Patent Application
20240245682
This disclosure relates generally to therapeutic agents that may be useful as αVβ8 integrin inhibitors. The therapeutic agents may be used in the treatment or prophylactic treatment of fibrosis such as idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP). The therapeutic agents may also be used in the treatment of cancer.
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. IPF currently affects approximately 200,000 people in the U.S., resulting in 40,000 deaths per year. Patients diagnosed with IPF experience progressive breathlessness and eventually, complete respiratory failure.
Primary biliary cholangitis (PBC), also known as primary biliary cirrhosis, is a chronic disease of the liver that causes damage and fibrosis in the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Over time, this leads to scarring and fibrosis in both the liver and biliary tract.
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. (Kim et al., Proc. Am. Thorac. Soc. (2006) 3:285-292; Lynch, D., Radiology (2001) 221:583-584; Kinder et al., Am. J. Respir. Crit. Care Med. (2007) 176:691-697)
Biliary atresia (BA) is a fibro-obliterative cholangiopathy that affects approximately 1:5,000 to 1:18,000 infants, causing inflammation leading to end-stage liver disease. Patients generally die by two years of age without surgical intervention. Portoenterostomy can be performed in order to restore biliary drainage. However, even with restoration of biliary drainage, almost all patients will develop hepatic fibrosis and will need a liver transplant in order to survive (see Mohanty et al., “Rotavirus Reassortant-Induced Murine Model of Liver Fibrosis Parallels Human Biliary Atresia,” Hepatology 71:1316 (2020)).
Ocular fibrosis encompasses numerous disorders of the eye. For example, TGFβ signaling in epithelial cells has been shown to cause an epithelial-mesenchymal transition (EMT) leading to fibrosis with similarities to cataract formation. Examples include anterior subcapsular cataracts (ASC) and posterior capsule opacification (PCO), which can occur after cataract surgery. Studies have shown that TGFβ-induced EMT is included in lens epithelial cell wound healing response and can induce expression of various extracellular matrix proteins associated with fibrosis and integrins, leading to vision-impairing production of myofibroblasts expressing α-smooth muscle actin (α-SMA) and lens fiber cells.
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 αVβ8 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.
Disclosed are amino acid compounds that are αVβ8 integrin inhibitors, compositions containing these compounds and methods for treating diseases mediated by αVβ8 integrin such as a fibrotic disease or cancer.
In one aspect, provided is a compound of formula (A), or any variation thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), as detailed herein.
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.
Further provided is a pharmaceutical composition comprising a compound of formula (A), or any variation thereof detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient.
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 (A), or any variation thereof detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), a checkpoint inhibitor, and a pharmaceutically acceptable carrier or excipient.
Also 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), a checkpoint inhibitor, and a pharmaceutically acceptable carrier or excipient.
In another aspect, provided is a method of treating a fibrotic disease or condition in an individual (such as a human) in need thereof comprising administering to the individual a therapeutically effective amount of a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof. In another aspect, provided is a method of treating a fibrotic disease or condition in an individual (such as a human) in need thereof comprising 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 or condition is pulmonary, liver, renal, cardiac, dermal, or gastrointestinal fibrosis. In other embodiments the fibrotic disease or condition is idiopathic pulmonary fibrosis, interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease induced fibrosis, Alport syndrome, primary sclerosing cholangitis, primarily biliary cholangitis (also known as primary biliary cirrhosis), systemic sclerosis associated interstitial lung disease, scleroderma (also known as systemic sclerosis), diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, biliary atresia, and Crohn's Disease.
In another aspect, provided is a method of delaying the onset and/or development of a fibrotic disease or condition in an individual (such as a human) who is at risk for developing a fibrotic disease or condition comprising administering to the individual a therapeutically effective amount of a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof. In another aspect, provided is a method of delaying the onset and/or development of a fibrotic disease or condition in an individual (such as a human) who is at risk for developing a fibrotic disease or condition comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is pulmonary, liver, renal, cardiac, dermal, or gastrointestinal fibrosis. In other embodiments the fibrotic disease or condition is idiopathic pulmonary fibrosis, interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease induced fibrosis, Alport syndrome, primary sclerosing cholangitis, primarily biliary cholangitis (also known as primary biliary cirrhosis), systemic sclerosis associated interstitial lung disease, scleroderma (also known as systemic sclerosis), diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, biliary atresia, and Crohn's Disease.
Also provided is a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutical composition thereof, for the treatment of a fibrotic disease.
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 (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.
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.
Further provided is use of a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of a disease mediated by cells that express αVβ1 and/or αVβ8. Further provided is use of a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of a disease mediated by cells that express αVβ1 and/or αVβ8. In some embodiments, the cells are associated with the intrahepatic biliary system. In some embodiments, the cells are associated with the extrahepatic biliary system. In some embodiments, the cells are associated with the intrahepatic biliary system and the extrahepatic biliary system.
Further provided is a kit comprising a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof. Further provided is a kit comprising a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises instructions for use according to a method described herein, such as a method of treating a fibrotic disease in an individual. In some embodiments, the kit comprises instructions for use according to a method described herein, such as a method of treating a cancer in an individual.
Also provided is a kit comprising a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, and a checkpoint inhibitor. Also provided is a kit comprising a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, and a checkpoint inhibitor. 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 some embodiments, the kit comprises instructions for use according to a method described herein, such as a method of treating a cancer in an individual.
Further provided is a method of inhibiting αVβ8 integrin in an individual comprising administering a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof.
Further provided is a method of inhibiting αVβ8 integrin in an individual comprising administering a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof.
Also provided is a method of inhibiting one or more of αVβ1, αVβ6, or αVβ8 integrin in an individual in need thereof, comprising administering to the individual a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
Also provided is a method of inhibiting one or more of αVβ1, αVβ6, or αVβ8 integrin in an individual in need thereof, comprising administering to the individual a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
Further provided is a method of inhibiting TGFβ activation in a cell comprising administering to the cell a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
Further 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 detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
Also provided is the use of a compound of formula (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.
Also provided is the 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 the use of a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease mediated by cells that express one or more of: αVβ1; αVβ6; and αVβ8. Also provided is the use of a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease mediated by cells that express one or more of: αVβ1; αVβ6; and αVβ8. For example, in some embodiments the disease is mediated by cells that express αVβ1. In some embodiments, the disease is mediated by cells that express αVβ6. In some embodiments, the disease is mediated by cells that express αVβ8. In some embodiments, the disease is mediated by cells that express αVβ1 and αVβ6. In some embodiments, the disease is mediated by cells that express αVβ1 and αVβ8. In some embodiments, the fibrotic disease is mediated by cells that express αVβ6 and αVβ8. In some embodiments, the fibrotic disease is mediated by cells that express αVβ1, αVβ6, and αVβ8.
In another aspect provided is a method of treating cancer in an individual in need thereof, comprising administering to the individual a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the method further comprises administering to the individual a checkpoint inhibitor.
In another aspect provided is a method of treating cancer in an individual in need thereof, comprising administering to the individual a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the method further comprises administering to the individual a checkpoint inhibitor.
Also provided is the use of a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a cancer.
Also provided is the use of a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a cancer.
Also provided is the use of a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a checkpoint inhibitor, together in the manufacture of a medicament for the treatment of a disease mediated by cells that express one or more of: αVβ1; αVβ6; and αVβ8. Also provided is the use of a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a checkpoint inhibitor, together in the manufacture of a medicament for the treatment of cancer.
Also provided is the use of a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a checkpoint inhibitor, together in the manufacture of a medicament for the treatment of a disease mediated by cells that express one or more of: αVβ1; αVβ6; and αVβ8. Also provided is the use of a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a checkpoint inhibitor, together in the manufacture of a medicament for the treatment of cancer.
Further provided is a method of treating a subject in need thereof. In some embodiments, the method includes providing the subject. In some embodiments, the subject includes at least one tissue in need of therapy. In some embodiments, the at least one tissue is characterized by at least one value that is elevated compared to a healthy value in a healthy state of the tissue. In some embodiments, the tissue includes an elevated value of αVβ1 integrin activity and/or expression. In some embodiments, the tissue includes an elevated value of αVβ6 integrin activity and/or expression. In some embodiments, the tissue includes an elevated value of αVβ8 integrin activity and/or expression. In some embodiments, the tissue includes an elevated value of a pSMAD/SMAD ratio. In some embodiments, the tissue includes an elevated value of new collagen formation or accumulation. In some embodiments, the tissue includes an elevated value of total collagen. In some embodiments, the tissue includes an elevated value of Type I Collagen gene Col1a1 expression. In some embodiments, the tissue includes an elevated value of perforin. In some embodiments, the tissue includes an elevated value of Granzyme B. In some embodiments, the tissue includes an elevated value of interferon γ. In some embodiments, the method includes administering to the subject a therapeutically effective amount of a compound of formula (A), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the method includes administering to the subject a therapeutically effective amount of a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
Also provided is a method of characterizing anticancer activity of a small molecule inhibitor in a subject. In some embodiments, the method includes providing a first live cell sample from the subject. In some embodiments, the first live cell sample is characterized by the presence of at least one integrin capable of activating transforming growth factor β (TGF-β) from latency associated peptide-TGF-β. In some embodiments, the method includes determining a first value in the first live cell sample. In some embodiments, the first value is a pSMAD2/SMAD2 ratio. In some embodiments, the first value is a pSMAD3/SMAD3 ratio. In some embodiments, the first value is a perforin level. In some embodiments, the first value is a granzyme B level. In some embodiments, the first value is an interferon γ level. In some embodiments, the method includes administering the small molecule to the subject. In some embodiments, the method includes providing a second live cell sample from the subject. In some embodiments, the second live cell sample is drawn from the same tissue in the subject as the first live cell sample. In some embodiments, the method includes determining a second value in the second live cell sample. In some embodiments, the second value corresponds to the pSMAD2/SMAD2 ratio, pSMAD3/SMAD3 ratio, perforin level, granzyme B level, or interferon γ level of the first value. In some embodiments, the method includes characterizing the anticancer activity of the small molecule in the subject by comparing the second value to the first value.
In another aspect, provided is a method of making a compound of formula (A) or any variation thereof. Also provided are compound intermediates useful in synthesis of a compound of formula (A), or any variation thereof.
In another aspect, provided is a method of making a compound of formula (I) or any variation thereof. Also provided are compound intermediates useful in synthesis of a compound of formula (I), or any variation thereof.
In another aspect, provided is a compound of formula (A) or any variation thereof produced by a process disclosed herein.
In another aspect, provided is a compound of formula (I) or any variation thereof produced by a process disclosed herein.
It is understood that aspects and variations described herein also include “consisting of” and/or “consisting essentially of” aspects and variations.
Provided herein are, inter alia, compounds of formula (A), and variations thereof, pharmaceutical compositions comprising compounds of formula (A), and methods of using such compounds and compositions in treating fibrotic diseases. Compounds and pharmaceutical compositions comprising salts of compounds of formula (A) are provided as well.
Also provided herein are, inter alia, compounds of formula (I), and variations thereof, pharmaceutical compositions comprising compounds of formula (I), and methods of using such compounds and compositions in treating fibrotic diseases. Compounds and pharmaceutical compositions comprising salts of compounds of formula (I) are provided as well.
Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art.
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”. Likewise, reference to a value “X” also includes description of “about 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 10 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, 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—), hexylene (—CH2(CH2)4CH2—), heptylene (—CH2(CH2)5CH2—), octylene (—CH2(CH2)6CH2—), and the like. It is understood that when alkylene is substituted (for example with a cycloalkyl group), the substituent is not one of the sites of bivalency. For example, propylene substitution with cyclopropyl may provide
but does not provide
wherein the wavy line denotes a site of bivalency.
“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 20 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 groups include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, and the like.
“Alkenylene” as used herein refers to the same residues as alkenyl, but having bivalency. Particular alkenylene groups are those having 2 to 20 carbon atoms (a “C2-C20 alkenylene”), having 2 to 10 carbon atoms (a “C2-C10 alkenylene”), having 6 to 10 carbon atoms (a “C6-C10 alkenylene”), having 2 to 6 carbon atoms (a “C2-C6 alkenylene”), 2 to 4 carbon atoms (a “C2-C4 alkenylene”) or 2 to 3 carbon atoms (a “C2-C3 alkenylene”). Examples of alkenylene include, but are not limited to, groups such as ethenylene (or vinylene) (—CH═CH—), propenylene (—CH═CHCH2—), 1,4-but-1-enylene (—CH═CH—CH2CH2—), 1,4-but-2-enylene (—CH2CH═CHCH2—), 1,6-hex-1-enylene (—CH═CH—(CH2)3CH2—), and the like.
“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-C8 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-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.
“Alkynylene” as used herein refers to the same residues as alkynyl, but having bivalency. Particular alkynylene groups are those having 2 to 20 carbon atoms (a “C2-C20 alkynylene”), having 2 to 10 carbon atoms (a “C2-C10 alkynylene”), having 6 to 10 carbon atoms (a “C6-C10 alkynylene”), having 2 to 6 carbon atoms (a “C2-C6 alkynylene”), 2 to 4 carbon atoms (a “C2-C4 alkynylene”) or 2 to 3 carbon atoms (a “C2-C3 alkynylene”). Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetylenylene) (—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 cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms. A preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C3-C8 cycloalkyl”), having 3 to 6 annular carbon atoms (a “C3-C6 cycloalkyl”), or having from 3 to 4 annular carbon atoms (a “C3-C4 cycloalkyl”). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, 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, spiro or bridged, or combinations thereof. Particular cycloalkylene groups are those having from 3 to 12 annular carbon atoms. A preferred cycloalkylene is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C3-C8 cycloalkylene”), having 3 to 6 carbon atoms (a “C3-C6 cycloalkylene”), or having from 3 to 4 annular carbon atoms (a “C3-C4 cycloalkylene”). Examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, and the like. A cycloalkylene may attach to the remaining structures via the same ring carbon atom (e.g., 1,1-cyclopropylene) or different ring carbon atoms (e.g., 1,2-cyclopropylene). When a cycloalkylene attaches to the remaining structures via two different ring carbon atoms, the connecting bonds may be cis or trans to each other (e.g., cis-1,2-cyclopropylene or trans-1,2-cyclopropylene). If points of attachment are not specified, the moiety can include any chemically possible attachments. For example, cyclopropylene can indicate 1,1-cyclopropylene or 1,2-cyclopropylene (e.g., cis-1,2-cyclopropylene, trans-1,2-cyclopropylene, or a mixture thereof), 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., C3-C10 means three to ten carbon atoms). Cycloalkenyl can consist of one ring, such as cyclohexenyl, or multiple rings, such as norbornenyl. A preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C3-C8 cycloalkenyl”). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, 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 are carbocyclic and may or may not be aromatic, provided at least one ring in the multiple condensed ring structure is aromatic. Particular aryl groups are those having from 6 to 14 annular carbon atoms (a “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”).
“Heteroaryl” as used herein refers to an unsaturated aromatic cyclic group having from 1 to 14 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur. A heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl) which condensed rings may be carbocyclic or may contain one or more annular heteroatom and which may or may not be aromatic, provided at least one ring in the multiple condensed ring structure is both aromatic and contains at least one annular heteroatom. Particular heteroaryl groups are 5 to 14-membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 5 to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5, 6 or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, particular heteroaryl groups are monocyclic aromatic 5-, 6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, particular heteroaryl groups are polycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. A heteroaryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, a heteroaryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position. A heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom.
“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 from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like. A heterocyclic group may have a single ring (e.g., pyrrolidinyl) or multiple condensed rings (e.g., decahydroisoquinolin-1-yl), which condensed rings may or may not be aromatic and which may be carbocylic or contain one or more annular heteroatoms, but which excludes heteroaryl rings. A heterocycle comprising more than one ring may be fused, bridged or spiro, or any combination thereof. In fused ring systems, one or more of the fused rings can be cycloalkyl or aryl, but excludes heteroaryl groups. The heterocyclyl group may be optionally substituted independently with one or more substituents described herein. Particular heterocyclyl groups are 3 to 14-membered rings having 1 to 13 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 12-membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 10-membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 8-membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3 to 6-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3, or 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, heterocyclyl includes polycyclic non-aromatic rings having from 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 one or more halogens, it may be referred to by using the prefix “halo,” e.g., haloaryl, haloalkyl, etc. refer to aryl and alkyl substituted with one or more halo groups, which in the case of two or more halo groups may be, but are not necessarily the same halogen. Where a residue is substituted with more than one halogen, it 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 haloalkyl, e.g., perhaloalkyl group is trifluoromethyl (—CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (—OCF3).
“Carbonyl” refers to the group C═O.
“Thiocarbonyl” refers to the group C═S.
“Oxo” refers to the moiety ═O.
“D” refers to deuterium (2H).
“Boc” refers to tert-butyloxycarbonyl.
“Cbz” refers to carboxybenzyl.
“HATU” refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate.
“BOP” refers to benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate.
“PyBOP” refers to benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.
“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 some embodiments, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In some embodiments, an optionally substituted group is unsubstituted.
Unless clearly indicated otherwise, “an individual” or “a subject” 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 or subject 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 disclosure, 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 herein contemplate any one or more of these aspects of treatment.
As used herein, the term “effective amount” intends such amount of a compound herein which should be effective in a given therapeutic form. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents (e.g., a compound, or pharmaceutically acceptable salt thereof), and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
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, the term “composition” or “pharmaceutical composition” refers to the combination of an active agent with an excipient or a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo. Pharmaceutical compositions may be prepared by known pharmaceutical methods. Suitable compositions, excipients, or carriers 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 in its entirety.
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. See, e.g., Handbook of Pharmaceutical Salts Properties, Selection, and Use, International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), hereby incorporated by reference in its entirety. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases which can be used to prepared salts include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound 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 as an active ingredient. See, e.g., Handbook of Pharmaceutical Excipients. 6th Edition, Pharmaceutical Press (2008), hereby incorporated by reference in its entirety. 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.; disintegrants 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.
Unless otherwise stated, “substantially pure” intends a composition that contains no more than 10% impurity, such as a composition comprising less than about 9%, 7%, 5%, 3%, 1%, 0.5% impurity.
The term “comprise” or variations such as “comprises” or “comprising,” will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. It is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments.
When a composition is described as “consisting essentially of” the listed components, the composition contains the components expressly listed, and may contain other components which do not substantially affect the disease or condition being treated such as trace impurities. However, the composition either does not contain any other components which do substantially affect the disease or condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the disease or condition being treated, the composition does not contain a sufficient concentration or amount of those extra components to substantially affect the disease or condition being treated. When a method is described as “consisting essentially of” the listed steps, the method contains the steps listed, and may contain other steps that do not substantially affect the disease or condition being treated, but the method does not contain any other steps which substantially affect the disease or condition being treated other than those steps expressly listed.
As used herein, where enantiomeric and/or diastereomeric forms exist of a given structure, “flat bonds” indicate that all stereoisomeric forms of the depicted structure may be present, e.g., Compound 1 in Table 1, as shown below.
In one aspect, provided is a compound of formula (A):
or a pharmaceutically acceptable salt thereof, wherein:
In one aspect, provided is a compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
In one variation is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, wherein the carbon bearing the CO2Q and N(H)C(O)C(R2)(R3)R4 moieties is in the “S” configuration. In another variation is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, wherein the carbon bearing the CO2Q and N(H)C(O)C(R2)(R3)R4 moieties is in the “R” configuration. Mixtures of a compound of the formula (I) are also embraced, including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.
In the descriptions herein, it is understood that every description, variation, embodiment or aspect of a moiety may be combined with every description, variation, embodiment or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, every description, variation, embodiment or aspect provided herein with respect to R4 of formula (I) or formula (A) may be combined with every description, variation, embodiment or aspect of R1, R2, R3, L1, L2, L3, Y, and/or Q the same as if each and every combination were specifically and individually listed. It is also understood that all descriptions, variations, embodiments or aspects of formula (I) or formula (A), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. For example, all descriptions, variations, embodiments or aspects of formula (I) or formula (A), where applicable, apply equally to any of formulae (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), and (IV) detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae.
In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L1 is unsubstituted C2-C4 alkylene. In a particular variation, L1 is —CH2—CH2—, —CH2—CH2—CH2—, or —CH2—CH2—CH2—CH2—. In a particular variation, L1 is —CH2CH2—.
In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2 is a bond.
In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2 is unsubstituted C1-C3 alkylene. In a particular variation, L2 is —CH2CH2—
In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L3 is unsubstituted C2-C4 alkylene. In a particular variation, L3 is —CH2CH2—. In a particular variation, L3 is —CH2CH2CH2CH2—.
In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, -L1-O-L2-Y-L3- are taken together to form
In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, at least one of RA, RAa, RAb, R5, R5a, R6, R7, R8, R9, R10, R11, or R12 is deuterium.
In some embodiments, the compound of formula (I) is of the formula (II-a):
or a pharmaceutically acceptable salt thereof, wherein R4 is as defined for formula (I). In some embodiments of the compound of formula (II-a), R4 is phenyl optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-a), R4 is 5-to-6-membered heteroaryl containing at least one nitrogen atom and is optionally fused to a phenyl group, wherein the 5-to-6-membered heteroaryl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-a), R4 is 5-to-6-membered heteroaryl containing at least one nitrogen atom, wherein the 5-to-6-membered heteroaryl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-a), R4 is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-a), R4 is pyridyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-a), R4 is pyrimidinyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-a), R4 is 6-membered heterocyclyl containing at least one nitrogen atom and is optionally fused to a phenyl group, wherein the 6-membered heterocyclyl is optionally substituted by one or more groups selected from the group consisting of R4a and oxo.
In some embodiments, the compound of formula (I) is of the formula (II-b):
or a pharmaceutically acceptable salt thereof, wherein R4 is as defined for formula (I). In some embodiments of the compound of formula (II-b), R4 is phenyl optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-b), R4 is 5-to-6-membered heteroaryl containing at least one nitrogen atom and is optionally fused to a phenyl group, wherein the 5-to-6-membered heteroaryl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-b), R4 is 5-to-6-membered heteroaryl containing at least one nitrogen atom, wherein the 5-to-6-membered heteroaryl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-b), R4 is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-b), R4 is pyridyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-b), R4 is pyrimidinyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-b), R4 is 6-membered heterocyclyl containing at least one nitrogen atom and is optionally fused to a phenyl group, wherein the 6-membered heterocyclyl is optionally substituted by one or more groups selected from the group consisting of R4a and oxo.
In some embodiments, the compound of formula (I) is of the formula (II-c):
or a pharmaceutically acceptable salt thereof, wherein R4 is as defined for formula (I). In some embodiments of the compound of formula (II-c), R4 is phenyl optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-c), R4 is 5-to-6-membered heteroaryl containing at least one nitrogen atom and is optionally fused to a phenyl group, wherein the 5-to-6-membered heteroaryl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-c), R4 is 5-to-6-membered heteroaryl containing at least one nitrogen atom, wherein the 5-to-6-membered heteroaryl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-c), R4 is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-c), R4 is pyridyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-c), R4 is pyrimidinyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-c), R4 is 6-membered heterocyclyl containing at least one nitrogen atom and is optionally fused to a phenyl group, wherein the 6-membered heterocyclyl is optionally substituted by one or more groups selected from the group consisting of R4a and oxo.
In some embodiments, the compound of formula (I) is of the formula (II-d):
or a pharmaceutically acceptable salt thereof, wherein R4 is as defined for formula (I). In some embodiments of the compound of formula (II-d), R4 is phenyl optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-d), R4 is 5-to-6-membered heteroaryl containing at least one nitrogen atom and is optionally fused to a phenyl group, wherein the 5-to-6-membered heteroaryl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-d), R4 is 5-to-6-membered heteroaryl containing at least one nitrogen atom, wherein the 5-to-6-membered heteroaryl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-d), R4 is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-d), R4 is pyridyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-d), R4 is pyrimidinyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-d), R4 is 6-membered heterocyclyl containing at least one nitrogen atom and is optionally fused to a phenyl group, wherein the 6-membered heterocyclyl is optionally substituted by one or more groups selected from the group consisting of R4a and oxo.
In some embodiments, the compound of formula (I) is of the formula (II-e):
or a pharmaceutically acceptable salt thereof, wherein R4 is as defined for formula (I). In some embodiments of the compound of formula (II-e), R4 is phenyl optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-e), R4 is 5-to-6-membered heteroaryl containing at least one nitrogen atom and is optionally fused to a phenyl group, wherein the 5-to-6-membered heteroaryl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-e), R4 is 5-to-6-membered heteroaryl containing at least one nitrogen atom, wherein the 5-to-6-membered heteroaryl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-e), R4 is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-e), R4 is pyridyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-e), R4 is pyrimidinyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-e), R4 is 6-membered heterocyclyl containing at least one nitrogen atom and is optionally fused to a phenyl group, wherein the 6-membered heterocyclyl is optionally substituted by one or more groups selected from the group consisting of R4a and oxo.
In some embodiments, the compound of formula (I) is of the formula (II-f):
or a pharmaceutically acceptable salt thereof, wherein R4 is as defined for formula (I). In some embodiments of the compound of formula (II-f), R4 is phenyl optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-f), R4 is 5-to-6-membered heteroaryl containing at least one nitrogen atom and is optionally fused to a phenyl group, wherein the 5-to-6-membered heteroaryl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-f), R4 is 5-to-6-membered heteroaryl containing at least one nitrogen atom, wherein the 5-to-6-membered heteroaryl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-f), R4 is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-f), R4 is pyridyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-f), R4 is pyrimidinyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-f), R4 is 6-membered heterocyclyl containing at least one nitrogen atom and is optionally fused to a phenyl group, wherein the 6-membered heterocyclyl is optionally substituted by one or more groups selected from the group consisting of R4a and oxo.
In some embodiments, the compound of formula (I) is of the formula (II-g):
or a pharmaceutically acceptable salt thereof, wherein R4 is as defined for formula (I). In some embodiments of the compound of formula (II-g), R4 is phenyl optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-g), R4 is 5-to-6-membered heteroaryl containing at least one nitrogen atom and is optionally fused to a phenyl group, wherein the 5-to-6-membered heteroaryl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-g), R4 is 5-to-6-membered heteroaryl containing at least one nitrogen atom, wherein the 5-to-6-membered heteroaryl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-g), R4 is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-g), R4 is pyridyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-g), R4 is pyrimidinyl is optionally substituted by one or more R4a. In some embodiments of the compound of formula (II-g), R4 is 6-membered heterocyclyl containing at least one nitrogen atom and is optionally fused to a phenyl group, wherein the 6-membered heterocyclyl is optionally substituted by one or more groups selected from the group consisting of R4a and oxo.
In some embodiments, the compound of formula (I) is of the formula (III-a):
or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4a are as defined for formula (I). In some embodiments of the compound of formula (III-a), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-a), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl. In some embodiments of the compound of formula (III-a), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl. In some embodiments of the compound of formula (III-a), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclobutyl. In some embodiments of the compound of formula (III-a), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl. In some embodiments of the compound of formula (III-a), R2 and R3 are taken together with the carbon atom to which they are attached to form a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-a), R2 and R3 are taken together with the carbon atom to which they are attached to form a 4-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-a), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-a), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-a), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-a), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-a), R2 and R3 are taken together with the carbon atom to which they are attached to form.
In some embodiments, the compound of formula (I) is of the formula (III-b-1):
or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4a are as defined for formula (I). In some embodiments of the compound of formula (III-b-1), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-1), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl. In some embodiments of the compound of formula (III-b-1), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl. In some embodiments of the compound of formula (III-b-1), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclobutyl. In some embodiments of the compound of formula (III-b-1), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl. In some embodiments of the compound of formula (III-b-1), R2 and R3 are taken together with the carbon atom to which they are attached to form a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-1), R2 and R3 are taken together with the carbon atom to which they are attached to form a 4-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-1), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-1), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-1), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-1), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-1), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments, the compound of formula (I) is of the formula (III-b-2):
or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4a are as defined for formula (I). In some embodiments of the compound of formula (III-b-2), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-2), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl. In some embodiments of the compound of formula (III-b-2), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl. In some embodiments of the compound of formula (III-b-2), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclobutyl. In some embodiments of the compound of formula (III-b-2), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl. In some embodiments of the compound of formula (III-b-2), R2 and R3 are taken together with the carbon atom to which they are attached to form a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-2), R2 and R3 are taken together with the carbon atom to which they are attached to form a 4-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-2), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-2), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-2), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-2), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-2), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments, the compound of formula (I) is of the formula (III-b-3):
or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4a are as defined for formula (I). In some embodiments of the compound of formula (III-b-3), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-3), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl. In some embodiments of the compound of formula (III-b-3), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl. In some embodiments of the compound of formula (III-b-3), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclobutyl. In some embodiments of the compound of formula (III-b-3), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl. In some embodiments of the compound of formula (III-b-3), R2 and R3 are taken together with the carbon atom to which they are attached to form a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-3), R2 and R3 are taken together with the carbon atom to which they are attached to form a 4-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-3), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-3), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-3), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-3), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-3), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments, the compound of formula (I) is of the formula (III-b-4):
or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4a are as defined for formula (I). In some embodiments of the compound of formula (III-b-4), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-4), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl. In some embodiments of the compound of formula (III-b-4), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl. In some embodiments of the compound of formula (III-b-4), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclobutyl. In some embodiments of the compound of formula (III-b-4), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl. In some embodiments of the compound of formula (III-b-4), R2 and R3 are taken together with the carbon atom to which they are attached to form a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-4), R2 and R3 are taken together with the carbon atom to which they are attached to form a 4-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-4), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-4), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-4), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-4), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-4), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments, the compound of formula (I) is of the formula (III-b-5):
or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4a are as defined for formula (I). In some embodiments of the compound of formula (III-b-5), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-5), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl. In some embodiments of the compound of formula (III-b-5), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl. In some embodiments of the compound of formula (III-b-5), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclobutyl. In some embodiments of the compound of formula (III-b-5), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl. In some embodiments of the compound of formula (III-b-5), R2 and R3 are taken together with the carbon atom to which they are attached to form a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-5), R2 and R3 are taken together with the carbon atom to which they are attached to form a 4-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-5), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-5), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-5), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-5), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-5), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments, the compound of formula (I) is of the formula (III-b-6):
or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4a are as defined for formula (I). In some embodiments of the compound of formula (III-b-6), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-6), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl. In some embodiments of the compound of formula (III-b-6), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl. In some embodiments of the compound of formula (III-b-6), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclobutyl. In some embodiments of the compound of formula (III-b-6), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl. In some embodiments of the compound of formula (III-b-6), R2 and R3 are taken together with the carbon atom to which they are attached to form a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-6), R2 and R3 are taken together with the carbon atom to which they are attached to form a 4-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-6), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-6), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-6), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-6), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-6), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments, the compound of formula (I) is of the formula (III-b-7):
or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4a are as defined for formula (I). In some embodiments of the compound of formula (III-b-7), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-7), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl. In some embodiments of the compound of formula (III-b-7), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl. In some embodiments of the compound of formula (III-b-7), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclobutyl. In some embodiments of the compound of formula (III-b-7), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl. In some embodiments of the compound of formula (III-b-7), R2 and R3 are taken together with the carbon atom to which they are attached to form a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-7), R2 and R3 are taken together with the carbon atom to which they are attached to form a 4-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-7), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-7), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-7), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-7), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-7), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments, the compound of formula (I) is of the formula (III-b-8):
or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4a are as defined for formula (I). In some embodiments of the compound of formula (III-b-8), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-8), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl. In some embodiments of the compound of formula (III-b-8), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl. In some embodiments of the compound of formula (III-b-8), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclobutyl. In some embodiments of the compound of formula (III-b-8), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl. In some embodiments of the compound of formula (III-b-8), R2 and R3 are taken together with the carbon atom to which they are attached to form a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-8), R2 and R3 are taken together with the carbon atom to which they are attached to form a 4-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-8), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-8), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-8), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-8), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-8), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments, the compound of formula (I) is of the formula (III-b-9):
or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4a are as defined for formula (I). In some embodiments of the compound of formula (III-b-9), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-9), R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl. In some embodiments of the compound of formula (III-b-9), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl. In some embodiments of the compound of formula (III-b-9), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclobutyl. In some embodiments of the compound of formula (III-b-9), R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl. In some embodiments of the compound of formula (III-b-9), R2 and R3 are taken together with the carbon atom to which they are attached to form a 3-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-9), R2 and R3 are taken together with the carbon atom to which they are attached to form a 4-to-6-membered heterocyclyl. In some embodiments of the compound of formula (III-b-9), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-9), R2 and R3 are taken together with the carbon atom to which they are attached to form an oxetane or pyran. In some embodiments of the compound of formula (III-b-9), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-9), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments of the compound of formula (III-b-9), R2 and R3 are taken together with the carbon atom to which they are attached to form
In some embodiments, the compound of formula (I) is of the formula (IV):
or a pharmaceutically acceptable salt thereof, wherein R3 is as defined for formula (I).
In some embodiments, the compound of Formula (I) is
Also provided in another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by one or more R1a, 1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by one or more R1b, 6-aminopyridin-2-yl optionally substituted by one or more R1c, or (pyridin-2-yl)amino optionally substituted by one or more R1d. In one aspect of the foregoing embodiment, R1 is 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by one or more R1a. In one aspect of the foregoing embodiment, R1 is unsubstituted 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl. In one aspect of the foregoing embodiment, R1 is 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl substituted by two R1a groups on the same carbon atom, wherein the two R1a groups are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl (e.g., cyclopropyl). In one aspect of the foregoing embodiment, R1 is 1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by one or more R1b. In one aspect of the foregoing embodiment, R1 is unsubstituted 1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl. In one aspect of the foregoing embodiment, R1 is 1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl substituted by two R1b groups on the same carbon atom, wherein the two R1b groups are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl (e.g., cyclopropyl).
Also provided in another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are independently H or C1-C6 alkyl. In one aspect of the foregoing embodiment, R2 and R3 are the same. In one aspect of the foregoing embodiment, R2 and R3 are different. In one aspect of the foregoing embodiment, R2 and R3 are both H. In one aspect of the foregoing embodiment, R2 is H and R3 is C1-C6 alkyl. In one aspect of the foregoing embodiment, R2 is H and R3 is C1-C3 alkyl. In one aspect of the foregoing embodiment, R2 is H and R3 is —CH3. In one aspect of the foregoing embodiment, R2 and R3 are independently C1-C6 alkyl. In one aspect of the foregoing embodiment, R2 and R3 are independently C1-C3 alkyl. In one aspect of the foregoing embodiment, R2 and R3 are independently methyl, ethyl, n-propyl, or isopropyl. In one aspect of the foregoing embodiment, R2 and R3 are both —CH3.
Also provided in another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are taken together with the carbon atom to which they are attached to form C3-C6 cycloalkyl. In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form C3-C4 cycloalkyl. In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl. In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form cyclobutyl.
Also provided in another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are taken together with the carbon atom to which they are attached to form a 3-to-6-membered heterocyclyl. In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form a 3-to-6-membered heterocyclyl, wherein the heterocyclyl contains at least one oxygen atom. In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form a 4-to-6-membered heterocyclyl. In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form a 4-to-6-membered heterocyclyl, wherein the heterocyclyl contains at least one oxygen atom. In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form oxetanyl. In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form tetrahydropyranyl. In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form
In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form
In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form
Also provided in another embodiment is a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl substituted by R2a. In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl substituted by deuterium or C1-C6 alkyl optionally substituted by halogen. In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl substituted by R2a. In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form
Also provided in another embodiment is a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are taken together with the carbon atom to which they are attached to form a 3-to-6-membered heterocyclyl substituted by R2a. In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form a 3-to-6-membered heterocyclyl substituted by deuterium or C1-C6 alkyl optionally substituted by halogen. In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form piperdine substituted by R2a. In one aspect of the foregoing embodiment, R2 and R3 are taken together with the carbon atom to which they are attached to form
Also provided in another embodiment is a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein R4 is phenyl optionally substituted by one or more R4a. In one aspect of the foregoing embodiment, R4 is unsubstituted phenyl. In one aspect of the foregoing embodiment, R4 is phenyl substituted by 1-5 R4a groups, wherein each R4a is independently selected from halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, —(C1-C6 alkylene)-O—(C1-C6 alkyl), C3-C6 cycloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —S(O)2(C1-C6 alkyl), or —C(═O)—NH2.
Also provided in another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R4 is phenyl optionally substituted by one or more R4a. In one aspect of the foregoing embodiment, R4 is unsubstituted phenyl. In one aspect of the foregoing embodiment, R4 is phenyl substituted by 1-5 R4a groups, wherein each R4a is independently selected from halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, —(C1-C6 alkylene)-O—(C1-C6 alkyl), C3-C6 cycloalkyl, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), and —S(O)2(C1-C6 alkyl). In one aspect of the foregoing embodiment, R4 is phenyl substituted by 1-5 R4a groups, wherein each R4a is independently selected from F, Cl, CN, C1-C3 alkyl, C1-C3 haloalkyl, —(C1-C3 alkylene)-O—(C1-C3 alkyl), C3-C6 cycloalkyl, —O—(C1-C3 alkyl), —O—(C1-C3 haloalkyl), and —S(O)2(C1-C3 alkyl). In one aspect of the foregoing embodiment, R4 is phenyl substituted by 1-5 R4a groups, wherein at least one R4a group is halo (e.g., F or Cl). In one aspect of the foregoing embodiment, R4 is phenyl substituted by 1-5 R4a groups, wherein at least one R4a group is CN. In one aspect of the foregoing embodiment, R4 is phenyl substituted by 1-5 R4a groups, wherein at least one R4a group is C1-C3 alkyl (e.g., —CH3). In one aspect of the foregoing embodiment, R4 is phenyl substituted by 1-5 R4a groups, wherein at least one R4a group is —O—(C1-C3 alkyl) (e.g., —O—CH3). In one aspect of the foregoing embodiment, R4 is phenyl substituted by 1-5 R4a groups, wherein at least one R4a group is —O—(C1-C3 haloalkyl) (e.g., —O—CHF2). In one aspect of the foregoing embodiment, R4 is phenyl substituted by 1-5 R4a groups, wherein at least one R4a group is —S(O)2(C1-C3 alkyl). In another aspect of the foregoing embodiment, R4 is phenyl substituted by 2-5 R4a groups, wherein each R4a is independently selected from halo, CN, —O—(C1-C6 alkyl), and —O—(C1-C6 haloalkyl). In another aspect of the foregoing embodiment, R4 is phenyl substituted by 2-5 R4a groups, wherein at least two of the R4a groups are halo (e.g., fluoro or chloro). In another aspect of the foregoing embodiment, R4 is phenyl substituted by 2-5 R4a groups, wherein at least one of the R4a groups is halo (e.g., fluoro or chloro) and at least one of the R4a groups is CN. In another aspect of the foregoing embodiment, R4 is phenyl substituted by 2-5 R4a groups, wherein at least one of the R4a groups is halo (e.g., fluoro or chloro) and at least one of the R4a groups is —O—(C1-C3 alkyl) (e.g., —O—CH3). In another aspect of the foregoing embodiment, R4 is phenyl substituted by 2-5 R4a groups, wherein at least one of the R4a groups is halo (e.g., fluoro or chloro) and at least one of the R4a groups is —O—(C1-C3 haloalkyl) (e.g., —O—CHF2). In another aspect of the foregoing embodiment, R4 is phenyl substituted by 2-5 R4a groups, wherein at least one of the R4a groups is CN and at least one of the R4a groups is —O—(C1-C3 alkyl) (e.g., —O—CH3).
Also provided in another embodiment is a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein R4 is 5-to-6-membered heteroaryl containing at least one nitrogen atom, wherein the 5-to-6-membered heteroaryl is optionally fused to a phenyl group and wherein the 5-to-6-membered heteroaryl is optionally substituted by one or more R4a. In another aspect of the foregoing embodiment, R4 is 5-to-6-membered heteroaryl, wherein the 5-to-6-membered heteroaryl contains at least one nitrogen atom and is optionally substituted by one or more R4a. In another aspect of the foregoing embodiment, R4 is 5-membered heteroaryl, wherein the 5-membered heteroaryl contains two nitrogen atoms (e.g., R4 is pyrazolyl, imidazolyl, or thiazolyl) and is optionally substituted by one or more R4a. In another aspect of the foregoing embodiment, R4 is 6-membered heteroaryl, wherein the 6-membered heteroaryl contains one nitrogen atom and is optionally substituted by one or more R4a. In another aspect of the foregoing embodiment, R4 is pyridinyl optionally substituted by one or more R4a. In another aspect of the foregoing embodiment, R4 is 6-membered heteroaryl, wherein the 6-membered heteroaryl contains two nitrogen atoms (e.g., R4 is pyrimidinyl or pyrazinyl) and is optionally substituted by one or more R4a. In another aspect of the foregoing embodiment, R4 is pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is substituted by 1-4 R4a groups, wherein the R4a groups are independently selected from the group consisting of halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, —(C1-C6 alkylene)-O—(C1-C6 alkyl), C3-C6 cycloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —S(O)2(C1-C6 alkyl), or —C(═O)—NH2.
Also provided in another embodiment is a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein R4 is 6-membered heterocyclyl containing at least one nitrogen atom, wherein the 6-membered heterocyclyl is optionally fused to a phenyl group and wherein the 6-membered heterocyclyl is optionally substituted by one or more R4a or oxo. In another aspect of the foregoing embodiment, R4 is 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains one nitrogen atom and is optionally substituted by one or more R4a or oxo. In another aspect of the foregoing embodiment, R4 is 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains two nitrogen atoms and is optionally substituted by one or more R4a or oxo. In another aspect of the foregoing embodiment, R4 is 6-membered heterocyclyl optionally fused to a phenyl group, wherein the 6-membered heterocyclyl contains one nitrogen atom, is substituted by one oxo group, and is optionally substituted by one or more R4a. In another aspect of the foregoing embodiment, R4 is substituted by 1-4 R4a or oxo groups, wherein the R4a groups are independently selected from the group consisting of halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, —(C1-C6 alkylene)-O—(C1-C6 alkyl), C3-C6 cycloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —S(O)2(C1-C6 alkyl), or —C(═O)—NH2. In another aspect of the foregoing embodiment, R4 is
optionally fused to a phenyl group and optionally substituted by one or more R4a. In another aspect of the foregoing embodiment, R4 is
In another aspect of the foregoing embodiment, R4 is
In another aspect of the foregoing embodiment, R4 is
Also provided in another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R4 is 5-to-6-membered heteroaryl containing at least one nitrogen atom, wherein the 5-to-6-membered heteroaryl is optionally fused to a phenyl group and wherein the 5-to-6-membered heteroaryl is optionally substituted by one or more R4a. In another aspect of the foregoing embodiment, R4 is 6-membered heteroaryl (e.g., pyrimidinyl) fused to phenyl. In another aspect of the foregoing embodiment, R4 is 5-to-6-membered heteroaryl, wherein the 5-to-6-membered heteroaryl contains at least one nitrogen atom and is optionally substituted by one or more R4a. In another aspect of the foregoing embodiment, R4 is 5-membered heteroaryl, wherein the 5-membered heteroaryl contains two nitrogen atoms (e.g., R4 is pyrazolyl, imidazolyl, or thiazolyl) and is optionally substituted by one or more R4a. In another aspect of the foregoing embodiment, R4 is 6-membered heteroaryl, wherein the 6-membered heteroaryl contains one nitrogen atom and is optionally substituted by one or more R4a. In another aspect of the foregoing embodiment, R4 is pyridinyl optionally substituted by one or more R4a. In another aspect of the foregoing embodiment, R4 is 6-membered heteroaryl, wherein the 6-membered heteroaryl contains two nitrogen atoms (e.g., R4 is pyrimidinyl or pyrazinyl) and is optionally substituted by one or more R4a. In another aspect of the foregoing embodiment, R4 is pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted. In another aspect of the foregoing embodiment, R4 is pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is substituted by 1-4 R4a groups, wherein the R4a groups are independently selected from the group consisting of halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, —(C1-C6 alkylene)-O—(C1-C6 alkyl), C3-C6 cycloalkyl, —O—(C1-C6 alkyl), and —O—(C1-C6 haloalkyl). In another aspect of the foregoing embodiment, R4 is pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is substituted by 1-4 R4a groups, wherein the R4a groups are independently selected from the group consisting of halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, —(C1-C3 alkylene)-O—(C1-C3 alkyl), C3-C6 cycloalkyl, —O—(C1-C3 alkyl), and —O—(C1-C3 haloalkyl). In another aspect of the foregoing embodiment, R4 is pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is substituted by 1-4 R4a groups, wherein the R4a groups are independently selected from the group consisting of F, Cl, CN, —CH3, —CF3, —CHF2, —CH2F, —CH2—O—CH3, cyclopropyl, —O—CH3, and —O—CHF2. In one aspect of the foregoing embodiment, R4 is substituted by 1-4 R4a groups, wherein at least one R4a group is F or Cl. In one aspect of the foregoing embodiment, R4 is substituted by 1-4 R4a groups, wherein at least one R4a group is CN. In one aspect of the foregoing embodiment, R4 is substituted by 1-4 R4a groups, wherein at least one R4a group is C1-C3 alkyl. In one aspect of the foregoing embodiment, R4 is substituted by 1-4 R4a groups, wherein at least one R4a group is C1-C3 haloalkyl. In one aspect of the foregoing embodiment, R4 is substituted by 1-4 R4a groups, wherein at least one R4a group is —(C1-C3 alkylene)-O—(C1-C3 alkyl). In one aspect of the foregoing embodiment, R4 is substituted by 1-4 R4a groups, wherein at least one R4a group is cyclopropyl. In one aspect of the foregoing embodiment, R4 is substituted by 1-4 R4a groups, wherein at least one R4a group is —O—(C1-C3 alkyl). In one aspect of the foregoing embodiment, R4 is substituted by 1-4 R4a groups, wherein at least one R4a group is —O—(C1-C3 haloalkyl). In one aspect of the foregoing embodiment, R4 is substituted by 2-4 R4a groups, wherein at least one R4a group is F, and wherein at least one R4a group is Cl. In one aspect of the foregoing embodiment, R4 is substituted by 2-4 R4a groups, wherein at least one R4a group is F, and wherein at least one R4a group is C1-C3 alkyl. In one aspect of the foregoing embodiment, R4 is substituted by 2-4 R4a groups, wherein at least one R4a group is Cl, and wherein at least one R4a group is C1-C3 alkyl. In one aspect of the foregoing embodiment, R4 is substituted by 2-4 R4a groups, wherein at least one R4a group is Cl, and wherein at least one R4a group is —O—(C1-C3 alkyl). In one aspect of the foregoing embodiment, R4 is substituted by 2-4 R4a groups, wherein at least two R4a groups are Cl.
Also provided in another embodiment is a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein R4 is pyridinyl substituted by 1-4 R4a groups, wherein the R4a groups are selected from the group consisting of halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, —(C1-C6 alkylene)-O—(C1-C6 alkyl), C3-C6 cycloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —S(O)2(C1-C6 alkyl), or —C(═O)—NH2.
Also provided in another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R4 is pyridinyl substituted by 1-4 R4a groups, wherein the R4a groups are selected from the group consisting of halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, —(C1-C6 alkylene)-O—(C1-C6 alkyl), C3-C6 cycloalkyl, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl). In one aspect of the foregoing embodiment, R4 is pyridinyl substituted by 1-4 R4a groups, wherein the R4a groups are independently selected from the group consisting of halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, —(C1-C3 alkylene)-O—(C1-C3 alkyl), C3-C6 cycloalkyl, —O—(C1-C3 alkyl), —O—(C1-C3 haloalkyl). In one aspect of the foregoing embodiment, R4 is pyridinyl substituted by 1-4 R4a groups, wherein the R4a groups are independently selected from the group consisting of F, Cl, CN, —CH3, —CF3, —CHF2, —CH2F, —CH2—O—CH3, cyclopropyl, —O—CH3, and —O—CHF2. In one aspect of the foregoing embodiment, R4 is pyridinyl substituted by 2-4 R4a groups, wherein the R4a groups are independently selected from the group consisting of halo (e.g., F or Cl), C1-C3 alkyl (e.g., —CH3), and —O—(C1-C3 alkyl) (e.g., —O—CH3). In one aspect of the foregoing embodiment, R4 is pyridinyl substituted by 2-4 R4a groups, wherein at least two of the R4a groups are halo (e.g., fluoro or chloro). In one aspect of the foregoing embodiment, R4 is pyridinyl substituted by 2-4 R4a groups, wherein at least one of the R4a groups is halo (e.g., fluoro or chloro), and at least one of the R4a groups is C1-C3 alkyl (e.g., —CH3). In one aspect of the foregoing embodiment, R4 is pyridinyl substituted by 2-4 R4a groups, wherein at least one of the R4a groups is halo (e.g., fluoro or chloro), and at least one of the R4a groups is —O—(C1-C3 alkyl) (e.g., —O—CH3).
Also provided in another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R4 is a 5-membered heteroaryl, wherein the 5-membered heteroaryl contains at least one nitrogen atom and is optionally substituted by one or more R4a. In one aspect of the foregoing embodiment, R4 is a 5-membered heteroaryl containing at least one nitrogen atom and at least one additional heteroatom selected from oxygen and sulfur (e.g., R4 is thiazolyl) and is optionally substituted by one or more R4a. In one aspect of the foregoing embodiment, R4 is a 5-membered heteroaryl, wherein the 5-membered heteroaryl contains one nitrogen atom and is optionally substituted by one or more R4a. In one aspect of the foregoing embodiment, R4 is a 5-membered heteroaryl, wherein the 5-membered heteroaryl contains two nitrogen atoms (e.g., R4 is pyrazolyl or imidazolyl) and is optionally substituted by one or more R4a. In one aspect of the foregoing embodiment, R4 is unsubstituted 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl). In one aspect of the foregoing embodiment, R4 is a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted by 1-3 R4a groups, wherein the R4a groups are independently selected from the group consisting of halo, CN, C1-C6 alkyl, and C1-C6 haloalkyl. In one aspect of the foregoing embodiment, R4 is a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted 1-3 R4a groups, wherein the R4a groups are independently selected from the group consisting of F, Cl, CN, C1-C3 alkyl (e.g., —CH3), and C1-C3 haloalkyl (e.g., —CF3). In one aspect of the foregoing embodiment, R4 is a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted by 2-3 R4a groups, wherein the R4a groups are independently selected from the group consisting of halo (e.g., F or Cl), CN, C1-C3 alkyl (e.g., —CH3), and C1-C3 haloalkyl (e.g., —CF3). In one aspect of the foregoing embodiment, R4 is a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted by 2-3 R4a groups, wherein at least two of the R4a groups are halo (e.g., chloro). In one aspect of the foregoing embodiment, R4 is a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted by 2-3 R4a groups, wherein at least one of the R4a groups is halo (e.g., chloro) and at least one of the R4a groups is C1-C3 alkyl (e.g., —CH3). In one aspect of the foregoing embodiment, R4 is a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted by 2-3 R4a groups, wherein at least one of the R4a groups is CN and at least one of the R4a groups is C1-C3 alkyl (e.g., —CH3). In one aspect of the foregoing embodiment, R4 is a 5-membered heteroaryl (e.g., pyrazolyl or imidazolyl) substituted by 2-3 R4a groups, wherein at least one of the R4a groups is C1-C3 alkyl (e.g., —CH3) and at least one of the R4a groups is C1-C3 haloalkyl (e.g., —CF3).
Also provided in another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R4 is a 6-membered heteroaryl, wherein the 6-membered heteroaryl contains two nitrogen atoms (e.g., R4 is pyrimidinyl or pyrazinyl) and is optionally substituted by one or more R4a. In one aspect of the foregoing embodiment, R4 is unsubstituted 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl). In one aspect of the foregoing embodiment, R4 is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted by 1-3 R4a groups, wherein the R4a groups are independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and —O—(C1-C6 alkyl). In one aspect of the foregoing embodiment, R4 is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted by 1-3 R4a groups, wherein the R4a groups are independently selected from the group consisting of halo, Ci-C alkyl, C1-C3 haloalkyl, and —O—(C1-C3 alkyl). In one aspect of the foregoing embodiment, R4 is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted by 1-3 R4a groups, wherein the R4a groups are independently selected from the group consisting of Cl, CH3, —CF3, —CHF2, and —O—CH3. In one aspect of the foregoing embodiment, R4 is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted by 2-3 R4a groups, wherein the R4a groups are independently selected from the group consisting of halo (e.g., Cl), C1-C6 alkyl (e.g., —CH3), and —O—(C1-C6 alkyl) (e.g., —O—CH3). In one aspect of the foregoing embodiment, R4 is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted by 2-3 R4a groups, wherein at least one of the R4a groups is halo (e.g., chloro) and at least one of the R4a groups is C1-C3 alkyl (e.g., —CH3). In one aspect of the foregoing embodiment, R4 is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted by 2-3 R4a groups, wherein at least one of the R4a groups is halo (e.g., chloro) and at least one of the R4a groups is —O—(C1-C3 alkyl) (e.g., —O—CH3). In one aspect of the foregoing embodiment, R4 is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted by 2-3 R4a groups, wherein at least two of the R4a groups are C1-C3 alkyl (e.g., —CH3). In one aspect of the foregoing embodiment, R4 is a 6-membered heteroaryl containing two nitrogen atoms (e.g., pyrimidinyl or pyrazinyl) substituted by 2-3 R4a groups, wherein at least one of the R4a groups is C1-C3 alkyl (e.g., —CH3) and at least one of the R4a groups is —O—(C1-C3 alkyl) (e.g., —O—CH3).
Also provided in another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R4 is a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains at least one nitrogen atom, is optionally fused to a phenyl group, and is optionally substituted by one or more groups selected from the group consisting of R4a (e.g., Cl) and oxo. In one aspect of the foregoing embodiment, R4 is a 6-membered heterocyclyl containing one nitrogen atom, wherein the 6-membered heterocyclyl is fused to a phenyl group and is substituted by oxo. In one aspect of the foregoing embodiment, R4 is a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains one nitrogen atom and is optionally substituted by one or more groups selected from the group consisting of R4a (e.g., Cl) and oxo. In one aspect of the foregoing embodiment, R4 is 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains two nitrogen atoms and is optionally substituted by one or more groups selected from the group consisting of R4a (e.g., Cl) and oxo. In one aspect of the foregoing embodiment, R4 is substituted by Cl and oxo. In one aspect of the foregoing embodiment, R4 is a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains one nitrogen atom and is substituted by Cl and oxo. In one aspect of the foregoing embodiment, R4 is a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains two nitrogen atoms and is substituted by Cl and oxo.
Also provided in another embodiment is a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein R4 is C1-C6 haloalkyl. In one aspect of the foregoing embodiment, R4 is C1-C6 fluoroalkyl. In one aspect of the foregoing, R4 is Cl haloalkyl. In one aspect of the foregoing, R4 is C1-C6 fluoroalkyl. In one aspect of the foregoing embodiment, R4 is
Also provided in another embodiment is a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4 are taken together to form a 5-membered heteroaryl containing two nitrogen atoms and substituted with phenyl, wherein the phenyl group is optionally substituted by one or more R4a. In one aspect of the foregoing embodiment, R2, R3, and R4 are taken together to form
Also provided in another embodiment is a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein each R4a is independently selected from the group consisting of halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, —(C1-C6 alkylene)-O—(C1-C6 alkyl), C3-C6 cycloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —S(O)2(C1-C6 alkyl), or —C(═O)—NH2.
Also provided in another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R4a is independently selected from the group consisting of halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, —(C1-C6 alkylene)-O—(C1-C6 alkyl), C3-C6 cycloalkyl, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), and —S(O)2(C1-C6 alkyl). In one aspect of the foregoing embodiment, each R4a is independently selected from the group consisting of halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, —(C1-C3 alkylene)-O—(C1-C3 alkyl), C3-C6 cycloalkyl, —O—(C1-C3 alkyl), —O—(C1-C3 haloalkyl), and —S(O)2(C1-C3 alkyl). In one aspect of the foregoing embodiment, each R4a is independently selected from the group consisting of F, Cl, CN, —CH3, —CH2F, —CHF2, —CF3, —CH2—O—CH3, cyclopropyl, —OCH3, —OCHF2, and —S(O)2CH3.
In some embodiments, R4a is halo. In some embodiments, R4a is F or Cl. In some embodiments, R4a is F. In some embodiments, R4a is Cl.
In some embodiments, R4a is CN.
In some embodiments, R4a is C1-C6 alkyl. In some embodiments, R4a is C1-C3 alkyl. In some embodiments, R4a is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R4a is methyl, ethyl, or isopropyl. In some embodiments, R4a is —CH3.
In some embodiments, R4a is C1-C6 haloalkyl. In some embodiments, R4a is C1-C3 haloalkyl. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of fluoro and chloro atoms. In some embodiments, R4a is —CF3, —CCl3, —CF2Cl, —CFCl2, —CHF2, —CH2F, —CHCl2, —CH2Cl, or —CHFCl. In some embodiments, R4a is —CF3, —CHF2, —CH2F. In some embodiments, R4a is —CF3. In some embodiments, R4a is —CHF2. In some embodiments, R4a is —CH2F.
In some embodiments, R4a is —(C1-C6 alkylene)-O—(C1-C6 alkyl). In some embodiments, R4a is —(C1-C3 alkylene)-O—(C1-C3 alkyl). In some embodiments, R4a is —CH2—O—CH3, —CH2—O—CH2CH3, —CH2—O—CH2CH2CH3, or —CH2O—CH(CH3)2. In some embodiments, R4a is —CH2CH2—O—CH3, —CH2CH2—O—CH2CH3, —CH2CH2—O—CH2CH2CH3, or —CH2CH2O—CH(CH3)2. In some embodiments, R4a is —CH2CH2CH2—O—CH3, —CH2CH2CH2—O—CH2CH3, —CH2CH2CH2—O—CH2CH2CH3, or —CH2CH2CH2O—CH(CH3)2. In some embodiments, R4a is —CH2—O—CH3.
In some embodiments, R4a is C3-C6 cycloalkyl. In some embodiments, R4a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R4a is cyclopropyl.
In some embodiments, R4a is —O—(C1-C6 alkyl). In some embodiments, R4a is —O—(C1-C3 alkyl). In some embodiments, R4a is —O—CH3, —O—CH2CH3, —O—CH2CH2CH3, or —O—CH(CH3)2. In some embodiments, R4a is —O—CH3.
In some embodiments, R4a is —O—(C1-C6 haloalkyl). In some embodiments, R4a is —O—(C1-C3 haloalkyl). In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of fluoro and chloro atoms. In some embodiments, R4a is —O—CF3, —O—CCl3, —O—CF2Cl, —O—CFCl2, —O—CHF2, —O—CH2F, —O—CHCl2, —O—CH2Cl, or —O—CHFCl. In some embodiments, R4a is —O—CHF2.
In some embodiments, R4a is —S(O)2(C1-C6 alkyl). In some embodiments, R4a is —S(O)2(C1-C4 alkyl). In some embodiments, R4a is —S(O)2CH3.
In some embodiments R4a is —OH. In some embodiments R4a is —C(═O)—NH2.
Also provided in another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R4a and R2 are taken together with the atoms to which they are attached to form a 6-membered heterocyclyl. In some embodiments, R4a and R2 are taken together with the atoms to which they are attached to form a 6-membered heterocyclyl, wherein the heterocyclyl contains one oxygen atom. In some embodiments, R4 is phenyl, R4a and R2 are taken together with the atoms to which they are attached to form a 6-membered heterocyclyl, wherein the heterocyclyl contains one oxygen atom. In some embodiments, R2, R3, and R4 are taken together with the carbon atom to which they are attached to form
In some embodiments, R2, R3, and R4 are taken together with the carbon atom to which they are attached to form
In some embodiments, R2, R3, and R4 are taken together with the carbon atom to which they are attached to form
Also provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R4 is selected from the group consisting of:
Also provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R4 is selected from the group consisting of:
Also provided is a compound of formula (A), or a pharmaceutically acceptable salt thereof, wherein R4 is selected from the group consisting of
Also provided in another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Q is H or C1-C8 alkyl. In one aspect of the foregoing embodiment, Q is H. In one aspect of the foregoing embodiment, Q is C1-C6 alkyl. In one aspect of the foregoing embodiment, Q is methyl, ethyl, n-propyl, or isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl. In one aspect of the foregoing embodiment, Q is methyl.
In one aspect, provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound has any one or more of the following features:
In the variations in the preceding paragraph, it is understood that each combination of variables is described. For example, it is understood that each variation of feature (IV) may be combined with each variation of feature (V) the same as if each and every variation of features (IV) and (V) were specifically and individually listed. Thus, it is understood that the following combinations are described: (IV)(i)+(V)(i); (IV)(i)+(V)(ii); (IV)(i)+(V)(iii); (IV)(i)+(V)(iv); (IV)(ii)+(V)(i); (IV)(ii)+(V)(ii); (IV)(ii)+(V)(iii); (IV)(ii)+(V)(iv); (IV)(iii)+(V)(i); (IV)(iii)+(V)(ii); (IV)(iii)+(V)(iii); and (IV)(iii)+(V)(iv).
In some embodiments, R1 is
R2 and R3 are independently H or methyl, or R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl; R4 is phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, 2-oxopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyridazinyl, or quinazolinyl; wherein the phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, 2-oxopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or quinazolinyl are optionally substituted by one or more R4a groups; and wherein the dihydropyridinyl, dihydropyrimidinyl, or dihydropyridazinyl are optionally substituted by one or more groups selected from the group consisting of R4a and oxo; each R4a is independently halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, —(C1-C3 alkylene)-O—(C1-C3 alkyl), C3-C6 cycloalkyl, —O—(C1-C3 alkyl), —O—(C1-C3 haloalkyl), or —S(O)2(C1-C3 alkyl); Q is H; and -L1-O-L2-Y-L3- are taken together to form
In some embodiments, R1 is
R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl; R4 is phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, 2-oxopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyridazinyl, or quinazolinyl; wherein the phenyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, 2-oxopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or quinazolinyl are optionally substituted by one or more R4a groups; and wherein the dihydropyridinyl, dihydropyrimidinyl, or dihydropyridazinyl are optionally substituted by one or more groups selected from the group consisting of R4a and oxo; each R4a is independently halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, —(C1-C3 alkylene)-O—(C1-C3 alkyl), C3-C6 cycloalkyl, —O—(C1-C3 alkyl), —O—(C1-C3 haloalkyl), or —S(O)2(C1-C3 alkyl); Q is H; and -L1-O-L2-Y-L3- are taken together to form
In some embodiments, R1 is
R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl; R4 is pyrazolyl, imidazolyl, thiazolyl, pyridinyl, 2-oxopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyridazinyl, or quinazolinyl; wherein the pyrazolyl, imidazolyl, thiazolyl, pyridinyl, 2-oxopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or quinazolinyl are optionally substituted by one or more R4a groups; and wherein the dihydropyridinyl, dihydropyrimidinyl, or dihydropyridazinyl are optionally substituted by one or more groups selected from the group consisting of R4a and oxo; each R4a is independently halo, CN, C1-C3 alkyl, C1-C3 haloalkyl, —(C1-C3 alkylene)-O—(C1-C3 alkyl), C3-C6 cycloalkyl, —O—(C1-C3 alkyl), —O—(C1-C3 haloalkyl), or —S(O)2(C1-C3 alkyl); Q is H; and -L1-O-L2-Y-L3- are taken together to form
When a moiety is contemplated, it is understood that the moiety can be attached to the rest of the structure at any available position. For example, 3-chloro-6-methoxypyridinyl may be attached to the rest of the structure at the 2-, 4-, or 5-position (such as in 3-chloro-6-methoxypyridin-2-yl, 3-chloro-6-methoxypyridin-4-yl, or 3-chloro-6-methoxypyridin-5-yl, respectively). The R4 groups described herein are shown as attached at specific positions (e.g., pyridin-2-yl or pyrimidin-5-yl) but they can also be attached via any other available valence (e.g., pyridin-3-yl or pyrimidin-4-yl respectively).
Any embodiments provided herein of a compound of formula (I), or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, apply where applicable to any other formula detailed herein, the same as if each and every embodiment were specifically and individually listed. In particular, any embodiments provided herein of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, apply where applicable to compounds of formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the same as if each and every embodiment were specifically and individually listed for formula (A). Thus, it is understood and described that each embodiment provided herein of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, such as embodiments related to R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, Q, L1, L2, L3, Y, R1a, R1b, R1c, R1d, R2a, R4a, R5a, L1a, L2a, L3a, RA, RAa, RAb, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the same as if each and every embodiment were specifically and individually listed. It also understood and described that all such embodiments may be used in any of the pharmaceutical compositions, methods, kits, uses, or other aspects detailed herein.
Representative compounds are listed in Table 1.
In some embodiments, provided is a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a salt of a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof. The “flat” versions of all compounds depicted in Table 1 are also contemplated in this disclosure, including flat versions of any specific stereoisomeric forms in the Table.
In some embodiments, provided is a compound selected from compounds 1-82 depicted in Table 1, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a salt of a compound selected from compounds 1-82 depicted in Table 1, or a stereoisomer thereof. The “flat” versions of compounds 1-82 depicted in Table 1 are also contemplated in this disclosure, including flat versions of any specific stereoisomeric forms of compounds 1-82 in the Table.
In some embodiments, provided is a compound selected from compounds 83-104 depicted in Table 1, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a salt of a compound selected from compounds 83-104 depicted in Table 1, or a stereoisomer thereof. The “flat” versions of compounds 83-104 depicted in Table 1 are also contemplated in this disclosure, including flat versions of any specific stereoisomeric forms of compounds 83-104 in the Table.
In one variation, the compound detailed herein is selected from the group consisting of:
In one variation, the compound detailed herein is selected from the group consisting of:
In various embodiments, the compound selected from the group consisting of the compounds of the enumerated Examples, e.g., Compounds 1-82, or a pharmaceutically acceptable salt thereof. For example, the compound may be selected from the group consisting of:
In various embodiments, the compound selected from the group consisting of the compounds of the enumerated Examples, e.g., Compounds 83-104, or a pharmaceutically acceptable salt thereof. For example, the compound may be selected from the group consisting of:
In one variation, the compound detailed herein is selected from the group consisting of:
In one variation, the compound detailed herein is selected from the group consisting of:
In one variation, the compound detailed herein is selected from the group consisting of:
In some embodiments of the species recited herein, the alkyl esters of the free acid species are also encompassed, such as C1-C8 alkyl esters or C1-C4 alkyl esters. In such embodiments, embraced are the alkyl esters (e.g., homoserinate esters) of the free acid, for example, the methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, sec-butyl ester, isobutyl ester, and tert-butyl ester, as well as the various constitutional isomers of higher alkyl groups, such as C5-C8 alkyl esters.
In some embodiments, a composition, such as a pharmaceutical composition, is provided wherein the composition comprises a compound selected from the group consisting of one or more of the compounds depicted in Table 1, or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of a salt of one or more of the compounds depicted in Table 1. In one aspect, the composition is a pharmaceutical composition that further comprises a pharmaceutically acceptable carrier.
In some embodiments, all salts of compounds referred to herein, such as pharmaceutically acceptable salts, are embraced. In some embodiments, any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds are embraced. 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 some embodiments, all forms of the compounds, such as crystalline or non-crystalline forms, are included. In some embodiments, prodrugs, solvates and metabolites of the compounds are embraced. Compositions comprising a compound of formula (A) or formula (I) are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof. In some embodiments, compositions comprising a mixture of compounds of formula (A) or formula (I) in any ratio are also embraced, including mixtures of two or more stereochemical forms of a compound of formula (A) or formula (I) in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound. In some embodiments, where one or more tertiary amine moiety is present in the compound, the N-oxides are also provided and described.
Further provided is a pharmaceutical composition comprising a compound of formula (A), or any variation thereof detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient.
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 (A), or any variation thereof detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), a checkpoint inhibitor, and a pharmaceutically acceptable carrier or excipient.
Also 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), a checkpoint inhibitor, and a pharmaceutically acceptable carrier or excipient.
In various embodiments, the checkpoint inhibitor inhibits one of, or one or more of: PD-1, PD-L1, and CTLA-4. For example, in some embodiments, the checkpoint inhibitor inhibits PD-1. In some embodiments, the checkpoint inhibitor inhibits PD-L1. In some embodiments, the checkpoint inhibitor inhibits CTLA-4.
As used herein, “PD-1” checkpoint inhibitors may include, for example: pembrolizumab (also known as MK-3475, lambrolizumab, or Keytruda), which has been targeted at, e.g., melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma; nivolumab, which has been targeted at, e.g., melanoma, squamous cell lung cancer, renal cell carcinoma, and Hodgkin's lymphoma; cemiplimab, which has been targeted at, e.g., cutaneous squamous cell carcinoma (CSCC); spartalizumab, which has been targeted at, e.g., solid tumors and lymphomas; camrelizumab, which has been targeted at, e.g., Hodgkin's lymphoma; sintilimab, which has been targeted at, e.g., non-small cell lung cancer; tislelizumab, which has been targeted at, e.g., solid tumors and hematologic cancers; toripalimab; dostarlimab; INCMGA00012 (MGA012); AMP-224; and AMP-514.
As used herein, “PD-L1” checkpoint inhibitors may include, for example: atezolizumab (Tecentriq), which has been targeted at, e.g., urothelial carcinoma and non-small cell lung cancer; avelumab (Bavencio), which has been targeted at, e.g., metastatic Merkel cell carcinoma and gastric cancer; durvalumab (Imfinzi), which has been targeted at, e.g., urothelial carcinoma and non-small cell lung cancer, e.g., unresectable non-small cell lung cancer after chemoradiation; KN035; CK-301; and BMS-986189.
As used herein, “CTLA4” checkpoint inhibitors may include, for example: ipilimumab, which has been targeted at, e.g., melanoma, lung cancer, and pancreatic cancer; and tremelimumab, which has been targeted at, e.g., melanoma, mesothelioma, and non-small cell lung cancer.
Other checkpoint inhibitors may include dual action compounds, for example: AUNP12, a dual PD-1/PD-L1 inhibitor; and CA-170, a PD-L1 and VISTA antagonist.
Accordingly, in various embodiments, the checkpoint inhibitor includes at least one of: pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, INCMGA00012, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab.
Further provided is the use of a compound of formula (A) or formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of a disease mediated by cells that express one or more of: αVβ1; αVβ6; and αVβ8.
In various embodiments, the use of the compound of formula (A) or formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of a disease mediated by cells that express one or more of: αVβ1; αVβ6; and αVβ8, is further provided in combination with a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor inhibits one of, or one or more of: PD-1, PD-L1, and CTLA-4. For example, in some embodiments, the checkpoint inhibitor inhibits PD-1. In some embodiments, the checkpoint inhibitor inhibits PD-L1. In some embodiments, the checkpoint inhibitor inhibits CTLA-4. For example, in some embodiments, the checkpoint inhibitor includes at least one of: pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, INCMGA00012, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab. In some embodiments, pembrolizumab is dosed at about 200 mg every three weeks or about 400 mg every six weeks. In some embodiments, pembrolizumab is administered as an injection (about 25 mg/mL) via infusion.
Also provided is a method of treating a subject in need thereof. In some embodiments, the method includes providing the subject. In some embodiments, the subject has at least one tissue in need of therapy. In some embodiments, the at least one tissue is characterized by at least one value that is elevated compared to a healthy value in a healthy state of the tissue. In some embodiments, the tissue has an elevated value of αVβ1 integrin activity and/or expression. In some embodiments, the tissue has an elevated value of αVβ6 integrin activity and/or expression. In some embodiments, the tissue has an elevated value of αVβ8 integrin activity and/or expression. In some embodiments, the tissue has an elevated value of a pSMAD/SMAD ratio. In some embodiments, the tissue has an elevated value of new collagen formation or accumulation. In some embodiments, the tissue has an elevated value of total collagen. In some embodiments, the tissue has an elevated value of Type I Collagen gene Col1a1 expression. In some embodiments, the tissue has an elevated value of perforin. In some embodiments, the tissue has an elevated value of Granzyme B. In some embodiments, the tissue has an elevated value of interferon γ. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of formula (A) or formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the method comprises administering the therapeutically effective amount of the compound decreasing the at least one value.
In several embodiments, the administering the therapeutically effective amount of the compound decreases the at least one value. For example, in some embodiments, the at least one value is measured after at least one administration of the compound to the subject to determine a post-administration value. In some embodiments, the at least one administration of the compound is therapeutically effective if the post-administration value is decreased compared to the at least one value. In some embodiments, the at least one administration of the compound is therapeutically effective if the post-administration value is about the same as the healthy value.
In some embodiments, the method comprises reducing the activity and/or expression, e.g., activity, of certain integrins. For example, in some embodiments, the method comprises reducing the activity and/or expression of αVβ1. In some embodiments, the method comprises reducing the activity and/or expression of αVβ8. In some embodiments, the method comprises reducing the activity and/or expression of αVβ1 and αVβ8. In some embodiments, the method comprises reducing the activity and/or expression of αVβ6 and αVβ8. In some embodiments, the method comprises reducing the activity and/or expression of αVβ1, αVβ6, and αVβ8. In some embodiments, the reducing the activity and/or expression of each integrin is selective compared to at least one other αV-containing integrin in the subject.
In several embodiments, the activity of αVβ1 integrin is reduced in one or more fibroblasts in the subject. In some embodiments, the activity of αVβ6 integrin is reduced in one or more epithelial cells in the subject. In some embodiments, the activity of αVβ8 integrin is reduced in one or more epithelial cells or cancer cells in the subject.
In various embodiments, the at least one tissue in the subject comprises lung tissue. In some embodiments, the at least one tissue in the subject comprises liver tissue. In some embodiments, the at least one tissue in the subject comprises skin tissue. In some embodiments, the at least one tissue in the subject comprises heart tissue. In some embodiments, the at least one tissue in the subject comprises kidney tissue. In some embodiments, the at least one tissue in the subject comprises gastrointestinal tissue. In some embodiments, the at least one tissue in the subject comprises gall bladder tissue. In some embodiments, the at least one tissue in the subject comprises bile duct tissue. In some embodiments, the at least one tissue in the subject comprises intrahepatic biliary system tissue. In some embodiments, the at least one tissue in the subject comprises extrahepatic biliary system tissue. In some embodiments, the at least one tissue in the subject comprises intrahepatic biliary system tissue and extrahepatic biliary system tissue.
In some embodiments, the at least one tissue in the subject comprises brain tissue. In some embodiments, the at least one tissue in the subject comprises lymph node tissue. In some embodiments, the at least one tissue in the subject comprises stomach tissue. In some embodiments, the at least one tissue in the subject comprises urethra tissue. In some embodiments, the at least one tissue in the subject comprises bladder tissue. In some embodiments, the at least one tissue in the subject comprises prostate tissue. In some embodiments, the at least one tissue in the subject comprises pancreas tissue. In some embodiments, the at least one tissue in the subject comprises mesothelium tissue. In some embodiments, the at least one tissue in the subject comprises breast tissue.
In various embodiments, the tissue has an elevated pSMAD2/SMAD2 value compared to the healthy state of the tissue. In some embodiments, the tissue has an elevated pSMAD3/SMAD3 value compared to the healthy state of the tissue.
In various embodiments, the tissue comprises the tissue of the eye. In some embodiments, the tissue of the eye expresses one, two, or three integrins selected from αVβ1, αVβ6, and αVβ8.
In some embodiments, the subject has cancer. In some embodiments, the subject has a cancer selected from the group consisting of melanoma, colon cancer, breast cancer, prostate cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, lymphoma (such as Hodgkin's lymphoma), cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, and mesothelioma. In some embodiments, the subject has Hodgkin's lymphoma. In some embodiments, the subject has a solid tumor. In some embodiments, the subject has melanoma. In some embodiments, the subject has colon cancer. In some embodiments, the subject has breast cancer. In some embodiments, the subject has prostate cancer. In some embodiments, the subject has non-small cell lung cancer. In some embodiments, the subject has head and neck squamous cell carcinoma. In some embodiments, the subject has squamous cell lung cancer. In some embodiments, the subject has renal cell carcinoma. In some embodiments, the subject has lymphoma, such as Hodgkin's lymphoma. In some embodiments, the subject has cutaneous squamous cell carcinoma (CSCC). In some embodiments, the subject has urothelial carcinoma. In some embodiments, the subject has metastatic Merkel cell carcinoma. In some embodiments, the subject has gastric cancer. In some embodiments, the subject has lung cancer. In some embodiments, the subject has pancreatic cancer. In some embodiments, the subject has pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the subject has mesothelioma.
In some embodiments, the subject has a solid tumor. In some embodiments, the subject has a cancer selected from the group consisting of: breast cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, CSCC, urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, and mesothelioma. In some embodiments, the subject has pancreatic cancer. In some embodiments, the subject has pancreatic ductal adenocarcinoma (PDAC).
In some embodiments, the subject has pulmonary fibrosis. In some embodiments, the subject has liver fibrosis. In some embodiments, the subject has skin fibrosis. In some embodiments, the subject has cardiac fibrosis. In some embodiments, the subject has kidney fibrosis. In some embodiments, the subject has gastrointestinal fibrosis. In some embodiments, the subject has primary sclerosing cholangitis. In some embodiments, the subject has biliary fibrosis. In some embodiments, the subject has biliary atresia.
Also provided is a method of characterizing anticancer activity of a small molecule inhibitor in a subject. In some embodiments, the method comprises providing a first live cell sample from the subject. In some embodiments, the first live cell sample is characterized by the presence of at least one integrin capable of activating transforming growth factor β (TGF-β) from latency associated peptide-TGF-β. In some embodiments, the method comprises determining a first value in the first live cell sample. In some embodiments, the first value is a pSMAD2/SMAD2 ratio. In some embodiments, the first value is a pSMAD3/SMAD3 ratio. In some embodiments, the first value is a perforin level. In some embodiments, the first value is a granzyme B level. In some embodiments, the first value is an interferon γ level. In some embodiments, the method comprises administering the small molecule to the subject. In some embodiments, the method comprises providing a second live cell sample from the subject. In some embodiments, the second live cell sample is drawn from the same tissue in the subject as the first live cell sample. In some embodiments, the method comprises determining a second value in the second live cell sample. In some embodiments, the second value corresponds to the pSMAD2/SMAD2 ratio, pSMAD3/SMAD3 ratio, perforin level, granzyme B level, or interferon γ level of the first value. In some embodiments, the method comprises characterizing the anticancer activity of the small molecule in the subject by comparing the second value to the first value.
In some embodiments, each live cell sample comprises a plurality of cancer cells derived from a tissue of the subject. In some embodiments, each live cell sample comprises a plurality of cancer cells derived from a hematocyte of the subject. In some embodiments, the at least one tissue in the subject comprises skin. In some embodiments, the at least one tissue in the subject comprises lung. In some embodiments, the at least one tissue in the subject comprises brain. In some embodiments, the at least one tissue in the subject comprises lymph node. In some embodiments, the at least one tissue in the subject comprises stomach. In some embodiments, the at least one tissue in the subject comprises urethra. In some embodiments, the at least one tissue in the subject comprises kidney. In some embodiments, the at least one tissue in the subject comprises bladder. In some embodiments, the at least one tissue in the subject comprises prostate. In some embodiments, the at least one tissue in the subject comprises liver. In some embodiments, the at least one tissue in the subject comprises pancreas. In some embodiments, the at least one tissue in the subject comprises mesothelium. In some embodiments, the at least one tissue in the subject comprises breast.
In several embodiments, the at least one integrin includes αV. In some embodiments, the at least one integrin is αVβ1. In some embodiments, the at least one integrin is αVβ6. In some embodiments, the at least one integrin is αVβ8. In some embodiments, the at least one integrin includes αVβ1 and αVβ6. In some embodiments, the at least one integrin includes αVβ6 and αVβ8. In some embodiments, the at least one integrin includes αVβ1, αVβ6, and αVβ8. In some embodiments, the first and second values are pSMAD2/SMAD2 ratios or pSMAD3/SMAD3 ratios.
In various embodiments, the administering the small molecule to the subject comprises administering any aspect of the compound of formula (A) or formula (I) or a salt thereof, or a pharmaceutical composition thereof, as described herein. In some embodiments, the method further comprise administering a checkpoint inhibitor to the subject. In some embodiments, the characterizing the anticancer activity of the small molecule in the subject comprise comparing the second value to a first value. In some embodiments, the method comprises characterizing the anticancer activity of the small molecule together with the checkpoint inhibitor.
In some embodiments, the subject has breast cancer. In some embodiments, an effective amount of Compound 39 is administered to the subject. In some embodiments, the effective amount of Compound 39 is administered to the subject in a solution. In some embodiments, the solution comprises ethanol, propylene glycol, and PBS. In some embodiments, the solution comprises about 5% to about 15% v/v ethanol, about 65% to about 75% w/v propylene glycol, and about 15% to about 25% v/v PBS. In some embodiments, the solution comprises about 10% v/v ethanol, about 70% w/v propylene glycol, and about 20% v/v PBS. In some embodiments, the effective amount of the Compound 39 is administered to the subject at a dose over a duration. In some embodiments, the dose is about 135 to about 150 mg/kg body weight of the subject. In some embodiments, the dose is about 144 mg/kg body weight of the subject. In some embodiments, the duration is about 20 days, about 25 days, or about 30 days. In some embodiments, the duration is about 28 days. In some embodiments, at least one of mAbs, anti-mPD-1 and anti-αVβ8 is administered to the subject. In some embodiments, at least one of mAbs, anti-mPD-1 and anti-αVβ8 is administered to the subject in PBS by intraperitoneal injection. In some embodiments, at least one of mAbs, anti-mPD-1 and anti-αVβ8 is administered to the subject in PBS by intraperitoneal injection at a dose of about 10 mg/kg body weight of the subject for a frequency during a time period. In some embodiments, at least one of mAbs, anti-mPD-1 and anti-αVβ8 is administered to the subject in PBS by intraperitoneal injection at a dose of about 10 mg/kg body weight of the subject twice a week during the time period of two weeks. In some embodiments, administering Compound 39+anti-mPD-1 to the subject reduces tumor volume in the subject having breast cancer. In some embodiments, administering Compound 39+anti-αVβ8+anti-mPD-1 to the subject having breast cancer reduces growth and volume of the tumor. In some embodiments, administering Compound 39 to the subject having breast cancer reduces tumor growth.
In some embodiments, the subject has pancreatic cancer. In some embodiments, an effective amount of Compound 39 is administered to the subject. In some embodiments, the effective amount of Compound 39 is administered to the subject in a solution. In some embodiments, the solution comprises ethanol, propylene glycol, and PBS. In some embodiments, the solution comprises about 5% to about 15% v/v ethanol, about 65% to about 75% w/v propylene glycol, and about 15% to about 25% v/v PBS. In some embodiments, the solution comprises about 10% v/v ethanol, about 70% w/v propylene glycol, and about 20% v/v PBS. In some embodiments, the effective amount of the Compound 39 is administered to the subject at a dose over a duration. In some embodiments, the dose is about 135 to about 150 mg/kg body weight of the subject. In some embodiments, the dose is about 144 mg/kg body weight of the subject. In some embodiments, the duration is about 20 days, about 25 days, or about 30 days. In some embodiments, the duration is about 28 days. In some embodiments, at least one of mAbs, anti-mPD-1 and anti-αVβ8 is administered to the subject. In some embodiments, at least one of mAbs, anti-mPD-1 and anti-αVβ8 is administered to the subject in PBS by intraperitoneal injection. In some embodiments, at least one of mAbs, anti-mPD-1 and anti-αVβ8 is administered to the subject in PBS by intraperitoneal injection at a dose of about 10 mg/kg body weight of the subject for a frequency during a time period. In some embodiments, at least one of mAbs, anti-mPD-1 and anti-αVβ8 is administered to the subject in PBS by intraperitoneal injection at a dose of about 10 mg/kg body weight of the subject twice a week during the time period of two weeks. In some embodiments, administering Compound 39 to the subject having pancreatic cancer reduces tumor growth.
In some embodiments, the subject has colon cancer. In some embodiments, an effective amount of Compound 39 is administered to the subject. In some embodiments, the effective amount of Compound 39 is administered to the subject in a solution. In some embodiments, the solution comprises ethanol, propylene glycol, and PBS. In some embodiments, the solution comprises about 5% to about 15% v/v ethanol, about 65% to about 75% w/v propylene glycol, and about 15% to about 25% v/v PBS. In some embodiments, the solution comprises about 10% v/v ethanol, about 70% w/v propylene glycol, and about 20% v/v PBS. In some embodiments, the effective amount of the Compound 39 is administered to the subject at a dose over a duration. In some embodiments, the dose is about 135 to about 150 mg/kg body weight of the subject. In some embodiments, the dose is about 144 mg/kg body weight of the subject. In some embodiments, the duration is about 20 days, about 25 days, or about 30 days. In some embodiments, the duration is about 28 days. In some embodiments, at least one of mAbs, anti-mPD-1 and anti-αVβ8 is administered to the subject. In some embodiments, at least one of mAbs, anti-mPD-1 and anti-αVβ8 is administered to the subject in PBS by intraperitoneal injection. In some embodiments, at least one of mAbs, anti-mPD-1 and anti-αVβ8 is administered to the subject in PBS by intraperitoneal injection at a dose of about 10 mg/kg body weight of the subject for a frequency during a time period. In some embodiments, at least one of mAbs, anti-mPD-1 and anti-αVβ8 is administered to the subject in PBS by intraperitoneal injection at a dose of about 10 mg/kg body weight of the subject twice a week during the time period of two weeks. In some embodiments, administering Compound 39 to the subject having colon cancer reduces tumor growth.
In some embodiments, the subject has pancreatic ductal adenocarcinoma (PDAC). In some embodiments, a compound of formula (A) or formula (I) is administered to the subject that has PDAC via a dosing route for a dosing frequency. In some embodiments, the compound of formula (A) or formula (I) is Compound 39. In some embodiments, the dosing route is an oral gavage dosing route. In some embodiments, the dosing route is the oral gavage dosing route at a dosing level and a dosing volume. In some embodiments, the dosing level is about 300 mg/kg BID and the dosing volume is between about 5 to about 10 mL/kg. In some embodiments, the dosing frequency is a daily dosing frequency for a time period. In some embodiments, the time period is a week, two weeks, three weeks, a month, two months, or three months. In some embodiments, the compound of formula (A) or formula (I) is administered in a solution. In some embodiments, the solution comprises at least one alcohol and a buffer. In some embodiments, the solution comprises ethanol, propylene glycol, and PBS. In some embodiments, the solution comprises between about 5 to about 15% v/v ethanol, between about 65 to about 75% w/v propylene glycol, and between about 15 to about 25% v/v PBS. In some embodiments, the solution comprises about 10% v/v ethanol, about 70% w/v propylene glycol, and about 20% v/v PBS. In some embodiments, the compound of formula (A) or formula (I) is administered to the subject via oral gavage at a dose of about 300 mg/kg body weight over the duration of the time period, where the time period is between about 20 to about 25 days or between about 75 to about 85 days. In some embodiments, the compound of formula (A) or formula (I) is administered to the subject via oral gavage at a dose of about 300 mg/kg body weight over the duration of the time period, where the time period is about 22 days or is about 80 days.
In some embodiments, the compound of formula (A) or formula (I) is co-administered with an antibody during the time period. In some embodiments, the compound of formula (A) or formula (I) is administered prior to administration of the antibody. In some embodiments, the compound of formula (A) or formula (I) is administered subsequent administration of the antibody. In some embodiments, the antibody is anti-PD-1. In some embodiments, the subject is administered the anti-PD-1 in a buffer by intraperitoneal injection. In some embodiments, the subject is administered the anti-PD-1 in PBS by intraperitoneal injection at a dose of 10 mg/kg body weight twice a week for a time period. In some embodiments, the subject is administered the anti-PD-1 in PBS by intraperitoneal injection at the dose of about 10 mg/kg body weight twice a week for the time period of two weeks. In some embodiments, administration of Compound 39 with the anti-PD-1 reduces a weight of a KPC tumor in the subject. In some embodiments, administration of Compound 39 with the anti-PD-1 increases at least one of: CD8+ T cell infiltration in a KPC tumor in the subject, CD4+ T cell infiltration in the KPC tumor in the subject, and survival of the subject having the KPC tumor.
In some embodiments, a compound of formula (A) or formula (I) is administered to the subject that has PDAC via a dosing route for a dosing frequency. In some embodiments, the compound of formula (A) or formula (I) is Compound 39. In some embodiments, the dosing route is an oral gavage dosing route. In some embodiments, the dosing route is an oral gavage dosing route at a dosing level. In some embodiments, the dosing level is about 300 mg/kg BID. In some embodiments, the dosing frequency is once a month.
In some embodiments, the compound of formula (A) or formula (I) is co-administered with a chemotherapy agent. In some embodiments, the compound of formula (A) or formula (I) is administered prior to administration of the chemotherapy agent. In some embodiments, the compound of formula (A) or formula (I) is administered subsequent administration of the chemotherapy agent. In some embodiments, the chemotherapy agent is gemcitabine or abraxane. In some embodiments, administering the chemotherapy agent in combination with the compound of formula (A) or formula (I) reduces at least one of a weight of the tumor in the subject and lung metastases in the subject. In some embodiments, administering the compound of formula (A) or formula (I) reduces lung metastases in the subject.
In some embodiments, the compound of formula (A) or formula (I) is co-administered with a chemotherapy regimen. In some embodiments, the chemotherapy regimen comprises at least two chemotherapy agents. In some embodiments, the chemotherapy regimen comprises folfirinox (FNX). In some embodiments, the compound of formula (A) or formula (I) is administered prior to administration of the chemotherapy regimen. In some embodiments, the compound of formula (A) or formula (I) is administered subsequent administration of the chemotherapy regimen. In some embodiments, administering the chemotherapy regimen in combination with the compound of formula (A) or formula (I) reduces a weight of the tumor in the subject. In some embodiments, administering the chemotherapy regimen in combination with the compound of formula (A) or formula (I) reduces a weight of the tumor in the subject, where the tumor is FNX-resistant.
In some embodiments, the subject has cancer. In some embodiments, the subject has a solid tumor. In some embodiments, the subject has an advanced solid tumor. In some embodiments, the subject has a metastatic solid tumor. In some embodiments, the cancer is treatment-resistant. In some embodiments, the subject is a human subject that is at least 18 years of age. In some embodiments, the subject has received more than one dose of an immunotherapy. In some embodiments, the subject has received at least three doses of the immunotherapy. In some embodiments, the subject has received the at least three doses (200 mg Q3W) of the immunotherapy. In some embodiments, the immunotherapy is pembrolizumab. In some embodiments, the subject has evidence of disease progression at least one month after initiation of the immunotherapy. In some embodiments, the subject has evidence of disease progression at least two months after initiation of the immunotherapy. In some embodiments, subject has evidence of disease progression at least three months after initiation of the immunotherapy. In some embodiments, the subject has no other available treatment options. In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. In some embodiments, the subject has adequate bone marrow and organ function. “Adequate bone marrow and organ function” includes hemoglobin ≥10.0 g/dL with no blood transfusions (packed red blood cells and platelet transfusions) in the past 28 days prior to the start of treatment, absolute neutrophil count (ANC) ≥1.5×109/L, no features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) on a peripheral blood smear, platelet count ≥100×109/L, white blood cells (WBC) >3×109/L, total bilirubin ≤1.5× institutional upper limit of normal, and aspartate transaminase (AST) (SGOT)/alanine transaminase (ALT) (SGPT) ≤2.5× institutional upper limit of normal. In some embodiments, Compound 39 is administered to the subject as a monotherapy for a time period. In some embodiments, the time period is at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days. In some embodiments, the time period is at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least three weeks, or at least a month. In some embodiments, the immunotherapy is administered in combination with Compound 39 to the subject for a frequency beginning on Day 15. In some embodiments, the frequency is every day, every week, every two weeks, every three weeks, or every month. In some embodiments, pembrolizumab (200 mg Q3W) is administered in combination with Compound 39 to the subject on Day 15 every three weeks. In some embodiments, dose-escalation is determined by a Bayesian optimal interval (BOIN) dose escalation design. In some embodiments, the dose levels comprise multiple levels. In some embodiments, a starting dose of Compound 39 is administered to the target number of subjects in a treatment cohort. In some embodiments, if the stopping rules are met, administration of Compound 39 is stopped. In some embodiments, if the stopping rules have not been met, an assumed dose-limiting toxicity (DLT) rate is calculated. The assumed DLT rate is calculated as (number of subjects experiencing at least one DLT at the current dose during the DLT assessment period)/(total number of subjects being exposed to the current dose). In some embodiments, the target DLT rate is 30%, indicating that less than one out of three subjects is experiencing at least one DLT at the current dose during the DLT assessment period). In some embodiments, if zero out of the three subjects has the DLT and the DLT rate is ≤23.7%, dose-escalation occurs. In some embodiments, if one out of three subjects has the DLT and the DLT rate is between 23.7% and 35.9% (e.g., a 95% confidence interval), the current dose is maintained and the cohort is expanded. In some embodiments, if two out of the three subjects have the DLT and the DLT rate is >35.9%, dose de-escalation occurs. In some embodiments, following the dose-escalation and dose-expansion cohorts, a Simon's 2-stage design is used. In some embodiments, biomarkers are collected from the subject during a time period. In some embodiments, the time period is at Day 28. In some embodiments, the biomarkers include circulating immune cells, circulating markers, circulating tumor DNA, and archival tissue. In some embodiments, the circulating immune cells are retrieved using a CyTOF human immune panel. In some embodiments, the circulating markers include Pro-C3, C4G, GzmB, IFN γ, IL-10, PD-1, PD-L1, TNFα, CXCL9, CCXL12, VEGFα, and αVβ8. In some embodiments, the archival tissue is retrieved using the RNA-Seq technique. In some embodiments, the treatment is concluded if one or more endpoints are reached.
Compounds described herein include inhibitors of at least one or more of αVβ8, αVβ1, and αVβ6 integrins. For example, in some embodiments, the compound inhibits αVβ8 integrin. In some embodiments, the compound inhibits αVβ1 integrin. In some instances, it is desirable for the compound to inhibit two or more integrins. For example, in some embodiments, the compound inhibits αVβ8 integrin and αVβ1 integrin. In some embodiments, the compound inhibits αVβ8 integrin and αVβ6 integrin. In some embodiments, the compound inhibits αVβ8 integrin, αVβ1 integrin, and αVβ6 integrin.
In some instances, it is desirable to avoid inhibition of other integrins. In some embodiments, the compound is a selective αVβ8 integrin inhibitor. For example, in some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit one or more integrins such as αVβ1, αVβ6, αVβ3, αVβ5, α4β1, or α5β1. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ6 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ1 integrin or αVβ6 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ3 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ5 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ3 integrin or αVβ5 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit α4β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit α5β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit α4β1 integrin or α5β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ3 integrin, αVβ5 integrin, α4β1 integrin, or α5β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ6 integrin, αVβ3 integrin, αVβ5 integrin, α4β1 integrin, or α5β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ1 integrin, αVβ3 integrin, αVβ5 integrin, α4β1 integrin, or α5β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ1 integrin, αVβ6 integrin, αVβ3 integrin, αVβ5 integrin, α4β1 integrin, or α5β1 integrin.
In some embodiments, isotopically-labeled and/or isotopically-enriched forms of compounds of formula (A) or formula (I) are included. 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 (A) or 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 formula (A) or formula (I) 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 or D) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances. In some embodiments, provided herein is an isotopically enriched form of any of the formulae described herein, wherein the compound comprises one or more deuterium atoms. In some embodiments, the compounds of formula (A) or formula (I) have one or more of the hydrogen atoms replaced by deuterium. Specific groups may be labeled preferentially with deuterium; for example, a cyclopropyl group can have its attached hydrogen atoms replaced by one or more deuterium atoms, or may be perdeuterated.
Isotopically-labeled compounds of formula (A) or formula (I) 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.
In some embodiments, any or all metabolites of any of the compounds described. In some embodiments, the metabolites 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 formula (A) or formula (I), or a salt or solvate thereof, in a suitable container are provided. In some embodiments, the container is a vial, jar, ampoule, preloaded syringe, IV 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.
The compounds of formula (A) or formula (I) may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.
Where it is desired to obtain a particular stereoisomer of a compound, this may be accomplished from a corresponding mixture of stereoisomers using any suitable conventional procedure for separating stereoisomers or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. 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 stereoisomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
Chromatography, recrystallization and other conventional separation procedures may also 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 and/or polymorphs of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and/or solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
Compounds provided herein may be prepared according to Schemes A, B, C, D, E, F, G, H, I, J, K, L, and M; General Procedures B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, and V; Examples 1-82 (i.e., Compounds 1-82), and Examples 83-104 (i.e., Compounds 83-104).
Intermediate 1A was prepared according to US20200109141A1, herein incorporated by reference in its entirety.
Intermediate 1B was prepared according to US20200109141A1, herein incorporated by reference in its entirety.
Procedures were adapted from Greszler et al. Org. Lett. 2017, 19, 2490-2493, herein incorporated by reference in its entirety.
It is understood that the schemes above may be modified to arrive at various compounds of formula (A) or formula (I) by selection of appropriate reagents and starting materials. For a general description of protecting groups and their use, see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis 4th edition, Wiley-Interscience, New York, 2006, herein incorporated by reference in its entirety.
Additional methods of preparing compounds according to formula (A) or formula (I), and salts thereof, are provided in the Examples. As a skilled artisan would recognize, the methods of preparation taught herein may be adapted to provide additional compounds within the scope of formula (A) or formula (I), for example, by selecting starting materials which would provide a desired compound.
Pharmaceutical compositions of any of the compounds detailed herein, including compounds of the formulae (A), (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), and (IV), or a pharmaceutically acceptable salt thereof, or compounds 1-82 depicted in Table 1, or compounds 83-104 depicted in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or mixtures thereof, are also provided. Thus, in some embodiments, pharmaceutical compositions comprising a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient are provided. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions according to the instant disclosure may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation. In some embodiments, the pharmaceutical composition is prepared from mixtures of any of the compounds detailed herein, or salts thereof. In some embodiments, the pharmaceutical composition is a composition for controlled release of any of the compounds detailed herein.
Pharmaceutical compositions of any of the compounds detailed herein, including compounds of the formulae (A), (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), and (IV), a compound of Table 1, or any one of compounds 1-82 or a stereoisomer thereof, or any one of compounds 83-104 depicted in Table 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or mixtures thereof, are also provided.
A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. In some embodiments, compositions have no more than about 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a pharmaceutically acceptable salt thereof, for example, in some embodiments, a composition of a compound selected from a compound of Table 1 contains no more than about 35% impurity, wherein the impurity denotes a compound other than the compound of Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, compositions contain no more than about 25% impurity. In some embodiments, compositions contain no more than about 20% impurity. In still further embodiments, compositions comprising a compound as detailed herein or a pharmaceutically acceptable salt thereof are provided as compositions of substantially pure compounds. “Substantially pure” compositions comprise no more than about 10% impurity, such as a composition comprising less than about 9%, about 7%, about 5%, about 3%, about 1%, or about 0.5% impurity. In some embodiments, a composition containing a compound as detailed herein or a pharmaceutically acceptable salt thereof is in substantially pure form. In still another variation, a composition of substantially pure compound or a pharmaceutically acceptable salt thereof is provided wherein the composition contains or no more than about 10% impurity. In a further variation, a composition of substantially pure compound or a pharmaceutically acceptable salt thereof is provided wherein the composition contains or no more than about 9% impurity. In a further variation, a composition of substantially pure compound or a pharmaceutically acceptable salt thereof is provided wherein the composition contains or no more than about 7% impurity. In a further variation, a composition of substantially pure compound or a pharmaceutically acceptable salt thereof is provided wherein the composition contains or no more than about 5% impurity. In another variation, a composition of substantially pure compound or a pharmaceutically acceptable salt thereof is provided wherein the composition contains or no more than about 3% impurity. In still another variation, a composition of substantially pure compound or a pharmaceutically acceptable salt thereof is provided wherein the composition contains or no more than about 1% impurity. In a further variation, a composition of substantially pure compound or a pharmaceutically acceptable salt thereof is provided wherein the composition contains or no more than about 0.5% impurity. In yet other variations, a composition of substantially pure compound means that the composition contains no more than about 10% or preferably no more than about 5% or more preferably no more than about 3% or even more preferably no more than about 1% impurity or most preferably no more than about 0.5% 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 about 10% or no more than about 5% or no more than about 3% or no more than about 1% or no more than about 0.5% of the I form of the compound.
In further embodiments, the purified forms and substantially pure forms of the compounds apply to any compounds of the formulae (A), (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), and (IV), a compound of Table 1, or any one of compounds 1-82, compounds 83-104, or a stereoisomer thereof.
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, pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier or excipient are provided. 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 compounds detailed herein or pharmaceutically acceptable salts thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound or pharmaceutically acceptable salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
One or several compounds described herein or a pharmaceutically acceptable salt thereof can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a pharmaceutically acceptable salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, 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 in its entirety.
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, emulators, 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 tablet of about 10 mg.
Compositions comprising a compound provided herein are also described. In one variation, the composition comprises a compound and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided. In some embodiments, the composition is for use as a human or veterinary medicament. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment of a disease or disorder described herein.
Compounds and compositions of, such as a pharmaceutical composition containing a compound of any formula provided herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. In some embodiments, the compounds and compositions are 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 (A) or formula (I), or any variation thereof, e.g., a compound of formulae (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, the individual is a human. In some embodiments, the individual, such as a human, is in need of treatment, such as a human who has or is suspected of having a fibrotic disease. In some embodiments, a variation of the compounds includes any stereoisomer thereof.
In a further aspect, provided is a method of treating a fibrotic disease in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of formula (A), formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds depicted in Table 1, or any one of compounds 1-82, or any one of compounds 83-104, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In one aspect, the individual is a human. In some embodiments, the individual, such as a human, is in need of treatment, such as a human who has or is suspected of having a fibrotic disease. In some embodiments, a variation of the compounds includes any stereoisomer thereof.
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 individual at risk for developing a fibrotic disease is an individual who has or is suspected of having NAFLD, NASH, CKD, scleroderma, Crohn's Disease, NSIP, PSC, PBC, biliary atresia, or is an individual who has had or is suspected of having had a myocardial infarction.
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 pulmonary fibrosis (such as IPF), liver fibrosis, skin fibrosis, scleroderma, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis (such as PBC).
In some embodiments, the fibrotic disease is a pulmonary fibrosis, e.g., idiopathic pulmonary fibrosis (IPF), interstitial lung disease, systemic sclerosis-associated interstitial lung disease, or radiation-induced pulmonary fibrosis. In some embodiments, the individual at risk for developing a fibrotic disease is an individual who has or is suspected of having a history of viral lung infections.
In some embodiments, the fibrotic disease is a primary sclerosing cholangitis, or biliary fibrosis. In some embodiments, the fibrotic disease is primary biliary cholangitis (also known as primary biliary cirrhosis). In some embodiments, the fibrotic disease is biliary atresia.
In some embodiments, the fibrotic disease is fibrotic nonspecific interstitial pneumonia (NSIP).
In some embodiments, the fibrotic disease is a liver fibrosis, e.g., infectious liver fibrosis (from pathogens such as HCV, HBV or parasites such as schistosomiasis), NASH, alcoholic liver disease induced fibrosis, alcoholic steatosis induced liver fibrosis, nonalcoholic fatty liver disease, biliary atresia and cirrhosis.
In some embodiments, the fibrotic disease is biliary tract fibrosis.
In some embodiments, the fibrotic disease is renal fibrosis, e.g., diabetic kidney disease, diabetic nephrosclerosis, hypertensive nephrosclerosis, diabetic nephropathy, focal segmental glomerulosclerosis (“FSGS”), Alport syndrome, chronic kidney disease, and acute kidney injury from contrast induced nephropathy.
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 gastrointestinal 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 (A) or formula (I), or any variation thereof, e.g., a compound of formulae (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a fibrotic disease.
Also provided is use of a compound of formula (A) or formula (I), or any variation thereof, e.g., a compound of formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a fibrotic disease.
In another aspect, provided is a method of inhibiting αVβ8 integrin in an individual comprising administering a compound of formula (A) or formula (I), or any variation thereof, e.g., a compound of formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a stereoisomer thereof, or a compound selected from the compounds depicted 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 (A) or formula (I), or any variation thereof, e.g., a compound of formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the cell expresses one of, or one or more of: αVβ1; αVβ6; and αVβ8. In some embodiments, the cell expresses αVβ1. In some embodiments, the cell expresses αVβ6. In some embodiments, the cell expresses αVβ8. In some embodiments, the cell expresses αVβ1 and αVβ6. In some embodiments, the cell expresses αVβ1 and αVβ8. In some embodiments, the cell expresses αVβ6 and αVβ8. In some embodiments, the cell expresses αVβ1, αVβ6, and αVβ8. In some embodiments, the cell or cells are associated with the eye.
In some embodiments, the method includes administering to the cell a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor inhibits PD-1. In some embodiments, the checkpoint inhibitor inhibits PD-L1. In some embodiments, the checkpoint inhibitor inhibits CTLA-4. In some embodiments, the checkpoint inhibitor inhibits one or more of: PD-1, PD-L1, and CTLA-4. In some embodiments, the checkpoint inhibitor includes one of, or one or more of: pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, INCMGA00012, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab. In some embodiments, the checkpoint inhibitor is pembrolizumab, which is marketed as Keytruda® (https://www.keytrudahcp.com/, U.S. Pat. Nos. 8,354,509 and 8,900,587, each of which is hereby incorporated by reference in its entirety). In some embodiments, pembrolizumab is dosed at about 200 mg every three weeks or about 400 mg every six weeks. In some embodiments, pembrolizumab is administered as an injection (about 25 mg/mL) via infusion.
In some embodiments, the cells comprise cells associated with a solid tumor. In various embodiments, the cells comprise cells associated with one of, or one or more of: melanoma, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, lymphoma (e.g., Hodgkin's lymphoma), cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, or mesothelioma. In some embodiments, the subject can have pancreatic cancer. In some embodiments, the subject has pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cells are associated with breast cancer. In some embodiments, the cells are associated with a disease mediated by one or more of αVβ1 integrin, αVβ6 integrin, and/or αVβ8 integrin, e.g., a fibrotic disease, or cancer. For example, in some embodiments, the cells are associated with one of, or one or more of: pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, kidney fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis. In some embodiments, the cells are human cells. In some embodiments, the cell or cells are associated with the eye. In some embodiments, the cell or cells express one, two, or three integrins selected from αVβ1, αVβ6, and αVβ8.
Also provided is a method of inhibiting at least one integrin in an individual in need thereof, comprising administering to the individual a compound of formula (A) or formula (I), or any variation thereof, e.g., a compound of formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In various embodiments of the method, compounds described herein inhibit at least one or more of αVβ8, αVβ1, and αVβ6 integrins. For example, in some embodiments, the compound inhibits αVβ8 integrin. In some embodiments, the compound inhibits αVβ1 integrin. In some instances, it is desirable for the compound to inhibit two or more integrins. For example, in some embodiments, the compound inhibits αVβ8 integrin and αVβ1 integrin. In some embodiments, the compound inhibits αVβ8 integrin and αVβ6 integrin. In some embodiments, the compound inhibits αVβ8 integrin, αVβ1 integrin, and αVβ6 integrin. In some instances of the method, it is desirable to avoid inhibition of other integrins. In some embodiments, the compound is a selective αVβ8 integrin inhibitor. For example, in some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit one or more integrins such as αVβ1, αVβ6, αVβ3, αVβ5, α4β1, or α5β1. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ6 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ1 integrin or αVβ6 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ3 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ5 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ3 integrin or αVβ5 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit α4β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit α5β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit α4β1 integrin or α5β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ3 integrin, αVβ5 integrin, α4β1 integrin, or α5β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ6 integrin, αVβ3 integrin, αVβ5 integrin, α4β1 integrin, or α5β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ1 integrin, αVβ3 integrin, αVβ5 integrin, α4β1 integrin, or α5β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ1 integrin, αVβ6 integrin, αVβ3 integrin, αVβ5 integrin, α4β1 integrin, or α5β1 integrin. In various embodiments of the method, compounds described herein inhibit at least one or more integrins, and/or selectively inhibit one or more integrins in any combination as described herein.
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 (A) or formula (I), or any variation thereof, e.g., a compound of formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds depicted in Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
Also provided is a method of modulating TGFβ activation in a cell, comprising contacting the cell with the compound of formula (A) or formula (I), or any variation thereof, e.g., a compound of formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a stereoisomer thereof, or a compound selected from the compounds depicted in Table 1, or a pharmaceutically acceptable salt thereof. In another aspect, the modulating comprises inhibiting TGFβ activation in the cell. In another aspect, the TGFβ activation being mediated in the cell by at least one or more of αVβ8, αVβ1, and αVβ6 integrins.
Also provided is a method of treating a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of the compound of formula (A) or formula (I), or any variation thereof, e.g., a compound of formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a stereoisomer thereof, or a compound selected from the compounds depicted in Table 1, or a pharmaceutically acceptable salt thereof, wherein the subject has at least one tissue in need of therapy and the tissue has at least one elevated level of: TGFβ activation and/or expression; αVβ8 integrin activity and/or expression; αVβ1 integrin activity and/or expression; or αVβ6 integrin activity and/or expression; wherein the at least one elevated level is elevated compared to a healthy state of the tissue. In some aspects, the method selectively inhibits at least one integrin as described herein for the compounds, for example, with respect to at least one other integrin such as an αV-containing integrin as described herein for the compounds. For example, in some embodiments, the method selectively inhibits αVβ8 integrin compared to αVβ6 integrin in the subject. In some embodiments, the method selectively inhibits αVβ8 integrin compared to αVβ1 integrin in the subject. In some embodiments, the method selectively inhibits αVβ8 integrin compared to αVβ1 integrin and αVβ6 integrin in the subject. In some embodiments, the method inhibits, e.g., selectively with respect to one or more other integrins as described herein such as an αV-containing integrin, αVβ8 and αVβ6 integrin in the subject. In some embodiments, the method inhibits, e.g., selectively with respect to one or more other integrins as described herein such as an αV-containing integrin, αVβ8 and αVβ1 integrin in the subject. In some embodiments, the method inhibits, e.g., selectively with respect to one or more other integrins as described herein such as an αV-containing integrin, αVβ8, αVβ1, and αVβ6 integrin in the subject. In some aspects, the αVβ1 integrin is inhibited in one or more fibroblasts in the subject. In some aspects, the αVβ6 integrin is inhibited in one or more epithelial cells in the subject. In some aspects, the at least one tissue in the subject comprises one or more of: lung tissue, liver tissue, skin tissue, cardiac tissue, kidney tissue, gastrointestinal tissue, gall bladder tissue, and bile duct tissue.
In some embodiments, the method comprises administering to the individual a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor inhibits PD-1. In some embodiments, the checkpoint inhibitor inhibits PD-L1. In some embodiments, the checkpoint inhibitor inhibits CTLA-4. In some embodiments, the checkpoint inhibitor inhibits one or more of: PD-1, PD-L1, and CTLA-4. In some embodiments, the checkpoint inhibitor includes one of, or one or more of: pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, INCMGA00012, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab. In some embodiments, the checkpoint inhibitor is pembrolizumab, which is marketed as Keytruda® (https://www.keytrudahcp.com/, U.S. Pat. Nos. 8,354,509 and 8,900,587, each of which is hereby incorporated by reference in its entirety). In some embodiments, pembrolizumab is dosed at about 200 mg every three weeks or about 400 mg every six weeks. In some embodiments, pembrolizumab is administered as an injection (about 25 mg/mL) via infusion.
In various embodiments, the individual in need of treatment thereof has a solid tumor. In various embodiments, the individual in need of treatment thereof has at least one of: melanoma, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, lymphoma (e.g., Hodgkin's lymphoma), cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, or mesothelioma. In some embodiments, the subject has pancreatic cancer. In some embodiments, the subject has pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the individual in need of treatment thereof has breast cancer. In some embodiments, the individual in need of treatment thereof has a disease mediated by one or more of αVβ1 integrin, αVβ6 integrin, and/or αVβ8 integrin, e.g., a fibrotic disease, or cancer. For example, in some embodiments, the individual has at least one of: pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, kidney fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis.
Also provided is a method of treating cancer in an individual in need thereof, comprising: administering to the subject a therapeutically effective amount of the compound of formula (A) or formula (I), or any variation thereof, e.g., a compound of formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a stereoisomer thereof, or a compound selected from the compounds depicted in Table 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer is selected from the group consisting of: melanoma, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, lymphoma (e.g., Hodgkin's lymphoma), cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, prostate cancer, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, and mesothelioma. In some embodiments, the cancer is breast cancer. In some embodiments, the subject has pancreatic cancer. In some embodiments, the subject has pancreatic ductal adenocarcinoma (PDAC).
In some embodiments, the method further comprise administering to the individual a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor inhibits PD-1. In some embodiments, the checkpoint inhibitor inhibits PD-L1. In some embodiments, the checkpoint inhibitor inhibits CTLA-4. In some embodiments, the checkpoint inhibitor inhibits one or more of: PD-1, PD-L1, and CTLA-4. In some embodiments, the checkpoint inhibitor includes one of, or one or more of: pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, INCMGA00012, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab. In some embodiments, the checkpoint inhibitor is pembrolizumab, which is marketed as Keytruda® (https://www.keytrudahcp.com/, U.S. Pat. Nos. 8,354,509 and 8,900,587, each of which is hereby incorporated by reference in its entirety). In some embodiments, pembrolizumab is dosed at about 200 mg every three weeks or about 400 mg every six weeks. In some embodiments, pembrolizumab is administered as an injection (about 25 mg/mL) via infusion.
In one aspect, provided is a compound of formula (A) or formula (I), or any variation thereof, e.g., a compound of formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds depicted in Table 1, or any one of compounds 1-82, or any one of compounds 83-104, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a fibrotic disease.
Also provided is use of a compound of formula (A), formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds depicted in Table 1, or any one of compounds 1-82, or any one of compounds 83-104, or a stereoisomer thereof, 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 at least one integrin in an individual comprising administering a compound of formulae (A), (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds depicted in Table 1, or any one of compounds 1-82, or any one of compounds 83-104, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In various embodiments of the method, compounds described herein inhibit at least one or more of αVβ8, αVβ1, and αVβ6 integrins, as described herein.
Also provided is a method of inhibiting TGFβ activation in a cell comprising administering to the cell a compound of formulae (A), (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV) a compound selected from the compounds depicted in Table 1, or any one of compounds 1-82, or any one of compounds 83-104, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
Also provided is a method of inhibiting at least one integrin in an individual in need thereof, comprising administering to the individual a compound of formulae (A), (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV) a compound selected from the compounds depicted in Table 1, or any one of compounds 1-82, or any one of compounds 83-104, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In various embodiments of the method, compounds described herein inhibit at least one or more of αVβ8, αVβ1, and αVβ6 integrins. For example, in some embodiments, the compound inhibits αVβ8 integrin. In some embodiments, the compound inhibits αVβ1 integrin. In some instances, it is desirable for the compound to inhibit two or more integrins. For example, in some embodiments, the compound inhibits αVβ8 integrin and αVβ1 integrin. In some embodiments, the compound inhibits αVβ8 integrin and αVβ6 integrin. In some embodiments, the compound inhibits αVβ8 integrin, αVβ1 integrin, and αVβ6 integrin. In some instances of the method, it is desirable to avoid inhibition of other integrins. In some embodiments, the compound is a selective αVβ8 integrin inhibitor. For example, in some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit one or more integrins such as αVβ1, αVβ6, αVβ3, αVβ5, α4β1, or α5β1. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ6 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ1 integrin or αVβ6 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ3 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ5 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ3 integrin or αVβ5 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit α4β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit α5β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit α4β1 integrin or α5β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ3 integrin, αVβ5 integrin, α4β1 integrin, or α5β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ6 integrin, αVβ3 integrin, αVβ5 integrin, α4β1 integrin, or α5β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ1 integrin, αVβ3 integrin, αVβ5 integrin, α4β1 integrin, or α5β1 integrin. In some embodiments, the compound is a selective αVβ8 integrin inhibitor that does not substantially inhibit αVβ1 integrin, αVβ6 integrin, αVβ3 integrin, αVβ5 integrin, α4β1 integrin, or α5β1 integrin. In various embodiments of the method, compounds described herein inhibit at least one or more integrins, and/or selectively inhibit one or more integrins in any combination as described herein.
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 formulae (A), (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV) a compound selected from the compounds depicted in Table 1, or any one of compounds 1-82, or any one of compounds 83-104, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
Also provided is a method of modulating at least one integrin in a subject, the at least one integrin comprising an αV subunit, the method comprising administering to the subject an effective amount of the compound of formulae (A), (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds depicted in Table 1, or any one of compounds 1-82, or any one of compounds 83-104, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the modulating comprises inhibiting the at least one integrin in the subject. In another aspect, the at least one integrin comprises at least one or more of αVβ8, αVβ1, and αVβ6 integrins. In another aspect, the subject has or is at risk of a fibrotic disease selected from the group consisting of: pulmonary fibrosis, skin fibrosis, liver fibrosis, cardiac fibrosis, kidney fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis. In another aspect, the subject has or is at risk of a fibrotic disease selected from the group consisting of: idiopathic pulmonary fibrosis (IPF), interstitial lung disease, radiation-induced pulmonary fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease induced fibrosis, Alport syndrome, primary sclerosing cholangitis (PSC), primary biliary cholangitis, biliary atresia, systemic sclerosis associated interstitial lung disease, scleroderma, diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, and Crohn's Disease; and the method comprises inhibiting at least one or more of αVβ8, αVβ1, and αVβ6 integrins, as described herein in the subject, thereby treating the fibrotic disease in the subject. In another aspect, the subject being in need of treatment for NASH, the effective amount administered to the subject being effective to inhibit, in the subject, at least one or more of αVβ8, αVβ1, and αVβ6 integrins, as described for the compounds herein, e.g., at least αVβ1 integrin, thereby treating the subject for NASH. In another aspect, the subject being in need of treatment for IPF, the effective amount administered to the subject being effective to inhibit, in the subject, at least one or more of αVβ8, αVβ1, and αVβ6 integrins, as described for the compounds herein, e.g., at least αVβ6 integrin, thereby treating the subject for IPF. In another aspect, the subject being in need of treatment for PSC, the effective amount administered to the subject being effective to inhibit, in the subject, at least one or more of αVβ8, αVβ1, and αVβ6 integrins, as described for the compounds herein, e.g., at least one of αVβ1 integrin and αVβ6 integrin, thereby treating the subject for PSC.
Also provided is a method of modulating TGFβ activation in a cell, comprising contacting the cell with the compound of formulae (A), (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds depicted in Table 1, or any one of compounds 1-82, or any one of compounds 83-104, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the modulating comprises inhibiting TGFβ activation in the cell. In another aspect, the TGFβ activation is mediated in the cell by at least one or more of αVβ8, αVβ1, and αVβ6 integrins, as described herein.
Also provided is a method of treating a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of the compound of formula (A) or formula (I), or any variation thereof, e.g., a compound of formulae (A), (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b-1), (III-b-2), (III-b-3), (III-b-4), (III-b-5), (III-b-6), (III-b-7), (III-b-8), (III-b-9), or (IV), a compound selected from the compounds depicted in Table 1, or any one of compounds 1-82, or any one of compounds 83-104, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the subject has at least one tissue in need of therapy and the tissue has at least one elevated level of: TGFβ activation and/or expression; αVβ8 integrin activity and/or expression; αVβ1 integrin activity and/or expression; or αVβ6 integrin activity and/or expression; wherein the at least one elevated level is elevated compared to a healthy state of the tissue. In some aspects, the method selectively inhibits αVβ8 integrin compared to αVβ6 integrin in the subject. In some aspects, the method selectively inhibits αVβ8 integrin compared to αVβ1 integrin in the subject. In some aspects, the method inhibits both of αVβ1 integrin and αVβ8 integrin in the subject. In some aspects, the method inhibits αVβ1 integrin, αVβ6 integrin, and αVβ8 integrin in the subject. In some aspects, the method selectively inhibits both αVβ1 integrin and αVβ8 integrin compared to at least one other αV-containing integrin in the subject. In some aspects, the method selectively inhibits αVβ1 integrin, αVβ6 integrin, and αVβ8 integrin compared to at least one other αV-containing integrin in the subject. In some aspects, the αVβ1 integrin is inhibited in one or more fibroblasts in the subject. In some aspects, the αVβ6 integrin is inhibited in one or more epithelial cells in the subject. In some aspects, the at least one tissue in the subject comprises one or more of: lung tissue, liver tissue, skin tissue, cardiac tissue, kidney tissue, gastrointestinal tissue, gall bladder tissue, and bile duct tissue.
In some embodiments, provided is a method of treating ocular fibrosis in an individual in need thereof comprising administering a compound of formula (A) or formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In some embodiments, provided is a method of treating anterior subcapsular cataracts or posterior capsule opacification in an individual in need thereof comprising administering a compound of formula (A) or formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In some embodiments, provided is use of a compound of formula (A) or formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of ocular fibrosis. In some embodiments, provided is the use of a compound of formula (A) or formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of anterior subcapsular cataracts or posterior capsule opacification.
In any of the described methods, in one aspect the individual is a human, such as a human in need of the method. In some embodiments, the individual is a human who has been diagnosed with or is suspected of having a fibrotic disease. In some embodiments, the individual is a human who does not have detectable disease but who has one or more risk factors for developing a fibrotic disease.
Also provided are kits for carrying out the methods, which comprises one or more compounds described herein, or a pharmaceutically acceptable salt thereof, or a pharmacological composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a pharmaceutically acceptable salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for use in the treatment of a fibrotic disease.
For example, provided is a kit comprising a compound of formula (A) or formula (I), 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 disease in an individual mediated by one or more of αVβ1 integrin, αVβ6 integrin, and/or αVβ8 integrin, e.g., a fibrotic disease, or cancer. In some embodiments, the kit comprises instructions for use according to a method described herein, such as a method of treating a cancer in an individual. In some embodiments, the kit includes instructions for use according to a method described herein, such as directing a user to administer the compound of the kit and a checkpoint inhibitor in a method of treating a cancer in an individual.
Also provided is a kit comprising a compound of formula (A) or formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, and a checkpoint inhibitor. In some embodiments, the kit comprises instructions for use according to a method described herein, such as a method of treating a disease in an individual that is mediated by one or more of αVβ1 integrin, αVβ6 integrin, and/or αVβ8 integrin, e.g., a fibrotic disease, or cancer. In some embodiments, the kit comprises instructions for use according to a method described herein, such as a method of treating a cancer in an individual. For example, the instructions may direct the user to administer to the subject: the checkpoint inhibitor; and the compound or the pharmaceutically acceptable salt thereof.
In various embodiments, the kit may include any checkpoint inhibitor as described herein. For example, in some embodiments, the checkpoint inhibitor inhibits PD-1. In some embodiments, the checkpoint inhibitor inhibits PD-L1. In some embodiments, the checkpoint inhibitor inhibits CTLA-4. In some embodiments, the checkpoint inhibitor inhibits one of, or one or more of PD-1, PD-L1, and CTLA-4. Further, for example, in some embodiments, the checkpoint inhibitor is selected from at least one of: pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, INCMGA00012, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab. In some embodiments, the checkpoint inhibitor is pembrolizumab, which is marketed as Keytruda® (https://www.keytrudahcp.com/, U.S. Pat. Nos. 8,354,509 and 8,900,587, each of which is hereby incorporated by reference in its entirety). In some embodiments, pembrolizumab is dosed at about 200 mg every three weeks or about 400 mg every six weeks. In some embodiments, pembrolizumab is administered as an injection (about 25 mg/mL) via infusion.
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 disclosure. The instructions included with the kit generally include information as to the components and their administration to an individual.
Embodiment 1. A compound of formula (I):
or a salt thereof, wherein:
Embodiment 2. The compound of Embodiment 1, or a salt thereof, wherein L1 is —CH2CH2—.
Embodiment 3. The compound of Embodiment 1, or a salt thereof, wherein -L1-O-L2-Y-L3- are taken together to form
Embodiment 4. The compound of any one of Embodiments 1-3, or a salt thereof, wherein R2 and R3 are independently C1-C6 alkyl.
Embodiment 5. The compound of Embodiment 4, or a salt thereof, wherein R2 and R3 are the same.
Embodiment 6. The compound of Embodiment 5, or a salt thereof, wherein R2 and R3 are —CH3.
Embodiment 7. The compound of any one of Embodiments 1-3, or a salt thereof, wherein R2 and R3 are taken together with the carbon atom to which they are attached to form cyclopropyl.
Embodiment 8. The compound of any one of Embodiments 1-7, or a salt thereof, wherein R4 is phenyl optionally substituted by R4a.
Embodiment 9. The compound of Embodiment 8, or a salt thereof, wherein R4 is unsubstituted phenyl.
Embodiment 10. The compound of Embodiment 8, or a salt thereof, wherein R4 is phenyl substituted by 1-5 R4a groups, wherein at least one R4a group is F or Cl.
Embodiment 11. The compound of Embodiment 8, or a salt thereof, wherein R4 is phenyl substituted by 1-5 R4a groups, wherein at least one R4a group is CN.
Embodiment 12. The compound of Embodiment 8, or a salt thereof, wherein R4 is phenyl substituted by 1-5 R4a groups, wherein at least one R4a group is C1-C3 alkyl.
Embodiment 13. The compound of Embodiment 8, or a salt thereof, wherein R4 is phenyl substituted by 1-5 R4a groups, wherein at least one R4a group is —O—(C1-C3 alkyl).
Embodiment 14. The compound of Embodiment 8, or a salt thereof, wherein R4 is phenyl substituted by 1-5 R4a groups, wherein at least one R4a group is —S(O)2(C1-C3 alkyl).
Embodiment 15. The compound of any one of Embodiments 1-7, or a salt thereof, wherein R4 is 5-to-6-membered heteroaryl, wherein the 5-to-6-membered heteroaryl contains at least one nitrogen atom and is optionally substituted by R4a.
Embodiment 16. The compound of Embodiment 15, or a salt thereof, wherein R4 is 5-membered heteroaryl, wherein the 5-membered heteroaryl contains two nitrogen atoms and is optionally substituted by R4a.
Embodiment 17. The compound of Embodiment 15, or a salt thereof, wherein R4 is 6-membered heteroaryl, wherein the 6-membered heteroaryl contains one nitrogen atom and is optionally substituted by R4a.
Embodiment 18. The compound of Embodiment 15, or a salt thereof, wherein R4 is 6-membered heteroaryl, wherein the 6-membered heteroaryl contains two nitrogen atoms and is optionally substituted by R4a.
Embodiment 19. The compound of any one of Embodiments 15-18, or a salt thereof, wherein R4 is substituted by 1-4 R4a groups, wherein at least one R4a group is F or Cl.
Embodiment 20. The compound of any one of Embodiments 15-18, or a salt thereof, wherein R4 is substituted by 1-4 R4a groups, wherein at least one R4a group is CN.
Embodiment 21. The compound of any one of Embodiments 15-18, or a salt thereof, wherein R4 is substituted by 1-4 R4a groups, wherein at least one R4a group is C1-C3 alkyl.
Embodiment 22. The compound of any one of Embodiments 15-18, or a salt thereof, wherein R4 is substituted by 1-4 R4a groups, wherein at least one R4a group is C1-C3 haloalkyl.
Embodiment 23. The compound of any one of Embodiments 15-18, or a salt thereof, wherein R4 is substituted by 1-4 R4a groups, wherein at least one R4a group-is —(C1-C3 alkylene)-O—(C1-C3 alkyl).
Embodiment 24. The compound of any one of Embodiments 15-18, or a salt thereof, wherein R4 is substituted by 1-4 R4a groups, wherein at least one R4a group is cyclopropyl.
Embodiment 25. The compound of any one of Embodiments 15-18, or a salt thereof, wherein R4 is substituted by 1-4 R4a groups, wherein at least one R4a group is —O—(C1-C3 alkyl).
Embodiment 26. The compound of any one of Embodiments 15-18, or a salt thereof, wherein R4 is substituted by 1-4 R4a groups, wherein at least one R4a group is —O—(C1-C3 haloalkyl).
Embodiment 27. The compound of any one of Embodiments 15-18, or a salt thereof, wherein R4 is substituted by 2-4 R4a groups, wherein at least one R4a group is F, and wherein at least one R4a group is Cl.
Embodiment 28. The compound of any one of Embodiments 15-18, or a salt thereof, wherein R4 is substituted by 2-4 R4a groups, wherein at least one R4a group is F, and wherein at least one R4a group is C1-C3 alkyl.
Embodiment 29. The compound of any one of Embodiments 15-18, or a salt thereof, wherein R4 is substituted by 2-4 R4a groups, wherein at least one R4a group is Cl, and wherein at least one R4a group is C1-C3 alkyl.
Embodiment 30. The compound of any one of Embodiments 15-18, or a salt thereof, wherein R4 is substituted by 2-4 R4a groups, wherein at least one R4a group is Cl, and wherein at least one R4a group is —O—(C1-C3 alkyl).
Embodiment 31. The compound of any one of Embodiments 15-18, or a salt thereof, wherein R4 is substituted by 2-4 R4a groups, wherein at least two R4a groups are Cl.
Embodiment 32. The compound of any one of Embodiments 1-7, or a salt thereof, wherein R4 is 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains at least one nitrogen atom and is optionally substituted by one or more groups selected from the group consisting of R4a and oxo.
Embodiment 33. The compound of Embodiment 32, or a salt thereof, wherein R4 is 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains one nitrogen atom and is optionally substituted by one or more groups selected from the group consisting of R4a and oxo.
Embodiment 34. The compound of Embodiment 32, or a salt thereof, wherein R4 is 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains two nitrogen atoms and is optionally substituted by one or more groups selected from the group consisting of R4a and oxo.
Embodiment 35. The compound of any one of Embodiments 32-34, or a salt thereof, wherein R4 is substituted by Cl and oxo.
Embodiment 36. The compound of any one of Embodiments 1-7, or a salt thereof, wherein R4 is selected from the group consisting of:
Embodiment 37. The compound of any one of Embodiments 1-7, or a salt thereof, wherein R4 is selected from the group consisting of:
Embodiment 38. The compound of any one of Embodiments 1-37, or a salt thereof, wherein R1 is 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by R1a.
Embodiment 39. The compound of any one of Embodiments 1-38, or a salt thereof, wherein Q is H.
Embodiment 40. A compound selected from one of Compound Nos. 1-82 in Table 1, or a salt thereof.
Embodiment 41. A pharmaceutical composition comprising a compound of any one of Embodiments 1-40, or a salt thereof, and a pharmaceutically acceptable carrier or excipient.
Embodiment 42. The pharmaceutical composition of Embodiment 41, further comprising a checkpoint inhibitor.
Embodiment 43. The pharmaceutical composition of Embodiment 41, further comprising a checkpoint inhibitor that inhibits one of: PD-1, PD-L1, and CTLA-4.
Embodiment 44. The pharmaceutical composition of Embodiment 41, further comprising at least one of: pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, INCMGA00012, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab.
Embodiment 45. A method of treating a fibrotic disease in an individual in need thereof comprising administering a compound of any one of Embodiments 1-40, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 41.
Embodiment 46. The method of Embodiment 45, wherein the fibrotic disease is pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, kidney fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis.
Embodiment 47. A kit comprising a compound of any one of Embodiments 1-40, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of Embodiments 41-44.
Embodiment 48. The kit of Embodiment 47, further comprising instructions for the treatment of a fibrotic disease.
Embodiment 49. The kit of Embodiment 47, further comprising instructions directing a user to treat cancer in a subject in need thereof, the instructions comprising directing the user to administer to the subject the compound or the pharmaceutically acceptable salt thereof.
Embodiment 50. The kit of Embodiment 47, further comprising:
Embodiment 51. The kit of Embodiment 47, further comprising:
Embodiment 52. The kit of Embodiment 47, further comprising:
Embodiment 53. A method of inhibiting αVβ8 integrin in an individual comprising administering a compound of any one of Embodiments 1-40, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition of any one of Embodiments 41-44.
Embodiment 54. A method of inhibiting one or more of αVβ1, αVβ6, or αVβ8 integrin in an individual in need thereof, comprising administering to the individual a compound of any one of Embodiments 1-40, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of Embodiments 41-44.
Embodiment 55. The method of Embodiment 54, comprising inhibiting in the individual one of:
Embodiment 56. The method of Embodiment 54, comprising administering to the individual the compound of any one of Embodiments 1-40, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 41, the method further comprising administering to the individual a checkpoint inhibitor.
Embodiment 57. The method of Embodiment 56, wherein the checkpoint inhibitor inhibits one of: PD-1, PD-L1, and CTLA-4.
Embodiment 58. The method of Embodiment 56, wherein the checkpoint inhibitor is one of: pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, INCMGA00012, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab.
Embodiment 59. The method of Embodiment 54, wherein the individual is in need of treatment for a disease or condition comprising a solid tumor.
Embodiment 60. The method of Embodiment 54, wherein the individual is in need of treatment for a disease or condition comprising at least one of: melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, Hodgkin's lymphoma, cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, or mesothelioma.
Embodiment 61. The method of Embodiment 54, wherein the individual is in need of treatment for breast cancer.
Embodiment 62. The method of Embodiment 54, wherein the individual is in need of treatment for a disease or condition comprising at least one of: pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, kidney fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis.
Embodiment 63. A method of inhibiting TGFβ activation in a cell comprising administering to the cell a compound of any one of Embodiments 1-40, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of Embodiments 41-44.
Embodiment 64. The method of Embodiment 63, wherein the cell expresses one or more of: αVβ1; αVβ6; and αVβ8.
Embodiment 65. The method of Embodiment 63, wherein the cell expresses one of:
Embodiment 66. The method of Embodiment 63, further comprising administering to the cell a checkpoint inhibitor.
Embodiment 67. The method of Embodiment 66, wherein the checkpoint inhibitor inhibits one of: PD-1, PD-L1, and CTLA-4.
Embodiment 68. The method of Embodiment 66, wherein the checkpoint inhibitor is one of: pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, INCMGA00012, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab.
Embodiment 69. The method of Embodiment 66, wherein the cells are cancer cells associated with a solid tumor.
Embodiment 70. The method of Embodiment 66, wherein the cells are cancer cells associated with at least one of: melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, Hodgkin's lymphoma, cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, or mesothelioma.
Embodiment 71. The method of Embodiment 66, wherein the cells are breast cancer cells.
Embodiment 72. The method of Embodiment 63, wherein the cells are human cells.
Embodiment 73. The method of Embodiment 63, wherein the cells are associated with a fibrotic disease that is at least one of: pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, kidney fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis.
Embodiment 74. Use of a compound of any one of Embodiments 1-40, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of Embodiments 41-44 in the manufacture of a medicament for the treatment of a fibrotic disease.
Embodiment 75. Use of a compound of any one of Embodiments 1-40, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of Embodiments 41-44 in the manufacture of a medicament for the treatment of a disease mediated by cells that express one or more of: αVβ1; αVβ6; and αVβ8.
Embodiment 76. Use of a compound of any one of Embodiments 1-40, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of Embodiments 41-44 in the manufacture of a medicament for the treatment of cancer.
Embodiment 77. Use of:
together in the manufacture of a medicament for the treatment of a disease mediated by cells that express one or more of: αVβ1; αVβ6; and αVβ8.
Embodiment 78. Use of:
together in the manufacture of a medicament for the treatment of cancer.
Embodiment 79. A method of therapy for a subject in need thereof, comprising:
Embodiment 80. The method of Embodiment 79, the administering the therapeutically effective amount of the compound decreasing the at least one value.
Embodiment 81. The method of Embodiment 79, comprising reducing the activity and/or expression of one of:
Embodiment 82. The method of Embodiment 79, wherein the reducing the activity and/or expression is selective compared to at least one other αV-containing integrin in the subject.
Embodiment 83. The method of Embodiment 79, wherein one of:
Embodiment 84. The method of any one of Embodiments 79-83, wherein the at least one tissue in the subject comprises one or more of: lung, liver, skin, heart, kidney, gastrointestinal, gall bladder, and bile duct.
Embodiment 85. The method of any one of Embodiments 79-83, wherein the at least one tissue in the subject comprises one or more of: skin, lung, brain, lymph node, stomach, urethra, kidney, bladder, prostate, liver, pancreas carcinoma, mesothelium, or breast.
Embodiment 86. The method of any one of Embodiments 79-83, wherein the tissue has an elevated pSMAD2/SMAD2 value or an elevated pSMAD3/SMAD3 value compared to the healthy state of the tissue.
Embodiment 87. The method of Embodiment 79, wherein the subject comprises a solid tumor.
Embodiment 88. The method of Embodiment 79, wherein the subject comprises at least one of: melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, Hodgkin's lymphoma, cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, or mesothelioma.
Embodiment 89. The method of Embodiment 79, wherein the subject comprises at least one of: pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, kidney fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, or biliary fibrosis.
Embodiment 90. A method of characterizing anticancer activity of a small molecule inhibitor in a subject, comprising:
Embodiment 91. The method of Embodiment 90, wherein each live cell sample comprises a plurality of cancer cells derived from a tissue of the subject or a hematocyte of the subject.
Embodiment 92. The method of Embodiment 90, wherein the at least one tissue in the subject comprises one or more of: skin, lung, brain, lymph node, stomach, urethra, kidney, bladder, prostate, liver, pancreas, mesothelium, or breast.
Embodiment 93. The method of Embodiment 90, wherein the subject comprises a solid tumor.
Embodiment 94. The method of Embodiment 90, wherein the subject comprises melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, Hodgkin's lymphoma, cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, or mesothelioma.
Embodiment 95. The method of Embodiment 90, wherein the at least one integrin comprises αV.
Embodiment 96. The method of Embodiment 90, wherein the at least one integrin is selected from the group consisting of: αVβ1, αVβ6, and αVβ8.
Embodiment 97. The method of Embodiment 90, wherein the first and second values are pSMAD2/SMAD2 ratios or pSMAD3/SMAD3 ratios.
Embodiment 98. The method of Embodiment 90, the administering the small molecule to the subject comprising administering the compound of any one of Embodiments 1-40 or the pharmaceutical composition of any one of Embodiments 41-44 to the subject.
Embodiment 99. The method of Embodiment 90, further comprising administering a checkpoint inhibitor to the subject, the characterizing the anticancer activity of the small molecule in the subject by comparing the second value to the first value comprising characterizing the anticancer activity of the small molecule together with the checkpoint inhibitor.
Embodiment 100. The method of any one of Embodiments 53-55 or 62 wherein the individual is in need of treatment for biliary atresia.
Embodiment 101. The method of any one of Embodiments 63-65 or 72-73, wherein the cell or cells are associated with the intrahepatic or extrahepatic biliary system.
Embodiment 102. The use of Embodiment 74 or 75, wherein the fibrotic disease or disease is biliary atresia.
Embodiment 103. The method of any one of Embodiments 79-86 or 89, wherein the subject is in need of treatment for biliary atresia.
Embodiment 104. The method of any one of Embodiments 79-86 or 89, wherein the tissue is tissue of the intrahepatic or extrahepatic biliary system.
Embodiment 105. The method of Embodiment 101, wherein the cell or cells express αVβ1 and αVβ8.
Embodiment 106. The method of Embodiment 104, wherein the tissue expresses αVβ1 and αVβ8.
Embodiment 107. The method of any one of Embodiments 53-55, wherein the individual is in need of treatment for ocular fibrosis.
Embodiment 108. The method of any one of Embodiments 53-55 or 107, wherein the individual is in need of treatment for anterior subcapsular cataracts or posterior capsule opacification.
Embodiment 109. The method of any one of Embodiments 63-65 or 72, wherein the cell or cells are associated with the eye.
Embodiment 110. The use of Embodiment 74 or 75, wherein the fibrotic disease or disease is ocular fibrosis.
Embodiment 111. The use of any one of Embodiments 74, 75, or 110, wherein the fibrotic disease or disease is anterior subcapsular cataracts or posterior capsule opacification.
Embodiment 112. The method of any one of Embodiments 79-83, or 86, wherein the tissue is the tissue of the eye.
Embodiment 113. The method of Embodiment 109, wherein the cell or cells express one, two, or three integrins selected from αVβ1, αVβ6, and αVβ8.
Embodiment 114. The method of Embodiment 112, wherein the tissue expresses one, two, or three integrins selected from αVβ1, αVβ6, and αVβ8.
Compounds provided herein may be prepared according to General Schemes, as exemplified by the General Procedures and Examples.
When a specific stereoisomer, or an unspecified stereoisomer, or a mixture of stereoisomers is shown in the following general procedures, it is understood that similar chemical transformations can be performed on other specific stereoisomers, or an unspecified stereoisomer, or mixtures thereof. For example, a hydrolysis reaction of an L-homoserinate ester to a corresponding free acid L-homoserine can also be performed on a D-homoserinate ester to prepare a corresponding free acid D-homoserine, or on a mixture of an L-homoserinate ester and a D-homoserinate ester to prepare a mixture of a corresponding free acid L-homoserine and a corresponding free acid D-homoserine.
Some of the following general procedures use specific compounds to illustrate a general reaction (e.g., deprotection of a compound having a Boc-protected amine to a compound having a deprotected amine using acid). The general reaction can be carried out on other specific compounds having the same functional group (e.g., a different compound having a protected amine where the Boc-protecting group can be removed using acid in the same manner) as long as such other specific compounds do not contain additional functional groups affected by the general reaction (i.e., such other specific compounds do not contain acid-sensitive functional groups), or if the effect of the general reaction on those additional functional groups is desired (e.g., such other specific compounds have another group that is affected by acid, and the effect of the acid on that other group is a desirable reaction).
Where specific reagents or solvents are specified for reactions in the general procedures, the skilled artisan will recognize that other reagents or solvents can be substituted as desired. For example, acetylation is performed in the general examples with acetic anhydride, but an active ester of acetic acid can also be used. As another example, where hydrochloric acid is used to remove a Boc group, trifluoroacetic acid can be used instead. As another example, where HATU is used as a coupling reagent, BOP or PyBOP can be used instead.
Intermediate 1A was prepared according to US20200109141A1, herein incorporated by reference in its entirety.
Methyl N-(2-methyl-2-phenylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserinate: To a solution of methyl 2-amino-4-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy]butanoate (11.4 mg, 35.47 μmol) in MeCN (70.94 μL) was added 2-methyl-2-phenylpropanoic acid (5.8 mg, 35.47 μmol), 1-methylimidazole (14.56 mg, 177.34 μmol, 14.14 μL), and N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate (11.94 mg, 42.56 μmol). The mixture was stirred at rt for 30 min then concentrated in vacuo. The crude residue was purified by normal phase chromatography to give the title compound.
N-(2-methyl-2-phenylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine: To a solution of methyl N-(2-methyl-2-phenylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserinate (16 mg, 34.2 μmol) in 1:1:1 MeOH/THF/H2O (1 mL) was added lithium hydroxide (8.2 mg, 342 μmol). The resulting solution was stirred for 1 h and then concentrated in vacuo. The crude residue was purified by reverse phase prep-HPLC to afford the title compound.
Intermediate 1B was prepared according to US20200109141A1, herein incorporated by reference in its entirety.
Methyl N-(2-methyl-2-phenylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserinate: To a solution of methyl (2S)-2-amino-4-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy]butanoate (45 mg, 114 μmol) in MeCN (70.94 μL) was added 2-methyl-2-phenylpropanoic acid (22.5 mg, 137 μmol), 1-methylimidazole (56.2 mg, 684 μmol, 54.6 μL), and N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate (38.3 mg, 137 μmol). The mixture was stirred at rt for 30 min then concentrated in vacuo. The crude residue was purified by normal phase chromatography to give the title compound.
N-(2-methyl-2-phenylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine: To a solution of methyl N-(2-methyl-2-phenylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserinate (647 mg, 137 μmol) in 1:1:1 MeOH/THF/H2O (1 mL) was added lithium hydroxide (56 mg, 1.4 mmol). The resulting solution was stirred for 1 h and then concentrated in vacuo. The crude residue was purified by reverse phase prep-HPLC to afford the title compound.
Procedures were adapted from Greszler et al. Org. Lett. 2017, 19, 2490-2493, herein incorporated by reference in its entirety.
Methyl 1-(2-methylpyridin-3-yl)cyclopropane-1-carboxylate: To a vial containing Q-Phos (16.53 mg, 23.25 μmol) and Pd(dba)2 (13.37 mg, 23.25 μmol) under nitrogen was added THF (0.73 mL) followed by 3-bromo-2-methyl-pyridine (200 mg, 1.16 mmol, 133.78 μL). The red solution was stirred for 5 min, then bromo-(1-methoxycarbonylcyclopropyl)zinc (0.16 M, 10.90 mL) was added and the solution stirred for 20 min. Upon completion, the mixture was diluted with MTBE and washed with saturate aqueous NH4Cl and brine. The organic layer was dried over sodium sulfate, concentrated, and purified by normal phase chromatography to afford the desired compound.
1-(2-methylpyridin-3-yl)cyclopropane-1-carboxylic acid: To a solution of methyl 1-(2-methyl-3-pyridyl)cyclopropanecarboxylate (230 mg, 1.20 mmol) in water (1 mL), MeOH (1 mL) and THF (1 mL) was added lithium hydroxide (144 mg, 6.01 mmol). The mixture was stirred at RT for 2 h and then purified by reverse phase chromatography to afford the desired product.
1-(6-methoxypyridin-2-yl)cyclopropanecarbonitrile: To a solution of 2-(6-methoxypyridin-2-yl)acetonitrile (1 g, 6.8 mmol) in KOH (10 mL, 75% purity) was added 1-bromo-2-chloro-ethane (1.94 g, 14 mmol, 1.1 mL) and tetrabutylammonium bromide (2.2 g, 6.8 mmol) and the resulting mixture was stirred at 50° C. for 1 h then was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase chromatography to give the title compound.
1-(6-methoxypyridin-2-yl)cyclopropanecarboxylic acid: To a solution of 1-(6-methoxypyridin-2-yl)cyclopropanecarbonitrile (0.8 g, 4.6 mmol) in EtOH (8 mL) was added 10 M aqueous NaOH (9.18 mL) and the resulting mixture was stirred at 100° C. for 16 h and then was diluted with water, acidified to pH=4. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase chromatography to give the title compound.
benzyl 2-(2,3-difluoro-6-methoxyphenyl)-2-methylpropanoate: To an ice-cold solution of benzyl 2-(2,3-difluoro-6-methoxy-phenyl)acetate (400 mg, 1.37 mmol) in DMF (5 mL) was added NaH (164 mg, 4.11 mmol) and the resulting mixture was stirred at 0° C. for 30 min. Methyl iodide (0.51 mL, 8.21 mmol) was added and the mixture was stirred at RT. Upon completion, the reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase chromatography to give the title compound.
2-(2,3-difluoro-6-methoxyphenyl)-2-methylpropanoic acid: To a solution of benzyl 2-(2,3-difluoro-6-methoxyphenyl)-2-methylpropanoate (304 mg, 0.95 mmol) in MeOH (3 mL) was added palladium hydroxide (66 mg, 0.95 mmol). The reaction mixture stirred under a balloon of hydrogen for 12 h and then filtered through celite. The filtrate was concentrated under vacuum and purified by normal phase chromatography to afford the desired compound.
2-(2-chloro-5-fluoropyridin-3-yl)-2-methylpropanenitrile: To a solution of 2,3-dichloro-5-fluoropyridine (2 g, 12.05 mmol) and isobutyronitrile (874.32 mg, 12.65 mmol) in THF (30 mL) was added LiHMDS (1 M, 13.25 mL) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 1 h and then quenched with NH4Cl (100 ml) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by normal phase chromatography to afford the desired compound.
2-(2-chloro-5-fluoropyridin-3-yl)-2-methylpropanal: To a solution of 2-(2-chloro-5-fluoropyridin-3-yl)-2-methylpropanenitrile (900 mg, 4.53 mmol) in toluene (10 mL) was added diisobutylaluminium hydride (1 M in toluene, 6.82 mL) at −78° C. The reaction mixture was stirred at −78° C. for 2 h and then quenched with saturated aqueous solution (8 mL) of Rochelle's salt at 0° C. The mixture was diluted with EtOAc, stirred for 2 h at RT, and then further extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired compound.
2-(2-chloro-5-fluoropyridin-3-yl)-2-methylpropanoic acid: A solution of NaH2PO4 (1.61 g, 13.39 mmol) in H2O (3 mL) was added to 2-(2-chloro-5-fluoropyridin-3-yl)-2-methylpropanal (900 mg, 4.46 mmol in t-BuOH (12 mL) at 20° C. Sodium chlorite (1.21 g, 13.39 mmol) was added in portions and the mixture was stirred overnight. After such time, the mixture was purified by reverse phase chromatography.
methyl 1-(3,5-dichloro-1H-pyrazol-1-yl)cyclopropanecarboxylate: To a solution of 3,5-dichloro-1H-pyrazole (2.00 g, 10.95 mmol) in DMF (20 mL) was added Cs2CO3 (14.27 g, 43.81 mmol) and methyl 2,4-dibromobutanoate (3.13 g, 12.05 mmol). The mixture was stirred at 25° C. for 2 h. The reaction mixture diluted with brine and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography to afford the desired compound.
1-(3,5-dichloro-1H-pyrazol-1-yl)cyclopropanecarboxylic acid: To a solution of methyl 1-(3,5-dichloro-1H-pyrazol-1-yl)cyclopropanecarboxylate (1.4 g, 5.96 mmol) in MeCN (7 mL) and H2O (7 mL) was added LiOH·H2O (625 mg, 14.89 mmol). The mixture was stirred at 20° C. for 1 h and then concentrated under reduced pressure to half the volume. The reaction mixture was adjusted to pH˜6 with 1 M aqueous HCl, and then concentrated under reduced pressure. The crude mixture was purified by reverse phase chromatography to afford the desired compound.
ethyl 2-(6-chloro-2-oxopyridin-1(2H)-yl)acrylate: 6-chloropyridin-2-ol (5 g, 38.6 mmol) and triphenylphosphine (1.52 g, 5.79 mmol) were added to a solution of ethyl propiolate (4.7 mL, 46.3 mmol) in dry DCM (190 mL) at 0° C. The resulting solution was warmed to reach room temperature and stirred overnight. The mixture was concentrated under reduced pressure and purified by normal phase chromatography to afford the desired compound.
ethyl 1-(6-chloro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylate: NaH (79 mg, 60% in mineral oil, 1.98 mmol) was suspended in dry DMSO (8 mL), under an argon atmosphere. Trimethylsulfonium iodide (538 mg, 2.64 mmol) was added to the suspension in three portions and the mixture was vigorously stirred at room temperature for 30 min. Then, a solution of ethyl 2-(6-chloro-2-oxopyridin-1(2H)-yl)acrylate (300 mg, 1.32 mmol) in dry DMSO (4 mL) was added dropwise and the resulting mixture was stirred for 2 h. Water was slowly added and the aqueous layer was extracted with EtOAc. The combined organics were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by normal phase chromatography to afford the desired compound.
1-(6-chloro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylic acid: A solution of LiOH monohydrate (1.52 g, 36.2 mmol) in water (36 mL) was added to a solution of ethyl 1-(6-chloro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylate (1.75 g, 7.24 mmol) in iPrOH (109 mL). The mixture was refluxed for 1 h, then neutralized to pH=7-8 with the addition of 2 N HCl and concentrated under reduce pressure. The crude mixture was purified by reverse phase chromatography to afford the desired compound.
methyl 1-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)cyclopropanecarboxylate: To a solution of methyl 1-(2-(benzyloxy)-4-chloropyridin-3-yl)cyclopropanecarboxylate (1.7 g, 5.35 mmol) in MeOH (50 mL) was added HCl (12 M, 4.46 mL). The reaction mixture was stirred at 70° C. for 3 h and then concentrated under reduced pressure to afford the desired compound.
methyl 1-(3-chloro-6-oxo-1,6-dihydropyridin-2-yl)cyclopropanecarboxylate: To a solution of methyl 1-(3-chloro-6-methoxypyridin-2-yl)cyclopropanecarboxylate (1.9 g, 7.86 mmol) in MeCN (20 mL) was added trimethylsilyl chloride (2.99 mL, 23.59 mmol) and sodium iodide (3.54 g, 23.59 mmol). The mixture was stirred at 30° C. for 12 h, then quenched with H2O at 0° C. and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by normal phase chromatography to afford the desired compound.
1-(4-chloro-1H-pyrazol-5-yl)cyclopropanecarboxylic acid: To a solution of 1-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)cyclopropanecarboxylic acid (1.26 g, 3.98 mmol) in DCM (10 mL) was added TFA (2 mL, 27.01 mmol). The mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure. The crude mixture was purified by column chromatography to afford the desired compound.
methyl 1-(5-chloro-3-methyl-1H-pyrazol-1-yl)cyclopropanecarboxylate: To a solution of methyl 1-(5-chloro-3-iodo-1H-pyrazol-1-yl)cyclopropanecarboxylate (900 mg, 2.76 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (269.72 μL, 1.93 mmol) in dioxane (10 mL) was added Cs2CO3 (1.80 g, 5.51 mmol) and Pd(PPh3)4 (31.85 mg, 27.56 μmol). The reaction mixture was stirred at 100° C. for 24 h. The reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by reverse phase chromatography to afford the desired compound.
methyl 2-(4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)acetate: A flame-dried 100 mL round-bottom flask was charged with formamidine hydrochloride (2.25 g, 27.9 mmol, 1.05 eq.) and anhydrous methanol (26.6 mL, 1 M). A separate flame-dried 100 mL round-bottom flask equipped with stir bar was charged with dimethyl acetylsuccinate (5.00 g, 26.6 mmol, 1 eq.) and sodium methoxide (25% in MeOH, 11.5 mL, 53.1 mmol, 2 eq.). The mixture of formamidine hydrochloride and methanol was added to the mixture of dimethyl acetylsuccinate and sodium methoxide, then heated at reflux overnight. After overnight reaction, LC-MS indicated a crude mixture of the desired methyl ester and the corresponding carboxylic acid. The cooled reaction mixture was acidified to pH ˜6-7 by dropwise addition of HCl in dioxane (4 M, ˜6 mL). The mixture was cooled on ice, followed by dropwise addition of thionyl chloride (3.92 mL, 53.1 mmol, 2 eq.). The resulting mixture was heated at reflux for 90 min, after which LC-MS indicated complete conversion of remaining carboxylic acid to the desired methyl ester product. The reaction was concentrated under reduced pressure. The desired product was isolated by dissolving the residue in minimal amount of methanol, followed by MTBE and hexanes. The resulting precipitate was isolated by filtration, and dried under high vacuum overnight to yield the desired product as a a greyish red solid. 1H NMR (CH3OH-d4, 300 MHz): δH 9.14 (1H, s), 3.74 (3H, s), 3.69 (2H, s), 2.45 (3H, s).
methyl 2-(4-chloro-6-methylpyrimidin-5-yl)acetate: A flame-dried flask equipped with a stir bar was charged with methyl 2-(4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)acetate (3.61 g, 19.8 mmol, 1 eq.), phosphorus(V) oxychloride (2.22 mL, 23.8 mmol, 1.2 eq), and anhydrous acetonitrile (21.8 mL, 0.91 M). The resulting mixture was cooled on ice, and N,N-diisopropylethylamine (5.23 mL, 29.7 mmol, 1.5 eq.) was added dropwise. After complete addition, the reaction mixture was heated to 80° C. for 3 h. The mixture was cooled to room temperature, then poured directly into saturated aqueous sodium bicarbonate (˜100 mL) and stirred vigorously for 10 min. The mixture was extracted three times with DCM. The combined organic phases were dried with sodium sulfate, decanted, and concentrated onto silica gel. Purification by normal phase chromatography afforded the desired product. 1H NMR (CHCl3-d, 300 MHz): δH 8.80 (1H, s), 3.88 (2H, s), 3.77 (3H, s), 2.59 (3H, s).
methyl 2-(4-chloro-6-methylpyrimidin-5-yl)acrylate-d2: An oven dried flask equipped with a stir bar was charged with methyl 2-(4-chloro-6-methylpyrimidin-5-yl)acetate (1.63 g, 8.14 mmol), anhydrous toluene (11.2 mL), K2CO3 (3.38 g, 24.4 mmol), paraformaldehyde-d2 (522 mg, 16.3 mmol) and tetrabutylammonium iodide (3.07 g, 8.14 mmol) in that order. The flask was equipped with an oven dried reflux condenser and heated at 55° C. for 20 h. The reaction mixture was diluted with water (70 mL) and EtOAc (30 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3×20 ml). The combined organic layers were washed with water, brine, dried over Na2SO4, and filtered under reduced pressure. The filtrate was concentrated in vacuo. The crude material was purified on silica gel afford the desired product. LCMS (ES, m/z) [M+H]+: 215.1; 1H NMR (CHCl3-d, 300 MHz): δH 8.82 (1H, s), 3.80 (3H, s), 2.46 (3H, s).
1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carboxylate-2,2,3,3-d4: Trimethyl-d9-sulfoxonium iodide (1.93 g, 8.42 mmol) was added portion wise over 1 h to a stirred mixture of sodium hydride (303 mg, 7.58 mmol) in DMSO-d6 (18.1 mL) under argon. This was stirred for 45 min and a solution of methyl 2-(4-chloro-6-methylpyrimidin-5-yl)acrylate-d2 (0.904 g, 4.21 mmol) in DMSO-d6 (12.8 mL) was then added dropwise. The flask containing methyl 2-(4-chloro-6-methylpyrimidin-5-yl)acrylate-d2 (0.904 g, 4.21 mmol) was subsequently rinsed with DMSO-d6 (3×5 mL). The solution was stirred for 1 h. The reaction was quenched with saturated aq. NH4Cl and diluted with water and EtOAc. The organic layer was separated, and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water (2×), brine, then dried over Na2SO4, filtered under reduced pressure. The filtrate was concentrated in vacuo. The crude material was purified by normal phase chromatography to afford the desired compound as a mixture of d4, d5, d6 and d7. LCMS (ES, m/z) [M+H]+ (d4): 231.1. 1H NMR (CHCl3-d, 300 MHz): δH 8.74 (1H, s), 3.65 (3H, s), 2.52-2.57 (2H, m). Multiplet at 2.52 to 2.57 is an overlap of a CH3 singlet, CDH2 triplet and a CHD2 quintet.
1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carboxylic-2,2,3,3-d4: A solution of lithium hydroxide monohydrate (947 mg, 22.6 mmol) in water (22.3 mL) was added to a solution of methyl 1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carboxylate-2,2,3,3-d4 (1.04 g, 4.51 mmol) in isopropanol (22.3 mL) at rt. The reaction was stirred for 16 h. The mixture was acidified by slowly adding HCl 2 N (pH=7-8). The reaction was then concentrated under reduced pressure to remove most of the organic solvent. This was diluted with water and washed with EtOAc. The aqueous layer was then acidified with HCl 2N to pH 2 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered under reduced pressure, and concentrated in vacuo. The resulting white solid was stirred briefly in pentane (10 mL) and the supernatant removed using a pipette. This was repeated 3 more times and the suspension concentrated to dryness. The solid was placed under vacuum to afford the desired product as a white solid. LCMS (ES, m/z) [M+H]+: 217.1. 1H NMR (CHCl3-d, 300 MHz): δH 8.77 (1H, s), 2.58-2.62 (3H, m).
The following Synthetic Examples are set forth for Compounds 1-104 below to enable this disclosure to be more fully understood. It should be understood that these Synthetic Examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner.
The chemical reactions in the Synthetic Examples described can be readily adapted to prepare a number of other compounds, and alternative methods for preparing the compounds are deemed to be within the scope of this disclosure. For example, the synthesis of non-exemplified compounds of formula (A) or formula (I) 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 formula (A) or formula (I). In the following Examples, certain compounds are noted as racemic, as separated isomers, or with unassigned absolute stereochemistry at some stereocenters, and the like. For some compounds, further separation of isomers and/or assignment of absolute stereochemistry was performed. The assigned stereochemistry of such compounds is shown in the structures as depicted in Table 1.
N-(2-methyl-2-phenylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine. Prepared according to Scheme A using General Procedure A with 2-methyl-2-phenylpropanoic acid and General Procedure B. LCMS theoretical m/z=453.3. [M+H]+, found 454.3.
N-(2-methyl-2-phenylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 2-methyl-2-phenylpropanoic acid and General Procedure D. LCMS theoretical m/z=453.3. [M+H]+, found 454.1.
N—((S)-2-phenylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with (S)-2-phenylpropanoic acid and General Procedure D. LCMS theoretical m/z=439.2. [M+H]+, found 440.1.
N-(2-(2,3-difluoro-6-methoxyphenyl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 2-(2,3-difluoro-6-methoxyphenyl)-2-methylpropanoic acid and General Procedure D, and Scheme E using General Procedure I with benzyl 2-(2,3-difluoro-6-methoxy-phenyl)acetate and General Procedure J. LCMS theoretical m/z=439.2. [M+H]+, found 440.1.
N-(2-(2-(difluoromethoxy)-6-fluorophenyl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 2-[2-(difluoromethoxy)-6-fluoro-phenyl]-2-methyl-propanoic acid and General Procedure D, and Scheme E using General Procedure I with benzyl 2-[2-(difluoromethoxy)-6-fluoro-phenyl]acetate and General Procedure J. LCMS theoretical m/z=519.3. [M+H]+, found 520.3.
N-(1-(2-chlorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(2-chlorophenyl)cyclopropane-1-carboxylic acid and General Procedure D. LCMS theoretical m/z=485.2. [M+H]+, found 486.2.
N-(1-(2,6-dichlorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(2,6-dichlorophenyl)cyclopropane-1-carboxylic acid and General Procedure D. LCMS theoretical m/z=519.2. [M+H]+, found 520.2.
N-(2-(2-chlorophenyl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 2-(2-chlorophenyl)-2-methylpropanoic acid and General Procedure D. LCMS theoretical m/z=487.2. [M+H]+, found 488.3.
N-(1-(2-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(2-fluorophenyl)cyclopropane-1-carboxylic acid and General Procedure D. LCMS theoretical m/z=469.2. [M+H]+, found 470.3.
N-(1-phenylcyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-phenylcyclopropane-1-carboxylic acid and General Procedure D. LCMS theoretical m/z=451.3. [M+H]+, found 452.3.
N-(1-(pyrazin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(pyrazin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D. LCMS theoretical m/z=453.2. [M+H]+, found 454.3.
N-(1-(pyrimidin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(pyrimidin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D. LCMS theoretical m/z=453.2. [M+H]+, found 454.3.
N-(1-(2-methylpyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(2-methylpyridin-3-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 3-bromo-2-methylpyridine and General Procedure F. LCMS theoretical m/z=466.3. [M+H]+, found 467.3.
N-(1-(3-chloro-5-fluoropyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-chloro-5-fluoropyridin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-3-chloro-5-fluoropyridine and General Procedure F. LCMS theoretical m/z=504.2. [M+H]+, found 505.2.
N-(1-(3-chloropyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-chloropyridin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-3-chloropyridine and General Procedure F. LCMS theoretical m/z=486.2. [M+H]+, found 487.2.
N-(1-(4-methylpyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-methylpyridin-3-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 3-bromo-4-methylpyridine and General Procedure F. LCMS theoretical m/z=466.3. [M+H]+, found 467.3.
O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(o-tolyl)cyclopropane-1-carbonyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(o-tolyl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 1-bromo-2-methylbenzene and General Procedure F. LCMS theoretical m/z=465.3. [M+H]+, found 466.3.
N-(1-(6-methoxypyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(6-methoxypyridin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme D using General Procedure G with 2-(6-methoxypyridin-2-yl)acetonitrile and General Procedure H. LCMS theoretical m/z=482.3. [M+H]+, found 483.3.
N-(1-(4-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-methylpyrimidin-5-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 5-bromo-4-methylpyrimidine and General Procedure F. LCMS theoretical m/z=467.3. [M+H]+, found 468.3.
N-(1-(6-methylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(6-methylpyridin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-6-methylpyridine and General Procedure F. LCMS theoretical m/z=466.3. [M+H]+, found 467.3.
N-(1-(2,5-difluoropyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(2,5-difluoropyridin-3-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme F using General Procedure K with 3-chloro-2,5-difluoropyridine and cyclopropanecarbonitrile, General Procedure L, and General Procedure M. LCMS theoretical m/z=488.2. [M+H]+, found 489.2.
N-(1-(pyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(pyrimidin-5-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 5-bromopyrimidine and General Procedure F. LCMS theoretical m/z=453.2. [M+H]+, found 454.3.
N-(2-(2-chloro-5-fluoropyridin-3-yl)-2-methylpropanoyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 2-(2-chloro-5-fluoropyridin-3-yl)-2-methylpropanoic acid and General Procedure D, and Scheme F using General Procedure K with 2,3-dichloro-5-fluoropyridine and isobutyronitrile, General Procedure L, and General Procedure M. LCMS theoretical m/z=506.2. [M+H]+, found 507.3.
N-(1-(3,5-dichloropyridin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3,5-dichloropyridin-4-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme F using General Procedure K with 3,5-dichloroisonicotinonitrile and cyclopropanecarbonitrile, General Procedure L, and General Procedure M. LCMS theoretical m/z=520.2. [M+H]+, found 521.3.
O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(3-(trifluoromethyl)pyridin-2-yl)cyclopropane-1-carbonyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-(trifluoromethyl)pyridin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme D using General Procedure G with 2-(3-(trifluoromethyl)pyridin-2-yl)acetonitrile and General Procedure H. LCMS theoretical m/z=520.2. [M+H]+, found 521.3.
N-(1-(3-chloro-6-methoxypyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-chloro-6-methoxypyridin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme D using General Procedure G with 2-(3-chloro-6-methoxypyridin-2-yl)acetonitrile and General Procedure H. LCMS theoretical m/z=516.2. [M+H]+, found 517.3.
N-(1-(5-cyanopyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(5-cyanopyridin-3-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 5-bromonicotinonitrile and General Procedure F. LCMS theoretical m/z=477.2. [M+H]+, found 478.3.
N-(1-(5-fluoro-2-methylpyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(5-fluoro-2-methylpyridin-3-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 3-bromo-5-fluoro-2-methylpyridine and General Procedure F. LCMS theoretical m/z=484.3. [M+H]+, found 485.3.
N-(1-(3-methylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-methylpyridin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-3-methylpyridine and General Procedure F. LCMS theoretical m/z=466.3. [M+H]+, found 467.3.
N-(1-(3-methoxypyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-methoxypyridin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-3-methoxypyridine and General Procedure F. LCMS theoretical m/z=482.3. [M+H]+, found 482.3.
N-(1-(quinazolin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(quinazolin-4-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 4-bromoquinazoline and General Procedure F. LCMS theoretical m/z=503.3. [M+H]+, found 504.3.
N-(1-(3-cyanopyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-cyanopyridin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromonicotinonitrile and General Procedure F. LCMS theoretical m/z=477.3. [M+H]+, found 478.3.
N-(1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme D using General Procedure G with 2-(5-fluoro-2-methoxypyridin-3-yl)acetonitrile and General Procedure H. LCMS theoretical m/z=500.3. [M+H]+, found 501.3.
N-(1-(3-chloro-5-methoxypyridin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-chloro-5-methoxypyridin-4-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme D using General Procedure G with 2-(3-chloro-5-methoxypyridin-4-yl)acetonitrile and General Procedure H. LCMS theoretical m/z=516.2. [M+H]+, found 517.3.
N-(1-(2-methoxypyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(2-methoxypyridin-3-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 3-bromo-2-methoxypyridine and General Procedure F. LCMS theoretical m/z=482.3. [M+H]+, found 483.3.
N-(1-(3-chloro-5-methylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-chloro-5-methylpyridin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-3-chloro-5-methylpyridine and General Procedure F. LCMS theoretical m/z=500.2. [M+H]+, found 501.3.
N-(1-(2-cyano-6-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(2-cyano-6-fluorophenyl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-3-fluorobenzonitrile and General Procedure F. LCMS theoretical m/z=494.2. [M+H]+, found 495.3.
N-(1-(3-(difluoromethoxy)pyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-(difluoromethoxy)pyridin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-3-(difluoromethoxy)pyridine and General Procedure F. LCMS theoretical m/z=518.2. [M+H]+, found 519.3.
N-(1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 5-bromo-4-chloro-6-methylpyrimidine and General Procedure F. LCMS theoretical m/z=501.2. [M+H]+, found 502.3.
N-(1-(3-(difluoromethyl)pyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-(difluoromethyl)pyridin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-3-(difluoromethyl)pyridine and General Procedure F. LCMS theoretical m/z=502.2. [M+H]+, found 503.3.
N-(1-(4,6-dimethylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4,6-dimethylpyrimidin-5-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 5-bromo-4,6-dimethylpyrimidine and General Procedure F. LCMS theoretical m/z=481.3. [M+H]+, found 482.3.
N-(1-(3-methylpyrazin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-methylpyrazin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-3-methylpyrazine and General Procedure F. LCMS theoretical m/z=467.3. [M+H]+, found 468.3.
N-(1-(2-cyano-4-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(2-cyano-4-fluorophenyl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-5-fluorobenzonitrile and General Procedure F. LCMS theoretical m/z=494.2. [M+H]+, found 495.2.
N-(1-(4-chloro-2-methoxypyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-chloro-2-methoxypyridin-3-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme D using General Procedure G with 2-(4-chloro-2-methoxypyridin-3-yl)acetonitrile and General Procedure H. LCMS theoretical m/z=516.2. [M+H]+, found 517.2.
N-(1-(2-cyanophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(2-cyanophenyl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromobenzonitrile and General Procedure F. LCMS theoretical m/z=476.2. [M+H]+, found 477.2.
N-(1-(2-(methylsulfonyl)phenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(2-(methylsulfonyl)phenyl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 1-bromo-2-(methylsulfonyl)benzene and General Procedure F. LCMS theoretical m/z=529.2. [M+H]+, found 530.2.
N-(1-(3-fluoro-5-methylpyridin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-fluoro-5-methylpyridin-4-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme D using General Procedure G with 2-(3-fluoro-5-methylpyridin-4-yl)acetonitrile and General Procedure H. LCMS theoretical m/z=484.3. [M+H]+, found 485.3.
O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(4-(trifluoromethyl)pyrimidin-5-yl)cyclopropane-1-carbonyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-(trifluoromethyl)pyrimidin-5-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 5-bromo-4-(trifluoromethyl)pyrimidine and General Procedure F. LCMS theoretical m/z=521.2. [M+H]+, found 522.2.
N-(1-(5-chloropyrimidin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(5-chloropyrimidin-4-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 4-bromo-5-chloropyrimidine and General Procedure F. LCMS theoretical m/z=487.2. [M+H]+, found 488.2.
N-(1-(3-methoxypyrazin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-methoxypyrazin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-3-methoxypyrazine and General Procedure F. LCMS theoretical m/z=483.3. [M+H]+, found 484.3.
N-(1-(4-chloro-1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-chloro-1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme D using General Procedure G with 2-(4-chloro-1-methyl-1H-pyrazol-5-yl)acetonitrile and General Procedure H. LCMS theoretical m/z=489.2. [M+H]+, found 490.2.
N-(1-(3-(fluoromethyl)pyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-(fluoromethyl)pyridin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-3-(fluoromethyl)pyridine and General Procedure F. LCMS theoretical m/z=484.3. [M+H]+, found 485.3.
N-(1-(3-(methoxymethyl)pyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-(methoxymethyl)pyridin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-3-(methoxymethyl)pyridine and General Procedure F. LCMS theoretical m/z=496.3. [M+H]+, found 497.3.
N-(1-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 5-iodo-1-methyl-1H-pyrazole and General Procedure F. LCMS theoretical m/z=455.3. [M+H]+, found 456.3.
N-(1-(3-chloro-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-chloro-1H-pyrazol-1-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme G using General Procedure N with 5-chloro-1H-pyrazole and General Procedure O. LCMS theoretical m/z=475.2. [M+H]+, found 476.2.
N-(1-(2-cyano-6-methoxyphenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(2-cyano-6-methoxyphenyl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-3-methoxybenzonitrile and General Procedure F. LCMS theoretical m/z=506.3. [M+H]+, found 507.3.
N-(1-(2-(difluoromethyl)pyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(2-(difluoromethyl)pyridin-3-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 3-bromo-2-(difluoromethyl)pyridine and General Procedure F. LCMS theoretical m/z=502.2. [M+H]+, found 503.2.
N-(1-(3-cyclopropylpyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-cyclopropylpyridin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-3-cyclopropylpyridine and General Procedure F. LCMS theoretical m/z=492.3. [M+H]+, found 493.3.
N-(1-(4-(difluoromethyl)pyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-(difluoromethyl)pyrimidin-5-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 5-bromo-4-(difluoromethyl)pyrimidine and General Procedure F. LCMS theoretical m/z=503.2. [M+H]+, found 504.3.
N-(1-(4-chloro-2,6-dimethylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-chloro-2,6-dimethylpyrimidin-5-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 5-bromo-4-chloro-2,6-dimethylpyrimidine and General Procedure F. LCMS theoretical m/z=515.2. [M+H]+, found 516.3.
N-(1-(4-methoxy-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-methoxy-6-methylpyrimidin-5-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 5-bromo-4-methoxy-6-methylpyrimidine and General Procedure F. LCMS theoretical m/z=497.3. [M+H]+, found 498.3.
N-(1-(4-chloro-6-methoxypyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-chloro-6-methoxypyrimidin-5-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 5-bromo-4-chloro-6-methoxypyrimidine and General Procedure F. LCMS theoretical m/z=517.2. [M+H]+, found 518.3.
N-(1-(4-chloro-6-oxo-1,6-dihydropyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-chloro-6-oxo-1,6-dihydropyrimidin-5-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme I using General Procedure E with 5-bromo-4-chloro-6-methoxypyrimidine, General Procedure T, and General Procedure O. LCMS theoretical m/z=503.2. [M+H]+, found 504.2.
N-(1-(5-(difluoromethyl)-1H-imidazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(5-(difluoromethyl)-1H-imidazol-1-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme G using General Procedure N with 5-(difluoromethyl)-1H-imidazole and General Procedure O. LCMS theoretical m/z=491.2. [M+H]+, found 492.3.
N-(1-(6-chloro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(6-chloro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme H using General Procedure P with 6-chloropyridin-2-ol, General Procedure Q and General Procedure R. LCMS theoretical m/z=502.2. [M+H]+, found 503.2.
N-(1-(3-chloro-6-oxo-1,6-dihydropyridin-2-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-chloro-6-oxo-1,6-dihydropyridin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme I using General Procedure E with 2-bromo-3-chloro-6-methoxypyridine, General Procedure T, and General Procedure O. LCMS theoretical m/z=502.2. [M+H]+, found 503.3.
O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(3-(trifluoromethyl)pyrazin-2-yl)cyclopropane-1-carbonyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3-(trifluoromethyl)pyrazin-2-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-3-(trifluoromethyl)pyrazine and General Procedure F. LCMS theoretical m/z=521.2. [M+H]+, found 522.3.
N-(1-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme I using General Procedure E with 2-(benzyloxy)-3-bromo-4-chloropyridine, General Procedure S, and General Procedure O. LCMS theoretical m/z=502.2. [M+H]+, found 503.3.
N-(1-(3,5-dichloro-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(3,5-dichloro-1H-pyrazol-1-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme G using General Procedure N with 3,5-dichloro-1H-pyrazole and General Procedure O. LCMS theoretical m/z=509.2. [M+H]+, found 510.3.
O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(2-(trifluoromethyl)-1H-imidazol-1-yl)cyclopropane-1-carbonyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(2-(trifluoromethyl)-1H-imidazol-1-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme G using General Procedure N with 2-(trifluoromethyl)-1H-imidazole and General Procedure O. LCMS theoretical m/z=509.2. [M+H]+, found 510.3.
N-(1-(4-chloro-1H-pyrazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-chloro-1H-pyrazol-5-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme J using General Procedure G with 2-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)acetonitrile, General Procedure H, and General Procedure U. LCMS theoretical m/z=475.2. [M+H]+, found 476.3.
N-(1-(5-chloro-3-methyl-1H-pyrazol-1-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(5-chloro-3-methyl-1H-pyrazol-1-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme L using General Procedure N with 5-chloro-3-iodo-1H-pyrazole, General Procedure V, and General Procedure O. LCMS theoretical m/z=489.2. [M+H]+, found 490.2
N-(1-(5-chloro-2-methylpyrimidin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(5-chloro-2-methylpyrimidin-4-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 4-bromo-5-chloro-2-methylpyrimidine and General Procedure F. LCMS theoretical m/z=489.2. [M+H]+, found 490.2.
N-(1-(5-chloro-1H-pyrazol-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(5-chloro-1H-pyrazol-4-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme J using General Procedure G with 2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)acetonitrile, General Procedure H, and General Procedure U. LCMS theoretical m/z=475.2. [M+H]+, found 476.3.
N-(1-(4-cyano-1-methyl-1H-pyrazol-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-cyano-1-methyl-1H-pyrazol-3-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 3-bromo-1-methyl-1H-pyrazole-4-carbonitrile and General Procedure F. LCMS theoretical m/z=480.3. [M+H]+, found 481.3.
N-(1-(5-chloro-3-oxo-2,3-dihydropyridazin-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(5-chloro-3-oxo-2,3-dihydropyridazin-4-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme K using General Procedure E with 4-bromo-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one, General Procedure U, and General Procedure F. LCMS theoretical m/z=503.2. [M+H]+, found 504.2.
N-(1-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme D using General Procedure G with 2-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl)acetonitrile and General Procedure H. LCMS theoretical m/z=523.2. [M+H]+, found 524.2.
N-(1-(4-cyano-1H-pyrazol-3-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-cyano-1H-pyrazol-3-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 3-bromo-1H-pyrazole-4-carbonitrile and General Procedure F. LCMS theoretical m/z=466.2. [M+H]+, found 467.2.
N-(1-(4-chloro-1H-imidazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-chloro-1H-imidazol-5-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme K using General Procedure E with 4,5-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole, General Procedure U, and General Procedure F. LCMS theoretical m/z=475.2. [M+H]+, found 476.2.
N-(1-(4-chloro-1-methyl-1H-imidazol-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-chloro-1-methyl-1H-imidazol-5-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 4,5-dichloro-1-methyl-1H-imidazole and General Procedure F. LCMS theoretical m/z=489.2. [M+H]+, found 490.2.
N-(2-phenylacetyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 2-phenylacetic acid and General Procedure D. LCMS theoretical m/z=425.2. [M+H]+, found 426.3.
N-(1-(5-chlorothiazol-4-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(5-chlorothiazol-4-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 4-bromo-5-chlorothiazole and General Procedure F. LCMS theoretical m/z=492.2. [M+H]+, found 493.1.
N-(3-(difluoromethyl)tetrahydrofuran-3-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 3-(difluoromethyl)tetrahydrofuran-3-carboxylic acid and General Procedure D. LCMS theoretical m/z=455.2. [M+H]+, found 456.4.
O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(trifluoromethyl)cyclohexane-1-carbonyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(trifluoromethyl)cyclohexane-1-carboxylic acid and General Procedure D. LCMS theoretical m/z=485.5. [M+H]+, found 486.5.
N-(4-(4-fluorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 4-(4-fluorophenyl)tetrahydro-2H-pyran-4-carboxylic acid and General Procedure D. LCMS theoretical m/z=513.3. [M+H]+, found 514.3.
O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(4-(3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-carbonyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 4-(3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-carboxylic acid and General Procedure D. LCMS theoretical m/z=563.3. [M+H]+, found 564.4.
N-(4-(3-methoxyphenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 4-(3-methoxyphenyl)tetrahydro-2H-pyran-4-carboxylic acid and General Procedure D. LCMS theoretical m/z=525.3. [M+H]+, found 526.4.
N-(4-(3-fluorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 4-(3-fluorophenyl)tetrahydro-2H-pyran-4-carboxylic acid and General Procedure D. LCMS theoretical m/z=513.3. [M+H]+, found 514.3.
N-(4-(3-chlorophenyl)tetrahydro-2H-pyran-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 4-(3-chlorophenyl)tetrahydro-2H-pyran-4-carboxylic acid and General Procedure D. LCMS theoretical m/z=529.2. [M+H]+, found 530.3.
N-(1-(2-oxoquinolin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(2-oxoquinolin-1(2H)-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme H using General Procedure P with quinolin-2(1H)-one, General Procedure Q and General Procedure R. LCMS theoretical m/z=518.3. [M+H]+, found 519.3.
N-(1-(6-cyclopropyl-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(6-cyclopropyl-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme H using General Procedure P with 6-cyclopropylpyridin-2(1H)-one, General Procedure Q and General Procedure R. LCMS theoretical m/z=508.3. [M+H]+, found 509.3.
N-(1-(6-methoxy-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(6-methoxy-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme H using General Procedure P with 6-methoxypyridin-2(1H)-one, General Procedure Q and General Procedure R. LCMS theoretical m/z=498.3. [M+H]+, found 499.3.
N-(1-(6-fluoro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(6-fluoro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme H using General Procedure P with 6-fluoropyridin-2(1H)-one, General Procedure Q and General Procedure R. LCMS theoretical m/z=486.2. [M+H]+, found 487.2.
N-(1-(6-bromo-2-oxopyridin-1(2H)-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(6-bromo-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme H using General Procedure P with 6-bromopyridin-2(1H)-one, General Procedure Q and General Procedure R. LCMS theoretical m/z=546.2. [M+H]+, found 547.2.
N-(1-(2-carbamoyl-6-fluorophenyl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(2-carbamoyl-6-fluorophenyl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 2-bromo-3-fluorobenzamide and General Procedure F. LCMS theoretical m/z=512.2. [M+H]+, found 513.3.
O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(1-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)piperidine-4-carbonyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)piperidine-4-carboxylic acid and General Procedure D. LCMS theoretical m/z=568.3. [M+H]+, found 569.5.
N-(1-phenyl-1H-pyrazole-3-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-phenyl-1H-pyrazole-3-carboxylic acid and General Procedure D. LCMS theoretical m/z=477.2. [M+H]+, found 478.3.
N-(1-phenyl-1H-pyrazole-4-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-phenyl-1H-pyrazole-4-carboxylic acid and General Procedure D. LCMS theoretical m/z=477.2. [M+H]+, found 478.3.
N-(1-phenyl-1H-pyrazole-5-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-phenyl-1H-pyrazole-5-carboxylic acid and General Procedure D. LCMS theoretical m/z=477.2. [M+H]+, found 478.3.
O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-N-(4-(trifluoromethyl)tetrahydro-2H-pyran-4-carbonyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 4-(trifluoromethyl)tetrahydro-2H-pyran-4-carboxylic acid and General Procedure D. LCMS theoretical m/z=487.2. [M+H]+, found 488.2.
N-(1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)homoserine. Prepared according to Scheme A using General Procedure A with 1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carboxylic acid and General Procedure B, and Scheme C using General Procedure E with 5-bromo-4-chloro-6-methylpyrimidine and General Procedure F. LCMS theoretical m/z=501.2. [M+H]+, found 502.3.
N-(1-(4-hydroxy-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carboxylic acid and General Procedure D, and Scheme C using General Procedure E with 5-bromo-4-chloro-6-methylpyrimidine and General Procedure F. LCMS theoretical m/z=483.3. [M+H]+, found 484.3.
methyl N-(1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserinate. Prepared according to Scheme B using General Procedure C with 1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carboxylic acid, and Scheme C using General Procedure E with 5-bromo-4-chloro-6-methylpyrimidine and General Procedure F. LCMS theoretical m/z=515.2. [M+H]+, found 516.3.
N-(1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carbonyl-2,2,3,3-d4)-O-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)-L-homoserine. Prepared according to Scheme B using General Procedure C with 1-(4-chloro-6-methylpyrimidin-5-yl)cyclopropane-1-carboxylic-2,2,3,3-d4 acid (prepared according to Scheme M) and General Procedure D. LCMS theoretical m/z=505.2. [M+H]+, found 506.5.
The following Biological Examples are set forth to enable this disclosure to be more fully understood. It should be understood that these Biological Examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner.
The biochemical potency of the disclosed compounds was determined using the AlphaScreen® (Perkin Elmer, Waltham, MA) proximity-based assay as described previously (Ullman E F et al., Luminescent oxygen channeling immunoassay: Measurement of particle binding kinetics by chemiluminescence. Proc. Natl. Acad. Sci. USA, Vol. 91, pp. 5426-5430, June 1994, herein incorporated by reference in its entirety). To gauge the potency of inhibitors of binding to each of human integrins αVβ1, αVβ6, and αVβ8, inhibitor compounds were independently incubated with one of αVβ1, αVβ6, or αVβ8, together with TGF-b1 LAP and biotinylated anti-LAP antibody plus acceptor and donor beads, following the manufacture's recommendations. The donor beads were coated with streptavidin. The acceptor beads had a nitrilotriacetic acid Ni chelator, for binding to a 6×His Tag on human integrin αVβ1, αVβ6, or αVβ8, respectively. All incubations occurred at room temperatures in 50 mM Tris-HCl, pH 7.5, 0.1% BSA supplemented with 1 mM each CaCl2 and MgCl2.
The order of reagent addition was as follows:
1. αVβ1, αVβ6, or αVβ8 integrin, test inhibitor compound, LAP, biotinylated anti-LAP antibody and acceptor beads were all added together.
2. After 2 hours, donor beads were added. After another 30 minute incubation, samples were then read.
Integrin binding was evaluated by exciting donor beads at 680 nm, and measuring the fluorescent signal produced, between 520-620 nm, using a Biotek Instruments (Winooski, VT, USA) SynergyNeo2 multimode plate reader. Compound potency was assessed by determining inhibitor concentrations required to reduce fluorescent light output by 50%. Data analysis for IC50 determinations was carried out by nonlinear four parameter logistic regression analysis using Dotmatics ELN Software (Core Informatics Inc., Branford, Ct). IC50 values for the compounds in the Examples are provided below in Table B-1 in ranges: below 50 nM; from above 50 nM to 250 nM; from above 250 nM to 500 nM; and above 500 nM. Comp #in the Table and Examples below refers to the compound of the corresponding Example number as described in the Synthetic Examples.
Compound 39 increases IFNγ Signature & Reduces TGFβ Gene Signatures.
Putative Circulating Biomarkers of Response to Compound 39.
Putative Circulating Biomarkers of Response to Compound 39+PD-1.
Individual subjects of various treatment Groups are assessed at 0, 3, and 7 days post-treatment.
The change in tumor volume for individual mice subjects and the median change in tumor volume among all subjects in each Group is assessed and shown.
pSMAD3/SMAD3 ratios for the corresponding Groups, a marker of TGFβ signaling, are assessed and shown.
Scores for interferon γ signaling for various treatment Groups as range and median are assessed and shown.
Scores for Granzyme B concentration for various treatment Groups as range and median are assessed and shown.
Scores for T cell activation for various treatment Groups as range and median are assessed and shown.
Genetically modified rotavirus strains will be injected into BALB/c pups to induce fibrosis, and the mice are monitored and studied, in procedures similar to those described in Mohanty et al., Hepatology 71:1316 (2020), herein incorporated by reference in its entirety. Starting at 2 weeks post injection of virus (21 days of life) pups will be administered one of the following: a testing compound, a known integrin inhibitor, a positive control, or vehicle as a negative control, by either subcutaneous or intraperitoneal injections. Mice will be tracked for symptoms of fibrosis with tissue/blood harvested at 4 weeks after viral injection (35 days of life). Samples will be analyzed by histology, serum chemistry, and gene expression. Sample type and respective aliquots and location will be taken as shown in Table B-2.
The effect of cataract surgery on lens cells is modelled in living mice by surgical removal of lens fiber cells as previously described (Mamuya et al., J Cell Mol Med 2014; 18:656-670; Desai et al., Differentiation 2010; 79: 111-9.29; Call et al., Exp Eye Res. 2004; 78:297-9; each of which is herein incorporated by reference in its entirety). Briefly, 3-month-old mice are anesthetized, a central corneal incision is made and the entire lens fiber cell mass is removed by a sharp forceps, leaving behind an intact lens capsule. The corneal incision is closed with a single 10-0 nylon corneal suture and normal saline is injected to inflate the eye back to its normal shape.
Mice are then randomized into a vehicle control group, three positive control groups, and two test groups per compound to be tested, with at least n=3 mice in each group.
Vehicle (e.g., phosphate buffered saline) is administered to the mice in the control group on day 0 post surgery.
Mice in the three positive control groups are administered a dose of an antibody on day 0 post surgery. The antibody is of one of αVβ1, αVβ6, and αVβ8, respectively, in vehicle, in an amount to deliver the antibody at an effective concentration in the lens capsule equivalent to the IC90 concentration of the antibody for that integrin.
Mice in the two test groups are administered a dose in vehicle of each compound of the Examples to be tested on day 0 post surgery. Any compound of the examples can be tested, e.g., the compound of Example 1. The dose is in an amount to deliver an effective concentration of the compound in the lens capsule equivalent to the IC50 or IC90 concentration for the compound's most potent integrin binding among αVβ1, αVβ6, and αVβ8. For example, when testing a compound such as that of Example 1, the mice are administered doses of the compound of Example 1 in vehicle to deliver a concentration in the lens capsule equivalent to the IC50 or IC90 concentration of αVβ6, the integrin to which the compound of Example 1 has the most potent binding. This is repeated for each desired compound of the Examples.
Mice are killed at a time after surgery effective to provide observable fibrosis in untreated mice, e.g., 5 days. The eyes are isolated, sliced under cryogenic conditions, and subjected to quantitative confocal immunofluorescence analysis of fibrotic marker expression performed. The efficacy of each tested compound of the Examples is compared to the vehicle control and the positive αVβ1, αVβ6, and αVβ8 antibody controls.
Each group included 6 mice (3 male and 3 female). A first group was associated with a 0-hour post-cataract surgery (PCS) control. A second group received the control and the buffer and Compound A (3 mg/mL, 30 mg/mL, and 300 mg/mL) for a time period of 6 days via osmotic pump. Osmotic pump implantation occurred on Day 1, cataract surgery occurred on Day 2 and samples were harvested on Day 6. A third group received, via tail vain injection, the control and Compound C for a time period of 5 days PCS. The samples were then harvested. A fourth group received, via tail injection, a control, Compound D, for a time period of 5 days PCS. The samples were then harvested.
The therapeutic impact of Compound 39 of the examples in combination with anti PD-1 was studied for several xenograft mouse models, as shown in Table B-3. For each model, four dosing regimens were studied, using a group size of 10 mice per dosing regimen per model, and a total of 40 mice per model.
Animals were prepared for injection using standard approved anesthesia. Mice were shaved and tumor cells as indicated in Table B-3 were subcutaneously implanted in a 100 μl cell suspension that was subcutaneously injected into the front/rear flank of each mouse (as indicated in Table B-3).
Palpable tumors (ranging from 50-100 mm3) were randomized into groups and treated with indicated compounds according to schema outlined in Table B-4. Compound 39 was administered in a solution containing 10% v/v ethanol, 70% w/v propylene glycol, and 20% v/v PBS and administered to mice via osmotic Alzet-2002 minipumps at a dose of 144 mg/kg body weight over the duration of 28 days (at a rate of 0.5 μL/h; charge replaced on Day 14). The mAbs, anti-mPD-1 and anti-αvβ8, were each administered in PBS by intraperitoneal injection at a dose of 10 mg/kg body weight twice a week (for 2 weeks). There was no dosing holiday. Dietary supplements were uniform for all animals in the same group. The mPD-1 (CD279) Ab was purchased from Bio X Cell Inc. (West Lebanon, NH). The anti-αvβ8 antibody was synthesized and manufactured by GenScript Biotech Corporation (Piscataway, NJ). The rat immunoglobulin G2a (IgG2A) antibody was purchased by Crown Bio Inc.
Animals were monitored weekly for changes in tumor volume. Tumors were measured at least once a week using calipers. Tumor volume was calculated using the equation: (longest diameter*shortest diameter2)/2. Additionally, body weight of mice and any change in behavior/appearance were monitored twice a week for any signs of discomfort/toxicity.
The study was terminated four weeks after the first dose or when the tumor sizes reached greater than 3000 mm3, whichever was first. Mice were euthanized and tumors were collected. Half of the tumor was snap frozen in liquid nitrogen, and the other half was fixed in formalin.
Tumor tissues (50 to 80 mg) were homogenized using metal beads in pre-chilled RINO screw cap tubes, using lysis matrix (MP Lysing Matrix S [⅛″], 2 mL Tube MP Biomedical Cat #116925100) on MP Fast Prep 24 instrument. Tumor RNA extraction from the tumor homogenate used the Ambion Purelink, RNA kit (Cat #12183018A) according to the manufacturers' protocol. A total of 100 ng RNA was used for the Nanostring analysis of the immuno-oncology and fibrosis panel, and 300 ng RNA was used for the analysis of the integrin panel. RNA was hybridized to gene expression Plexset according to the manufacturers' protocol. Hybridized reactions were read on nCounter MAX (Nanostring), and data were analyzed using nCounter software.
Formalin (10%) fixed tissues were sent to Histowiz for paraffin embedding and sectioning. Tissue sections were stained for hematoxylin and eosin and immunostained for CD8, CD4, and FoxP3, which are specific membrane markers for cytotoxic, helper, and regulator T cells, respectively, and immunostained for granzyme B (a marker for activated cytotoxic T cells and program death-ligand 1 [PD-L1]). Table B-5 lists the catalog numbers of the antibodies used in the immunohistochemical (IHC) studies. Quantification of staining was done using the HALO software package (Indica Labs, Albaquerque, NM).
Compound 39+anti-mPD-1 reduces EMT6 tumor growth. In mice with EMT6 tumors, the mean tumor volumes of mice treated with Compound 39+anti-mPD-1 were significantly lower (mean tumor volume 1017.96±293.26 mm3) than the tumor volumes of mice treated with vehicle (mean tumor volume 2145.39±287.13 mm3) or vehicle+anti-PD1 (mean tumor volume 2162.10±117.49 mm3) (
Compound 39+anti-mPD-1 treatment results in increased CD8+ T cells recruitment in EMT6 tumors. In mice with EMT6 tumors, those treated with Compound 39+anti-mPD-1 showed higher infiltration and numbers of CD8+ T cells within the tumors (mean CD8+ T cell count 414.86±163.27/mm2 of tumor tissue) than those treated with vehicle (mean CD8+ T cell count 145.79±77.70/mm2 of tumor tissue) or vehicle+anti-mPD-1 (mean CD8+ T cell count 151.82±59.27/mm2 of tumor tissue) (
Compound 39+anti-mPD-1 treatment has similar anti-tumor effect as treatment with anti-αVβ8+anti-mPD-1 treatment in EMT6 tumors. The efficacy of Compound 39 in tumor growth reduction was compared with that of a mAb targeting αVβ8 (anti-αVβ8). Like the Compound 39+anti-mPD-1 treatment, anti-αVβ8+anti-mPD-1 treatment of mice with EMT6 tumors reduced growth and volumes of tumors comparted with EMT6 tumors from mice treated with vehicle or vehicle+anti-mPD-1 treatment (
Compound 39+anti-mPD-1 treatment was similar in reducing the tumor growth compared to anti-αVβ8 treatment+anti-mPD-1. As observed by comparison of immune-staining shown in
There was greater expression of PD-L1 in EMT6 tumors cells of mice treated with Compound 39+anti-mPD-1 (Mean cell count 397.18±202.09/mm2 of tumor tissue) compared to EMT6 tumors cells of mice treated with vehicle+anti-mPD-1 (mean cell count 190.12±158.94/mm2 of tumor tissue) (
To investigate whether the Compound 39+anti-mPD-1 treatment causes activation of immunosuppressive mechanisms via increased infiltration of regulatory T cells (Treg) cells, EMT6 tumor sections were immunostained for FoxP3, a marker of Treg cells. This analysis did not show any significant difference between the mean cell counts of FoxP3+ cells between mice treated with Compound 39+anti-mPD-1 (mean cell count 122.92±75.88/mm2 of tumor tissue) and mice treated with vehicle+anti-mPD-1 (mean cell count 86.02±49.62/mm2 of tumor tissue) (
αVβ8 and αVβ1 inhibition reduces fibrosis and TGFβ regulated genes more than αVβ8 alone in EMT6 model.
Integrin αVβ1 is expressed in multiple solid tumors and drives the adhesion of cancer-associated fibroblasts (CAFs) to latent TGFβ. In human tumor tissues and in CAFs, αVβ1 protein expression was evaluated via immunohistochemistry (IHC) and custom electroluminescence assay, respectively. CAF adhesion to the TGFβ latency-associated peptide (LAP) was quantified in the presence or absence of Compound 39 in vitro by high-content microscopy imaging. The activity of Compound 39 in combination with anti-mPD-1 on fibrotic markers was evaluated in the EMT6 tumor model in vivo by gene expression analysis using the Nanostring® nCounter analysis system. Compound 39-treated human breast tumor tissue was analyzed for fibrotic marker α-smooth muscle actin (αSMA) using immunofluorescence.
Inhibition of αVβ1 prevents cell adhesion to LAP.
Compound 39 decreases fibroblast activation marker αSMA.
Compound 39 reduces fibrotic markers in EMT6 tumors.
Compound 39 in combination with anti-mPD-1 reduces the expression of fibrotic markers and tissue fibrosis in the tumor microenvironment compared to anti-αVβ8 in combination with anti-mPD-1.
Compound 39 in combination with anti-mPD-1 inhibits tumor growth compared to anti-mPD-1 and increases the survival of animals. αVβ1 protein expression was detected by IHC analysis in both tumor regions and stromal-rich areas of human tumors. Compared to normal human lung fibroblasts, αVβ1 protein was elevated in primary human CAFs, with pancreatic stellate CAFs showing the highest protein expression (2.8-fold). Inhibition of αVβ1 with Compound 39 blocked the binding of CAFs to LAP; the integrin RGD binding region of latent TGFβ, in a dose-dependent manner, demonstrating an αVβ1-specific interaction with latent TGFβ. EMT6 tumors treated with Compound 39 and anti-mPD-1 showed a significant reduction in fibrotic markers compared to anti-αVβ8 and anti-mPD-1. Human breast tumor tissues treated with Compound 39 ex vivo showed reduced expression of the fibroblast activation marker αSMA (2.9-fold) compared to vehicle-treated tissues, indicating a decreased TGFβ activity within the stromal regions of the TME. The TGFβ activating integrin αVβ1 is expressed in multiple human tumors, is present on primary human CAFs, mediates CAF interaction with latent TGFβ, and has a functional role in mediating fibrotic gene expression in murine and human tumors.
Compound 39 treatment is effective in reducing tumor growth of EMT6, Pan02 and CT26 tumors. To ascertain whether the effects of the Compound 39 observed in EMT6 tumors (breast cancer model), applies to other tumor types, mice bearing Pan02 tumors (murine pancreatic cancer model) and CT26 (murine colon cancer model) were treated with (i) vehicle+rat IgG2A (control group), (ii) vehicle+anti-mPD-1, (iii) Compound 39+anti-mPD-1, and (iv) anti-αVβ8 antibody+anti-mPD-1 (as described in Methods).
As in the EMT6 model, Pan02 tumors in mice treated with Compound 39+anti-mPD-1 or anti-αVβ8+anti-mPD-1 showed markedly lower growth rates compared to Pan02 tumors in mice of the other treatment groups.
CT26 tumors in mice treated with Compound 39+anti-mPD-1 showed markedly lower growth rates compared to CT26 tumors in mice of the Rat IgG2A+vehicle treated group (
αVβ1 IHC Detects Expression Across Human Cancers.
Compound 39+anti-mPD-1 treatment does not impair tumor growth of A20, RM-1, and B16F10 tumors. RM-1 (murine prostate cancer model), A20 (murine lymphoma model) and B16F10 (murine melanoma model) treated with Compound 39+anti-mPD-1 did not show a significant growth impairment compared to corresponding Rat IgG2A+vehicle treated groups. There were no significant differences in CD8+ cell infiltration in these tumors (
Compound 39 increases IFNγ Signature & Reduces TGFβ Gene Signatures.
In models of three separate mouse tumor types (breast, pancreas, and colon), Compound 39+anti-mPD-1 was significantly more effective than vehicle+anti-mPD-1 in reducing tumor growth. With this treatment, there was increased infiltration of cytotoxic T cells (marked by the expression of CD8) and granzyme B+ cells (mainly secreted by activated cytotoxic T cells). Additionally, there was a significant increase in anti-tumor cytokines, such as IFNγ, CXCL9, CXCL10, and CCL4, as well as MHC class II molecules, such as h2-Ab1 and H2DMa as tested in EMT6 model. The Compound 39+anti-mPD-1 treatment evokes a greater anti-tumor immunological response by blocking immunosuppressive processes.
TGF-β promotes stromal cell reprogramming, immunosuppression, and fibrinogenesis in cancers, including pancreatic ductal adenocarcinoma (PDA). See A. T. Krishnamurty, et al. (2022) Nature 611(7934):148 and G. Biffi, et al. (2019) Cancer Discovery 9(2):282, each of which are incorporated herein by reference in their entirety. Integrins αVβ8 and αVβ1 are important activators of TGF-β signaling. Selective integrin blockade is therapeutic approach to address TGF-β-mediated immunotherapy and chemotherapy resistance and improve anti-tumor response across cancer models. See E. Dodagatta-Marri, et al. (2021) Cell Reports 36(1):109309 and N. Takasaka, et al. (2018) JCI Insight 3(20):e122591, each of which are incorporated herein by reference in their entirety.
The preclinical efficacy of Compound 39 of the examples was determined in genetically-defined (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC), and Pan02) and genomically diverse patient-derived PDA xenograft models. Clinically relevant combinations with standard of care (SoC) chemotherapy and anti-programmed death receptor-1 antibody (anti mPD-1) were tested by monitoring tumor growth, metastasis, and animal survival. Mechanistic assessment of alterations in the tumor microenvironment (TME) was performed using transcriptomic, immunohistochemical, and immunofluorescence approaches.
Single cell analysis of KPC pancreatic tumors revealed restricted expression of integrin αVβ8 (ITGB8) within the T-reg and NK cell subsets, while components of TGF-β signaling were more widely represented across cancer and stromal cell subsets. Dual targeting of αVβ8 and αVβ1 with Compound 39 in this setting effectively reduced tumor growth (45% reduction in tumor weight compared with Vehicle; P=0.003) and significantly delayed disease progression in vivo (median OS Vehicle 29.5 days vs Compound 39 45 days, P<0.0001). Combining Compound 39 with anti mPD-1 antibody further improved survival in this aggressive model of metastatic PDA (median OS anti mPD-1 33 days vs Compound 39+anti mPD-1 51 days, 22% CR; P<0.0001).
In a second syngeneic model of PDA (Pan02), Compound 39 in combination with immune checkpoint blockade (ICB) significantly reduced tumor growth TGF-β signaling, and fibrosis, while increasing CD8+lymphocyte infiltration.
Compound 39 in combination with ICB significantly reduces tumor growth and metastases, while increasing CD8+ lymphocyte infiltration. Compound 39 combined with ICB significantly increases major histocompatibility complex (MHC) and type-I interferon (IFN) gene expression.
Utilizing patient-derived models of metastatic PDA revealed that Compound 39 significantly blocked tumor growth, improved the response to SoC chemotherapy Gemcitabine/Abraxane, and reduced the number and size of lung metastases.
These data demonstrate that Compound 39 significantly enhances ICB or SoC chemotherapy response in advanced PDA models and provide scientific rationale for future combination studies testing Compound 39 in pancreatic cancer.
Inhibition of transforming growth factor-β (TGF-β) activity is an attractive strategy to augment the response of human tumors to immune checkpoint blockade (ICB). It has been demonstrated that dual inhibition of integrins αvβ8 and αvβ1, two cell-surface proteins that activate latent TGF-β, significantly improves response to ICB in multiple pre-clinical tumor models. Integrin αvβ8 is known to be expressed by tumor infiltrating lymphocytes (TILs) along with some tumor cell types and has previously been associated with poor patient outcomes. However, integrin αvβ1, thought to be primarily expressed by mesenchymal cells and previously demonstrated to drive TGF-β activity in several fibrotic diseases, has not been well characterized in solid tumors. Here, αvβ1 protein expression in diverse human tumor tissues is evaluated; and the role of integrin αvβ1 in primary human cancer associated fibroblasts (CAFs) and tumor tissues is investigated using Compound 39 (a dual inhibitor of αvβ8/αvβ1), or a small molecule selective inhibitor of αvβ1.
αvβ1 protein expression was evaluated in human tumor tissues via immunohistochemistry. αvβ1 protein levels in primary human CAFs isolated from pancreatic carcinoma, lung adenocarcinoma, and lung squamous cell carcinoma were quantified via custom electrochemiluminescence assay. CAF adhesion to latency associated peptide (LAP), the integrin-binding region of latent TGF-β, was quantified in the presence or absence of Compound 39 of the examples and a small molecule selective inhibitor of αvβ1 by high-content imaging in vitro. Anti-fibrotic activity of Compound 39 on ex vivo cultured human breast tumor tissue slices was assessed via immunofluorescence of fibrotic markers α smooth muscle actin (αSMA) and fibroblast activating protein (FAP).
Human cancer-associated fibroblasts (CAFs) Express Integrin αvβ1 by MSD.
αvβ1 protein expression was confirmed in both tumor cell and CAF-rich areas of several human cancer types including breast and pancreatic tumors. Expression of αvβ1 protein by primary human CAFs was confirmed in vitro. Inhibition of αvβ1 with either Compound 39 or a small molecule selective inhibitor of αvβ1 was also shown to significantly block in vitro binding of primary human CAFs to LAP, demonstrating an αvβ1-specific interaction with latent TGF-β. Furthermore, human breast tumor tissues treated with Compound 39 ex vivo showed reduced expression of fibrotic markers αSMA and FAP, indicating a reduced TGF-β activity within the stromal regions of the tumor microenvironment.
Here it is demonstrated that the TGF-β activating integrin αvβ1 is expressed by multiple human cancer types, is present on primary human CAFs, and mediates CAF interaction with latent TGF-β.
Inhibition of transforming growth factor-β (TGF-β) activity is an attractive strategy to augment the response to immune checkpoint blockade (ICB) therapies for the treatment of human cancers. Integrins αvβ8 and αvβ1 activate TGF-β in a disease and tissue-specific manner. Thus, unlike systemic inhibition of TGF-β, inhibition of αvβ8/αvβ1 offers an innocuous approach to enhance ICB efficacy. Integrin αvβ8, upregulated on tumor cells and expressed on tumor infiltrating lymphocytes (TILs), is associated with poor cancer patient survival. Integrin αvβ1 is expressed on cancer associated fibroblasts (CAFs), but its role in cancer is not understood. The pro-inflammatory, anti-fibrotic activity, and anti-tumor efficacy of Compound 39 alone, or in combination with ICB, is evaluated using murine and human tumor models.
Inhibition of αvβ1 and TGF-β mediated by Compound 39 of the examples was monitored via cell adhesion assays and transcriptomic analyses. αvβ1 protein expression was evaluated on human tumor tissues via immunohistochemistry using an indigenously developed anti-αvβ1 antibody. Efficacy of Compound 39 monotherapy and in combination with ICB was evaluated in syngeneic mouse models bearing EMT6 and Pan02 tumors. Animal survival, tumor growth, transcriptomic analyses, tissue fibrosis, and TILs were monitored along with circulating lymphocytes and cytokines. Tissue and circulating biomarkers of response to Compound 39 were identified. Human breast and melanoma tumor tissues were cultured ex vivo and Compound 39 activity was assessed by measuring CD8+ cytotoxic T cells and tumor apoptosis.
αvβ1 protein expression was detected on tumor cells and CAFs in several tumor types. Compound 39 prevented the binding of latency associated peptide (LAP) to αvβ1—an essential step of αvβ1-mediated TGF-β activation. Compound 39 alone, and in combination with ICB significantly reduced TGF-β signaling, tumor growth, and significantly increased CD8+ TILs and pro-inflammatory cytokines in pre-clinical models. The changes in CD8+ T cells and cytokines (e.g. CXCL9) were also detected in blood. Compared to treatment with an αvβ8-specific antibody, the Compound 39 significantly reduced fibrosis within the tumor micro-environment (TME) attributable to an added inhibition of integrin αvβ1-mediated TGF-β activation. Human breast and melanoma tumor tissues treated with Compound 39 showed a significant increase in cytotoxic CD8+T cells and a reduction in fibrotic markers.
Compound 39 has distinct activities on tumor-immune and stromal compartments within the TME. These activities synergize to promote immune activation and reduce the fibrosis leading to augmented ICB efficacy.
Analyses of transforming growth factor-β (TGF-β) expression in tumors treated with immune checkpoint inhibitors (ICIs) suggest that increased expression of TGF-β in the tumor microenvironment may play a role in poor response to ICIs. Compound 39 is an orally bioavailable small molecule that inhibits integrin αVβ8 and αVβ1 binding to the latency-associated peptide of TGF-β, prevents its activation, and enhances the anti-tumor activity of ICIs including CD8+ T-cell infiltration in preclinical models.
A Phase 1a, first-in-human, dose-escalation, consecutive-cohort, open-label study is designed to evaluate the safety, tolerability and pharmacokinetics of Compound 39 of the examples as monotherapy and in combination with pembrolizumab in patients with advanced or metastatic solid tumors progressing on treatment with pembrolizumab. Eligible subjects will be ≥18 years, have received at least 3 doses (200 mg Q3W) of pembrolizumab, have evidence of disease progression at least 3 months after initiation of pembrolizumab, have no other available effective treatment options, have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and have adequate bone marrow and organ function. The ECOG performance scale is used to assess how a subjects disease is progressing, to assess how the disease affects the daily living abilities of the subject, and to determine an appropriate treatment and prognosis for the subject. Compound 39 will be administered as a lead-in monotherapy for 14 days, followed by Compound 39 in combination with pembrolizumab Q3W every three weeks, starting on Day 15. The five dose levels will be as follows:
Dose-escalation will be determined by a Bayesian optimal interval (BOIN) dose escalation design with accelerated titration (n=1) permitted for dose levels 1 and 2 (
Table B-6 is associated with
1b
aWhen none of the actions (escalate, de-escalate, or eliminate) are triggered, the current dose will be maintained and the cohort will be expanded to treat additional subjects.
bIn a dose level with accelerated titration, if one DLT is observed in the first subject, the cohort will be expanded with two additional subjects.
c“N/A” refers to “not applicable.”
d“DLT” refers to “dose-limiting toxicity.”
A minimum of 3 participants are accrued to dose levels 3 to 5. Following the dose-escalation cohorts, dose-expansion cohorts using a Simon's 2-stage design are planned.
The primary endpoint is safety and tolerability following administration of escalating doses of Compound 39 as the monotherapy for 14 days, followed by Compound 39 in combination with pembrolizumab starting on Day 15 for 21 days. The subjects will be regularly monitored for treatment-emergent adverse events (AEs) and serious AEs. The number of subjects with DLTs (e.g., treatment-emergent AEs within the first 35 days of dosing) will be summarized by Compound 39 dose cohort for the DLT population and for the number of subjects with the DLTs leading to treatment discontinuation. An additional safety follow-up visit for evaluation of any latent serious AEs will be conducted at 16 weeks after completion of dosing with Compound 39 and pembrolizumab.
The secondary endpoint includes the pharmacokinetics of Compound 39 given as a monotherapy and in combination with pembrolizumab.
The exploratory endpoints include the following:
This first-in-human trial will evaluate the safety and tolerability of Compound 39, administered first as monotherapy to re-sensitize participants' tumors to pembrolizumab, and subsequently in combination with pembrolizumab. Enrolled patients have demonstrated primary or acquired resistance to pembrolizumab and therefore serve as their own control for assessing anti-tumor activity and pharmacodynamic effects. This trial design allows for the efficient conduct of dose escalation trials involving ICI-sensitizing drugs in patients with resistance to ICIs.
Table B-7 depicts the KPC model details associated with Example B11. Table B-8 depicts the KPC study groups and dosing regimen, which included a twenty-two-day timepoint (6-9 subjects in each group) and up to 80 days survival (8-9 subjects in each group).
Animals were prepared for injection using standard approved anesthesia. Mice were shaved and tumor cells 500 KPC cells were orthotopically implanted (in pancreas) in a 100 μL cell suspension.
Tumor cells were allowed to form pancreatic tumors for one week. Mice were randomized into groups and treated with indicated compounds and dose regimens according to the schema outlined in Table B-7.
Compound 39 was administered in a solution containing 10% v/v ethanol, 70% w/v propylene glycol, and 20% v/v PBS and administered to mice via oral gavage at a dose of 300 mg/kg body weight over the duration of 22 days (for timepoint study) or 80 days (survival study). The mAbs, anti-mPD-1 and anti-αVβ8, were each administered in PBS by intraperitoneal injection at a dose of 10 mg/kg body weight twice a week (for 2 weeks). The mPD-1 (CD279) Ab was purchased from Bio X Cell Inc. (West Lebanon, NH). The anti-αVβ8 antibody ADWA11 was synthesized and manufactured by GenScript Biotech Corporation (Piscataway, NJ). The rat immunoglobulin G2a (IgG2A) antibody was purchased by Crown Bio Inc.
Since these were orthotopic tumors, tumor volume measurement was not possible. Tumor weights were determined at the end of the study. Additionally, body weight of mice and any change in behavior/appearance were monitored twice a week for any signs of discomfort/toxicity.
The study was terminated either at 22 days after the first dose, or at 80 days for the survival study. Mice were euthanized and tumors were collected. Half of the tumor was snap frozen in liquid nitrogen and the other half was fixed in formalin.
Formalin (10%) fixed tissues were sent to Histowiz (a clinical research organization providing complete histology services) for paraffin embedding and sectioning. Using standard protocols optimized by Histowiz, tissue sections were stained for hematoxylin and eosin and immunostained for CD8, CD4, Cleaved caspase-3, and FoxP3, which are specific membrane markers for cytotoxic, helper, and regulator T cells, respectively. Additionally, tissues were stained with Pico Sirius Red (PSR) and second harmonic imaging (SHG) analysis was performed to evaluate stromal collagen density.
Compound 39 Alone and in Combination with Anti PD-1 Significantly Reduced KPC Tumor Weight
Compound 39 in Combination with Anti PD-1 Significantly Increased CD8+ T Cell Infiltration in KPC Tumors
Paraffin-fixed KPC tumor slices were stained for CD8 antigen to identify cytotoxic T cells.
As shown in
Compound 39 in Combination with Anti PD-1 Increased CD4+ T Cell Infiltration in KPC Tumors
Paraffin-fixed KPC tumor slices were stained for CD4 antigen to identify helper T cells.
Paraffin-fixed KPC tumor slices were stained with Pico Sirius Red (PSR) and were evaluated for changes in stromal collagen content (indicative of fibrosis) using SHG imaging. Specifically,
Compound 39 in Combination with Anti PD-1 Significantly Increased Survival of KPC Tumor Bearing Mice.
To assess if Compound 39 treatment increased the survival of the KPC tumor bearing mice, the KPC tumor bearing mice were treated with Compound 39 or ADWA-11 alone and in combination with anti PD-1 for 80 days according to the schematic diagram of the treatment regimen depicted in
Compound 39 treatment significantly increased the survival of animals compared to vehicle treated animals (median survival 45 days compared to 29.5 days in the vehicle treated animals), and compared to ADWA11 treated animals (median survival 34 days in ADWA11 treated animals compared to 45 days in the Compound 39 treated animals). Compound 39+anti PD-1 treatment further increased the survival as compared to anti PD-1 treatment (median survival 51 days in the Compound 39+anti PD-1 arm as compared to 33 days in the anti PD-1 arm) or compared to the ADWA-11+anti PD-1 arm (median survival of 41.5 days in the ADWA11+anti PD-1 arm compared to 51 days in the Compound 39+anti PD-1 arm). Two out of nine mice responded completely (22% complete response) with the Compound 39+anti PD-1 treatment.
Table B-9 depicts the study design to determine the efficacy of selective αvβ1/αvβ8 SMI in the orthotopic ECM-high PDX models of PDAC. Table B-10 depicts the study design for the TKCC-10 PDX model.
TKCC-10 PDX bearing mice were treated with dose regimen according to the schematic in Table B-9 and
Compound 39 significantly reduced the tumor weight of the TKCC-10 PDX bearing mice (mean tumor weight 0.798±0.17 g in the Compound 39 treated animals compared to 1.152±0.23 g in the vehicle treated animals) compared to the vehicle treated arm (see
Compound 39 Alone and in Combination with G/A Reduced the Lung Metastases in the TKCC-10 PDX Model.
Treatment of TKCC-10 PDX bearing ice with Compound 39 alone reduced the number of lung metastases as compared to the vehicle (see
Compound 39 in Combination with Gemcitabine/Abraxane (G/A) Significantly Reduces Tumor Growth and Metastases in a PDX-10 Orthotopic Model
Utilizing subject-derived models of metastatic PDA showed that Compound 39 significantly blocked tumor growth and improved the response to the standard of care (SOC) chemotherapy G/A. Significantly less mice had lung metastasis when treated with Compound 39 in combination with G/A. However, this effect was not observed with ADWA-11. ADWA-11 in combination with G/A decreased tumor weight, but not number and size of lung metastases (
Assessment of Compound 39 Alone and in Combination with G/A to Reduce Tumor Weight in TKCC-05 Tumor Bearing Mice.
Table B-11 depicts the study design for the TKCC-05 model.
Compound 39 Alone and in Combination with G/A Significantly Reduced the Tumor Weight in the TKCC-05 Tumor Bearing Mice
TKCC-05 cells were inoculated in the pancreas of MSG mice and were allowed to grow into tumors for 1 week. The mice were then treated according to schema outlined in Table B-10, and
Treatment of TKCC-05 tumor bearing mice with Compound 39 significantly reduced the tumor weight of the TKCC-05 tumors (mean tumor weight 0.23±0.08 g in the Compound 39 treated group, and 0.228±0.06 g in the Compound 39 group as compared to 0.464±0.09 in the vehicle treated animals) (see
Compound 39 in Combination with G/A Reduces Tumor Growth and Metastases In Vivo
Assessment of Compound 39 Alone and in Combination with Folfirinox (FNX) to Reduce Tumor Weight in TKCC-08 Tumor Bearing Mice
Table B-12 depicts the study design for the TKCC-08 model.
Compound 39 Alone and in Combination with FNX Significantly Reduced the Tumor Weight in the FNX-Resistant TKCC-08 PDX Model of PDAC
FNX is a standard of care chemotherapy regimen for pancreatic ductal adenocarcinoma. However, the clinical response to FNX remains bleak. To assess if Compound 39 augmented the therapeutic benefit of FNX, Compound 39 was tested alone and in combination with FNX in the TKCC-08 model, which is made FNX-resistant by continuous exposure to the FNX.
In the syngeneic KPC model of PDAC, Compound 39 had single agent efficacy and Compound 39+anti PD-1 significantly reduced the tumor weights, compared to the vehicle control. Compound 39 alone and in combination with anti PD-1 also significantly increased the survival of KPC tumor bearing mice. Similarly, in three different PDX models of PDAC in Example B12, Compound 39 had single agent efficacy, and it augmented the response to G/A and FNX. Compound 39+G/A treatment significantly reduced the metastasis of TKCC-10 cells to lung. As such, in some embodiments described herein, Compound 39 is combined with immune checkpoint blockade therapy, as well as with standard of care chemotherapy.
Assessment of Compound 39 in Combination with Folfirinox (FNX) to Reduce Tumor Volume and Weight in an FNX Resistance Model
Compound 39 in combination with FNX treatment delayed disease progression and reduced tumor growth by 66% compared with vehicle (p=0.003) in vivo in a RNF43 mutant PDA model of FNX resistance.
This application refers to various published patent applications, journal articles, and other publications, each of which is incorporated herein by reference.
The foregoing has been described of certain non-limiting embodiments of the present disclosure. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.
This application claims the benefit of U.S. Provisional Patent Appl. No. 63/435,496 filed Dec. 27, 2022, of U.S. Provisional Patent Appl. No. 63/585,565 filed Sep. 26, 2023, and of U.S. Provisional Patent Appl. No. 63/593,454 filed Oct. 26, 2023. The contents of those applications are hereby incorporated by reference herein in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63593454 | Oct 2023 | US | |
| 63585565 | Sep 2023 | US | |
| 63435496 | Dec 2022 | US |
