X is methylene.
  • X is ethylene, in some embodiments, X is propylene.
  • n, m and R 5 described herein may be combined with each and every variation of X described herein, the same as if each and every combination is individually and specifically described.
  • a is 1, m is 0, and X is ethylene.
  • n is 2, m is 0, and X is ethylene.
  • the compound is of the formula (IV):
  • R 1 , R 7 , R 8 , p and q are as defined for formula (I) or (II).
  • the compound of the formula (IV) is of the formula (IVa):
  • R 1 , R 7 , R 8 , p and q are as defined for formula (I) or (II).
  • the compound of the formula (IV) is of the formula (IVb):
  • R 1 , R 7 , R 8 , p and q are as defined for formula (I) or (II).
  • the compound of the formula (IV) is of the formula (IVc):
  • R 1 , R 7 , R 8 , p and q are as defined for formula (I) or (II).
  • the compound of the formula (IV) is of the formula (IVd):
  • R 1 , R 7 , R 8 , p and q are as defined for formula (I) or (II).
  • the compound is of the formula (V):
  • R 1 , R 7 , R 8 , p and q are as defined for formula (I) or (III).
  • the compound of the formula (V) is of the formula (Va):
  • R 1 , R 7 , R 8 , p and q are as defined for formula (I) or (III).
  • the compound of the formula (V) is of the formula (Vb):
  • R 1 , R 7 , R 8 , p and q are as defined for formula (I) or (III).
  • R 1 is C 1 -C 6 alkyl optionally substituted by R 10 ; C 3 -C 8 cycloalkyl optionally substituted by C 6 -C 14 aryl optionally substituted by R 10 ; 5- to 10-membered heteroaryl optionally substituted by R 10 ; 3- to 12-membered heterocyclyl optionally substituted by R 10 ; OR 2 ; or —NR 3a R 3b .
  • R 1 is a C 1 -C 6 alkyl (e.g., t-butyl) optionally substituted by R 10 .
  • R 1 is a C 1 -C 6 alkyl (e.g., t-butyl) optionally substituted by R 10 .
  • R 1 is —OR 2 or —NR 3a R 3b .
  • R 1 is —OR 2 .
  • R 2 is C 1 -C 6 alkyl (e.g., t-butyl).
  • R 1 is —NR 3a R 3b . In some embodiments, R 1 is a 4- to 8-membered heterocyclyl optionally substituted by R 10 formed by R 3a and R 3b taken together with the nitrogen to which they are attached.
  • R 1 is C 3 -C 8 cycloalkyl (e.g., cyclohexyl) optionally substituted by R 10 . In some embodiments, R 1 is 4,4-difluorocyclohexyl.
  • R 1 is C 6 -C 14 aryl optionally substituted by R 10 . In some embodiments, R 1 is phenyl optionally substituted by R 10 .
  • R 1 is 5- or 10-membered heteroaryl optionally substituted by R 10 .
  • R 1 is 5- to 6-membered monocyclic heteroaryl optionally substituted by R 10 .
  • R 1 is pyridyl (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl) optionally substituted by R 10 .
  • R 1 is 8- to 10-membered bicyclic heteroaryl optionally substituted by R 10 .
  • R 1 is indazolyl (e.g., 4-indozyl, 5-indozyl, 6-indozyl or 7-indozyl) optionally substituted by R 10 .
  • R 1 is 3- to 12-membered heterocyclyl optionally substituted by R 10 .
  • R 1 is piperidinyl (e.g., piperidin-4-yl) optionally substituted by R 10 .
  • R 1 is 1-cyclopropylpiperidin-4-yl.
  • R 1 is tetrahydropyranyl (e.g., tetrahydropyran-4-yl) optionally substituted by R 10 .
  • R 1 is 4-methyltetrahydropyran-4-yl.
  • R 1 is selected from the group consisting of
  • the 5,6,7,8-tetrahydro-1,8-naphthyridine ring may be unsubstituted or substituted.
  • p is 0.
  • q is 0.
  • p and q are 0.
  • each R 7 is independently C 1 -C 6 alkyl optionally substituted by halogen or —OH, C 3 -C 6 cycloalkyl, halogen, —CN, —NO 2 , —OR 7a , or —NR 7b R 7c ; where each R 7a , R 7b and R 7c is independently hydrogen or C 1 -C 3 alkyl.
  • R 7 is —CH 3 , —CHF 2 , —CH 2 F, —CF 3 , or —CH 2 OH.
  • each R 8 is independently C 1 -C 6 alkyl optionally substituted by R 10 , C 3 -C 6 cycloalkyl optionally substituted by R 10 , halogen, oxo or —OR 8a .
  • R 8 is —OR 8a a where R 8a is hydrogen or C 1 -C 6 alkyl. In some embodiments, R 8a is hydrogen.
  • each optional substituent R 9 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 11 , —SR 11 , —NO 2 , —C ⁇ NH(OR 11 ), —C(O)R 11 , —OC(O)R 11 , —C(O)OR 11 , —C(O)NR 12 R 13 , —NR 11 C(O)R 12 , —NR 11 C(O)OR 12 , —NR 11 C(O)NR 12 R 13 , —S(O)R 11 , —S(O) 2 R 11 , —NR 11 S(O)R 12 , —NR 11 S(O) 2 R 12 , —S(O)NR 12 R 13 , —S(O) 2 NR 12 R 13 , —P(O)(OR 12 ) (OR 13 ), C 3 -C
  • R 9 is independently C 1 -C 6 alkyl, halogen, —CN, —OR 11 , —NR 12 R 13 , —C(O)R 11 , C 3 -C 8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl, wherein each R 4 is independently optionally substituted by halogen, oxo, —OR 14 , —NR 14 R 15 , —C(O)R 14 , —CN, C 3 -C 8 cycloalkyl, 3- to 12-metnbered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14 aryl, or C 1 -C 6 alkyl optionally substituted by oxo, —OH or halogen.
  • R 9 is independently selected from F, Cl, —CN, methyl, —CHF 2 , —CF 3 , cyclopropylmethyl, tert-butyl, cyclopropyl and phenyl. In some embodiments, R 9 is independently F, Cl or —CN. In some embodiments, R 9 is independently methyl, —CHF 2 , —CF 3 , cyclopropylmethyl, tert-butyl or cyclopropyl. In some embodiments, R 9 is independently phenyl optionally substituted by halogen or C 1 -C 6 alkyl. In some embodiments, R 9 is 5- to 10-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • R 9 is 3,5-dimehylpyrazol-1-yl. In some embodiments, R 9 is independently 3- to 12-membered heterocyclyl optionally substituted by oxo or C 1 -C 6 alkyl. In some embodiments, R 9 is morpholin-4-yl.
  • R 10 is independently oxo or any variation detailed herein for R 9 .
  • R 10 is independently oxo, C 1 -C 6 alkyl, halogen, —CN, —OR 11 , —NR 12 R 13 , —C(O)R 11 , C 3 -C 8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl, wherein each R 9 is independently optionally substituted by halogen, oxo, —ORhu14, —NR 14 R 15 , —CN, C 3 -C 8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14 aryl, or C 1 -C 6 alkyl optionally substituted by oxo, —OH or halogen.
  • R 10 is independently selected from oxo, F, Cl, —CN, methyl, —CHF 2 , —CF 3 , cyclopropylmethyl, tert-butyl, cyclopropyl and phenyl.
  • R 10 is independently phenyl optionally substituted by halogen or C 1 -C 6 alkyl.
  • R 10 is 5- to 10-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • R 10 is 3,5-dimehylpyrazol-1-yl.
  • R 10 is independently 3- to 12-membered heterocyclyl optionally substituted by oxo or C 1 -C 6 alkyl.
  • R 10 is motpholin-4-yl.
  • R 11 , R 12 and R 13 are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments, R 11 is hydrogen. In some embodiments, R 12 and R 13 are each hydrogen.
  • R 14 and R 15 are each independently hydrogen or C 1 -C 6 alkyl.
  • a compound of the formula (I), or a salt thereof wherein the carbon bearing the CO 2 H and NHC(O)R 1 moieties is in the “S” configuration.
  • a compound of the formula (I), or a salt thereof wherein the carbon bearing the CO 2 H and NHC(O)R 1 moieties is in the “R” configuration.
  • a compound of the formula (I), or a salt thereof wherein the carbon bearing the X moiety is in the “S” configuration.
  • a compound of the formula (I), or a salt thereof wherein the carbon bearing the X moiety is in the “R” configuration.
  • the carbon bearing the CO 2 H and NHC(O)R 1 moieties is in the “S” configuration and the carbon bearing the X moiety is in the “S” configuration.
  • the carbon hearing the CO 2 H and NHC(O)R 1 moieties is in the “S” configuration and the carbon bearing the X moiety is in the “R” configuration.
  • the carbon bearing the CO 2 H and NHC(O)R 1 moieties is in the “R” configuration and the carbon hearing the X moiety is in the “S” configuration.
  • the carbon bearing the CO 2 H and NHC(O)R 1 moieties is in the “R” configuration and the carbon bearing the X moiety is in the “R” configuration. It is understood that the stereochemistry described is equally applicable to and described for other compounds detailed herein, such as compounds of the formula (I-A) and compounds in the associated compound tables, such as Table 1 and Table 1-A.
  • the compound is selected from the group consisting of Compound Nos 1a, 1b, 1c, 1d, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4h, 4c, 4d, 5a, 5b, 5c, 5d, Ca, 6h, 6c, 6d, 7a, 7b, 7c, 7d, 8a, 8b, 8c, 8d, 9a, 9b, 9c, 9d, 10a, 10b, 10c, 10d, 11a, 11b, 11c, 11d, 12a, 12b, 13a, 13b, 13c, 13d, 14a, 14b, 14c, 14d, 15a, 15b, 15c, 16a, 16b, 16c, 16d, 17a, 17b, 17c, 17d, 18a, 18b, 18c, 18d, 19a, 19b, 19c, 19d, 20a, 20b, 20d, 21a, 21h, 21c,
  • the compound is selected from the group consisting of one or more of Compound Nos. 1-31 in Table 1, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof.
  • the compound is selected from the group consisting of one or more of Compound Nos 1a, 1b, 1c, 1d, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, 4d, 5a, 5b, 5c, 5d, 6a, 6b, 6c, 6d, 7a, 7b, 7c, 7d, 8a, 8b, 8c, 8d, 9a, 9b, 9c, 9d, 10a, 10b, 10c, 10d, 11a, 11b, 11c, 11d, 12a, 12b, 13a, 13b, 13c, 13d, 14a, 14b, 14c, 14d, 15a, 15b, 15c, 15d,
  • 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 diastereomeric 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 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 invention 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 invention in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced,
  • ⁇ v ⁇ 6 integrin inhibitors are ⁇ v ⁇ 6 integrin inhibitors. In some instances, it is desirable for the compound to inhibit other integrins in addition to ⁇ v ⁇ 6 integrin. In some embodiments, the compound inhibits ⁇ v ⁇ 6 integrin and one or more of ⁇ b ⁇ 1, ⁇ v ⁇ 3, ⁇ v ⁇ 5, ⁇ 2 ⁇ 1, ⁇ 3 ⁇ 1, ⁇ 6 ⁇ 1 integrin, ⁇ 7 ⁇ 1 and ⁇ 11 ⁇ 1. In some embodiments, the compound inhibits ⁇ v ⁇ 6 integrin and ⁇ v ⁇ 1 integrin. In some embodiments, the compound inhibits ⁇ v ⁇ 6 integrin, ⁇ v ⁇ 3 integrin and ⁇ v ⁇ 5 integrin.
  • the compound inhibits ⁇ v ⁇ 6 integrin and ⁇ 2 ⁇ 1 integrin, in some embodiments, the compound inhibits ⁇ v ⁇ 6 integrin, ⁇ 2 ⁇ 1 integrin and ⁇ 3 ⁇ 1 integrin. In some embodiments, the compound inhibits ⁇ v ⁇ 6 integrin and ⁇ 6 ⁇ 1 integrin. In some embodiments, the compound inhibits ⁇ v ⁇ 6 integrin and ⁇ 7 ⁇ 1 integrin In some embodiments, the compound inhibits ⁇ v ⁇ 6 integrin and ⁇ 11 ⁇ 1 integrin,
  • the compound is a selective ⁇ v ⁇ 6 integrin inhibitor. In some embodiments, the compound does not inhibit substantially ⁇ 4 ⁇ 1, ⁇ v ⁇ 8 and/or ⁇ 2 ⁇ 3 integrin. In some embodiments, the compound inhibits ⁇ v ⁇ 6 integrin but does not inhibit substantially azIfil integrin. In some embodiments, the compound inhibits ⁇ v ⁇ 6 integrin but does not inhibit substantially ⁇ v ⁇ 8 integrin. In some embodiments, the compound inhibits ⁇ v ⁇ 6 integrin but does not inhibit substantially ⁇ 2 ⁇ 3 integrin. In some embodiments, the compound inhibits ⁇ v ⁇ 6 integrin but does not inhibit substantially the ⁇ v ⁇ 8 integrin and the ⁇ 4 ⁇ 1 integrin.
  • 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, 11 C, 13 C, 14 C 13 N, 15 O, 17 O, 32 P, 35 S, 18 F, 36 Cl.
  • Incorporation of heavier isotopes such as deuterium ( 2 H) 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.
  • Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically-labeled reagents in place of the corresponding non-labeled reagent.
  • the invention also includes any or all metabolites of any of the compounds 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.
  • 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 bioavailable.
  • 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.
  • the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein,
  • enantiomer of a compound this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers.
  • diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, 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 enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
  • Chromatography, recrystallization and other conventional separation procedures may also be 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 andlor 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, andlor solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • R 1 , R 2 , R 7 , R 8 , X, m, n, p and q are as defined for formula (I), or any applicable variations detailed herein;
  • P 0 and P 1 are independently an amine protecting group, (e.g., t-butoxycarbonyl (Boc));
  • P 2 is a carboxylic acid protecting group (e.g., ethyl);
  • Lv is a leaving group (e.g., OH, O-acyl, OAt, Cl, 1-imidazolyl, and the like).
  • R 1 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R 1 are independently optionally substituted by R 10 .
  • a method for preparing a compound of formula (I), or a salt thereof comprising performing one or more steps of Scheme 1 or Scheme 1a.
  • compositions of any of the compounds detailed herein are embraced by this invention.
  • the invention includes pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceuticallw acceptable salt is an 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 tbr administration by inhalation.
  • compositions comprising a compound as detailed herein are provided, such as compositions of substantially pure compounds.
  • a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
  • substantially pure intends a composition that contains 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.
  • a composition of a substantially pure compound selected from a compound of Table 1 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound or a salt thereof.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25% impurity.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 20% impurity.
  • 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 5% impurity.
  • a composition of substantially pure compound or a salt thereof 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 15% or preferably no more than 10% or more preferably no more than 5% or even more preferably no more than 3% and most preferably no more than 1% impurity, which impurity may be the compound in a different stereochemical form. For instance, a composition of substantially pure (S) compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound.
  • 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 carrier or excipient.
  • methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
  • the compound 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
  • parenteral e.g., intramuscular, subcutaneous or intravenous
  • topical or transdermal delivery form e.g., topical or transdermal delivery form.
  • a compound 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 (poultices),
  • One or several compounds described herein can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds 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 in various forms.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, butlers, coating agents or antioxidants.
  • Formulations comprising the 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, 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, corn 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.
  • Compounds and compositions of the invention such as a pharmaceutical composition containing a compound of any formula provided herein or a salt thereof and a pharmaceutically acceptable carder or excipient, may be used in methods of administration and treatment as provided herein.
  • the compounds and compositions may also he 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 effective amount of a compound of formula (I), or any variation thereof, e,g., a compound of formula (Ia), (IIb), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va) or (Vb), a compound selected from Compound Nos. 1-31 in Table 1, or a pharmaceutically acceptable salt thereof.
  • the individual is a human.
  • the individual, such as human may he in need of treatment, such as a human who has or is suspected of having a fibrotic disease.
  • 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 developing 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.
  • 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.
  • 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).
  • pulmonary fibrosis 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 a pulmonary fibrosis, e.g., idiopathic pulmonary fibrosis (IPF).
  • pulmonary fibrosis e.g., idiopathic pulmonary fibrosis (IPF).
  • the fibrotic disease is a primary sclerosing cholangitis, or biliary fibrosis.
  • the fibrotic disease is fibrotic nonspecific interstitial pneumonia (NSW).
  • NSW fibrotic nonspecific interstitial pneumonia
  • the fibrotic disease is a liver fibrosis, e.g., infectious liver fibrosis (from pathogens such as HCV, HBV or parasites such as schistosomiasis), NASH, alcoholic steatosis induced liver fibrosis, and cirrhosis.
  • infectious liver fibrosis from pathogens such as HCV, HBV or parasites such as schistosomiasis
  • NASH alcoholic steatosis induced liver fibrosis
  • cirrhosis cirrhosis
  • the fibrotic disease is biliary tract fibrosis.
  • the fibrotic disease is kidney fibrosis, diabetic nephrosclerosis, hypertensive nephrosclerosis, focal segmental glomerulosclerosis (“FSGS”), and acute kidney injury from contrast induced nephropathy.
  • FSGS focal segmental glomerulosclerosis
  • 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 gstrointestinal fibrosis, e.g., Crohn's disease.
  • 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 a compound of formula (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va) or (Vb), a compound selected from Compound Nos. 1-31 in Table 1, 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 (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVA), (V), (Va) or (Vb), a compound selected from Compound Nos. 1-31 in Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.
  • a method of inhibiting ⁇ v ⁇ 6 integrin in an individual comprising administering a compound of formula (I), or any variation thereof, e.g., a compound of formula (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va) or (Vb), a compound selected from Compound Nos. 1-31 in Table 1, or a pharmaceutically acceptable salt thereof.
  • Also provided is a method of inhibiting TGF ⁇ activation in a cell comprising administering to the cell a compound of formula (I), or any variation thereof, e.g., a compound of formula (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va) or (Vb), a compound selected from Compound Nos. 1-31 in Table 1, or a pharmaceutically acceptable salt thereof.
  • the compound is a selective ⁇ v ⁇ 6 integrin inhibitor.
  • the compound does not inhibit substantially ⁇ 4 ⁇ 1, ⁇ v ⁇ 8 and/or ⁇ 2 ⁇ 3 integrin.
  • the compound inhibits ⁇ v ⁇ 6 integrin but does not inhibit substantially ⁇ 4 ⁇ 1 integrin.
  • the compound inhibits ⁇ v ⁇ 6 integrin but does not inhibit substantially ⁇ v ⁇ 8 integrin.
  • the compound inhibits ⁇ v ⁇ 6 integrin but does not inhibit substantially ⁇ 2 ⁇ 3 integrin.
  • a method of inhibiting ⁇ v ⁇ 6 integrin and ⁇ v ⁇ 1 integrin In another embodiment is provided a method of inhibiting ⁇ v ⁇ 6 integrin, ⁇ v ⁇ 3 integrin and ⁇ b ⁇ 5 integrin.
  • a method of inhibiting ⁇ v ⁇ 6 integrin and ⁇ 2 ⁇ 1 integrin is provided.
  • a method of inhibiting ⁇ v ⁇ 6 integrin, ⁇ 2 ⁇ 1 integrin and ⁇ 3 ⁇ 1 integrin In another embodiment is provided a method of inhibiting ⁇ v ⁇ 6 integrin and ⁇ 6 ⁇ 1 integrin. In another embodiment is provided a method of inhibiting ⁇ v ⁇ 6 integrin and ⁇ 7 ⁇ 1 integnn. In another embodiment is provided a method of inhibiting ⁇ v ⁇ 6 integrin and ⁇ 11 ⁇ 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 (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va) or (Vb), a compound selected from Compound Nos. 1-31 in Table 1, or a pharmaceutically acceptable salt thereof.
  • 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 pharmacological composition comprising a compound described herein.
  • the 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 instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of 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.
  • Microplates were coated with recombinant human integrin ⁇ v ⁇ 6 (2 ug/ml) in PBS (100 ul/well 2.5° C., overnight). The coating solution was removed, washed with wash buffer (0.05% Tween MnCl2; in 1 ⁇ TBS). Plate was blocked with 200 ul/well of Block Buffer (1% BSA; 5% sucrose; 0.5 mM MnCl2; in 1 ⁇ TBS) at 37° C. for 2 h. Dilutions of testing compounds and recombinant TGF ⁇ 1 LAP (0.67 ug/ml) in binding buffer (0.05% BSA; 2.5% sucrose; 0.5 mM MnCl2; in 1 ⁇ TBS) were added.
  • Block Buffer 1% BSA; 5% sucrose; 0.5 mM MnCl2; in 1 ⁇ TBS
  • the plate was incubated for 2 hours at 25° C., washed, and incubated for 1 hour with Biotin-Anti-hLAP. Bound antibody was detected by peroxidase-conjugated streptavidin.
  • the IC 50 values for testing compounds were calculated by a four-parameter logistic regression.
  • IC 50 values obtained for ⁇ v ⁇ 6 integrin inhibition for exemplary compounds are shown in Table B-1.
  • the compounds tested were compound samples prepared according to procedures described in the Synthetic Examples section, with the stereochemical purity as indicated in the Examples indicated.

Abstract

The invention relates to compounds of formula (I):or a salt thereof, wherein R1, R5, R7, R8, X, m, n, p and q are as described herein. Compounds of formula (I) and pharmaceutical compositions thereof are αvβ6 integrin inhibitors that are useful for treating tissue specific fibrosis such as idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSW).

Description

    CROSS-REFERENCE, TO RELATED APPLICATIONS
  • This application claims priority benefit of U.S. Provisional Patent Application No. 62/438,951 filed Dec. 23, 2016, and of U.S. Provisional Patent Application No. 62/538,564 filed Jul. 28, 2017. The entire contents of those applications are hereby incorporated by reference herein.
    • TECHNICAL FIELD OF THE INVENTION
  • This invention relates to amino acid compounds, pharmaceutical compositions comprising the amino acid compounds, and methods of use of the compounds and compositions in treating diseases, such as fibrotic diseases.
    • BACKGROUND OF THE INVENTION
  • 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.
  • 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.
  • 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.
  • 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 limited areas, but for others, it can spread to other major organs.
  • 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.
  • Crohn's Disease is a chronic disease of unknown etiology tending to progress even in the 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 (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. HT 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.
  • 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 cells of the interstitium. The 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.
  • http://my.clevelandchnic.org/health/disees_conditions/hic_Pneurnonialhic-nonspecific-interstitial-pneumonia.
  • Available 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 αvβ6 integrin is expressed in epithelial cells, and binds to the latency-associated peptide of transforming growth factor-β1 (TGFβ1) and mediates TGFβ1 activation. Its expression level is significantly increased after injury to lung and cholangiocytes, and plays a critical in vivo role in tissue fibrosis. Increased levels are also associated with increased mortality in IPF and NSIP patients.
  • 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 αvβ6 is elevated in liver and bile duct of PSC patients.
  • The present disclosure provides for αvβ36 integrin inhibitors that may be useful for tissue-specific treatment of fibrosis.
    • BRIEF SUMMARY OF THE INVENTION
  • Disclosed are amino acid compounds that are αvβ6 integrin inhibitors, compositions containing these compounds and methods for treating diseases mediated by αvβ6 integrin such as a fibrotic disease.
  • 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. Also provided is a compound of (I-A), or any variation thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), as detailed herein.
  • Further provided is a pharmaceutical composition comprising a compound of formula (I), or any variation thereof detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient. Also provided is a pharmaceutical composition comprising a compound of formula (I-A), or any variation thereof detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient.
  • In another aspect, provided is a method of treating a fibrotic disease in an individual (such as a human) in need thereof comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the fibrotic disease is pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, kidney fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis. A compound of formula (I-A), or any variation thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), as detailed herein may also be used in any of the methods detailed herein, such as in 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 developing a fibrotic disease.
  • 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 developing a fibrotic disease.
  • 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.
  • Also provided is use of a compound of formula (I), 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. Also provided is use of a compound of formula (I-A), 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.
  • Further provided is a kit comprising a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof. Further provided is a kit comprising a compound of formula (I-A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises instructions for use according to a method described herein, such as a method of treating a fibrotic disease in an individual.
  • In another aspect, provided is a method of making a compound of formula (I) or any variation thereof. Also provided is a method of making a compound of formula (I-A) or any variation thereof. Also provided are compound intermediates useful in synthesis of a compound of formula (I) or (I-A), or any variation thereof.
    • DETAILED DESCRIPTION OF THE INVENTION
  • 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. Also provided are compounds of formula (I-A), and variations thereof, pharmaceutical compositions comprising compounds of formula (I-A), and methods of using such compounds and compositions in treating fibrotic diseases.
    • Definitions
  • For use herein, unless clearly indicated otherwise, use of the terms “a”, “an” and the like refers to one or more.
  • 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”.
  • “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., C1-C10 means one to ten carbon atoms). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-C20 alkyl”), having 1 to carbon atoms (a “C1-C10 alkyl”), having 6 to 10 carbon atoms (a “C6-C10 alkyl”), having 1 to 6 carbon atoms (a “C1-C6 alkyl”), having 2 to 6 carbon atoms (a “C2-C6 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-propyl, isopropyl, n-butyl, t-butyl, isobutyl sec-butyl, homologs and isomers of, for example, n-pentyl, 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 “C6-C10 alkylene”), having 1 to 6 carbon atoms (a “C1-C6 alkylene”), 1 to 5 carbon atoms (a “C1-C5 alkylene”), 1 to 4 carbon atoms (a “C1-C4 alkylene”) or 1 to 3 carbon atoms (a “C1-C3 alkylene”). Examples of alkylene include, but are not limited to, groups such as methylene (—CH2—), ethylene (—CH2CH2—), propylene (—CH2CH2CH2—), isopropylene (—CH2CH(CH3)—), butylene (—CH2(CH2)2CH2—), isobutylene (—CH2CH(CH3)CH2—), pentylene (—CH2(CH2)3CH2—), hex (—CH2(CH2)4CH2—), heptylene (—CH2(CH2)5CH2—), octylene (—CH2(CH2)6CH2—), and the like.
  • “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 olefinic 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 carbon atoms (a “C2-C20 alkenyl”), having 6 to 10 carbon atoms (a “C6-C10 alkenyl”), having 2 to 8 carbon atoms (a “C2 -C8 alkenyl”), having 2 to 6 carbon atoms (a “C2-C6 alkenyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkenyl”). Examples of alkenyl group include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, beta-1,3-dienyl, 2-methylbuta-1,3-dienyl, homologs and isomers thereof, for example, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, and the like.
  • “Alkenylene” as used herein refers to the same residues as alkenyl, but having bivalency. Particular alkylene groups are those having 2 to 20 carbon atoms (a “C2-C20 alkenylene”), having 2 to 10 carbon atoms (a “C2-C10 alkenylene”), having 6 to 10 carbon atoms (a “C6-C10 alkenylene”), having 2 to 6 carbon atoms (a “C2-C6 alkenylene”), 2 to 4 carbon atoms (a “C2-C4 alkenylene”) or 2 to 3 carbon atoms (a “C2-C2 alkenylene”). Examples of alkenylene include, but are not limited to, groups such as ethenylene (or vinylene) (—CH═CH—), propenylene (—CH═CHCH2—), 1,4-but-1-enylene (—CH═CH—CH2CH2—), 1,4-but-2-enylene (—CH2CH═CHCH2—), 1,6-hex-1-enylene (—CH═CH—(CH2)3CH2—), and the like.
  • “Alkynyl” 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 acetylenic 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). Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C2-C20 alkynyl”), having 6 to 10 carbon atoms (a “C6-C10 alkynyl”), having 2 to 8 carbon atoms (a “C2-C5 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-2-vinyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.
  • “Alkynylene” as used herein refers to the same residues as alkynyl, but having bivalency. Particular alkylene 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 “C6-C10 is alkynylen.e”), having 2 to 6 carbon atoms (a “C2-C6 alkynylene”), 2 to 4 carbon atoms (a “C2-C4 alkynylene”) or 2 to 3 carbon atoms (a “C2-C3 alkynylene”). Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetyl enylene) (—C≡C—), propynylene (—C≡CCH2—), and the like.
  • “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 cyciohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms. A preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C3-C8 cycloalkyl”), having 3 to 6 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, cycloheptyl, norbomyl, and the like.
  • “Cycloalkylene” as used herein refers to the same residues as cycloalkyl, but having bivalency. Cycloalkylene can consist of one ring or multiple rings which may be fused, spino or bridged, or combinations thereof. Particular cycloalkylene groups are those having from 3 to 12 annular carbon atoms. A preferred cycloalkylene is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C3-C8 cycloalkylene”), having 3 to 6 carbon atoms (a “C3-C6 cycloalkylene”), or having from 3 to 4 annular carbon atoms (a “C3-C4 cycloalkylene”). Examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbomylene, and the like. A cycloalkylene may attach to the remaining structures via the same ring carbon atom or different ring carbon atoms. When a cycloalkylene attaches to the remaining structures via two different ring carbon atoms, the connecting bonds may be cis- or trans- to each other. For example, cyclopropylene may include 1,1-cyclopropylene and 1,2-cyclopropylene (e.g., cis-1,2-cyclopropylene or trans-1,2-cyclopropylene), or a mixture thereof.
  • “Cycloalkenyl” refers to and includes, unless otherwise stated, an unsaturated cyclic non-aromatic univalent hydrocarbon structure, having at least one site of olefinic 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). Cycloalkenyl can consist of one ring, such as cyclohexyl, or multiple rings, such as norbomenyl. A preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C3-C8 cycloalkenyl”). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbomenyl, and the like.
  • “Cycloalkenylene” as used herein refers to the same residues as cycloalkenyl, but having bivalency.
  • “Aryl” or “Ar” as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic. Particular aryl groups are those having from 6 to 14 annular carbon atoms (a “C6-C14 aryl”). An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at 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.
  • “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 “C6-C14 arylene”).
  • “Iieteroaryl” 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 or may not be aromatic. Particular heteroaryl groups are 5 to 14-membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 5 to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5, 6 or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, particular heteroaryl groups are monocvclic 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 al an aromatic ring position. A heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom.
  • “Heteroarylene” as used herein refers to the same residues as heteroaryl, but having bivalency,
  • “Heterocycle”, “heterocyclic”, or “heterocyclyl” as used herein refers to a saturated or an unsaturated non-aromatic cyclic group having a single ring or multiple condensed rings, and having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like. A heterocycle comprising more than one ring may be fused, bridged or spiro, or any combination thereof. In fused ring systems, one or more of the fused rings can be cycloalkyl, aryl or heteroaryl. 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 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • “Heterocyclylene” as used herein refers to the same residues as heterocyclyl, but having bivalency.
  • “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 more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl trihaloaryl etc. refer to aryl 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 perhaloalkyl group is trifluoroalkyl (—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 trifluoroniethoxy (—OCF3).
  • “Carbonyl” refers to the group C═O.
  • “Thiocarbonyl” refers to the group C═S.
  • “Oxo” refers to the moiety ═O.
  • “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.
  • 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.
  • 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 the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, delaying the occurrence or recurrence of the disease, 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.
  • 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 he 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.
  • 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 forms may contain a single or a combination therapy.
  • 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, i.e., 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).
  • 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.
  • “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, hydrobrotnic 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 ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodi urn hydroxide, and the like. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.
  • 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. Various substances may be 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 phthalate, 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.; disintearants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, 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 in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, 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.
    • Compounds
  • In one aspect, provided is a compound of formula (I):
  • Figure US20240043421A1-20240208-C00002
  • or a salt thereof, wherein:
      • R1 is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocvclyl, —OR2 or —NR3aR3b, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 2-membered heterocyclyl of R1 are independently optionally substituted by R10;
      • R2 is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to heteroaryl, and 3- to 12-membered heterocyclyl of R2 are independently optionally substituted by R10;
      • R3a and R3b are independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R3a and R3b are independently optionally substituted by R10;
      • or R3a and R3b are taken together with the nitrogen to which they are attached to form a 4- to 8-membered heterocyclyl optionally substituted by R10;
      • n is 1or 2;
      • m is 0 to 6;
      • each R5, where present, is independently C1-C6 alkyl, C3-C6 cycloalkyl, halogen, —CN, —OR5a—C(O)OR5a, —NR5aC(O)R5b; —CR5cR5d, —C(O)NR5cR5d, —SO2R5c, or —SO2NR5cR5d, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are independently optionally substituted by R10;
      • each R5a and R5b is independently hydrogen, C3-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-menibered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C3 -C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R5a and R5b are independently optionally substituted by R10;
      • each R5c and R5d is independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R5c and R5d are independently optionally substituted by R10;
      • or R5c and R5d are taken together with the nitrogen to which they are attached to form a 4- to 8-membered heterocyclyl optionally substituted by R10;
      • each R5e is independently C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R5e are independently optionally substituted by R10,
      • X is C1-C3 alkylene optionally substituted by R10;
      • p is 0 to 2;
      • q is 0 to 6;
      • each R7, where present, is independently C1-C6 alkyl optionally substituted by halogen or —OH, C3-C6 cycloalkyl, halogen, —CN, —NO2, —OR7a, or —NR7bR7c;
      • each R7a, R7b and R7c is independently hydrogen or C1-C3 alkyl;
      • each R8, where present, is independently C1-C6 alkyl, C3-C6 cycloalkyl; halogen, oxo or —OR8a, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are independently optionally substituted by R10;
      • R8a is hydrogen or C1-C6 alkyl;
      • each R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, —CN, —OR11, —SR11, —NR12R13, —NO2, —C═NH(OR11), —C(O)R11, —OC(O)R11, —C(O)OR11, —C(O)NR12R13, —NR11C(O)R12, —NR11C(O)OR12, —NR11C(O)NR12R13, —S(O)R11, —S(O)2R11, —NR11S(O)R12, —NR11S(O)2R12, —S(O)NR12R13, —S(O)2NR12R13, —P(O)(OR12) (OR13), C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroanil, C6-C14 aryl, wherein each R9 is independently optionally substituted by halogen, oxo, —OR14, —NR14R15, —C(O)R14, —CN, —S(O)R14, —S(O)2R14, —P(O)(OR14)(OR15), C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C-C14 aryl, or C1-C6 alkyl optionally substituted by oxo, —OH or halogen;
      • each R10 is independently oxo or R9;
      • R11 is independently hydrogen, C1-C6 alkyl, C7-C6 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are independently optionally substituted by haloizen, oxo, —CN, —OR16, —NR16R17, —P(O)(OR16)(OR17), or C7-C6 alkyl optionally substituted by halogen, —OH or oxo;
      • R12 and R13 are each independently hydrogen, C1-C6 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are independently optionally substituted by halogen, oxo, —CN, —OR16, —NR16R17 or C1-C6 alkyl optionally , substituted by haloizen, —OH or oxo;
      • or R12 and R13 are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo, —OR16, —NR16R17 or C1-C6 alkyl optionally substituted by halogen, oxo or —OH;
      • R14 and R15 are each independently hydrogen, C1-C6 alkyl optionally substituted by halogen or oxo, C2-C6 alkenyl optionally substituted by halogen or oxo, or C2-C6 alkynyl optionally substituted by halogen or oxo;
      • or R14 and R15 are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo or C1-C6 alkyl optionally substituted by halogen or oxo; and
      • R16 and R17 are each independently hydrogen, C1-C6 alkyl optionally substituted by halogen or oxo, C2-C6 alkenyl optionally substituted by halogen or oxo, or C2-C6 alkynyl optionally substituted by halogen or oxo;
      • or R16 and R17 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C1-C6 alkyl optionally substituted by oxo or halogen.
  • In another aspect is provided is a compound of formula (I-A):
  • Figure US20240043421A1-20240208-C00003
  • or a salt thereof, wherein:
      • R1 is C1-C6 alkyl C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, —OR2 or —NR3aR3b, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R1 are independently optionally substituted by R10;
      • R2 is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to heteroaryl, and 3- to 12-membered heterocyclyl of R2 are independently optionally substituted by R10;
      • R3a and R3b are independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R3a and R3b are independently optionally substituted by R10;
      • or R3a and R3b are taken together with the nitrogen to which they are attached to form a 4- to 8-membered heterocyclyl optionally substituted by R10;
      • n is 1 or 2;
      • s is 0, 1 or 2, wherein the sum of n and s is 1, 2 or 3;
      • the ring defined by - - - - - - is present or absent;
      • m is 0 to 6;
      • each R5, where present, is independently C1-C6 alkyl, C3-C6 cycloalkyl, halogen, —CN, —OR5a, —C(O)OR5a, —NR5aC(O)R5b; —C(O)NR5cR5d, —SO2R5c, or —SO2NR5cR5d, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are independently optionally substituted h R10;
      • each R5a and R5b is independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl ; wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R5a and R5b are independently optionally substituted by R10;
      • each R5c and R5d is independently hydrogen, C1-C6 alkyl, C3-C5 cycloalkyl. C6 -C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C3-C5 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R5c and R5d are independently optionally substituted by R10;
      • or R5c nd R5d are taken together with the nitrogen to which they are attached to form a 4- to 8-membered heterocyclyl optionally substituted by R10;
      • each R5c is independently C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R5c are independently optionally substituted by R10;
      • X is C1-C3 alkylene optionally substituted by R10, —NR(R11)—CC1-C3 alkylene optionally substituted by R10, —C1-C3 alkylene-N(R11)— optionally substituted by R10, —C1-C3 alkylene-N(R11)— C1-C3 alkylene- optionally substituted by R10, —O—C1-C3 alkylene optionally substituted by R10, —C1-C3 alkylene-O— optionally substituted by R10, —C1-C3 alkylene-O—C1-C3 alkylene-optionally substituted by R10;
      • Y is C(R3a)(R3b) or N(R11);
      • each of R3a and R3b is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, —CN, —OR5a, —C(O)OR5a, —NR5aC(O)R5b; —NR5cR5d, —C(O)NR5cR5d, —SO2R5e, or —SO2NR5cR5d, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are independently optionally substituted by R10;
      • p is 0 to 2;
      • q is 0 to 6;
      • each R7, where present, is independently C1-C6 alkyl optionally substituted by halogen or —OH, C3-C6 cycloalkyl, halogen, —CN, —NO2, —OR7a, or —NR7bR7c;
      • each R7a, R7b and R7c is independently hydrogen or C1-C3 alkyl;
      • each R8, where present, is independently C1-C6 alkyl, C3 -C6 cycloalkyl; halogen, oxo or —OR8a, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are independently optionally substituted by R10;
      • R9a is hydrogen or C1-C6 alkyl;
      • each R9 is independently C1-C6 C2-C6 alkenyl, C2-C6 alkynyl, halogen, —CN, —OR11, —SR11, —NR12R13, —NO2, —C═NH(OR11), —C(O )R11, —OC(O)R11, —C(O)OR11, —C(O)NR12R13, —NR11C(O)R12, —NR11C(O)OR12, —NR11C(O)NR12R13, —S(O)R11, —S(O)2R11, —NR11S(O)R12, —NR11S(O)2R12, —S(O)NR12R13, —S(O)2NR12R13, —P(O)(OR12) (OR13), C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroanil, C6-C14 aryl, wherein each R9 is independently optionally substituted by halogen, oxo, —OR14, —NR14R15, —C(O)R14, —CN, —S(O)R14, —S(O)2R14, —P(O)(OR14)(OR15), C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-C14 aryl, or C1-C6 alkyl optionally , substituted by oxo, —OH or halogen;
      • each R11 is independently oxo or R9;
      • R11 is independently hydrogen, C1-C6 alkyl, C7-C6 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are independently optionally substituted by haloizen, oxo, —CN, —OR16, —NR16R17, —P(O)(OR16)(OR17), or C7-C6 alkyl optionally substituted by halogen, —OH or oxo;
      • R12 and R13 are each independently hydrogen, C1-C6 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are independently optionally substituted by halogen, oxo, —CN, —OR16, —NR16R17 or C1-C6 alkyl optionally, substituted by haloizen, —OH or oxo;
      • or R12 and R13 are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo, —NR16R17 or C1-C6 alkyl optionally substituted by halogen, oxo or —OH;
      • R14 and R15 are each independently hydrogen, C1-C6 alkyl optionally substituted by halogen or oxo, C2-C6 alkenyl optionally substituted by halogen or oxo, or C2-C6 alkynyl optionally substituted by halogen or oxo;
      • or R14 and R15 are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo or C1-C6 alkyl optionally substituted by halogen or oxo; and
      • R16 and R17 are each independently hydrogen, C1-C6 alkyl optionally substituted by halogen or oxo, C2-C6 alkenyl optionally substituted by halogen or oxo, or C2-C6 alkynyl optionally substituted by halogen or oxo;
      • or R16 and R17 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C1-C6 alkyl optionally substituted by oxo or halogen.
  • It is understood that when the ring defined by - - - - - - is present, only one such ring is present.
  • In some embodiments, the compound of the formula (I) is a derivative of (5)-2-acylaminobutanoic acid, having the formula (Ia):
  • Figure US20240043421A1-20240208-C00004
  • or a salt thereof, wherein R1, R5, R7, R8, X, m, n, p and q are as defined for formula (I).
  • In some embodiments, the compound of the formula (I) is a derivative of (R)-2-acylaminobutanoic acid, having the formula (Ib):
  • Figure US20240043421A1-20240208-C00005
  • or a salt thereof, wherein R1, R5, R7, R8, X, m, n, p and q are as defined for formula (I).
  • In some embodiments of the compound of formula (I), (Ia) or (Ib), or a salt thereof, n is 1. In some embodiments, n is 2. In some of these embodiments, m is 0. In some these embodiments, m is 1. In some these embodiments, m is 2. In some these embodiments, m is 3. In some these embodiments, m is 4. In some these embodiments, m is 5. In some these embodiments, m is 6. In some embodiments, m is 1 or 2.
  • In some embodiments of the compound of formula (I), (Ia) or (Ib), or a salt thereof, each R5, where present, is independently C1-C5 alkyl optionally substituted by R10, C3-C6 cycloalkyl optionally substituted by R10, halogen, —CN, —OR5a, —C(O)OR5a, —NR5aC(O)R5b; —NR5cR5d, —C(O)NR5cR5d, —SO2R5e, or —SO2NR5cR5d. In some of these embodiments, each R5a and R5b is independently hydrogen, C1-C6 alkyl optionally substituted by R10; C3C8 cycloalkyl optionally substituted by R10; C6-C14 aryl optionally substituted by R10; 5- to 10-membered heteroaryl optionally substituted by R10; or 3- to 12-membered heterocyclyl optionally substituted by R10. In some of these embodiments, each R5c and R5d is independently hydrogen, C1-C6 alkyl optionally substituted by R10; C3-C8 cycloalkyl optionally substituted by R10; C6-C14 aryl optionally substituted by R10; 5- to 10-membered heteroaryl optionally substituted by R10; or 3- to 12-membered heterocyclyl optionally substituted by R10; or R5c and R5d are taken together with the nitrogen to which they are attached to form a 4- to 8-membered heterocyclyl optionally substituted by R10. In some of these embodiments, R5c is C1-C6 alkyl optionally substituted by R10; C3-C8 cycloalkyl optionally substituted by R10; C6-C14 aryl optionally substituted by R10; 5- to 10-membered heteroaryl optionally substituted by e; or 3- to 12-membered heterocyclyl optionally substituted by R10.
  • In some embodiments of the compound of formula (I), where n is 1 and m is 0, the compound is of the formula (II):
  • Figure US20240043421A1-20240208-C00006
  • or a salt thereof, wherein R1, R7, R8, X, p and q are as defined for formula (I).
  • In some embodiments, the compound of the formula (H) is a derivative of (S)-2-acylaminobutanoic acid, having the formula (IIa):
  • Figure US20240043421A1-20240208-C00007
  • or a salt thereof, wherein R1, R7, R8, X, p and q are as defined for formula (I) or (II).
  • In some embodiments, the compound of the formula (II) is a derivative of (R)-2-acylaminobutanoic acid, having the formula (IIb):
  • Figure US20240043421A1-20240208-C00008
  • or a salt thereof, wherein R1, R7, R8, X, p and q are as defined for formula (I) or (II).
  • In some embodiments of the compound of formula (I), where n is 2 and m is 0, the compound is of the formula (III):
  • Figure US20240043421A1-20240208-C00009
  • or a salt thereof, wherein R1, R7, R8, X, p and q are as defined for formula (I).
  • In some embodiments, the compound of the formula (III) is a derivative of (8)-2-acylaminobutanoic acid, having the formula (IIIa):
  • Figure US20240043421A1-20240208-C00010
  • or a salt thereof, wherein R1, R7, R8, X, p and q are as defined for formula (I) or (III).
  • In some embodiments, the compound of the formula (III) is a derivative of (R)-2-acylaminobutanoic acid, having the formula (IIIb):
  • Figure US20240043421A1-20240208-C00011
  • or a salt thereof, wherein R1, R7, R8, p and q are as defined for formula (I) or (III).
  • In some embodiments of the compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa) or (IIIb), or a salt thereof, X is C1-C3 alkylene optionally substituted by R10. In some embodiments, X is C1-C2 alkylene optionally substituted by e. In some embodiments, X is methylene optionally substituted by 1 or 2 groups selected from R10. In some embodiments, X is ethylene optionally substituted by 1 to 4 groups selected from R10. In some embodiments, X is propylene optionally substituted by 1 or 5 groups selected from R10. In some embodiments, X is methylene. In some embodiments, X is ethylene, in some embodiments, X is propylene.
  • It is intended and understood that each and every variation of n, m and R5 described herein, may be combined with each and every variation of X described herein, the same as if each and every combination is individually and specifically described. For example, in some embodiments of the compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa) or (IIIb), or a salt thereof, a is 1, m is 0, and X is ethylene. In some embodiments of the compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa) or (IIIb), or a salt thereof, n is 2, m is 0, and X is ethylene.
  • In some embodiments of the compound of formula (I), where n is 1, m is 0, and X is ethylene, the compound is of the formula (IV):
  • Figure US20240043421A1-20240208-C00012
  • or a salt thereof, wherein R1, R7, R8, p and q are as defined for formula (I) or (II).
  • In some embodiments, the compound of the formula (IV) is of the formula (IVa):
  • Figure US20240043421A1-20240208-C00013
  • or a salt thereof, wherein R1, R7, R8, p and q are as defined for formula (I) or (II).
  • In some embodiments, the compound of the formula (IV) is of the formula (IVb):
  • Figure US20240043421A1-20240208-C00014
  • or a salt thereof, wherein R1, R7, R8, p and q are as defined for formula (I) or (II).
  • In some embodiments, the compound of the formula (IV) is of the formula (IVc):
  • Figure US20240043421A1-20240208-C00015
  • or a salt thereof, wherein R1, R7, R8, p and q are as defined for formula (I) or (II).
  • In some embodiments, the compound of the formula (IV) is of the formula (IVd):
  • Figure US20240043421A1-20240208-C00016
  • or a salt thereof, wherein R1, R7, R8, p and q are as defined for formula (I) or (II).
  • In some embodiments of the compound of formula (I), where n is 2, m is 0, and X is ethylene, the compound is of the formula (V):
  • Figure US20240043421A1-20240208-C00017
  • or a salt thereof, wherein R1, R7, R8, p and q are as defined for formula (I) or (III).
  • In some embodiments, the compound of the formula (V) is of the formula (Va):
  • Figure US20240043421A1-20240208-C00018
  • or a salt thereof, wherein R1, R7, R8, p and q are as defined for formula (I) or (III).
  • In some embodiments, the compound of the formula (V) is of the formula (Vb):
  • Figure US20240043421A1-20240208-C00019
  • or a salt thereof, wherein R1, R7, R8, p and q are as defined for formula (I) or (III).
  • In some embodiments of the compound of formula (I), (Ia), (Ib), (b), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va) or (Vb), or a salt thereof, R1 is C1-C6 alkyl optionally substituted by R10; C3-C8 cycloalkyl optionally substituted by C6-C14 aryl optionally substituted by R10; 5- to 10-membered heteroaryl optionally substituted by R10; 3- to 12-membered heterocyclyl optionally substituted by R10; OR2; or —NR3aR3b.
  • In some embodiments, R1 is a C1-C6 alkyl (e.g., t-butyl) optionally substituted by R10. In some embodiments,
    Figure US20240043421A1-20240208-P00999
  • In some embodiments, R1 is —OR2 or —NR3aR3b.
  • In some embodiments, R1 is —OR2. In some embodiments, R2 is C1-C6 alkyl (e.g., t-butyl).
  • In some embodiments, R1 is —NR3aR3b. In some embodiments, R1 is a 4- to 8-membered heterocyclyl optionally substituted by R10 formed by R3a and R3b taken together with the nitrogen to which they are attached.
  • In some embodiments, R1 is C3-C8 cycloalkyl (e.g., cyclohexyl) optionally substituted by R10. In some embodiments, R1 is 4,4-difluorocyclohexyl.
  • In some embodiments, R1 is C6-C14 aryl optionally substituted by R10. In some embodiments, R1 is phenyl optionally substituted by R10.
  • In some embodiments, R1 is 5- or 10-membered heteroaryl optionally substituted by R10. In some embodiments, R1 is 5- to 6-membered monocyclic heteroaryl optionally substituted by R10. In some embodiments, R1 is pyridyl (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl) optionally substituted by R10. In some embodiments, R1 is 8- to 10-membered bicyclic heteroaryl optionally substituted by R10. In some embodiments, R1 is indazolyl (e.g., 4-indozyl, 5-indozyl, 6-indozyl or 7-indozyl) optionally substituted by R10.
  • In some embodiments, R1 is 3- to 12-membered heterocyclyl optionally substituted by R10. In some embodiments, R1 is piperidinyl (e.g., piperidin-4-yl) optionally substituted by R10. In some embodiments, R1 is 1-cyclopropylpiperidin-4-yl. In some embodiments, R1 is tetrahydropyranyl (e.g., tetrahydropyran-4-yl) optionally substituted by R10. In some embodiments, R1 is 4-methyltetrahydropyran-4-yl.
  • It is intended and understood that each and every variation of R1 described herein, may be combined with each and every variation of X, n, m and R5 described herein, the same as if each and every combination is individually and specifically described. For example, in some embodiments of the compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va) or (a), or a salt thereof, R1 is selected from the group consisting of
  • Figure US20240043421A1-20240208-C00020
    Figure US20240043421A1-20240208-C00021
  • In the compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va) or (Vb), or a salt thereof, the 5,6,7,8-tetrahydro-1,8-naphthyridine ring may be unsubstituted or substituted. In some embodiments, p is 0. In some embodiments, q is 0. In some embodiments, p and q are 0. In some embodiments, p is 1 or 2, and each R7 is independently C1-C6 alkyl optionally substituted by halogen or —OH, C3-C6 cycloalkyl, halogen, —CN, —NO2, —OR7a, or —NR7bR7c; where each R7a, R7b and R7c is independently hydrogen or C1-C3 alkyl. In some embodiments, R7 is —CH3, —CHF2, —CH2F, —CF3, or —CH2OH. In some embodiments, q is 1 to 6, and each R8 is independently C1-C6 alkyl optionally substituted by R10, C3-C6 cycloalkyl optionally substituted by R10, halogen, oxo or —OR8a. In some embodiments, R8 is —OR8a a where R8a is hydrogen or C1-C6 alkyl. In some embodiments, R8a is hydrogen.
  • In some embodiments, each optional substituent R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, —CN, —OR11, —SR11, —NO2, —C═NH(OR11), —C(O)R11, —OC(O)R11, —C(O)OR11, —C(O)NR12R13, —NR11C(O)R12, —NR11C(O)OR12, —NR11C(O)NR12R13, —S(O)R11, —S(O)2R11, —NR11S(O)R12, —NR11S(O)2R12, —S(O)NR12R13, —S(O)2NR12R13, —P(O)(OR12) (OR13), C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to heteroaryl or C6-C14 aryl, wherein each R is independently optionally substituted by halogen, oxo, —OR14, —NR14R15, —C(O)R14, —CN, —S(O)R14, —S(O)2R14, —P(O)(OR14)(OR15), C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-C14 aryl, or C1-C6 alkyl optionally substituted by oxo, —Oh or halogen.
  • In some embodiments, R9 is independently C1-C6 alkyl, halogen, —CN, —OR11, —NR12R13, —C(O)R11, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl or C6-C14 aryl, wherein each R4 is independently optionally substituted by halogen, oxo, —OR14, —NR14R15, —C(O)R14, —CN, C3-C8 cycloalkyl, 3- to 12-metnbered heterocyclyl, 5- to 10-membered heteroaryl, C6-C14 aryl, or C1-C6 alkyl optionally substituted by oxo, —OH or halogen. In some embodiments, R9 is independently selected from F, Cl, —CN, methyl, —CHF2, —CF3, cyclopropylmethyl, tert-butyl, cyclopropyl and phenyl. In some embodiments, R9 is independently F, Cl or —CN. In some embodiments, R9 is independently methyl, —CHF2, —CF3, cyclopropylmethyl, tert-butyl or cyclopropyl. In some embodiments, R9 is independently phenyl optionally substituted by halogen or C1-C6 alkyl. In some embodiments, R9 is 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl. In some embodiments, R9 is 3,5-dimehylpyrazol-1-yl. In some embodiments, R9 is independently 3- to 12-membered heterocyclyl optionally substituted by oxo or C1-C6 alkyl. In some embodiments, R9 is morpholin-4-yl.
  • In some embodiments, R10 is independently oxo or any variation detailed herein for R9. In some embodiments, R10 is independently oxo, C1-C6 alkyl, halogen, —CN, —OR11, —NR12R13, —C(O)R11, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl or C6-C14 aryl, wherein each R9 is independently optionally substituted by halogen, oxo, —ORhu14, —NR14R15, —CN, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-C14 aryl, or C1-C6 alkyl optionally substituted by oxo, —OH or halogen. In some embodiments, R10 is independently selected from oxo, F, Cl, —CN, methyl, —CHF2, —CF3, cyclopropylmethyl, tert-butyl, cyclopropyl and phenyl. In some embodiments, R10 is independently phenyl optionally substituted by halogen or C1-C6 alkyl. In some embodiments, R10 is 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl. In some embodiments, R10 is 3,5-dimehylpyrazol-1-yl. In some embodiments, R10 is independently 3- to 12-membered heterocyclyl optionally substituted by oxo or C1-C6 alkyl. In some embodiments, R10 is motpholin-4-yl.
  • In some embodiments, R11, R12 and R13 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R11 is hydrogen. In some embodiments, R12 and R13 are each hydrogen.
  • In some embodiments, R14 and R15 are each independently hydrogen or C1-C6 alkyl.
  • In one variation is provided a compound of the formula (I), or a salt thereof, wherein the carbon bearing the CO2H and NHC(O)R1 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 NHC(O)R1 moieties is in the “R” configuration. In one variation is provided a compound of the formula (I), or a salt thereof, wherein the carbon bearing the X moiety 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 X moiety is in the “R” configuration. In one aspect of formula (I), the carbon bearing the CO2H and NHC(O)R1 moieties is in the “S” configuration and the carbon bearing the X moiety is in the “S” configuration. In one aspect of formula (I), the carbon hearing the CO2H and NHC(O)R1 moieties is in the “S” configuration and the carbon bearing the X moiety is in the “R” configuration. In one aspect of formula (I), the carbon bearing the CO2H and NHC(O)R1 moieties is in the “R” configuration and the carbon hearing the X moiety is in the “S” configuration. In one aspect of formula (I), the carbon bearing the CO2H and NHC(O)R1 moieties is in the “R” configuration and the carbon bearing the X moiety is in the “R” configuration. It is understood that the stereochemistry described is equally applicable to and described for other compounds detailed herein, such as compounds of the formula (I-A) and compounds in the associated compound tables, such as Table 1 and Table 1-A.
  • Representative compounds are listed in Table 1.
  • TABLE 1
    Compound
    No. Structure Chemical Name 1
     1
    Figure US20240043421A1-20240208-C00022
         		2-pivalamido-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
    1a (S)-2-pivalamido-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    1b (S)-2-pivalamido-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    1c (R)-2-pivalamido-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    1d (R)-2-pivalamido-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
     2
    Figure US20240043421A1-20240208-C00023
         		2-((tert-butoxycarbonyl)amino)-4-(3- (2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid
    2a (S)-2-((tert-butoxycarbonyl)amino)-4-
    ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    2b (S)-2-((tert-butoxycarbonyl)amino)-4-
    ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    2c (R)-2-((tert-butoxycarbonyl)amino)-4-
    ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    2d (R)-2-((tert-butoxycarbonyl)amino)-4-
    ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
     3
    Figure US20240043421A1-20240208-C00024
         		2-benzamido-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
    3a (S)-2-benzamido-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    3b (S)-2-benzamido-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    3c (R)-2-benzamido-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    3d (R)-2-benzamido-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
     4
    Figure US20240043421A1-20240208-C00025
         		2-(2,6-dimethylbenzamido)-4-(3-(2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
    4a (S)-2-(2,6-dimethylbenzamido)-4-((R)-
    3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    4b (S)-2-(2,6-dimethylbenzamido)-4-((S)-
    3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    4c (R)-2-(2,6-dimethylbenzamido)-4-((R)-
    3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    4d (R)-2-(2,6-dimethylbenzamido)-4-((S)-
    3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
     5
    Figure US20240043421A1-20240208-C00026
         		2-(2-chloro-3-fluorobenzamido)-4-(3- (2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid
    5a (S)-2-(2-chloro-3-fluorobenzamido)-4-
    ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    5b (S)-2-(2-chloro-3-fluorobenzamido)-4-
    ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    5c (R)-2-(2-chloro-3-fluorobenzamido)-4-
    ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    5d (R)-2-(2-chloro-3-fluorobenzamido)-4-
    ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
     6
    Figure US20240043421A1-20240208-C00027
    6a (S)-2-(2,6-dichlorobenzamido)-4-((R)-
    3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    6b (S)-2-(2,6-dichlorobenzamido)-4-((S)-
    3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    6c (R)-2-(2,6-dichlorobenzamido)-4-((R)-
    3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    6d (R)-2-(2,6-dichlorobenzamido)-4-((S)-
    3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
     7
    Figure US20240043421A1-20240208-C00028
         		2-(2,6-dichloro-4-cyanobenzamido)-4- (3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid
    7a (S)-2-(2,6-dichloro-4-
    cyanobenzamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    7b (S)-2-(2,6-dichloro-4-
    cyanobenzamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    7c (R)-2-(2,6-dichloro-4-
    cyanobenzamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    7d (R)-2-(2,6-dichloro-4-
    cyanobenzamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
     8
    Figure US20240043421A1-20240208-C00029
         		4-(3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)-2-(2- (trifluoromethyl)benzamido)butanoic acid
    8a (S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)-2-(2-
    (trifluoromethyl)benzamido)butanoic
    acid
    8b (S)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)-2-(2-
    (trifluoromethyl)benzamido)butanoic
    acid
    8c (R)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)-2-(2-
    (trifluoromethyl)benzamido)butanoic
    acid
    8d (R)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)-2-(2-
    (trifluoromethyl)benzamido)butanoic
    acid
     9
    Figure US20240043421A1-20240208-C00030
         		4-(3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)-2-(3- (trifluoromethyl)benzamido)butanoic acid
    9a (S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)-2-(3-
    (trifluoromethyl)benzamido)butanoic
    acid
    9b (S)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)-2-(3-
    (trifluoromethyl)benzamido)butanoic
    acid
    9c (R)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)-2-(3-
    (trifluoromethyl)benzamido)butanoic
    acid
    9d (R)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)-2-(3-
    (trifluoromethyl)benzamido)butanoic
    acid
    10
    Figure US20240043421A1-20240208-C00031
         		4-(3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)-2-(4- (trifluoromethyl)benzamido)butanoic acid
    10a (S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)-2-(4-
    (trifluoromethyl)benzamido)butanoic
    acid
    10b (S)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)-2-(4-
    (trifluoromethyl)benzamido)butanoic
    acid
    10c (R)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)-2-(4-
    (trifluoromethyl)benzamido)butanoic
    acid
    10d (R)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)-2-(4-
    (trifluoromethyl)benzamido)butanoic
    acid
    11
    Figure US20240043421A1-20240208-C00032
         		2-(2,6-dichlorobenzamido)-4-(3-(2- (5,6,7,8-tetrahydro-1,8-naphthyridin- 2-yl)ethyl)pyrrolidin-1-yl)butanoic acid
    11a (S)-2-(2,6-dichlorobenzamido)-4-((R)-
    3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    11b (S)-2-(2,6-dichlorobenzamido)-4-((S)-
    3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    11c (R)-2-(2,6-dichlorobenzamido)-4-((R)-
    3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    11dyl)butanoic acid
    11d (R)-2-(2,6-dichlorobenzamido)-4-((S)-
    3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    12
    Figure US20240043421A1-20240208-C00033
         		2-(3-(3,5-dimethyl-1H-pyrazol-1- yl)benzamido)-4-(4-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)ethyl)piperidin-1-yl)butanoic acid
    12a (S)-2-(3-(3,5-dimethyl-1H-pyrazol-1-
    yl)benzamido)-4-(4-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)piperidin-1-yl)butanoic acid
    12b (R)-2-(3-(3,5-dimethyl-1H-pyrazol-1-
    yl)benzamido)-4-(4-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)piperidin-1-yl)butanoic acid
    13
    Figure US20240043421A1-20240208-C00034
         		2-(3-(3,5-dimethyl-1H-pyrazol-1- yl)benzamido)-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
    13a (S)-2-(3-(3,5-dimethyl-1H-pyrazol-1-
    yl)benzamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    13b (S)-2-(3-(3,5-dimethyl-1H-pyrazol-1-
    yl)benzamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    13c (R)-2-(3-(3,5-dimethyl-1H-pyrazol-1-
    yl)benzamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    13d (R)-2-(3-(3,5-dimethyl-1H-pyrazol-1-
    yl)benzamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    14
    Figure US20240043421A1-20240208-C00035
         		2-(2-morpholinobenzamido)-4-(3-(2- (5,6,7,8-tetrahydro-1,8-naphthyridin- 2-yl)ethyl)pyrrolidin-1-yl)butanoic acid
    14a (S)-2-(2-morpholinobenzamido)-4-
    ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    14b (S)-2-(2-morpholinobenzamido)-4-
    ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    14c (S)-2-(2-morpholinobenzamido)-4-
    ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    14d (R)-2-(2-morpholinobenzamido)-4-
    ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    15
    Figure US20240043421A1-20240208-C00036
         		2-(3-morpholinobenzamido)-4-(3-(2- (5,6,7,8-tetrahydro-1,8-naphthyridin- 2-yl)ethyl)pyrrolidin-1-yl)butanoic acid
    15a (S)-2-(3-morpholinobenzamido)-4-
    ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    15b (S)-2-(3-morpholinobenzamido)-4-
    ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    15c (R)-2-(3-morpholinobenzamido)-4-
    ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    15d (R)-2-(3-morpholinobenzamido)-4-
    ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    16
    Figure US20240043421A1-20240208-C00037
         		2-(4-morpholinobenzamido)-4-(3-(2- (5,6,7,8-tetrahydro-1,8-naphthyridin- 2-yl)ethyl)pyrrolidin-1-yl)butanoic acid
    16a (S)-2-(4-morpholinobenzamido)-4-
    ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    16b (S)-2-(4-morpholinobenzamido)-4-
    ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    16c (R)-2-(4-morpholinobenzamido)-4-
    ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    16d (R)-2-(4-morpholinobenzamido)-4-
    ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    17
    Figure US20240043421A1-20240208-C00038
         		2-(picolinamido)-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
    17a (S)-2-(picolinamido)-4-((R)-3-(2-
    (5,6,7,8-tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    17b (S)-2-(picolinamido)-4-((S)-3-(2-
    (5,6,7,8-tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    17c (R)-2-(picolinamido)-4-((R)-3-(2-
    (5,6,7,8-tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    17d (R)-2-(picolinamido)-4-((S)-3-(2-
    (5,6,7,8-tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    18
    Figure US20240043421A1-20240208-C00039
         		2-(isonicotinamido)-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
    18a (S)-2-(isonicotinamido)-4-((R)-3-(2-
    (5,6,7,8-tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    18b (S)-2-(isonicotinamido)-4-((S)-3-(2-
    (5,6,7,8-tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    18c (R)-2-(isonicotinamido)-4-((R)-3-(2-
    (5,6,7,8-tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    18d (R)-2-(isonicotinamido)-4-((S)-3-(2-
    (5,6,7,8-tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    19
    Figure US20240043421A1-20240208-C00040
         		2-(nicotinamido)-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
    19a (S)-2-(nicotinamido)-4-((R)-3-(2-
    (5,6,7,8-tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    19b (S)-2-(nicotinamido)-4-((S)-3-(2-
    (5,6,7,8-tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    19c (R)-2-(nicotinamido)-4-((R)-3-(2-
    (5,6,7,8-tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    19d (R)-2-(nicotinamido)-4-((S)-3-(2-
    (5,6,7,8-tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    20
    Figure US20240043421A1-20240208-C00041
         		2-(3,5-dichloroisonicotinamido)-4-(3- (2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid
    20a (S)-2-(3,5-dichloroisonicotinamido)-4-
    ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    20b (S)-2-(3,5-dichloroisonicotinamido)-4-
    ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    20c (R)-2-(3,5-dichloroisonicotinamido)-4-
    ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    20d (R)-2-(3,5-dichloroisonicotinamido)-4-
    ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    21
    Figure US20240043421A1-20240208-C00042
         		2-(4,4-difluorocyclohexane-1- carboxamido)-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
    21a (S)-2-(4,4-difluorocyclohexane-1-
    carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    21b (S)-2-(4,4-difluorocyclohexane-1-
    carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    21c (R)-2-(4,4-difluorocyclohexane-1-
    carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    21d (R)-2-(4,4-difluorocyclohexane-1-
    carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    22
    Figure US20240043421A1-20240208-C00043
         		2-(4-methyltetrahydro-2H-pyran-4- carboxamido)-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
    22a (S)-2-(4-methyltetrahydro-2H-pyran-4-
    carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    22b (S)-2-(4-methyltetrahydro-2H-pyran-4-
    carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    22c (R)-2-(4-methyltetrahydro-2H-pyran-4-
    carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    22d (R)-2-(4-methyltetrahydro-2H-pyran-4-
    carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    23
    Figure US20240043421A1-20240208-C00044
         		2-(1-cyclopropylpiperidine-4- carboxamido)-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
    23a (S)-2-(1-cyclopropylpiperidine-4-
    carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    23b (S)-2-(1-cyclopropylpiperidine-4-
    carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    23c (R)-2-(1-cyclopropylpiperidine-4-
    carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    23d (R)-2-(1-cyclopropylpiperidine-4-
    carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    24
    Figure US20240043421A1-20240208-C00045
         		2-(1-methyl-1H-indazole-6- carboxamido)-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
    24a (S)-2-(1-methyl-1H-indazole-6-
    carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    24b (S)-2-(1-methyl-1H-indazole-6-
    carboxamido)-4-((s)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    24c (r)-2-(1-methyl-1H-indazole-6-
    carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    24d (r)-2-(1-methyl-1H-indazole-6-
    carboxamido)-4-((s)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    25
    Figure US20240043421A1-20240208-C00046
         		2-(1-methyl-1H-indazole-5- carboxamido)-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
    25a (S)-2-(1-methyl-1H-indazole-5-
    carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    25b (S)-2-(1-methyl-1H-indazole-5-
    carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    25c (R)-2-(1-methyl-1H-indazole-5-
    carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    25d (R)-2-(1-methyl-1H-indazole-5-
    carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    26
    Figure US20240043421A1-20240208-C00047
         		2-(1H-indazole-7-carboxamido)-4-(3- (2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid
    26a (S)-2-(1H-indazole-7-carboxamido)-4-
    ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    26b (S)-2-(1H-indazole-7-carboxamido)-4-
    ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    26c (R)-2-(1H-indazole-7-carboxamido)-4-
    ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    26a (R)-2-(1H-indazole-7-carboxamido)-4-
    ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-
    naphthyridin-2-yl)ethyl)pyrrolidin-1-
    yl)butanoic acid
    27
    Figure US20240043421A1-20240208-C00048
         		2-(1-methyl-1H-indazole-4- carboxamido)-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
    27a (S)-2-(1-methyl-1H-indazole-4-
    carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    27b (S)-2-(1-methyl-1H-indazole-4-
    carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    27c (R)-2-(1-methyl-1H-indazole-4-
    carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    27d (R)-2-(1-methyl-1H-indazole-4-
    carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    28
    Figure US20240043421A1-20240208-C00049
         		2-(1-methyl-1H-indazole-7- carboxamido)-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
    28a (S)-2-(1-methyl-1H-indazole-7-
    carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    28b (S)-2-(1-methyl-1H-indazole-7-
    carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    28c (R)-2-(1-methyl-1H-indazole-7-
    carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    28d (R)-2-(1-methyl-1H-indazole-7-
    carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    29
    Figure US20240043421A1-20240208-C00050
         		2-(1-(difluoromethyl)-1H-indazole- 6-carboxamido)-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
    29a (S)-2-(1-(difluoromethyl)-1H-indazole-
    6-carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    29b (S)-2-(1-(difluoromethyl)-1H-indazole-
    6-carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    29c (R)-2-(1-(difluoromethyl)-1H-indazole-
    6-carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    29d (R)-2-(1-(difluoromethyl)-1H-indazole-
    6-carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    30
    Figure US20240043421A1-20240208-C00051
         		2-(1-(difluoromethyl)-1H-indazole-5- carboxamido)-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
    30a (S)-2-(1-(difluoromethyl)-1H-indazole-
    5-carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    30b (S)-2-(1-(difluoromethyl)-1H-indazole-
    5-carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    30c (R)-2-(1-(difluoromethyl)-1H-indazole-
    5-carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    30d (R)-2-(1-(difluoromethyl)-1H-indazole-
    5-carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    31
    Figure US20240043421A1-20240208-C00052
         		2-(benzo[d]oxazole-5-carboxamido)- 4-(3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid
    31a (S)-2-(benzo[d]oxazole-5-
    carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    31b (S)-2-(benzo[d]oxazole-5-
    carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    31c (R)-2-(benzo[d]oxazole-5-
    carboxamido)-4-((R)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    31d (R)-2-(benzo[d]oxazole-5-
    carboxamido)-4-((S)-3-(2-(5,6,7,8-
    tetrahydro-1,8-naphthyridin-2-
    yl)ethyl)pyrrolidin-1-yl)butanoic acid
    1 Chemical names are generated using the ChemBioDraw ® Ultra version 14.0.0.117 software.
  • Additional representative compounds are listed in Table 1-A.
  • Compound
    No. Structure
     32
    Figure US20240043421A1-20240208-C00053
     33
    Figure US20240043421A1-20240208-C00054
     34
    Figure US20240043421A1-20240208-C00055
     35
    Figure US20240043421A1-20240208-C00056
     36
    Figure US20240043421A1-20240208-C00057
     37
    Figure US20240043421A1-20240208-C00058
     38
    Figure US20240043421A1-20240208-C00059
     39
    Figure US20240043421A1-20240208-C00060
     40
    Figure US20240043421A1-20240208-C00061
     41
    Figure US20240043421A1-20240208-C00062
     42
    Figure US20240043421A1-20240208-C00063
     43
    Figure US20240043421A1-20240208-C00064
     44
    Figure US20240043421A1-20240208-C00065
     45
    Figure US20240043421A1-20240208-C00066
     46
    Figure US20240043421A1-20240208-C00067
     47
    Figure US20240043421A1-20240208-C00068
     48
    Figure US20240043421A1-20240208-C00069
     49
    Figure US20240043421A1-20240208-C00070
     50
    Figure US20240043421A1-20240208-C00071
     51
    Figure US20240043421A1-20240208-C00072
     52
    Figure US20240043421A1-20240208-C00073
     53
    Figure US20240043421A1-20240208-C00074
     54
    Figure US20240043421A1-20240208-C00075
     55
    Figure US20240043421A1-20240208-C00076
     56
    Figure US20240043421A1-20240208-C00077
     57
    Figure US20240043421A1-20240208-C00078
     58
    Figure US20240043421A1-20240208-C00079
     59
    Figure US20240043421A1-20240208-C00080
     60
    Figure US20240043421A1-20240208-C00081
     61
    Figure US20240043421A1-20240208-C00082
     62
    Figure US20240043421A1-20240208-C00083
     63
    Figure US20240043421A1-20240208-C00084
     64
    Figure US20240043421A1-20240208-C00085
     65
    Figure US20240043421A1-20240208-C00086
     66
    Figure US20240043421A1-20240208-C00087
     67
    Figure US20240043421A1-20240208-C00088
     68
    Figure US20240043421A1-20240208-C00089
     69
    Figure US20240043421A1-20240208-C00090
     70
    Figure US20240043421A1-20240208-C00091
     71
    Figure US20240043421A1-20240208-C00092
     72
    Figure US20240043421A1-20240208-C00093
     73
    Figure US20240043421A1-20240208-C00094
     74
    Figure US20240043421A1-20240208-C00095
     75
    Figure US20240043421A1-20240208-C00096
     76
    Figure US20240043421A1-20240208-C00097
     77
    Figure US20240043421A1-20240208-C00098
     78
    Figure US20240043421A1-20240208-C00099
     79
    Figure US20240043421A1-20240208-C00100
     80
    Figure US20240043421A1-20240208-C00101
     81
    Figure US20240043421A1-20240208-C00102
     82
    Figure US20240043421A1-20240208-C00103
     83
    Figure US20240043421A1-20240208-C00104
     84
    Figure US20240043421A1-20240208-C00105
     85
    Figure US20240043421A1-20240208-C00106
     86
    Figure US20240043421A1-20240208-C00107
     87
    Figure US20240043421A1-20240208-C00108
     88
    Figure US20240043421A1-20240208-C00109
     89
    Figure US20240043421A1-20240208-C00110
     90
    Figure US20240043421A1-20240208-C00111
     91
    Figure US20240043421A1-20240208-C00112
     92
    Figure US20240043421A1-20240208-C00113
     93
    Figure US20240043421A1-20240208-C00114
     94
    Figure US20240043421A1-20240208-C00115
     95
    Figure US20240043421A1-20240208-C00116
     96
    Figure US20240043421A1-20240208-C00117
     97
    Figure US20240043421A1-20240208-C00118
     98
    Figure US20240043421A1-20240208-C00119
     99
    Figure US20240043421A1-20240208-C00120
    100
    Figure US20240043421A1-20240208-C00121
    101
    Figure US20240043421A1-20240208-C00122
    102
    Figure US20240043421A1-20240208-C00123
    103
    Figure US20240043421A1-20240208-C00124
    104
    Figure US20240043421A1-20240208-C00125
    105
    Figure US20240043421A1-20240208-C00126
    106
    Figure US20240043421A1-20240208-C00127
    107
    Figure US20240043421A1-20240208-C00128
    108
    Figure US20240043421A1-20240208-C00129
    109
    Figure US20240043421A1-20240208-C00130
    110
    Figure US20240043421A1-20240208-C00131
    111
    Figure US20240043421A1-20240208-C00132
    112
    Figure US20240043421A1-20240208-C00133
    113
    Figure US20240043421A1-20240208-C00134
    114
    Figure US20240043421A1-20240208-C00135
    115
    Figure US20240043421A1-20240208-C00136
    116
    Figure US20240043421A1-20240208-C00137
    117
    Figure US20240043421A1-20240208-C00138
    118
    Figure US20240043421A1-20240208-C00139
    119
    Figure US20240043421A1-20240208-C00140
    120
    Figure US20240043421A1-20240208-C00141
    121
    Figure US20240043421A1-20240208-C00142
    122
    Figure US20240043421A1-20240208-C00143
    123
    Figure US20240043421A1-20240208-C00144
    124
    Figure US20240043421A1-20240208-C00145
    125
    Figure US20240043421A1-20240208-C00146
    126
    Figure US20240043421A1-20240208-C00147
    127
    Figure US20240043421A1-20240208-C00148
    128
    Figure US20240043421A1-20240208-C00149
    129
    Figure US20240043421A1-20240208-C00150
    130
    Figure US20240043421A1-20240208-C00151
    131
    Figure US20240043421A1-20240208-C00152
    132
    Figure US20240043421A1-20240208-C00153
    133
    Figure US20240043421A1-20240208-C00154
    134
    Figure US20240043421A1-20240208-C00155
    135
    Figure US20240043421A1-20240208-C00156
    136
    Figure US20240043421A1-20240208-C00157
    137
    Figure US20240043421A1-20240208-C00158
    138
    Figure US20240043421A1-20240208-C00159
    139
    Figure US20240043421A1-20240208-C00160
    140
    Figure US20240043421A1-20240208-C00161
    141
    Figure US20240043421A1-20240208-C00162
    142
    Figure US20240043421A1-20240208-C00163
    143
    Figure US20240043421A1-20240208-C00164
    144
    Figure US20240043421A1-20240208-C00165
    145
    Figure US20240043421A1-20240208-C00166
    146
    Figure US20240043421A1-20240208-C00167
    147
    Figure US20240043421A1-20240208-C00168
  • In some embodiments, provided is a compound selected from Compound Nos. 1-31 in Table 1, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, provided is a compound selected from Compound Nos. 1-147, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof. In some embodiments, the compound is selected from the group consisting of Compound Nos 1a, 1b, 1c, 1d, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4h, 4c, 4d, 5a, 5b, 5c, 5d, Ca, 6h, 6c, 6d, 7a, 7b, 7c, 7d, 8a, 8b, 8c, 8d, 9a, 9b, 9c, 9d, 10a, 10b, 10c, 10d, 11a, 11b, 11c, 11d, 12a, 12b, 13a, 13b, 13c, 13d, 14a, 14b, 14c, 14d, 15a, 15b, 15c, 16a, 16b, 16c, 16d, 17a, 17b, 17c, 17d, 18a, 18b, 18c, 18d, 19a, 19b, 19c, 19d, 20a, 20b, 20d, 21a, 21h, 21c, 21d, 22a, 22b, 22c, 22d, 23a, 23b, 23c, 23d, 24a, 24h, 24c, 24d, 25a, 25c, 25d, 26a, 26b, 26c, 26d, 27a, 27b, 27c, 27d, 28a, 28b, 28c, 28d, 29a, 29b, 29c, 29d, 30b, 30c, 30d, 31a, 31b, 31c and 31d, or a salt thereof.
  • In some embodiments, the compound is selected from the group consisting of one or more of Compound Nos. 1-31 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 selected from the group consisting of one or more of Compound Nos 1a, 1b, 1c, 1d, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, 4d, 5a, 5b, 5c, 5d, 6a, 6b, 6c, 6d, 7a, 7b, 7c, 7d, 8a, 8b, 8c, 8d, 9a, 9b, 9c, 9d, 10a, 10b, 10c, 10d, 11a, 11b, 11c, 11d, 12a, 12b, 13a, 13b, 13c, 13d, 14a, 14b, 14c, 14d, 15a, 15b, 15c, 15d, 16a, 16b, 16c, 16d, 17a, 17b, 17c, 17d, 18a, 18b, 18c, 18d, 19a, 19b, 19c, 19d, 20a, 20b, 20c, 20d, 21a, 21b, 21c, 21d, 22a, 22b, 22c, 22d, 23a, 23b, 23c, 23d, 24a, 24h, 24c, 24d, 25a, 25b, 25c, 25d, 26a, 26h, 26c, 26d, 27a, 27h, 27c, 27d, 28a, 28b, 28c, 28d, 29a, 29b, 29c, 29d, 30a, 30b, 30c, 30d, 31a, 31b, 31c and 31d, or a salt thereof.
  • In some embodiments, provided is a compound selected from Compound Nos. 32-147 in Table 1-A, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a salt thereof.
  • 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 diastereomeric 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 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 invention 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 invention in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced,
  • Compounds described herein are αvβ6 integrin inhibitors. In some instances, it is desirable for the compound to inhibit other integrins in addition to αvβ6 integrin. In some embodiments, the compound inhibits αvβ6 integrin and one or more of αbβ1, αvβ3, αvβ5, α2β1, α3β1, α6β1 integrin, α7β1 and α11β1. In some embodiments, the compound inhibits αvβ6 integrin and αvβ1 integrin. In some embodiments, the compound inhibits αvβ6 integrin, αvβ3 integrin and αvβ5 integrin. In some embodiments, the compound inhibits αvβ6 integrin and α2β1 integrin, in some embodiments, the compound inhibits αvβ6 integrin, α2β1 integrin and α3β1 integrin. In some embodiments, the compound inhibits αvβ6 integrin and α6β1 integrin. In some embodiments, the compound inhibits αvβ6 integrin and Ε7β1 integrin In some embodiments, the compound inhibits αvβ6 integrin and α11β1 integrin,
  • In some instances, it is desirable to avoid inhibition of other integrins. In some embodiments, the compound is a selective αvβ6 integrin inhibitor. In some embodiments, the compound does not inhibit substantially α4β1, αvβ8 and/or α2β3 integrin. In some embodiments, the compound inhibits αvβ6 integrin but does not inhibit substantially azIfil integrin. In some embodiments, the compound inhibits αvβ6 integrin but does not inhibit substantially αvβ8 integrin. In some embodiments, the compound inhibits αvβ6 integrin but does not inhibit substantially α2β3 integrin. In some embodiments, the compound inhibits αvβ6 integrin but does not inhibit substantially the αvβ8 integrin and the α4β1 integrin.
  • 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, 11C, 13C, 14C 13N, 15O, 17O, 32P, 35S, 18F, 36Cl. Incorporation of heavier isotopes such as deuterium (2H) 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.
  • Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically-labeled reagents in place of the corresponding non-labeled reagent.
  • The invention also includes any or all metabolites of any of the compounds 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.
  • 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.
  • Preferably, the compounds detailed herein are orally bioavailable. However, 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. Depending on the therapeutic form of the medication, the carrier may be in various forms.
    • General Synthetic Methods
  • The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. 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,
  • Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, 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 enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
  • Chromatography, recrystallization and other conventional separation procedures may also be 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 andlor 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, andlor solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • Compounds of the formula (I) can be prepared according to Scheme 1, wherein R1, R2, R7, R8, X, m, n, p and q are as defined for formula (I), or any applicable variations detailed herein; P0 and P1 are independently an amine protecting group, (e.g., t-butoxycarbonyl (Boc)); P2 is a carboxylic acid protecting group (e.g., ethyl); and Lv is a leaving group (e.g., OH, O-acyl, OAt, Cl, 1-imidazolyl, and the like).
  • Figure US20240043421A1-20240208-C00169
  • Reduction (e.g., catalytic hydrogenation) of 1,8-naphthyridine compound (G), for example, using H2 over palladium hydroxide in methanol, gives tetrahydro-1,8-naphthyridine compound (F), which is deprotected to give compound (E). Reductive alkylation of compound (E) with aldehyde (D) (a protected 2-amino-4-oxobutanoic acid) produces intermediate compound (C), which is deprotected to give amine compound (B). Coupling of amine compound (B) with activated carbonyl compound R1C(O)-Lv gives intermediate compound (A). Deprotection of the carboxylic acid (e.g., hydrolysis) provides a compound of formula (I).
  • It is understood that the schemes above may be modified to arrive at various compounds of the invention by selection of appropriate reagents and starting materials. It is also understood that where protection of certain active or incompatible groups (e.g., an amine or a carboxylic acid) is required, the formulae in Scheme 1 intend and include compounds where such active or incompatible groups are in appropriate protected forms. 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.
  • An exemplary embodiment of the preparative method in Scheme 1 is shown in Scheme 1a. In some embodiments, R1 is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1 -C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R1 are independently optionally substituted by R10.
  • Figure US20240043421A1-20240208-C00170
  • Provided is a method for preparing a compound of formula (I), or a salt thereof, comprising performing one or more steps of Scheme 1 or Scheme 1a.
    • Pharmaceutical Compositions and Formulations
  • Pharmaceutical compositions of any of the compounds detailed herein are embraced by this invention. Thus, the invention includes pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceuticallw acceptable salt is an 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 tbr administration by inhalation.
  • 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. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. In one variation, “substantially pure” intends a composition that contains 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 substantially pure compound selected from a compound of Table 1 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound or a salt thereof. In one variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25% impurity. In another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 20% 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 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 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 15% or preferably no more than 10% or more preferably no more than 5% or even more preferably no more than 3% and most preferably no more than 1% impurity, which impurity may be the compound in a different stereochemical form. For instance, a composition of substantially pure (S) compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound.
  • 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 carrier or excipient. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
  • The compound 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 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.
  • One or several compounds described herein can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds 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 in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, butlers, coating agents or antioxidants. Formulations comprising the 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.
  • 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, corn 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.
  • 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. 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.
    • Methodsof Use
  • Compounds and compositions of the invention, such as a pharmaceutical composition containing a compound of any formula provided herein or a salt thereof and a pharmaceutically acceptable carder or excipient, may be used in methods of administration and treatment as provided herein. The compounds and compositions may also he 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.
  • 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 effective amount of a compound of formula (I), or any variation thereof, e,g., a compound of formula (Ia), (IIb), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va) or (Vb), a compound selected from Compound Nos. 1-31 in Table 1, or a pharmaceutically acceptable salt thereof. In one aspect, the individual is a human. The individual, such as human, may he in need of treatment, such as a human who has or is suspected of having a fibrotic disease.
  • 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 developing 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 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).
  • In some embodiments, the fibrotic disease is a pulmonary fibrosis, e.g., idiopathic pulmonary fibrosis (IPF).
  • In some embodiments, the fibrotic disease is a primary sclerosing cholangitis, or biliary fibrosis.
  • In some embodiments, the fibrotic disease is fibrotic nonspecific interstitial pneumonia (NSW).
  • In some embodiments, the fibrotic disease is a liver fibrosis, e.g., infectious liver fibrosis (from pathogens such as HCV, HBV or parasites such as schistosomiasis), NASH, alcoholic steatosis induced liver fibrosis, and cirrhosis.
  • In some embodiments, the fibrotic disease is biliary tract fibrosis.
  • In some embodiments, the fibrotic disease is kidney fibrosis, diabetic nephrosclerosis, hypertensive nephrosclerosis, focal segmental glomerulosclerosis (“FSGS”), and acute kidney injury from contrast induced nephropathy.
  • In some embodiments, the fibrotic disease is systemic and local sclerosis or scleroderma, keloids and hypertrophic scars, or post surgical adhesions.
  • In some embodiments, the fibrotic disease is atherosclerosis or restenosis.
  • In some embodiments, the fibrotic disease is a gstrointestinal fibrosis, e.g., Crohn's disease.
  • In some embodiments, the fibrotic disease is cardiac fibrosis, e.g., post myocardial infarction induced fibrosis and inherited cardiomyopathy.
  • in one aspect, provided is a compound of formula (I), or any variation thereof, a compound of formula (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va) or (Vb), a compound selected from Compound Nos. 1-31 in Table 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of a fibrotic disease.
  • Also provided is use of a compound of formula (I), or any variation thereof, e.g., a compound of formula (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVA), (V), (Va) or (Vb), a compound selected from Compound Nos. 1-31 in Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.
  • In another aspect, provided is a method of inhibiting αvβ6 integrin in an individual comprising administering a compound of formula (I), or any variation thereof, e.g., a compound of formula (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va) or (Vb), a compound selected from Compound Nos. 1-31 in Table 1, or a pharmaceutically acceptable salt thereof.
  • Also provided is a method of inhibiting TGFβ activation in a cell comprising administering to the cell a compound of formula (I), or any variation thereof, e.g., a compound of formula (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va) or (Vb), a compound selected from Compound Nos. 1-31 in Table 1, or a pharmaceutically acceptable salt thereof.
  • Also provided is a method of inhibiting αvβ6 integrin in an individual in need thereof, comprising administering to the individual a compound of formula (I), or any variation thereof, e.g., a compound of formula (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (Wc), (IVd), (V), (Va) or (Vb), a compound selected from Compound Nos. 1-31 in Table 1, or a pharmaceutically acceptable salt thereof. In one such method, the compound is a selective αvβ6 integrin inhibitor. In another such method, the compound does not inhibit substantially α4β1, αvβ8 and/or α2β3 integrin. In yet another such method, the compound inhibits αvβ6 integrin but does not inhibit substantiallyα4β1 integrin. In still another such method, the compound inhibits αvβ6 integrin but does not inhibit substantially αvβ8 integrin. In a further such method, the compound inhibits αvβ6 integrin but does not inhibit substantially α2β3 integrin. In one embodiment is provided a method of inhibiting avv, integrin and one or more of αvβ1, αvβ3, αvβ5, α2β1, α6β1 integrin, α7β1 and α11β1 in an individual in need thereof. In another embodiement is provided a method of inhibiting αvβ6 integrin and αvβ1 integrin. In another embodiment is provided a method of inhibiting αvβ6 integrin, αvβ3 integrin and αbβ5 integrin. In another embodiment is provided a method of inhibiting αvβ6 integrin and α2β1 integrin. In another embodiment is provided a method of inhibitingαvβ6 integrin, α2β1 integrin and α3β1 integrin. In another embodiment is provided a method of inhibiting αvβ6 integrin and α6β1 integrin. In another embodiment is provided a method of inhibiting αvβ6 integrin and α7β1 integnn. In another embodiment is provided a method of inhibiting αvβ6 integrin and α11β1 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 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 (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va) or (Vb), a compound selected from Compound Nos. 1-31 in Table 1, or a pharmaceutically acceptable salt thereof.
  • 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
  • The invention further provides kits for carrying out the methods of the invention, which comprises one or more compounds described herein 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.
  • 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.
  • 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).
  • The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of 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.
    • SYNTHETIC EXAMPLES
  • The chemical reactions in the Synthetic Examples described can be readily adapted to prepare a number of other compounds of the invention, and alternative methods for preparing the compounds of this invention are 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.
    • Example 1 Synthesis of tert-butyl (R)-3-(2-(5,6,7,8-tetrahydro1,8-naphthyridin-2-yl)ethyl)pyrrolidine-1-carboxylate
  • Figure US20240043421A1-20240208-C00171
  • A flask equipped with a magnetic stir bar was charged with fiat-butyl (R)-3-(2-(1,8-naphthyridin-2-yl)ethyl)pyrrolidine-1-carboxylate (3.10 g, 9.47 mmol, 1.0 equiv) and 20 wt % Fd(OH)2/C (310 mg) and then diluted in MeOH (31 mL). The flask was then evacuated and then backfilled with H2 for three cycles and then stirred under an H2 atmosphere for 18 h, at which time, LC/MS had indicated complete conversion to the desired product. The mixture was filtered through a pad of Celite and concentrated in vacuo to give a crude residue that was purified by normal phase silica gel chromatography (MeOH/EtOAc 0-20% gradient) to give tert-butyl (R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidine-1-carboxylate. MS (ESI+, m/e) 332 (M+1).
    • Example 2 Synthesis of (R)-7-(2-(pyrrolidin-3-yl)ethyl)-1,2,3,4-tetrabydro-1,8-naphthyridine dihydrochloride
  • Figure US20240043421A1-20240208-C00172
  • A flask containing tern-butyl (R)-3-(2(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidine-1-carboxylate (909 mg, 2,74 mmol, 1.0 equiv) was equipped with a stir bar then diluted in 10:1 DCM/MeOH (9 mL). To this was then slowly added 4M HCl in dioxane (2.8 mL, 11.2 mmol, 4.1 equiv) and the mixture was allowed to stir at room temperature for 4 hr and then concentrated in vacua to give (R)-7-(2-(pyrolidin-3-yl)ethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride that was used without further purification. MS (ESI+, m/e) 232 (M+1).
    • Example 3 Synthesis of ethyl (S)-2-((tert-butoxycarbonyl)amino)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoate
  • Figure US20240043421A1-20240208-C00173
  • To a solution of (R)-7-(2-(pyrrolidin-3-yl)ethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (446 mg, 1.47 mmol, 1.0 equiv) in MeOH (5 mL) was added AcOH (84 μL, 1.47 mmol, 1.0 equiv) then NaCNBH3 (184 mg, 2.93 mmol, 2.0 equiv) at room temperature. To this was then added ethyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (607 mg, 2.48 mmol, 1.7 equiv) and the resulting mixture was stirred for 1.5 hr at room temperature and then concentrated in vacua. The crude residue was purified by normal phase silica gel chromatography (2.0 M NH3 in MeOH/EtOAc 0-30%) to give ethyl (S)-2-((tert-butoxycarbonyl)amino)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoate. MS (ESI+, m/e) 461 (M+1).
    • Example 4 Synthesis of ethyl (S)-2-amino-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoate trihydrochloride
  • Figure US20240043421A1-20240208-C00174
  • A flask containing ethyl (S)-2-((tert-butoxycarbonyl)amino)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoate (605 mg, 1.31 mmol, 1.0 equiv) was equipped with a stir bar then diluted in 10:1 DCM/MeOH (6 mL). To this was then slowly added 4M HCl in dioxane (1.3 mL, 5.2 mmol, 4.0 equiv) and the mixture was allowed to stir at room temperature for 4 hr and then concentrated in vacua to give ethyl (S)-2-amino-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoate trihydrochloride that was used without further purification. MS (ESI+, m/e) 361 (M+1).
    • Example 5 General Procedure for Amide Coupling
  • Figure US20240043421A1-20240208-C00175
  • A flask containing ethyl (5)-2-amino-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoate trihydrochloride (50 mg, 0.1 mmol, 1.0 equiv) was diluted with 10:1 THF/DMF (2 mL) and to this was added DIPEA (93 μL, 0.5 mmol, 5.0 equiv) followed by the appropriate carboxylic acid (1.5 equiv) and then HATU (57 mg, 0.15 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 1 hr and then concentrated in vacua to provide a crude residue that was purified by normal phase silica gel chromatography (2.0 M NH3 in MeOH/EtOAc 0-30%) to give the desired product.
    • Example 6 General Procedure for Hydrolysis
  • Figure US20240043421A1-20240208-C00176
  • A flask containing the appropriate ester (50 mg, 1.0 equiv) was diluted with THF/MeOH/H2O (1.0 mL) and to this was added LiOH (3.0 equiv) at room temperature. The resulting mixture was stirred until LC/MS indicated complete hydrolysis of the ester to the desired carboxylic. acid. The mixture was neutralized by the addition of AcOH (3.0 equiv) and then filtered through a 0.2 micron filter and purified by preparative reverse phase HPLC (MeCN/H2O containing 0.1% TFA, 5-95% gradient) to give the desired carboxylic acid as the trifluoroacetic acid salt.
    • Example 7 Synthesis of Exemplary Compounds
  • Certain exemplary compounds were synthesized using general procedures described herein, for example, procedures in Examples 5 and 6. The structures of the compounds and. mass spectroscopy data (m/z) are listed below.
  • Compound
    No Structure m/z
    1a and 1c
    Figure US20240043421A1-20240208-C00177
         		417.2
    2a
    Figure US20240043421A1-20240208-C00178
         		433.3
    3a and 3c
    Figure US20240043421A1-20240208-C00179
         		437.2
    4a and 4c
    Figure US20240043421A1-20240208-C00180
         		465.2
    5a
    Figure US20240043421A1-20240208-C00181
         		489.2
    6a
    Figure US20240043421A1-20240208-C00182
         		505.2
    6c
    Figure US20240043421A1-20240208-C00183
         		505.1
    7a and 7c
    Figure US20240043421A1-20240208-C00184
         		530.1
    8a
    Figure US20240043421A1-20240208-C00185
         		505.2
    9a
    Figure US20240043421A1-20240208-C00186
         		505.2
    10a
    Figure US20240043421A1-20240208-C00187
         		505.2
    11a
    Figure US20240043421A1-20240208-C00188
         		555.2
    12a
    Figure US20240043421A1-20240208-C00189
         		545.3
    13a and 13c
    Figure US20240043421A1-20240208-C00190
         		531.3
    13a
    Figure US20240043421A1-20240208-C00191
         		531.3
    13c
    Figure US20240043421A1-20240208-C00192
         		531.3
    14a
    Figure US20240043421A1-20240208-C00193
         		522.3
    15a
    Figure US20240043421A1-20240208-C00194
         		577.3
    16a
    Figure US20240043421A1-20240208-C00195
         		522.3
    17a
    Figure US20240043421A1-20240208-C00196
         		438.2
    18a
    Figure US20240043421A1-20240208-C00197
         		438.2
    19a
    Figure US20240043421A1-20240208-C00198
         		438.2
    20a and 20c
    Figure US20240043421A1-20240208-C00199
         		506.1
    21a
    Figure US20240043421A1-20240208-C00200
         		479.3
    21c
    Figure US20240043421A1-20240208-C00201
         		479.3
    22a
    Figure US20240043421A1-20240208-C00202
         		459.3
    23a and 23c
    Figure US20240043421A1-20240208-C00203
         		484.3
    24a
    Figure US20240043421A1-20240208-C00204
         		491.3
    25a
    Figure US20240043421A1-20240208-C00205
         		491.3
    26a
    Figure US20240043421A1-20240208-C00206
         		477.3
    27a
    Figure US20240043421A1-20240208-C00207
         		491.3
    28a
    Figure US20240043421A1-20240208-C00208
         		491.3
    29a
    Figure US20240043421A1-20240208-C00209
         		527.2
    30a
    Figure US20240043421A1-20240208-C00210
         		527.3
    31a and 31c
    Figure US20240043421A1-20240208-C00211
         		478.2
    • BIOLOGICAL EXAMPLES Example B1—Solid Phase Integrin αvβ6 Binding Assay
  • Microplates were coated with recombinant human integrin αvβ6 (2 ug/ml) in PBS (100 ul/well 2.5° C., overnight). The coating solution was removed, washed with wash buffer (0.05% Tween MnCl2; in 1×TBS). Plate was blocked with 200 ul/well of Block Buffer (1% BSA; 5% sucrose; 0.5 mM MnCl2; in 1×TBS) at 37° C. for 2 h. Dilutions of testing compounds and recombinant TGFβ1 LAP (0.67 ug/ml) in binding buffer (0.05% BSA; 2.5% sucrose; 0.5 mM MnCl2; in 1×TBS) were added. The plate was incubated for 2 hours at 25° C., washed, and incubated for 1 hour with Biotin-Anti-hLAP. Bound antibody was detected by peroxidase-conjugated streptavidin. The IC50 values for testing compounds were calculated by a four-parameter logistic regression.
  • The IC50 values obtained for αvβ6 integrin inhibition for exemplary compounds are shown in Table B-1. The compounds tested were compound samples prepared according to procedures described in the Synthetic Examples section, with the stereochemical purity as indicated in the Examples indicated.
  • TABLE B-1
    Compound αvβ6 Inhibition
    No. IC50 (nM)-range
      1c <50
      2a <50
    3a and 3c <50
    4a and 4c <50
      5a <50
      6a <50
      6c 250-1000
    7a and 7c <50
      8a <50
      9a <50
     10a <50
     11a <50
     12a >1000
    13a and 13c <50
     13a <50
     13c <50
     14a 50-250
     15a <50
     16a >1000
     17a 50-250
     18a <50
     19a 50-250
    20a and 20c <50
     21a <50
     21c <50
     22a 50-250
    23a and 23c 50-250
     24a <50
     25a 50-250
     26a <50
     27a <50
     28a <50
     29a <50
     30a <50
    31a and 31c <50
     33 >1000
     34 >1000
     35 <50
     36 <50
     37 <50
     38 <50
     39 50-250
     40 250-1000
     41 50-250
     42 250-1000
     43 <50
     44 <50
     45 <50
     46 <50
     47 <50
     48 <50
     49 <50
     50 <50
     51 <50
     52 50-250
     53 <50
     54 <50
     55 <50
     56 <50
     57 <50
     58 <50
     59 <50
     60 <50
     61 <50
     62 50-250
     63 50-250
     64 50-250
     65 50-250
     66 <50
     67 <50
     68 <50
     69 50-250
     70 <50
     71 <50
     72 <50
     73 <50
     74 <50
     75 <50
     76 <50
     77 <50
     78 <50
     79 <50
     80 <50
     81 50-250
     82 <50
     83 <50
     84 <50
     85 <50
     86 <50
     87 <50
     88 <50
     89 <50
     90 <50
     91 50-250
     92 <50
     93 50-250
     94 50-250
     95 <50
     96 50-250
     97 50-250
     98 250-1000
     99 <50
    100 50-250
    101 250-1000
    102 250-1000
    103 <50
    104 <50
    105 50-250
    106 50-250
    107 50-250
    108 250-1000
    109 50-250
    110 <50
    111 >1000
    112 >1000
    113 >1000
    114 250-1000
    115 <50
    116 >1000
    117 250-1000
    118 250-1000
    119 250-1000
    120 50-250
    121 250-1000
    122 250-1000
    123 <50
    124 50-250
    125 250-1000
    126 >1000
    127 <50
    128 250-1000
    129 250-1000
    130 250-1000
    131 50-250
    132 50-250
    133 250-1000
    134 250-1000
    135 >1000
    136 >1000
    137 >1000
    138 250-1000
    139 250-1000
    140 >1000
    141 <50
    142 >1000
    143 >1000
    144 >1000
    145 >1000
    146 <50
    147 >1000
  • All references throughout, such as publications, patents, patent applications and published patent applications, are incorporated herein by reference in their entireties.
  • Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims (10)

1.-33. (canceled)
34. A compound selected from the group consisting of:
(S)-2-(4,4-difluorocyclohexane-1-carboxamido)-4-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-carboxamido)piperidin-1-yl)butanoic acid,
(S)-2-(4,4-difluorocyclohexane-1-carboxamido)-4-(4-(((5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)amino)piperidin-1-yl)butanoic acid,
(S)-2-benzamido-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,
(S)-2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,
(2S)-2-benzamido-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,
(S)-2-(2-chloro-3-fluorobenzamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid
(S)-2-(2-ethylbutanamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,
(S)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)-2-(3-morpholinobenzamido)butanoic acid,
(S)-2-(3,5-difluorobenzamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,
(S)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)-2-(3-(2-methoxyethoxy)benzamido)butanoic acid,
(S)-2-(2,6-dichlorobenzamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,
(S)-2-(2-chloro-3-fluorobenzamido)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,
(S)-2-(3,5-difluorobenzamido)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,
(S)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)-2-(3-fluoro-5-(trifluoromethyl)benzamido)butanoic acid,
(S)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)-2-(1-methyl-1H-indazole-6-carboxamido)butanoic acid,
(S)-2-(4,4-difluorocyclohexane-1-carboxamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,
(S)-2-(2-ethylbutanamido)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,
(S)-2-(4,4-difluorocyclohexane-1-carboxamido)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoic acid,
(S)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)-2-(1-methyl-1H-indazole-6-carboxamido)butanoic acid,
(S)-2-((tert-butoxycarbonyl)amino)-4-((R)-3-((5,6,7 ,8-tetrahydro-1,8-naphthyridin-2-yl)methoxy)pyrrolidin-1-yl)butanoic acid,
(S)-2-benzamido-4-((R)-3-((5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methoxy)pyrrolidin-1-yl)butanoic acid,
(S)-2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)-4-((R)-3-((5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methoxy)pyrrolidin-1-yl)butanoic acid,
(S)-2-(2,6-dichlorobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,
(S)-2-(2,6-dichlorobenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,
(S)-4-((S)-4-acetyl-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperazin-1-yl)-2-benzamidobutanoic acid,
(S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)-2-(tetrahydro-2H-pyran-4-carboxamido)butanoic acid,
(S)-2-(2-methyl-2-phenylpropanamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,
(S)-2-(2,2-dimethyl-3-phenylpropanamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,
(S)-2-(2-methyl-2-phenylpropanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,
(S)-2-((S)-1-benzylpyrrolidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,
(S)-2-(2-methyl-2-(pyridin-3-yl)propanamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,
(S)-2-((S)-1-benzylpyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,
(S)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)-2-(tetrahydro-2H-pyran-4-carboxamido)butanoic acid,
(S)-2-((R)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-44(R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,
(S)-2-((S)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-44(R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,
(S)-2-((S)-1-phenylpyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,
(S)-2-(2-methyl-2-(pyridin-3-yl)propanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,
(S)-2-((S)-1-phenylpyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoic acid,
(S)-2-(2,2-dimethyl-3-phenylpropanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,
(S)-2-((R)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,
(S)-2-((S)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,
(S)-2-((S)-1-phenylpyrrolidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,
(2S)-2-(1-(2-hydroxy-2-methylpropyl)pyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoic acid,
(2S)-2-(1-benzylpyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoic acid,
(S)-2-(2-methyl-2-phenylpropanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoic acid,
(S)-2-(2,2-dimethyl-3-phenylpropanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoic acid,
(S)-2-((S)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoic acid,
(S)-2-(2,6-dichlorobenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoic acid,
(S)-2-(3-fluoro-5-(trifluoromethyl)benzamido)-4-((1R,2R,4S)-2-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-7-azabicyclo[2.2.1]heptan-7-yl)butanoic acid,
(S)-2-(3-fluoro-5-(trifluoromethyl)benzamido)-4-((1R,2R,4S)-2-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-7-azabicyclo[2.2.1]heptan-7-yl)butanoic acid,
(S)-2-((S)-1-(2-hydroxy-2-methylpropyl)pyrrolidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoic acid,
(S)-2-((S)-1-benzylpyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoic acid,
(S)-2-(2-methyl-2-(pyridin-3-yl)propanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoic acid, and
(S)-2-(2-ethylbutanamido)-4-((1R,2R,4S)-2-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-7-azabicyclo[2.2.1]heptan-7-yl)butanoic acid,
or a pharmaceutically acceptable salt thereof.
35. A pharmaceutical composition comprising a compound of claim 34, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
36. A method of treating a fibrotic disease in an individual in need thereof comprising administering a compound of claim 34 or a pharmaceutically acceptable salt thereof.
37. The method of claim 36, wherein the fibrotic disease is selected from the group consisting of: pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, kidney fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, and biliary fibrosis.
38. A kit comprising a compound of claim 34, or a pharmaceutically acceptable salt thereof.
39. The kit of claim 38, further comprising instructions for the treatment of a fibrotic disease.
40. The kit of claim 39, wherein the fibrotic disease is selected from the group consisting of: pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, kidney fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, and biliary fibrosis.
41. A method of inhibiting a v (36 integrin in an individual comprising administering a compound of claim 34 or a pharmaceutically acceptable salt thereof.
42. A method of inhibiting TGFP activation in a cell comprising administering to the cell a compound of claim 34 or a pharmaceutically acceptable salt thereof.
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