Amino acid compounds and methods of use

Abstract

The present invention relates to compounds of formula (A) and compounds of formula (I): or salts thereof, wherein R 1 、R 2 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、q and p are as described herein. The compounds of formula (A), the compounds of formula (I), and their pharmaceutical compositions are αvβ6 integrin inhibitors, which can be used for the treatment of fibrosis, such as idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP).

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 639,988, filed Mar. 7, 2018, and U.S. Provisional Patent Application No. 62 / 690,933, filed Jun. 27, 2018. The disclosures of these applications are hereby incorporated herein by reference in their entireties. Background of the Invention

[0003] Fibrosis is a pathological feature of many diseases and is caused by a malfunction of the body's natural ability to repair damaged tissues. If left untreated, fibrosis can lead to scarring of vital organs, causing irreversible damage and ultimately organ failure.

[0004] Patients with non-alcoholic fatty liver disease (NAFLD) may progress from simple steatosis to non-alcoholic steatohepatitis (NASH), and then develop fibrosis. Although hepatic fibrosis is reversible in its initial stages, progressive hepatic fibrosis can lead to cirrhosis.

[0005] Kidney fibrosis, characterized by glomerulosclerosis and tubulointerstitial fibrosis, is the final common manifestation of many chronic kidney diseases (CKD). Regardless of the initial cause, progressive CKD often leads to extensive tissue scarring, resulting in destruction of the renal parenchyma and end-stage renal failure, a debilitating condition that requires dialysis or kidney replacement.

[0006] Scleroderma encompasses a complex and variable spectrum of disorders, characterized primarily by fibrosis, vasculopathy, and autoimmunity. The scleroderma spectrum of diseases shares the common feature of fibrosis, leading to skin hardening or thickening. For some patients, this hardening occurs only in restricted areas, while for other patients, the hardening may spread to other major organs.

[0007] After a myocardial infarction, cardiac structural remodeling is associated with an inflammatory response, leading to scar formation at the site of infarction. This scar formation is the result of fibrotic tissue deposition, which may lead to reduced cardiac function and disruption of electrical activity within the heart.

[0008] Crohn's Disease is a chronic disease of unknown etiology that has a tendency to progress even with medical or surgical treatment. Intestinal fibrosis is one of the most common complications of Crohn's Disease, leading to the formation of strictures in the small intestine and colon.

[0009] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic disease of unknown etiology that occurs in adults and is confined to the lungs. In IPF, the lung tissue becomes thickened, stiffened, and scarred. As pulmonary fibrosis progresses, it becomes more difficult for the lungs to transfer oxygen into the blood, and the organs do not receive the oxygen needed to function properly. IPF currently affects approximately 200,000 people in the United States and causes 40,000 deaths each year. Patients diagnosed with IPF experience progressive shortness of breath and ultimately complete respiratory failure.

[0010] Primary biliary cholangitis (PBC), also known as primary biliary cirrhosis, is a chronic liver disease that causes liver damage and fibrosis. Primary biliary cholangitis is caused by the slow, progressive destruction of the small bile ducts in the liver, which leads to the accumulation of bile and other toxins in the liver, a condition known as cholestasis. Over time, this results in scarring and fibrosis in the liver and biliary tract.

[0011] Non-specific interstitial pneumonia (NSIP) is a rare disease that affects the tissue surrounding and separating the tiny air sacs in the lungs. These air sacs are called alveoli and are the sites where the exchange of oxygen and carbon dioxide occurs between the lungs and the blood. Interstitial pneumonia is a disease in which the alveolar reticular walls become inflamed. The pleura (the thin covering that protects and cushions the lungs and the individual lobes of the lungs) may also become inflamed. NSIP has two main forms - cellular and fibrotic. The cellular form is mainly defined by the inflammation of interstitial cells. The fibrotic form is defined by the thickening and scarring of the lung tissue. This scarring is called fibrosis and is irreversible. When the lung tissue thickens or scars, it functions less effectively. Respiratory efficiency decreases, and the oxygen content in the blood decreases. (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)

[0012] Since there are currently no options on the market that have been proven to have an impact on long-term patient survival or symptomatology, there are few available treatment options. There is still a need for treatments for fibrotic diseases.

[0013] αvβ6 integrin is expressed in epithelial cells and binds to and mediates the activation of latent transforming growth factor-β1 (TGFβ1) by binding to a latent-associated peptide. After injury to lung and bile duct cells, its expression level increases significantly and plays a crucial in vivo role in tissue fibrosis. Elevated levels are also associated with increased mortality in patients with IPF and NSIP.

[0014] Primary sclerosing cholangitis (PSC) involves inflammation of the bile ducts and fibrosis that obstructs the bile ducts. The resulting impairment of bile flow to the intestine can lead to cirrhosis and subsequent complications such as liver failure and liver cancer. The expression of αvβ6 in the liver and bile ducts of PSC patients is elevated.

[0015] The present disclosure provides αvβ6 integrin inhibitors that can be used to treat fibrosis. SUMMARY OF THE INVENTION

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

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

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

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

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

[0021] Also provided is a compound of formula (A) or any variant thereof as detailed herein or a pharmaceutical composition thereof for treating fibrotic diseases.

[0022] Also provided is the use of a compound having formula (A) or any variant thereof detailed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing, in the preparation of a medicament for treating fibrotic diseases.

[0023] Further provided is a kit that comprises a compound having formula (A) or any variant thereof detailed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises instructions for use according to the methods described herein (such as methods for treating fibrotic diseases in an individual).

[0024] In another aspect, provided is a method for preparing a compound having formula (A) or any variant thereof or a pharmaceutically acceptable salt thereof. Also provided are compound intermediates useful for synthesizing the compound of formula (A) or a compound of any variant thereof.

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

[0026] Further provided is a pharmaceutical composition that comprises a compound having formula (I) or any variant thereof detailed herein or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier or excipient.

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

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

[0029] Also provided is a compound having formula (I) or any variant thereof as detailed herein or a pharmaceutical composition thereof for treating fibrotic diseases.

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

[0031] Further provided is a kit comprising a compound having formula (I) or any variant thereof as detailed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises instructions for use according to the methods described herein (such as a method for treating fibrotic diseases in an individual).

[0032] In another aspect, provided is a method for preparing a compound having formula (I) or any variant thereof or a pharmaceutically acceptable salt thereof. Also provided are compound intermediates useful for synthesizing the compound of formula (I) or any variant thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 Shows compounds 1 - 780 disclosed herein.

[0034] Figure 2 Shows Table B - 3, which has biological data for various compounds disclosed herein. DETAILED DESCRIPTION

[0035] The present disclosure particularly provides compounds having formula (A) and variants thereof or salts thereof, pharmaceutical compositions comprising the compounds of formula (A) or salts thereof, and methods for treating fibrotic diseases using these compounds and compositions.

[0036] The present disclosure particularly provides compounds having formula (I) and variants thereof or salts thereof, pharmaceutical compositions comprising the compounds of formula (I) or salts thereof, and methods for treating fibrotic diseases using these compounds and compositions.

[0037] DEFINITIONS

[0038] As used herein, unless otherwise expressly stated, the use of the term "a / an" and the like refers to one or more.

[0039] References herein to "about" a value or parameter include (and describe) embodiments that refer to the value or parameter itself. For example, a description of "about X" includes a description of "X".

[0040] As used herein, unless otherwise specified, "alkyl" refers to and includes having a specified number of carbon atoms (i.e., C1 - C 10represents a saturated straight-chain (i.e., unbranched) or branched monovalent hydrocarbon chain having from one to ten carbon atoms or a combination thereof. Specific alkyl groups are alkyl groups having from 1 to 20 carbon atoms (“C1-C 20 alkyl”), alkyl groups having from 1 to 10 carbon atoms (“C1-C 10 alkyl”), alkyl groups having from 6 to 10 carbon atoms (“C6-C 10 alkyl”), alkyl groups having from 1 to 6 carbon atoms (“C1-C6 alkyl”), alkyl groups having from 2 to 6 carbon atoms (“C2-C6 alkyl”), or alkyl groups having from 1 to 4 carbon atoms (“C1-C4 alkyl”). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0041] As used herein, “alkylene” refers to the same residue as an alkyl group, but having a divalent nature. Specific alkylene groups are alkylene groups having from 1 to 20 carbon atoms (“C1-C 20 alkylene”), alkylene groups having from 1 to 10 carbon atoms (“C1-C 10 alkylene”), alkylene groups having from 6 to 10 carbon atoms (“C6-C 10 alkylene”), alkylene groups having from 1 to 6 carbon atoms (“C1-C6 alkylene”), alkylene groups having from 1 to 5 carbon atoms (“C1-C5 alkylene”), alkylene groups having from 1 to 4 carbon atoms (“C1-C4 alkylene”), or alkylene groups having from 1 to 3 carbon atoms (“C1-C3 alkylene”). Examples of alkylene groups 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.

[0042] As used herein, unless otherwise specified, “alkenyl” refers to and includes an unsaturated straight-chain (i.e., unbranched) or branched monovalent hydrocarbon chain having at least one ethylenic unsaturation site (i.e., having at least one moiety of the formula C═C) and having a specified number of carbon atoms (i.e., C2-C 10 representing from two to ten carbon atoms) or a combination thereof. The alkenyl group can have a “cis” or “trans” configuration, or alternatively, an “E” or “Z” configuration. Specific alkenyl groups are alkenyl groups having from 2 to 20 carbon atoms (“C2-C 20"alkenyl"), alkenyl having 6 to 10 carbon atoms ("C6-C 10 alkenyl"), alkenyl having 2 to 8 carbon atoms ("C2-C8 alkenyl"), alkenyl having 2 to 6 carbon atoms ("C2-C6 alkenyl") or alkenyl having 2 to 4 carbon atoms ("C2-C4 alkenyl"). Examples of alkenyl include, but are not limited to, groups such as vinyl (or ethenyl), 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, etc.

[0043] As used herein, "alkenylene" refers to the same residue as alkenyl, but with a divalent valence. Specific alkenylenes are alkenylenes having 2 to 20 carbon atoms ("C2-C 20 alkenylene"), alkenylenes having 2 to 10 carbon atoms ("C2-C 10 alkenylene"), alkenylenes having 6 to 10 carbon atoms ("C6-C 10 alkenylene"), alkenylenes having 2 to 6 carbon atoms ("C2-C6 alkenylene"), alkenylenes having 2 to 4 carbon atoms ("C2-C4 alkenylene") or alkenylenes having 2 to 3 carbon atoms ("C2-C3 alkenylene"). Examples of alkenylenes include, but are not limited to, groups such as vinylene (or ethenylene) (-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-), etc.

[0044] As used herein, unless otherwise specified, "alkynyl" refers to and includes an unsaturated straight-chain (i.e., unbranched) or branched monovalent hydrocarbon chain or a combination thereof having at least one alkynyl unsaturation site (i.e., having at least one moiety of the formula C≡C) and having a specified number of carbon atoms (i.e., C2-C 10 representing two to ten carbon atoms). Specific alkynyls are alkynyls having 2 to 20 carbon atoms ("C2-C 20 alkynyl"), alkynyls having 6 to 10 carbon atoms ("C6-C 10"alkynyl"), alkynyl having 2 to 8 carbon atoms ("C2-C8 alkynyl"), alkynyl having 2 to 6 carbon atoms ("C2-C6 alkynyl"), or alkynyl having 2 to 4 carbon atoms ("C2-C4 alkynyl"). Examples of alkynyl 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.

[0045] As used herein, "alkynylene" refers to the same residue as alkynyl, but having a divalent nature. Specific alkynylenes are alkynylenes having 2 to 20 carbon atoms ("C2-C 20 alkynylene"), alkynylene having 2 to 10 carbon atoms ("C2-C 10 alkynylene"), alkynylene having 6 to 10 carbon atoms ("C6-C 10 alkynylene"), alkynylene having 2 to 6 carbon atoms ("C2-C6 alkynylene"), alkynylene having 2 to 4 carbon atoms ("C2-C4 alkynylene"), or alkynylene having 2 to 3 carbon atoms ("C2-C3 alkynylene"). Examples of alkynylene include, but are not limited to, groups such as acetylenediyl (or diethynyl) (-C≡C-), propynylene (-C≡CCH2-), and the like.

[0046] As used herein, unless otherwise specified, "cycloalkyl" refers to and includes a saturated cyclic monovalent hydrocarbon structure having the specified number of carbon atoms (i.e., C3-C 10 representing three to ten carbon atoms). The cycloalkyl can consist of one ring (such as cyclohexyl), or multiple rings (such as adamantyl). The cycloalkyl including more than one ring can be fused, spiro, bridged, or a combination thereof. Specific cycloalkyls are cycloalkyls having 3 to 12 cyclic carbon atoms. Preferred cycloalkyls are cyclic hydrocarbons having 3 to 8 cyclic carbon atoms ("C3-C8 cycloalkyl"), cyclic hydrocarbons having 3 to 6 cyclic carbon atoms ("C3-C6 cycloalkyl"), or cyclic hydrocarbons having 3 to 4 cyclic carbon atoms ("C3-C4 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0047] As used herein, "subcycloalkyl" refers to the same residue as cycloalkyl, but with divalency. A subcycloalkyl can consist of one or more rings, which can be fused, spiro, or bridged, or combinations thereof. Specific subcycloalkyls are those having 3 to 12 ring carbon atoms. Preferred subcycloalkyls are cyclic hydrocarbons having 3 to 8 ring carbon atoms ("C3-C8 subcycloalkyl"), cyclic hydrocarbons having 3 to 6 carbon atoms ("C3-C6 subcycloalkyl"), or cyclic hydrocarbons having 3 to 4 ring carbon atoms ("C3-C4 subcycloalkyl"). Examples of subcycloalkyls include, but are not limited to, subcyclopropyl, subcyclobutyl, subcyclopentyl, subcyclohexyl, subcycloheptyl, norbornylene, and the like. A subcycloalkyl can be attached to the rest of the structure via the same ring carbon atoms or different ring carbon atoms. When a subcycloalkyl is attached to the rest of the structure through two different ring carbon atoms, the linking bonds can be cis or trans to each other. For example, subcyclopropyl can include 1,1-subcyclopropyl and 1,2-subcyclopropyl (e.g., cis-1,2-subcyclopropyl or trans-1,2-subcyclopropyl) or mixtures thereof.

[0048] Unless otherwise indicated, "cycloalkenyl" refers to and includes an unsaturated cyclic non-aromatic monovalent hydrocarbon structure having at least one ethylenic unsaturation site (i.e., having at least one moiety of the formula C═C) and having a specified number of carbon atoms (i.e., C3-C 10 representing three to ten carbon atoms). A cycloalkenyl can consist of one ring (such as cyclohexenyl), or of multiple rings (such as norbornenyl). Preferred cycloalkenyls are unsaturated cyclic hydrocarbons having 3 to 8 ring carbon atoms ("C3-C8 cycloalkenyl"). Examples of cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like.

[0049] As used herein, "subcycloalkenyl" refers to the same residue as cycloalkenyl, but with divalency.

[0050] As used herein, "aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracenyl), where the fused rings can be aromatic or can not be aromatic. Specific aryls are aryls having 6 to 14 ring carbon atoms ("C6-C 14 aryl"). An aryl having more than one ring, where at least one ring is non-aromatic, can be attached to the parent structure at an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl having more than one ring, where at least one ring is non-aromatic, is attached to the parent structure at an aromatic ring position.

[0051] As used herein, "arylene" refers to the same residue as aryl, but with a divalent nature. Specific arylenes are arylenes having 6 to 14 ring carbon atoms ("C6-C 14 arylene").

[0052] As used herein, "heteroaryl" refers to an unsaturated aromatic cyclic group having 1 to 14 ring carbon atoms and at least one ring heteroatom, said ring heteroatom including but not limited to heteroatoms such as nitrogen, oxygen, and sulfur. Heteroaryl can have a single ring (e.g., pyridyl, furyl) or multiple fused rings (e.g., indolizinyl, benzothienyl), and the fused rings can be aromatic or not aromatic. Specific heteroaryls are 5- to 14-membered rings having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered rings having 1 to 8 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-, 6-, or 7-membered rings having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, specific heteroaryls are monocyclic aromatic 5-, 6-, or 7-membered rings having 1 to 6 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, specific heteroaryls are polycyclic aromatic rings having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. A heteroaryl having more than one ring (where at least one ring is non-aromatic) can be attached to the parent structure at an aromatic ring position or at a non-aromatic ring position. In one variation, a heteroaryl having more than one ring (where at least one ring is non-aromatic) is attached to the parent structure at an aromatic ring position. Heteroaryl can be attached to the parent structure at a ring carbon atom or at a ring heteroatom.

[0053] As used herein, "heteroarylene" refers to the same residue as heteroaryl, but with a divalent nature.

[0054] As used herein, "heterocyclic", "heterocyclic ring", or "heterocyclic group" refers to a saturated or unsaturated non-aromatic cyclic group having a single ring or multiple fused rings and having 1 to 14 ring carbon atoms and 1 to 6 ring heteroatoms (such as nitrogen, sulfur, or oxygen, etc.). The heterocyclic group including more than one ring can be fused, bridged, or spiro, or any combination thereof, but does not include heteroaryl. The heterocyclic group can be optionally independently substituted by one or more substituents described herein. Specific heterocyclic groups are 3- to 14-membered rings having 1 to 13 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 12-membered rings having 1 to 11 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 10-membered rings having 1 to 9 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 8-membered rings having 1 to 7 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 3- to 6-membered rings having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, the heterocyclic group comprises a monocyclic 3-, 4-, 5-, 6-, or 7-membered ring having 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 ring carbon atoms and 1 to 2, 1 to 3, or 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, the heterocyclic group comprises a polycyclic non-aromatic ring having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0055] As used herein, "heterocyclylene" refers to the same residue as the heterocyclic group, but having a divalent nature.

[0056] "Halogen group" or "halogen" refers to Group 17 series elements having an atomic number from 9 to 85. Preferred halogen groups include groups of fluorine, chlorine, bromine, and iodine. If a residue is substituted by more than one halogen, it can be referred to by using a prefix corresponding to the number of the attached halogen moieties. For example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl groups substituted by two ("di") or three ("tri") halogen groups, and the halogen groups may be the same halogen but not necessarily the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced by a halogen group is called "perhaloalkyl". Preferred perhaloalkyl is trifluoromethyl (-CF3). Similarly, "perhaloalkoxy" refers to an alkoxy group in which in the hydrocarbon of the alkyl moiety constituting the alkoxy group, a halogen replaces each H. An example of perhaloalkoxy is trifluoromethoxy (–OCF3).

[0057] "Carbonyl" refers to the group C=O.

[0058] "Thiocarbonyl" refers to the group C=S.

[0059] "Oxo group" means a moiety =O.

[0060] "D" means deuterium ( 2 H).

[0061] "T" means tritium ( 3 H).

[0062] An alkyl group in which each hydrogen is replaced by deuterium is referred to as "perdeuterated". An alkyl group in which each hydrogen is replaced by tritium is referred to as "pertritiated".

[0063] Unless otherwise specified, "optionally substituted" means that the group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for the group, where the substituents may be the same or different. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In another embodiment, the optionally substituted group has four substituents. In some embodiments, the optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, the optionally substituted group is unsubstituted.

[0064] It should be understood that if the number of available valences on the optionally substituted moiety permits, the optionally substituted moiety may be substituted by more than five substituents. For example, a propyl group may be substituted by seven halogen atoms to provide a perhalogenated propyl group. The substituents may be the same or different.

[0065] Unless otherwise expressly stated, "individual" as used herein refers to a mammal, including but not limited to primates, humans, cows, horses, cats, dogs, or rodents. In one variation, the individual is a human.

[0066] As used herein, "treatment" is a method for obtaining a beneficial or desired result (including a clinical result). Beneficial or desired results include, but are not limited to, one or more of the following: alleviating one or more symptoms caused by a disease; reducing the severity of the disease; stabilizing the disease (e.g., preventing or delaying the progression of the disease); preventing or delaying the spread of the disease; delaying the onset or recurrence of the disease; delaying or slowing the progression of the disease; improving the disease state; alleviating the disease (either in part or in whole); reducing the dosage of one or more other drugs required to treat the disease; enhancing the effect of another drug; delaying the progression of the disease; improving the quality of life and / or extending the survival period. "Treatment" also encompasses reducing the pathological consequences of fibrosis. The methods of the present invention contemplate any one or more of these aspects of treatment.

[0067] As used herein, the term "effective amount" refers to the amount of a compound of the present invention that is effective in a given therapeutic form. As understood in the art, an effective amount can be one or more doses, i.e., it may be necessary to administer a single dose or multiple doses to achieve the desired therapeutic endpoint. The effective amount can be considered in the context of administering one or more therapeutic agents (e.g., a compound or a pharmaceutically acceptable salt thereof), and if the desired or beneficial result can be achieved or obtained in combination with one or more other agents, the administration of a single agent in an effective amount can be considered. Due to the combined action of the compounds (e.g., additive or synergistic), the appropriate dose of any one of the co-administered compounds can optionally be reduced.

[0068] A "therapeutically effective amount" refers to the amount of a compound or its salt that is sufficient to produce the desired therapeutic result.

[0069] As used herein, "unit dosage form" refers to a physically discrete unit suitable as a unit dose, each unit containing a predetermined amount of the active ingredient, which is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The unit dosage form can contain a single therapy or a combination therapy.

[0070] As used herein, the term "controlled release" refers to a medicated formulation or a fraction thereof in which the release of the drug is not immediate, i.e., with a "controlled release" formulation, the administered dose does not result in an immediate release of the drug into the absorption pool. The term encompasses depot formulations that are designed to gradually release the drug compound over an extended period of time. Controlled release formulations can incorporate a variety of drug delivery systems, typically involving mixing the drug compound with a carrier, polymer, or other compound having the desired release characteristics (e.g., pH-dependent or non-pH-dependent solubility, varying degrees of water solubility, etc.) and formulating the mixture according to the desired route of delivery (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, etc.).

[0071] As used herein, "pharmaceutically acceptable" or "pharmacologically acceptable" refers to a material that is not biologically or otherwise undesirable, e.g., the material can be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in any harmful way with any other components of the composition containing the material. Pharmaceutically acceptable carriers or excipients preferably meet the required standards of toxicological and manufacturing tests and / or are included in the "Inactive Ingredient Guide" prepared by the U.S. Food and Drug Administration.

[0072] "Pharmaceutically acceptable salts" are salts that retain at least some of the biological activity of the free (non-salt) compound and can be administered to an individual as a medicine or drug. Such salts include, for example: (1) acid addition salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or with organic acids (such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, etc.); (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion); or salts complexed with organic bases. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc. Pharmaceutically acceptable salts can be prepared in situ during the manufacturing process or by reacting the purified free acid or base form of the compound of the present invention with a suitable organic or inorganic base or acid, respectively, and isolating the subsequently formed salt.

[0073] As used herein, the term "excipient" refers to an inert or inactive substance that can be used in the production of a drug or pharmaceutical product, such as a tablet containing a compound of the present invention as an active ingredient. The term excipient can encompass a variety of substances, including but not limited to any substance used as a binder, disintegrant, coating agent, compression / encapsulation aid, cream or lotion, lubricant, parenteral administration solution, material for chewable tablets, sweetening or flavoring agent, suspending / gelling agent, or wet granulating agent, etc. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coating agents include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coating, etc.; compression / encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "direct compressible"), honey dc, lactose (anhydrous or monohydrate; optionally combined with aspartame, cellulose or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, for example, sodium croscarmellose, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, for example, dextrose, fructose dc, lactose (monohydrate, optionally combined with aspartame or cellulose), etc.; suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweetening agents include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0074] Unless otherwise specified, "substantially pure" refers to a composition containing no more than 10% impurities, such as a composition including less than 9%, 7%, 5%, 3%, 1%, 0.5% impurities.

[0075] It should be understood that aspects and embodiments described herein as "comprising" include embodiments of "consisting of" and "consisting essentially of".

[0076] Compound

[0077] In one aspect, there is provided a compound of formula (A):

[0078]

[0079] or a salt thereof, wherein:

[0080] R 1 is C6-C 14 aryl or 5- to 10-membered heteroaryl, wherein the C6-C 14 aryl and 5- to 10-membered heteroaryl are optionally substituted by R 1a substituted;

[0081] R 2is hydrogen; deuterium; C1-C6 alkyl optionally substituted by R 2a ; -OH; -O-C1-C6 alkyl optionally substituted by R 2a ; C3-C6 cycloalkyl optionally substituted by R 2b ; -O-C3-C6 cycloalkyl optionally substituted by R 2b ; 3- to 12-membered heterocyclic group optionally substituted by R 2c ; or -S(O)2R 2d ; provided that any carbon atom directly bonded to a nitrogen atom is optionally substituted by R other than halogen 2a moiety;

[0082] Each R 1a is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, 3- to 12-membered heterocyclic group, 5- to 10-membered heteroaryl, C6-C 14 aryl, deuterium, halogen, -CN, -OR 3 , -SR 3 , -NR 4 R 5 , -NO2, -C=NH(OR 3 ), -C(O)R 3 , -OC(O)R 3 , -C(O)OR 3 , -C(O)NR 4 R 5 , -NR 3 C(O)R 4 , -NR 3 C(O)OR 4 , -NR 3 C(O)NR 4 R 5 , -S(O)R 3 , -S(O)2R 3 , -NR 3 S(O)R 4 , -NR 3 S(O)2R 4 , -S(O)NR 4 R 5 , -S(O)2NR 4 R 5 or -P(O)(OR 4 )(OR 5 ), where each R 1a is independently optionally substituted by deuterium, halogen, oxo group, -OR 6 , -NR 6 R 7 , -C(O)R6 、 -CN, -S(O)R 6 、 -S(O)2R 6 、 -P(O)(OR 6 )(OR 7 )、 C3 - C8 cycloalkyl, 3 - to 12 - membered heterocyclic group, 5 - to 10 - membered heteroaryl, C6 - C 14 aryl or C1 - C6 alkyl optionally substituted by deuterium, oxo group, -OH or halogen;

[0083] Each R 2a 、 R 2b 、 R 2c 、 R 2e and R 2f is independently an oxo group or R 1a ;

[0084] R 2d is C1 - C6 alkyl optionally substituted by R 2e or C3 - C5 cycloalkyl optionally substituted by R 2f ;

[0085] R 3 is independently hydrogen, deuterium, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl, C6 - C 14 aryl, 5 - to 6 - membered heteroaryl or 3 - to 6 - membered heterocyclic group, wherein the C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl, C6 - C 3 aryl, 5 - to 6 - membered heteroaryl and 3 - to 6 - membered heterocyclic group of R 14 are independently optionally substituted by halogen, deuterium, oxo group, -CN, -OR 8 、 -NR 8 R 9 -P(O)(OR 8 )(OR 9 ) or C1 - C6 alkyl optionally substituted by deuterium, halogen, -OH or oxo group;

[0086] R 4 and R 5 are each independently hydrogen, deuterium, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl, C6 - C 14 aryl, 5 - to 6 - membered heteroaryl or 3 - to 6 - membered heterocyclic group, wherein the C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl, C6 - C 4 and R 5 of C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl, C6 - C 14An aryl group, a 5- to 6-membered heteroaryl group, and a 3- to 6-membered heterocyclic group are each independently optionally substituted with deuterium, a halogen, an oxo group, -CN, -OR 8 、-NR 8 R 9 or a C1-C6 alkyl group optionally substituted with deuterium, a halogen, -OH, or an oxo group;

[0087] or R 4 and R 5 together with the atom to which they are attached form a 3- to 6-membered heterocyclic group, which heterocyclic group is optionally substituted with deuterium, a halogen, an oxo group, -OR 8 、-NR 8 R 9 or a C1-C6 alkyl group optionally substituted with deuterium, a halogen, an oxo group, or -OH;

[0088] R 6 and R 7 are each independently hydrogen, deuterium, a C1-C6 alkyl group optionally substituted with deuterium, a halogen, or an oxo group, a C2-C6 alkenyl group optionally substituted with deuterium, a halogen, or an oxo group, or a C2-C6 alkynyl group optionally substituted with deuterium, a halogen, or an oxo group;

[0089] or R 6 and R 7 together with the atom to which they are attached form a 3- to 6-membered heterocyclic group, which heterocyclic group is optionally substituted with deuterium, a halogen, an oxo group, or a C1-C6 alkyl group optionally substituted with deuterium, a halogen, or an oxo group;

[0090] R 8 and R 9 are each independently hydrogen, deuterium, a C1-C6 alkyl group optionally substituted with deuterium, a halogen, or an oxo group, a C2-C6 alkenyl group optionally substituted with deuterium, a halogen, or an oxo group, or a C2-C6 alkynyl group optionally substituted with deuterium, a halogen, or an oxo group;

[0091] or R 8 and R 9 together with the atom to which they are attached form a 3- to 6-membered heterocyclic group, which heterocyclic group is optionally substituted with deuterium, a halogen, an oxo group, or a C1-C6 alkyl group optionally substituted with deuterium, an oxo group, or a halogen;

[0092] Each R 10 、R 11 、R 12 and R 13 is independently hydrogen or deuterium;

[0093] R 14 is deuterium;

[0094] q is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0095] Each R 15 is independently selected from hydrogen, deuterium or a halogen;

[0096] Each R 16 is independently selected from hydrogen, deuterium or a halogen; and

[0097] p is 3, 4, 5, 6, 7, 8 or 9.

[0098] In one variation, there is provided a compound of formula (A) or a salt thereof, wherein the carbon atom bearing the CO2H and NHR 1 moiety is in the "S" configuration. In another variation, there is provided a compound of formula (A) or a salt thereof, wherein the carbon atom bearing the CO2H and NHR 1 moiety is in the "R" configuration. Also covered are mixtures of compounds of formula (A), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds having different chemical formulas.

[0099] In one variation of formula (A), R 2 is such that any carbon atom directly bonded to the nitrogen atom is unsubstituted or substituted with deuterium.

[0100] In the description herein, it should be understood that each description, variation, embodiment or aspect of one part can be combined with each description, variation, embodiment or aspect of the other parts, as if each combination was specifically and separately listed. For example, each description, variation, embodiment or aspect provided herein regarding R 1 can be combined with each description, variation, embodiment or aspect of R 2 as if each combination was specifically and separately listed.

[0101] In one aspect, there is provided a compound of formula (I)

[0102]

[0103] or a salt thereof, wherein:

[0104] R 1 is C6-C 14 aryl or 5- to 10-membered heteroaryl, wherein said C6-C 14 aryl and 5- to 10-membered heteroaryl are optionally substituted with R 1a ;

[0105] R 2 is C1-C6 alkyl optionally substituted with R 2a ; C3-C6 cycloalkyl optionally substituted with R 2b ; optionally substituted with R 2cA substituted 3- to 12-membered heterocyclic group; or -S(O)2R 2d ;

[0106] Each R 1a is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, a 3- to 12-membered heterocyclic group, a 5- to 10-membered heteroaryl, C6-C 14 aryl, deuterium, halogen, -CN, -OR 3 , -SR 3 , -NR 4 R 5 , -NO2, -C=NH(OR 3 ), -C(O)R 3 , -OC(O)R 3 , -C(O)OR 3 , -C(O)NR 4 R 5 , -NR 3 C(O)R 4 , -NR 3 C(O)OR 4 , -NR 3 C(O)NR 4 R 5 , -S(O)R 3 , -S(O)2R 3 , -NR 3 S(O)R 4 , -NR 3 S(O)2R 4 , -S(O)NR 4 R 5 , -S(O)2NR 4 R 5 or -P(O)(OR 4 )(OR 5 ), where each R 1a is independently optionally substituted by deuterium, halogen, oxo, -OR 6 , -NR 6 R 7 , -C(O)R 6 , -CN, -S(O)R 6 , -S(O)2R 6 , -P(O)(OR 6 )(OR 7 ), C3-C8 cycloalkyl, a 3- to 12-membered heterocyclic group, a 5- to 10-membered heteroaryl, C6-C 14 aryl or C1-C6 alkyl optionally substituted by deuterium, oxo, -OH or halogen;

[0107] Each R 2a 、R 2b 、R 2c 、R 2e and R 2f is independently an oxo group or R 1a ;

[0108] R 2d is an optionally R 2e -substituted C1-C6 alkyl or an optionally R 2f -substituted C3-C5 cycloalkyl;

[0109] R 3 is independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclic group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 3 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclic group of R 14 are independently optionally substituted by halogen, deuterium, oxo group, -CN, -OR 8 、-NR 8 R 9 、-P(O)(OR 8 )(OR 9 ) or a C1-C6 alkyl optionally substituted by deuterium, halogen, -OH or oxo group;

[0110] R 4 and R 5 are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclic group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 4 and R 5 of R 14 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclic group are independently optionally substituted by deuterium, halogen, oxo group, -CN, -OR 8 、-NR 8 R 9 or a C1-C6 alkyl optionally substituted by deuterium, halogen, -OH or oxo group;

[0111] or R 4 and R 5 together with the atom to which they are attached form a 3- to 6-membered heterocyclic group, and the heterocyclic group is optionally substituted by deuterium, halogen, oxo group, -OR 8, -NR 8 R 9 or is substituted by C1-C6 alkyl optionally substituted by deuterium, halogen, an oxo group or -OH;

[0112] R 6 and R 7 are each independently hydrogen, deuterium, C1-C6 alkyl optionally substituted by deuterium, halogen or an oxo group, C2-C6 alkenyl optionally substituted by deuterium, halogen or an oxo group or C2-C6 alkynyl optionally substituted by deuterium, halogen or an oxo group;

[0113] or R 6 and R 7 together with the atom to which they are attached form a 3- to 6-membered heterocyclic group, which heterocyclic group is optionally substituted by deuterium, halogen, an oxo group or C1-C6 alkyl optionally substituted by deuterium, halogen or an oxo group;

[0114] R 8 and R 9 are each independently hydrogen, deuterium, C1-C6 alkyl optionally substituted by deuterium, halogen or an oxo group, C2-C6 alkenyl optionally substituted by deuterium, halogen or an oxo group or C2-C6 alkynyl optionally substituted by deuterium, halogen or an oxo group;

[0115] or R 8 and R 9 together with the atom to which they are attached form a 3-6-membered heterocyclic group, which heterocyclic group is optionally substituted by deuterium, halogen, an oxo group or C1-C6 alkyl optionally substituted by deuterium, an oxo group or halogen;

[0116] Each R 10 , R 11 , R 12 and R 13 is independently hydrogen or deuterium;

[0117] R 14 is deuterium;

[0118] q is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and

[0119] p is 3, 4, 5, 6, 7, 8 or 9.

[0120] In one variant, there is provided a compound of formula (I) or a salt thereof, wherein the carbon bearing the CO2H and NHR 1 moiety is in the "S" configuration. In another variant, there is provided a compound of formula (I) or a salt thereof, wherein the carbon bearing the CO2H and NHR 1 moiety is in the "R" configuration. Also covered are mixtures of compounds of formula (I), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds having different chemical formulas.

[0121] In one variation of formula (I), R 2 includes the condition that any carbon atom directly bonded to the nitrogen atom is optionally substituted by R other than halogen 2a moieties. In one variation of formula (I), R 2 includes the condition that any carbon atom directly bonded to the nitrogen atom is unsubstituted or substituted by deuterium.

[0122] In the description herein, it should be understood that each description, variation, embodiment or aspect of one part can be combined with each description, variation, embodiment or aspect of other parts as if each combination was specifically and separately listed. For example, each description, variation, embodiment or aspect provided herein regarding R of formula (I) 1 can be combined with each description, variation, embodiment or aspect of R 2 as if each combination was specifically and separately listed.

[0123] In some embodiments of the compound of formula (I) or its salt, R 1a , R 2a , R 2b , R 2c , R 2e , R 2f , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , or R 16 is deuterium.

[0124] In some embodiments of the compound of formula (I) or its salt, R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a . In some embodiments, R 1 is a pyrimidin-4-yl optionally substituted by R 1a . In some embodiments, R 1 is a pyrimidin-4-yl optionally substituted by R 1a , where R 1a is a 5- to 10-membered heteroaryl (e.g., pyrazolyl) or a C1-C6 alkyl (e.g., methyl, difluoromethyl, and trifluoromethyl) optionally substituted by halogen. In some embodiments, R 1is a pyrimidin-4-yl optionally substituted by R 1a , wherein R 1a is a 5- to 10-membered heteroaryl optionally substituted by halogen (e.g., pyrazolyl or pyridyl) or C1-C6 alkyl (e.g., methyl, difluoromethyl, and trifluoromethyl). In some embodiments, R 1 is a pyrimidin-4-yl substituted by both methyl and trifluoromethyl. In some embodiments, R 1 is a pyrimidin-4-yl substituted by both methyl and pyridyl. In some embodiments, R 1 is a pyrimidin-4-yl optionally substituted by R 1a , wherein R 1a is C6-C 14 aryl (e.g., phenyl). In some embodiments, R 1 is a pyrimidin-4-yl optionally substituted by R 1a , wherein R 1a is –CN. In some embodiments, R 1 is a pyrimidin-2-yl optionally substituted by R 1a . In some embodiments, R 1 is a pyrimidin-2-yl optionally substituted by R 1a , wherein R 1a is halogen, C1-C6 alkyl optionally substituted by halogen (e.g., methyl or trifluoromethyl), -CN, or C3-C8 cycloalkyl (e.g., cyclopropyl). In some embodiments of the compound of formula (I) or its salt, R 1 is a quinazolin-4-yl optionally substituted by R 1a . In some embodiments, R 1 is a quinazolin-4-yl optionally substituted by R 1a , wherein R 1a is halogen (e.g., fluorine and chlorine), C1-C6 alkyl optionally substituted by halogen (e.g., methyl or trifluoromethyl), or C1-C6 alkoxy (e.g., methoxy). In some embodiments, R 1 is a quinazolin-4-yl optionally substituted by R 1a , wherein R 1a is a 5- to 10-membered heteroaryl (e.g., pyridyl). In some embodiments, R 1 is a pyrazolopyrimidinyl optionally substituted by R 1a . In some embodiments, R 1 is a pyrazolopyrimidinyl optionally substituted by R 1a , wherein R 1a is C1-C6 alkyl (e.g., methyl). In some embodiments, wherein R 1 is indicated as optionally substituted by R 1a , R 1The moiety is unsubstituted. In some embodiments, wherein R 1 is indicated as optionally being substituted by R 1a the R 1 moiety is substituted by one R 1a In some embodiments, wherein R 1 is indicated as optionally being substituted by R 1a the R 1 moiety is substituted by 2 to 6 or 2 to 5 or 2 to 4 or 2 to 3 identical or different R 1a moieties.

[0125] In some embodiments of formula (I) (including embodiments describing the R 1 variable), each of R 10 , R 11 , R 12 and R 13 is hydrogen. In some embodiments of formula (I) (including embodiments describing the R 1 variable and / or R 10 , R 11 , R 12 and R 13 variable), q is 0. In some embodiments (including embodiments describing the R 1 variable and / or R 10 , R 11 , R 12 and R 13 variable and / or the q variable), p is 3, 4 or 5.

[0126] In some embodiments of formula (I), R 10 , R 11 , R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound is a compound of formula (II): (II) or a salt thereof, wherein R 1 and R 2 are as defined in formula (I).

[0127] In some embodiments of the compound of formula (I), wherein R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a , the compound is a compound of formula (I-A):

[0128]

[0129] or a salt thereof, wherein R 1a , R 2 , R 10 , R 11 , R 12 , R13 , R 14 , q and p are as defined in formula (I), m is 0, 1, 2 or 3, and the positions on the pyrimidine ring and the tetrahydronaphthyridine ring are as shown.

[0130] In one embodiment, there is provided a compound of formula (I-A) or a salt thereof, wherein the carbon bearing the CO2H and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-A) or a salt thereof, wherein the carbon bearing the CO2H and NH moieties is in the "R" configuration. Also covered are mixtures of compounds of formula (I-A), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds having different chemical formulas.

[0131] In some embodiments of the compound of formula (I-A), m is 0, 1, 2 or 3, and each R 1a is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, where the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium. In further embodiments of the compound of formula (I-A), m is 0, 1, 2 or 3, and each R 1a is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which may be C1-C6 perhaloalkyl in one variant), C1-C6 alkoxy, hydroxy, -CN or 5- to 10-membered heteroaryl, where the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and 5- to 10-membered heteroaryl of R 1a are independently optionally substituted with deuterium. In some embodiments of formula (I-A), m is 1, 2 or 3.

[0132] In some embodiments of the compound of formula (I-A), m is 0. In some embodiments of the compound of formula (I-A), m is 1, and R 1a is at the 2-position. In some embodiments of the compound of formula (I-A), m is 1, and R 1a is at the 5-position. In some embodiments of the compound of formula (I-A), m is 1, and R 1a is at the 6-position. In some embodiments of the compound of formula (I-A), m is 2, and the R 1a groups are at the 2- and 5-positions. In some embodiments of the compound of formula (I-A), m is 2, and the R 1a groups are at the 2- and 6-positions. In some embodiments of the compound of formula (I-A), m is 2, and the R 1a groups are at the 5- and 6-positions. In some embodiments of the compound of formula (I-A), m is 3, and R 1aThe group is located at the 2-position, 5-position and 6-position. As long as there are more than one R 1a groups, the R 1a groups can be independently selected. In any of these embodiments of the compound of formula (I-A) or its salt, the carbon bearing the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0133] In some embodiments of formula (I-A) (including the embodiments describing R 1a and the m variable), each of R 10 , R 11 , R 12 and R 13 is hydrogen. In some embodiments of formula (I-A) (including the embodiments describing R 1a and the m variable and / or R 10 , R 11 , R 12 and R 13 variables), q is 0. In some embodiments of formula (I-A) (including the embodiments describing R 1a and the m variable and / or R 10 , R 11 , R 12 and R 13 variables and / or the q variable), p is 3, 4 or 5.

[0134] In some embodiments of formula (I-A), R 10 , R 11 , R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound is a compound of formula (II-A):

[0135]

[0136] or its salt, wherein R 1a and R 2 are as defined in formula (I), m is 0, 1, 2 or 3, and the positions on the pyrimidine ring are as shown. All descriptions of R 1a , R 2 and m in formula (I) apply equally to formula (I-A) and (II-A).

[0137] In some embodiments of the compound of formula (I), wherein R 1 is a 5- to 10-membered heteroaryl optionally substituted with R 1a , the compound is a compound of formula (I-B):

[0138]

[0139] or its salt, wherein R1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined in formula (I), m is 0, 1, 2, 3, 4 or 5, and the positions on the quinazoline ring are as shown.

[0140] In one embodiment, there is provided a compound of formula (I-B) or a salt thereof, wherein the carbon bearing the CO2H and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-B) or a salt thereof, wherein the carbon bearing the CO2H and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (I-B), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds having different chemical formulas.

[0141] In some embodiments of the compound of formula (I-B), m is 0, 1, 2, 3, 4 or 5, and each R 1a is independently, where applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium. In further embodiments of the compound of formula (I-B), m is 0, 1, 2, 3, 4 or 5, and each R 1a is independently, where applicable, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which may be C1-C6 perhaloalkyl in one variant), C1-C6 alkoxy, hydroxy, -CN or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and 5- to 10-membered heteroaryl of R 1a are independently optionally substituted with deuterium. In some embodiments of the compound of formula (I-B), m is 1, 2, 3, 4 or 5.

[0142] In some embodiments of the compound of formula (I-B), m is 0. In some embodiments of the compound of formula (I-B), m is 1, and R 1a is at the 2-position. In some embodiments of the compound of formula (I-B), m is 1, and R 1a is at the 5-position. In some embodiments of the compound of formula (I-B), m is 1, and R 1a is at the 6-position. In some embodiments of the compound of formula (I-B), m is 1, and R 1a is at the 7-position. In some embodiments of the compound of formula (I-B), m is 1, and R 1ais at the 8-position. In some embodiments of the compound of formula (I-B), m is 2, and the R 1a group is at the 2-position and the 5-position. In some embodiments of the compound of formula (I-B), m is 2, and the R 1a group is at the 2-position and the 6-position. In some embodiments of the compound of formula (I-B), m is 2, and the R 1a group is at the 2-position and the 7-position. In some embodiments of the compound of formula (I-B), m is 2, and the R 1a group is at the 2-position and the 8-position. In some embodiments of the compound of formula (I-B), m is 2, and the R 1a group is at the 5-position and the 6-position. In some embodiments of the compound of formula (I-B), m is 2, and the R 1a group is at the 5-position and the 7-position. In some embodiments of the compound of formula (I-B), m is 2, and the R 1a group is at the 5-position and the 8-position. In some embodiments of the compound of formula (I-B), m is 2, and the R 1a group is at the 6-position and the 7-position. In some embodiments of the compound of formula (I-B), m is 2, and the R 1a group is at the 6-position and the 8-position. In some embodiments of the compound of formula (I-B), m is 2, and the R 1a group is at the 7-position and the 8-position. In some embodiments of the compound of formula (I-B), m is 3, and the R 1a group is at the 2-position, the 5-position and the 6-position. In some embodiments of the compound of formula (I-B), m is 3, and the R 1a group is at the 2-position, the 5-position and the 7-position. In some embodiments of the compound of formula (I-B), m is 3, and the R 1a group is at the 2-position, the 5-position and the 8-position. In some embodiments of the compound of formula (I-B), m is 3, and the R 1a group is at the 2-position, the 6-position and the 7-position. In some embodiments of the compound of formula (I-B), m is 3, and the R 1a group is at the 2-position, the 6-position and the 8-position. In some embodiments of the compound of formula (I-B), m is 3, and the R 1a group is at the 2-position, the 7-position and the 8-position. In some embodiments of the compound of formula (I-B), m is 3, and the R 1a group is at the 5-position, the 6-position and the 7-position. In some embodiments of the compound of formula (I-B), m is 3, and the R 1a group is at the 5-position, the 6-position and the 8-position. In some embodiments of the compound of formula (I-B), m is 3, and the R 1aThe group is located at the 5-, 7-, and 8-positions. In some embodiments of the compound of formula (I-B), m is 3, and R 1a The group is located at the 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-B), m is 4, and R 1a The group is located at the 2-, 5-, 6-, and 7-positions. In some embodiments of the compound of formula (I-B), m is 4, and R 1a The group is located at the 2-, 5-, 6-, and 8-positions. In some embodiments of the compound of formula (I-B), m is 4, and R 1a The group is located at the 2-, 5-, 7-, and 8-positions. In some embodiments of the compound of formula (I-B), m is 4, and R 1a The group is located at the 2-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-B), m is 4, and R 1a The group is located at the 5-, 6-, 7-, and 8-positions. In some embodiments of the compound of formula (I-B), m is 5, and R 1a The group is located at the 2-, 5-, 6-, 7-, and 8-positions. As long as there is more than one R 1a group, R 1a groups can be independently selected. In any of these embodiments of the compound of formula (I-B) or its salt, the carbon bearing the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0143] In some embodiments of formula (I-B) (including embodiments describing the R 1a and m variables), each of R 10 , R 11 , R 12 and R 13 is hydrogen. In some embodiments of formula (I-B) (including embodiments describing the R 1a and m variables and / or R 10 , R 11 , R 12 and R 13 variables), q is 0. In some embodiments of formula (I-B) (including embodiments describing the R 1a and m variables and / or R 10 , R 11 , R 12 and R 13 variables and / or the q variable), p is 3, 4, or 5.

[0144] In some embodiments of formula (I-B), R 10 , R 11 , R 12 and R 13Hydrogen, p is 3, q is 0, and the compound is a compound of formula (II-B):

[0145]

[0146] or a salt thereof, wherein R 1a and R 2 are as defined in formula (I), m is 0, 1, 2, 3, 4 or 5, and the positions on the quinazoline ring are as shown. All descriptions of R 1a , R 2 and m in formula (I) apply equally to formula (I-B) and (II-B).

[0147] In some embodiments of the compounds of formula (I), wherein R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a , the compound is a compound of formula (I-C):

[0148]

[0149] or a salt thereof, wherein R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined in formula (I), m is 0, 1, 2, 3 or 4, and the positions on the pyrido[3,2-d]pyrimidine ring are as shown.

[0150] In one embodiment, there is provided a compound of formula (I-C) or a salt thereof, wherein the carbon bearing the CO2H and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-C) or a salt thereof, wherein the carbon bearing the CO2H and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (I-C), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds having different chemical formulas.

[0151] In some embodiments of the compounds of formula (I-C), m is 0, 1, 2, 3 or 4, and each R 1a , where applicable, is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted by deuterium. In further embodiments of the compounds of formula (I-C), m is 0, 1, 2, 3 or 4, and each R 1aIndependently, when applicable, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which can be C1-C6 perhaloalkyl in one variation), C1-C6 alkoxy, hydroxy, -CN, or 5- to 10-membered heteroaryl, where R 1a The C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, and 5- to 10-membered heteroaryl of are independently optionally substituted with deuterium. In some embodiments of the compound of formula (I-C), m is 1, 2, 3, or 4

[0152] In some embodiments of the compound of formula (I-C), m is 0. In some embodiments of the compound of formula (I-C), m is 1, and R 1a Is located at the 2-position. In some embodiments of the compound of formula (I-C), m is 1, and R 1a Is located at the 6-position. In some embodiments of the compound of formula (I-C), m is 1, and R 1a Is located at the 7-position. In some embodiments of the compound of formula (I-C), m is 1, and R 1a Is located at the 8-position. In some embodiments of the compound of formula (I-C), m is 2, and R 1a Groups are located at the 2-position and the 6-position. In some embodiments of the compound of formula (I-C), m is 2, and R 1a Groups are located at the 2-position and the 7-position. In some embodiments of the compound of formula (I-C), m is 2, and R 1a Groups are located at the 2-position and the 8-position. In some embodiments of the compound of formula (I-C), m is 2, and R 1a Groups are located at the 6-position and the 7-position. In some embodiments of the compound of formula (I-C), m is 2, and R 1a Groups are located at the 6-position and the 8-position. In some embodiments of the compound of formula (I-C), m is 2, and R 1a Groups are located at the 7-position and the 8-position. In some embodiments of the compound of formula (I-C), m is 3, and R 1a Groups are located at the 2-position, the 6-position, and the 7-position. In some embodiments of the compound of formula (I-C), m is 3, and R 1a Groups are located at the 2-position, the 6-position, and the 8-position. In some embodiments of the compound of formula (I-C), m is 3, and R 1a Groups are located at the 2-position, the 7-position, and the 8-position. In some embodiments of the compound of formula (I-C), m is 3, and R 1a Groups are located at the 6-position, the 7-position, and the 8-position. In some embodiments of the compound of formula (I-C), m is 4, and R 1a Groups are located at the 2-position, the 6-position, the 7-position, and the 8-position. As long as there is more than one R 1aFor the group, R can be independently selected. 1a For the group. In any of these embodiments of the compound of formula (I-C) or its salt, the carbon bearing the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0153] In some embodiments of formula (I-C) (including the embodiments describing R 1a and the m variable), R 10 、R 11 、R 12 and R 13 each is hydrogen. In some embodiments of formula (I-C) (including the embodiments describing R 1a and the m variable and / or R 10 、R 11 、R 12 and R 13 variables), q is 0. In some embodiments of formula (I-C) (including the embodiments describing R 1a and the m variable and / or R 10 、R 11 、R 12 and R 13 variables and / or the q variable), p is 3, 4 or 5.

[0154] In some embodiments of formula (I-C), R 10 、R 11 、R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound is a compound of formula (II-C):

[0155]

[0156] or its salt, wherein R 1a and R 2 are as defined in formula (I), m is 0, 1, 2, 3 or 4, and the positions on the pyrido[3,2-d]pyrimidine ring are as shown. All descriptions of R 1a 、R 2 and m of formula (I) apply equally to formula (I-C) and (II-C).

[0157] In some embodiments of the compound of formula (I), wherein R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a , the compound is a compound of formula (I-D):

[0158]

[0159] or its salt, wherein R 1a 、R 2 、R10 , R 11 , R 12 , R 13 , R 14 , q and p are defined as in formula (I), m is 0, 1, 2, 3 or 4, and the positions on the pyrido[3,4-d]pyrimidine ring are as shown.

[0160] In one embodiment, there is provided a compound of formula (I-D) or a salt thereof, wherein the carbon bearing the CO2H and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-D) or a salt thereof, wherein the carbon bearing the CO2H and NH moieties is in the "R" configuration. Also covered are mixtures of compounds of formula (I-D), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds having different chemical formulas.

[0161] In some embodiments of the compound of formula (I-D), m is 0, 1, 2, 3 or 4, and each R 1a is independently, where applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium. In further embodiments of the compound of formula (I-D), m is 0, 1, 2, 3 or 4, and each R 1a is independently, where applicable, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which may be C1-C6 perhaloalkyl in one variant), C1-C6 alkoxy, hydroxy, -CN or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and 5- to 10-membered heteroaryl of R 1a are independently optionally substituted with deuterium. In some embodiments of the compound of formula (I-D), m is 1, 2, 3 or 4.

[0162] In some embodiments of the compound of formula (I-D), m is 0. In some embodiments of the compound of formula (I-D), m is 1, and R 1a is at the 2-position. In some embodiments of the compound of formula (I-D), m is 1, and R 1a is at the 5-position. In some embodiments of the compound of formula (I-D), m is 1, and R 1a is at the 6-position. In some embodiments of the compound of formula (I-D), m is 1, and R 1a is at the 8-position. In some embodiments of the compound of formula (I-D), m is 2, and R 1a groups are at the 2- and 5-positions. In some embodiments of the compound of formula (I-D), m is 2, and R 1aThe group is at the 2- and 6-positions. In some embodiments of the compound of formula (I-D), m is 2, and R 1a The group is at the 2- and 8-positions. In some embodiments of the compound of formula (I-D), m is 2, and R 1a The group is at the 5- and 6-positions. In some embodiments of the compound of formula (I-D), m is 2, and R 1a The group is at the 5- and 8-positions. In some embodiments of the compound of formula (I-D), m is 2, and R 1a The group is at the 6- and 8-positions. In some embodiments of the compound of formula (I-D), m is 3, and R 1a The group is at the 2-, 5- and 6-positions. In some embodiments of the compound of formula (I-D), m is 3, and R 1a The group is at the 2-, 5- and 8-positions. In some embodiments of the compound of formula (I-D), m is 3, and R 1a The group is at the 2-, 6- and 8-positions. In some embodiments of the compound of formula (I-D), m is 3, and R 1a The group is at the 5-, 6- and 8-positions. In some embodiments of the compound of formula (I-D), m is 4, and R 1a The group is at the 2-, 5-, 6- and 8-positions. As long as there is more than one R 1a group, the R 1a group can be independently selected. In any of these embodiments of the compound of formula (I-D) or its salt, the carbon bearing the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0163] In some embodiments of formula (I-D) (including embodiments describing R 1a and the m variable), R 10 , R 11 , R 12 and R 13 are each hydrogen. In some embodiments of formula (I-D) (including embodiments describing R 1a and the m variable and / or R 10 , R 11 , R 12 and R 13 variables), q is 0. In some embodiments of formula (I-D) (including embodiments describing R 1a and the m variable and / or R 10 , R 11 , R 12 and R 13 variables and / or the q variable), p is 3, 4 or 5.

[0164] In some embodiments of formula (I-D), R 10 , R 11 , R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound is a compound of formula (II-D):

[0165]

[0166] or a salt thereof, wherein R 1a and R 2 are as defined in formula (I), m is 0, 1, 2, 3 or 4, and the positions on the pyrido[3,4-d]pyrimidine ring are as shown. All descriptions of R 1a , R 2 and m in formula (I) apply equally to formula (I-D) and (II-D).

[0167] In some embodiments of the compound of formula (I), wherein R 1 is a 5- to 10-membered heteroaryl optionally substituted with R 1a , the compound is a compound of formula (I-E):

[0168]

[0169] or a salt thereof, wherein R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined in formula (I), m is 0, 1, 2, 3 or 4, and the positions on the pyrido[2,3-d]pyrimidine ring are as shown.

[0170] In one embodiment, there is provided a compound of formula (I-E) or a salt thereof, wherein the carbon bearing the CO2H and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-E) or a salt thereof, wherein the carbon bearing the CO2H and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (I-E), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds having different chemical formulas.

[0171] In some embodiments of the compound of formula (I-E), m is 0, 1, 2, 3 or 4, and each R 1a is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, where R 1aThe alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl groups are each independently optionally substituted with deuterium. In further embodiments of the compounds of formula (I-E), m is 0, 1, 2, 3 or 4, and each R 1a is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which may be C1-C6 perhaloalkyl in one variation), C1-C6 alkoxy, hydroxy, -CN or 5- to 10-membered heteroaryl, where the R 1a groups of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and 5- to 10-membered heteroaryl are each independently optionally substituted with deuterium. In some embodiments of the compounds of formula (I-E), m is 1, 2, 3 or 4.

[0172] In some embodiments of the compounds of formula (I-E), m is 0. In some embodiments of the compounds of formula (I-E), m is 1, and R 1a is at the 2-position. In some embodiments of the compounds of formula (I-E), m is 1, and R 1a is at the 5-position. In some embodiments of the compounds of formula (I-E), m is 1, and R 1a is at the 6-position. In some embodiments of the compounds of formula (I-E), m is 1, and R 1a is at the 7-position. In some embodiments of the compounds of formula (I-E), m is 2, and the R 1a groups are at the 2- and 5-positions. In some embodiments of the compounds of formula (I-E), m is 2, and the R 1a groups are at the 2- and 6-positions. In some embodiments of the compounds of formula (I-E), m is 2, and the R 1a groups are at the 2- and 7-positions. In some embodiments of the compounds of formula (I-E), m is 2, and the R 1a groups are at the 5- and 6-positions. In some embodiments of the compounds of formula (I-E), m is 2, and the R 1a groups are at the 5- and 7-positions. In some embodiments of the compounds of formula (I-E), m is 2, and the R 1a groups are at the 6- and 7-positions. In some embodiments of the compounds of formula (I-E), m is 3, and the R 1a groups are at the 2-, 5- and 6-positions. In some embodiments of the compounds of formula (I-E), m is 3, and the R 1a groups are at the 2-, 5- and 7-positions. In some embodiments of the compounds of formula (I-E), m is 3, and the R 1a groups are at the 2-, 6- and 7-positions. In some embodiments of the compounds of formula (I-E), m is 3, and the R 1aThe group is located at the 5-, 6-, and 7-positions. In some embodiments of the compound of formula (I-E), m is 4, and R 1a The group is located at the 2-, 5-, 6-, and 7-positions. As long as there is more than one R 1a group, the R 1a group can be independently selected. In any of these embodiments of the compound of formula (I-E) or its salt, the carbon bearing the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0173] In some embodiments of formula (I-E) (including the embodiments describing R 1a and the m variable), each of R 10 , R 11 , R 12 , and R 13 is hydrogen. In some embodiments of formula (I-E) (including the embodiments describing R 1a and the m variable and / or R 10 , R 11 , R 12 , and R 13 variables), q is 0. In some embodiments of formula (I-E) (including the embodiments describing R 1a and the m variable and / or R 10 , R 11 , R 12 , and R 13 variables and / or the q variable), p is 3, 4, or 5.

[0174] In some embodiments of formula (I-E), R 10 , R 11 , R 12 , and R 13 are hydrogen, p is 3, q is 0, and the compound is a compound of formula (II-E):

[0175]

[0176] or its salt, wherein R 1a and R 2 are as defined in formula (I), m is 0, 1, 2, 3, or 4, and the positions on the pyrido[2,3-d]pyrimidine ring are as shown. All descriptions of R 1a , R 2 , and m in formula (I) apply equally to formula (I-E) and (II-E).

[0177] In some embodiments of the compound of formula (I), wherein R 1 is a 5- to 10-membered heteroaryl optionally substituted with R 1a , the compound is a compound of formula (I-F):

[0178]

[0179] or a salt thereof, wherein R 1a 、R 2 、R 10 、R 11 、R 12 、R 13 、R 14 、q and p are as defined in formula (I), m is 0, 1, 2, 3, 4, 5 or 6, and the positions on the quinoline ring are as shown.

[0180] In one embodiment, there is provided a compound of formula (I-F) or a salt thereof, wherein the carbon bearing the CO2H and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-F) or a salt thereof, wherein the carbon bearing the CO2H and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (I-F), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds having different chemical formulas.

[0181] In some embodiments of the compound of formula (I-F), m is 0, 1, 2, 3, 4, 5 or 6, and each R 1a is independently, where applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium. In further embodiments of the compound of formula (I-F), m is 0, 1, 2, 3, 4, 5 or 6, and each R 1a is independently, where applicable, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which may be C1-C6 perhaloalkyl in one variation), C1-C6 alkoxy, hydroxy, -CN or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and 5- to 10-membered heteroaryl of R 1a are independently optionally substituted with deuterium. In some embodiments of the compound of formula (I-F), m is 1, 2, 3, 4, 5 or 6.

[0182] In some embodiments of the compound of formula (I-F), m is 0. In some embodiments of the compound of formula (I-F), m is 1, and R 1a is at the 2-position. In some embodiments of the compound of formula (I-F), m is 1, and R 1a is at the 3-position. In some embodiments of the compound of formula (I-F), m is 1, and R 1a is at the 5-position. In some embodiments of the compound of formula (I-F), m is 1, and R 1ais at the 6-position. In some embodiments of the compound of formula (I-F), m is 1, and R 1a is at the 7-position. In some embodiments of the compound of formula (I-F), m is 1, and R 1a is at the 8-position. In some embodiments of the compound of formula (I-F), m is 2, and R 1a groups are at the 2- and 3-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a groups are at the 2- and 5-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a groups are at the 2- and 6-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a groups are at the 2- and 7-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a groups are at the 2- and 8-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a groups are at the 3- and 5-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a groups are at the 3- and 6-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a groups are at the 3- and 7-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a groups are at the 3- and 8-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a groups are at the 5- and 6-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a groups are at the 5- and 7-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a groups are at the 5- and 8-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a groups are at the 6- and 7-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a groups are at the 6- and 8-positions. In some embodiments of the compound of formula (I-F), m is 2, and R 1a groups are at the 7- and 8-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a groups are at the 2-, 3- and 5-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1a groups are at the 2-, 3- and 6-positions. In some embodiments of the compound of formula (I-F), m is 3, and R 1aThe group is located at the 2-position, 3-position and 7-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 2-position, 3-position and 8-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 2-position, 5-position and 6-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 2-position, 5-position and 7-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 2-position, 5-position and 8-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 2-position, 6-position and 7-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 2-position, 6-position and 8-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 2-position, 7-position and 8-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 3-position, 5-position and 6-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 3-position, 5-position and 7-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 3-position, 5-position and 8-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 3-position, 6-position and 7-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 3-position, 6-position and 8-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 3-position, 7-position and 8-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 5-position, 6-position and 7-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 5-position, 6-position and 8-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 5-position, 7-position and 8-position. In some embodiments of the compound of formula (I-F), m is 3, and R 1a The group is located at the 6-position, 7-position and 8-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1aThe group is located at the 2-position, 3-position, 5-position, and 6-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is located at the 2-position, 3-position, 5-position, and 7-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is located at the 2-position, 3-position, 5-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is located at the 2-position, 3-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is located at the 2-position, 3-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is located at the 2-position, 3-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is located at the 2-position, 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is located at the 2-position, 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is located at the 2-position, 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is located at the 2-position, 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is located at the 3-position, 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is located at the 3-position, 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is located at the 3-position, 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is located at the 3-position, 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 4, and R 1a The group is located at the 5-position, 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 5, and R 1a The group is located at the 2-position, 3-position, 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-F), m is 5, and R 1a The group is located at the 2-position, 3-position, 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-F), m is 5, and R 1aThe group is located at the 2-, 3-, 5-, 7- and 8-positions. In some embodiments of the compound of formula (I-F), m is 5, and R 1a The group is located at the 2-, 3-, 6-, 7- and 8-positions. In some embodiments of the compound of formula (I-F), m is 5, and R 1a The group is located at the 2-, 5-, 6-, 7- and 8-positions. In some embodiments of the compound of formula (I-F), m is 5, and R 1a The group is located at the 3-, 5-, 6-, 7- and 8-positions. In some embodiments of the compound of formula (I-F), m is 6, and R 1a The group is located at the 2-, 3-, 5-, 6-, 7- and 8-positions. As long as there is more than one R 1a group, the R 1a group can be independently selected. In any of these embodiments of the compound of formula (I-F) or its salt, the carbon bearing the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0183] In some embodiments of formula (I-F) (including the embodiments describing the R 1a and m variables), R 10 , R 11 , R 12 and R 13 are each hydrogen. In some embodiments of formula (I-F) (including the embodiments describing the R 1a and m variables and / or R 10 , R 11 , R 12 and R 13 variables), q is 0. In some embodiments of formula (I-F) (including the embodiments describing the R 1a and m variables and / or R 10 , R 11 , R 12 and R 13 variables and / or the q variable), p is 3, 4 or 5.

[0184] In some embodiments of formula (I-F), R 10 , R 11 , R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound is a compound of formula (II-F):

[0185]

[0186] or its salt, wherein R 1a and R 2As defined by formula (I), m is 0, 1, 2, 3, 4, 5 or 6, and the positions on the quinoline ring are as shown. Regarding R of formula (I) 1a 、R 2 and all descriptions of m apply equally to formulae (I-F) and (II-F).

[0187] In some embodiments of the compounds of formula (I), wherein R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a , the compound is a compound of formula (I-G):

[0188]

[0189] or a salt thereof, wherein R 1a 、R 2 、R 10 、R 11 、R 12 、R 13 、R 14 、q and p are as defined by formula (I), m is 0, 1, 2, 3, 4, 5 or 6, and the positions on the isoquinoline ring are as shown.

[0190] In one embodiment, there is provided a compound of formula (I-G) or a salt thereof, wherein the carbon bearing the CO2H and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-G) or a salt thereof, wherein the carbon bearing the CO2H and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (I-G), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds having different chemical formulae.

[0191] In some embodiments of the compounds of formula (I-G), m is 0, 1, 2, 3, 4, 5 or 6, and each R 1a is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted by deuterium. In further embodiments of the compounds of formula (I-G), m is 0, 1, 2, 3, 4, 5 or 6, and each R 1a is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which may be C1-C6 perhaloalkyl in one variant), C1-C6 alkoxy, hydroxy, -CN or 5- to 10-membered heteroaryl, wherein R 1aThe C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxyl, and 5- to 10-membered heteroaryl are each independently and optionally substituted with deuterium. In some embodiments of the compound of formula (I-G), m is 1, 2, 3, 4, 5, or 6.

[0192] In some embodiments of the compound of formula (I-G), m is 0. In some embodiments of the compound of formula (I-G), m is 1, and R 1a is at the 3-position. In some embodiments of the compound of formula (I-G), m is 1, and R 1a is at the 4-position. In some embodiments of the compound of formula (I-G), m is 1, and R 1a is at the 5-position. In some embodiments of the compound of formula (I-G), m is 1, and R 1a is at the 6-position. In some embodiments of the compound of formula (I-G), m is 1, and R 1a is at the 7-position. In some embodiments of the compound of formula (I-G), m is 1, and R 1a is at the 8-position. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are at the 3- and 4-positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are at the 4- and 5-positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are at the 4- and 6-positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are at the 4- and 7-positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are at the 4- and 8-positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are at the 3- and 5-positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are at the 3- and 6-positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are at the 3- and 7-positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are at the 3- and 8-positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are at the 5- and 6-positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1a groups are at the 5- and 7-positions. In some embodiments of the compound of formula (I-G), m is 2, and R 1aThe group is located at the 5-position and 8-position. In some embodiments of the compound of formula (I-G), m is 2, and R 1a The group is located at the 6-position and 7-position. In some embodiments of the compound of formula (I-G), m is 2, and R 1a The group is located at the 6-position and 8-position. In some embodiments of the compound of formula (I-G), m is 2, and R 1a The group is located at the 7-position and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 3-position, 4-position and 5-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 3-position, 4-position and 6-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 3-position, 4-position and 7-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 3-position, 4-position and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 4-position, 5-position and 6-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 4-position, 5-position and 7-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 4-position, 5-position and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 4-position, 6-position and 7-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 4-position, 6-position and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 4-position, 7-position and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 3-position, 5-position and 6-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 3-position, 5-position and 7-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 3-position, 5-position and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 3-position, 6-position and 7-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 3-position, 6-position and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R1a The group is located at the 3-position, 7-position and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 5-position, 6-position and 7-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 5-position, 6-position and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 5-position, 7-position and 8-position. In some embodiments of the compound of formula (I-G), m is 3, and R 1a The group is located at the 6-position, 7-position and 8-position. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is located at the 3-position, 4-position, 5-position and 6-position. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is located at the 3-position, 4-position, 5-position and 7-position. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is located at the 3-position, 4-position, 5-position and 8-position. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is located at the 3-position, 4-position, 6-position and 7-position. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is located at the 4-position, 3-position, 6-position and 8-position. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is located at the 3-position, 4-position, 7-position and 8-position. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is located at the 4-position, 5-position, 6-position and 7-position. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is located at the 4-position, 5-position, 6-position and 8-position. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is located at the 4-position, 5-position, 7-position and 8-position. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is located at the 4-position, 6-position, 7-position and 8-position. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is located at the 3-position, 5-position, 6-position and 7-position. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is located at the 3-position, 5-position, 6-position and 8-position. In some embodiments of the compound of formula (I-G), m is 4, and R 1aThe group is located at the 3-position, 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is located at the 3-position, 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 4, and R 1a The group is located at the 5-position, 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 5, and R 1a The group is located at the 3-position, 4-position, 5-position, 6-position, and 7-position. In some embodiments of the compound of formula (I-G), m is 5, and R 1a The group is located at the 3-position, 4-position, 5-position, 6-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 5, and R 1a The group is located at the 3-position, 4-position, 5-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 5, and R 1a The group is located at the 3-position, 4-position, 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 5, and R 1a The group is located at the 4-position, 5-position, 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 5, and R 1a The group is located at the 3-position, 5-position, 6-position, 7-position, and 8-position. In some embodiments of the compound of formula (I-G), m is 6, and R 1a The group is located at the 3-position, 4-position, 5-position, 6-position, 7-position, and 8-position. As long as there is more than one R 1a group, the R 1a groups can be independently selected. In any of these embodiments of the compound of formula (I-G) or its salt, the carbon bearing the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0193] In some embodiments of formula (I-G) (including the embodiments describing the R 1a and m variables), each of R 10 , R 11 , R 12 , and R 13 is hydrogen. In some embodiments of formula (I-G) (including the embodiments describing the R 1a and m variables and / or the R 10 , R 11 , R 12 , and R 13 variables), q is 0. In some embodiments of formula (I-G) (including the embodiments describing the R 1a and m variables and / or the R 10 , R 11 , R12 and R 13 In embodiments of the p variable and / or the q variable), p is 3, 4, or 5.

[0194] In some embodiments of formula (I-G), R 10 , R 11 , R 12 and R 13 is hydrogen, p is 3, q is 0, and the compound is a compound of formula (II-G):

[0195]

[0196] or a salt thereof, wherein R 1a and R 2 are as defined in formula (I), m is 0, 1, 2, 3, 4, 5, or 6, and the positions on the isoquinoline ring are as shown. Regarding R 1a , R 2 and m in formula (I), all descriptions thereof apply equally to formula (I-G) and (II-G).

[0197] In some embodiments of the compound of formula (I), wherein R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a , the compound is a compound of formula (I-H):

[0198]

[0199] or a salt thereof, wherein R 1a , R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , q and p are as defined in formula (I), m is 0, 1, or 2, and the positions on the 1-methyl-1H-pyrazolo[3,4-d]pyrimidine ring are as shown.

[0200] In one embodiment, there is provided a compound of formula (I-H) or a salt thereof, wherein the carbon bearing the CO2H and NH moieties is in the "S" configuration. In another embodiment, there is provided a compound of formula (I-H) or a salt thereof, wherein the carbon bearing the CO2H and NH moieties is in the "R" configuration. Also encompassed are mixtures of compounds of formula (I-H), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds having different chemical formulas.

[0201] In some embodiments of the compound of formula (I-H), m is 0, 1, or 2, and each R 1aIndependently, when applicable, is deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, where R 1a The alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl are independently optionally substituted with deuterium. In further embodiments of the compound of formula (I-H), m is 0, 1 or 2, and each R 1a Independently, when applicable, is deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which may be C1-C6 perhaloalkyl in one variation), C1-C6 alkoxy, hydroxy, -CN or 5- to 10-membered heteroaryl, where R 1a The C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and 5- to 10-membered heteroaryl are independently optionally substituted with deuterium. In some embodiments of the compound of formula (I-H), m is 1 or 2.

[0202] In some embodiments of the compound of formula (I-H), m is 0. In some embodiments of the compound of formula (I-H), m is 1 and R 1a Is at the 3-position. In some embodiments of the compound of formula (I-H), m is 1 and R 1a Is at the 6-position. In some embodiments of the compound of formula (I-H), m is 2 and R 1a Groups are at the 3- and 6-positions. As long as there is more than one R 1a Group, the R 1a Groups can be independently selected. In any of these embodiments of the compound of formula (I-H) or its salt, the carbon bearing the CO2H and NH moieties can be in the "S" configuration or the "R" configuration.

[0203] In some embodiments of formula (I-H) (including embodiments describing the R 1a And m variables), R 10 , R 11 , R 12 And R 13 Each of which is hydrogen. In some embodiments of formula (I-H) (including embodiments describing the R 1a And m variables and / or R 10 , R 11 , R 12 And R 13 Variables), q is 0. In some embodiments of formula (I-H) (including embodiments describing the R 1a And m variables and / or R 10 , R 11 , R 12 And R 13 Variables and / or q variables), p is 3, 4 or 5.

[0204] In some embodiments of formula (I-H), R 10 , R 11 , R 12 and R 13 are hydrogen, p is 3, q is 0, and the compound is a compound of formula (II-H):

[0205]

[0206] or a salt thereof, wherein R 1a and R 2 are as defined in formula (I), m is 0, 1 or 2, and the positions on the 1-methyl-1H-pyrazolo[3,4-d]pyrimidine ring are as shown. All descriptions of R 1a , R 2 and m in formula (I) also apply to formula (I-H) and (II-H).

[0207] There is also provided a compound of formula (I) or a compound of formula (II) or a salt thereof, wherein R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a . In some embodiments, R 1 is an unsubstituted 5- to 10-membered heteroaryl (e.g., pyridyl, pyrimidinyl, quinoxalinyl, quinazolinyl, pyrazolopyrimidinyl, quinolinyl, pyridopyrimidinyl, thienopyrimidinyl, pyridyl, pyrrolopyrimidinyl, benzothiazolyl, isoquinolinyl, purinyl or benzoxazolyl). In some embodiments, R 1 is a 5- to 10-membered heteroaryl substituted by 1, 2, 3, 4 or 5 identical or different R 1a groups, wherein each R 1a is independently selected from halogen (e.g., fluorine, chlorine or bromine), C1-C6 alkyl optionally substituted by halogen (e.g., -CH3, -CHF2, -CF3 or C(CH3)3), C3-C6 cycloalkyl (e.g., cyclopropyl), 5- to 10-membered heteroaryl (e.g., pyridyl or pyrazolyl), C6-C 14 aryl (e.g., phenyl), -CN, -OR 3 (e.g., -OCH3) and -NR 4 R 5 (e.g., -N(CH3)2). In some embodiments, R 1 is a 5-membered heteroaryl (e.g., pyrazolyl) substituted by 1, 2, 3 or 4 R 1a groups, the R 1a groups may be the same or different and are selected from -CH3, -CH2F, -CHF2 and -CF3. In some embodiments, R 1 is a 5- to 10-membered heteroaryl substituted by 1, 2, 3, 4 or 5 R 1aGroup-substituted 6-membered heteroaryl (e.g., pyridyl, pyrimidinyl or pyrazinyl), said R 1a groups may be the same or different and are selected from halogen (e.g., fluorine, chlorine or bromine), C3-C6 cycloalkyl (e.g., cyclopropyl), 5- to 6-membered heteroaryl (e.g., pyridyl or pyrazolyl), C6-C 10 aryl (e.g., phenyl), C1-C4 alkyl optionally substituted with halogen (e.g., -CH3, -CF3 or C(CH3)3), -CN, -OR 3 (e.g., -OCH3) and NR 4 R 5 (e.g., -N(CH3)2). In some embodiments, R 1 is a 9-membered heteroaryl (e.g., pyrazolopyrimidinyl, pyrrolopyrimidinyl, thiophenopyrimidinyl, indazolyl, indolyl or benzimidazolyl) substituted with 1, 2, 3, 4 or 5 R 1a groups, said R 1a groups may be the same or different and are selected from -CH3, -CH2F, -CHF2 and -CF3. In some embodiments, R 1 is a 10-membered heteroaryl (e.g., quinazolinyl) substituted with 1, 2, 3, 4 or 5 R 1a groups, said R 1a groups may be the same or different and are selected from halogen (e.g., fluorine or chlorine), 5- to 6-membered heteroaryl (e.g., pyridyl), C1 alkyl optionally substituted with halogen (e.g., -CH3 or -CF3) and -OR 3 (e.g., -OCH3).

[0208] There is also provided a compound of formula (I) or a compound of formula (II) or a salt thereof, wherein R 1 is selected from the group consisting of: and any one of the foregoing groups, wherein any one or more hydrogen atoms are replaced by one or more deuterium atoms. There is also provided a compound of formula (I) or a compound of formula (II) or a salt thereof, wherein R 1 is selected from any one of the foregoing groups in which any one or more hydrogen atoms are replaced by one or more tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon in the foregoing groups may be replaced by the corresponding isotope (e.g., deuterium or tritium). Each hydrogen bonded to an acyclic carbon (e.g., methyl or methoxy carbon) in the foregoing groups may be replaced by the corresponding isotope (e.g., deuterium or tritium). Further, for example, the foregoing groups may be fully deuterated, where each hydrogen is replaced by deuterium; or fully tritiated, where each hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the foregoing groups may be13 C substitution. For example, in the polycycles of the foregoing groups, one or more ring carbons directly bonded to the rest of the compound in the ring can be 13 C substitution. In the polycycles of the foregoing groups, one or more ring carbons can be 13 C substitution, and the ring where the ring substitution is bonded to the rest of the compound or fused to the ring bonded to the rest of the compound. Further, for example, each ring carbon in the foregoing groups can be 13 C substitution.

[0209] There is also provided a compound of formula (I) or a compound of formula (II) or a salt thereof, wherein R 1 is selected from the group consisting of: and any one of the foregoing groups, wherein any one or more hydrogen atoms are replaced by one or more deuterium atoms. There is also provided a compound of formula (I) or a compound of formula (II) or a salt thereof, wherein R1 is selected from any one of the foregoing groups in which any one or more hydrogen atoms are replaced by one or more tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon in the foregoing groups can be replaced by the corresponding isotope (e.g., deuterium or tritium). Each hydrogen bonded to an acyclic carbon (e.g., methyl or methoxy carbon) in the foregoing groups can be replaced by the corresponding isotope (e.g., deuterium or tritium). Further, for example, the foregoing groups can be fully deuterated, where each hydrogen is replaced by deuterium; or fully tritiated, where each hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the foregoing groups can be 13 C substitution. For example, in the polycycles of the foregoing groups, one or more ring carbons directly bonded to the rest of the compound in the ring can be 13 C substitution. In the polycycles of the foregoing groups, one or more ring carbons can be 13 C substitution, and the ring where the ring substitution is bonded to the rest of the compound or fused to the ring bonded to the rest of the compound. Further, for example, each ring carbon in the foregoing groups can be 13 C substitution.

[0210] There is also provided a compound of formula (I) or a compound of formula (II) or a salt thereof, wherein R 1 is selected from the group consisting of: and any one of the foregoing groups, wherein any one or more hydrogen atoms are replaced by one or more deuterium atoms. Also provided is a compound of formula (I) or a compound of formula (II) or a salt thereof, wherein R1 is selected from any one of the foregoing groups in which any one or more hydrogen atoms are replaced by one or more tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon in the foregoing group may be replaced by a corresponding isotope (e.g., deuterium or tritium). Each hydrogen bonded to an acyclic carbon (e.g., methyl or methoxy carbon) in the foregoing group may be replaced by a corresponding isotope (e.g., deuterium or tritium). Further, for example, the foregoing group may be fully deuterated, wherein each hydrogen is replaced by deuterium; or fully tritiated, wherein each hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the foregoing group may be replaced by 13 C. For example, in a polycycle in the foregoing group, one or more ring carbons directly bonded to the rest of the compound in the ring may be replaced by 13 C. In a polycycle in the foregoing group, one or more ring carbons may be replaced by 13 C in the ring, and the ring substitution bonds to the ring bonded to the rest of the compound or is fused to the ring bonded to the rest of the compound. Further, for example, each ring carbon in the foregoing group may be replaced by 13 C.

[0211] Also provided is a compound of formula (I) or a compound of formula (II) or a salt thereof, wherein R 1 is selected from the group consisting of: and any one of the foregoing groups, wherein any one or more hydrogen atoms are replaced by one or more deuterium atoms. Also provided is a compound of formula (I) or a compound of formula (II) or a salt thereof, wherein R1 is selected from any one of the foregoing groups in which any one or more hydrogen atoms are replaced by one or more tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon in the foregoing group may be replaced by a corresponding isotope (e.g., deuterium or tritium). Each hydrogen bonded to an acyclic carbon (e.g., methyl or methoxy carbon) in the foregoing group may be replaced by a corresponding isotope (e.g., deuterium or tritium). Further, for example, the foregoing group may be fully deuterated, wherein each hydrogen is replaced by deuterium; or fully tritiated, wherein each hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the foregoing group may be replaced by 13 C. For example, in a polycycle in the foregoing group, one or more ring carbons directly bonded to the rest of the compound in the ring may be replaced by 13 C. In a polycycle in the foregoing group, one or more ring carbons may be replaced by 13C substitution, wherein the ring substitution is a ring bonded to the remainder of the compound or fused to the ring bonded to the remainder of the compound. Further, for example, each ring carbon in the foregoing groups may be replaced by 13 C substitution.

[0212] There is also provided a compound of formula (I) or a compound of formula (II) or a salt thereof, wherein R 1 is selected from the group consisting of: and any one of the foregoing groups, wherein any one or more hydrogen atoms are replaced by one or more deuterium atoms. There is also provided a compound of formula (I) or a compound of formula (II) or a salt thereof, wherein R 1 is selected from any one of the foregoing groups in which any one or more hydrogen atoms are replaced by one or more tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon in the foregoing groups may be replaced by the corresponding isotope (e.g., deuterium or tritium). Each hydrogen bonded to an acyclic carbon (e.g., methyl or methoxy carbon) in the foregoing groups may be replaced by the corresponding isotope (e.g., deuterium or tritium). Further, for example, the foregoing groups may be fully deuterated, wherein each hydrogen is replaced by deuterium; or fully tritiated, wherein each hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the foregoing groups may be replaced by 13 C substitution. For example, in a polycycle in the foregoing groups, one or more ring carbons directly bonded to the remainder of the compound in the ring may be replaced by 13 C substitution. In a polycycle in the foregoing groups, one or more ring carbons may be replaced by 13 C substitution in the ring, wherein the ring substitution is a ring bonded to the remainder of the compound or fused to the ring bonded to the remainder of the compound. Further, for example, each ring carbon in the foregoing groups may be replaced by 13 C substitution.

[0213] R described herein as part of 1 the group (shown with the symbol) is shown as being connected at a specific position (e.g., pyrimidin-4-yl, quinazolin-4-yl, isoquinolin-1-yl), but it may also be connected by any other available valence (e.g., pyrimidin-2-yl). In some embodiments of the compound of formula (I) or the compound of formula (II) or a salt thereof, R 1 is wherein m is 0, 1, 2 or 3, and each R 1a is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl when applicable, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium. In further embodiments of the compound of formula (I) or the compound of formula (II) or a salt thereof, R1 is wherein m is 1, 2 or 3, and each R 1a independently is deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium. In another embodiment, R 1 is wherein m is 0, 1, 2, 3, 4 or 5, and each R 1a independently is deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, where applicable, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium. In a further embodiment of the compound of formula (I) or formula (II) or a salt thereof, R 1 is wherein m is 1, 2, 3, 4 or 5, and each R 1a independently is deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium. In a further variation of such embodiments, each R 1a independently is deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl (which may be C1-C6 perhaloalkyl in one variation), C1-C6 alkoxy, hydroxy, -CN or 5- to 10-membered heteroaryl, where applicable, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and 5- to 10-membered heteroaryl of R 1a are independently optionally substituted with deuterium.

[0214] In some embodiments of the compounds of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or salts thereof, R 2 is C1-C6 alkyl optionally substituted with R 2a . In some embodiments, R 2 is C1-C6 alkyl optionally substituted with R 2a , wherein R 2ais: halogen (e.g., fluorine); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluorine); 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., pyrazolyl optionally substituted by methyl); -S(O)2R 3 ; -NR 4 R 5 ; -NR 3 C(O)R 4 ; oxo group; or -OR 3 。In some embodiments, R 2 is C1-C6 alkyl optionally substituted by R 2a , where R 2a is: halogen (e.g., fluorine); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluorine); 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., pyrazolyl optionally substituted by methyl); 3- to 12-membered heterocyclic group optionally substituted by halogen (e.g., oxetanyl optionally substituted by fluorine); -S(O)2R 3 ; -NR 4 R 5 ; -NR 3 C(O)R 4 ; oxo group; or -OR 3 。In some embodiments, R 2 is C1-C6 alkyl optionally substituted by -OR 3 , where R 3 is: hydrogen; C1-C6 alkyl optionally substituted by halogen (e.g., methyl, ethyl, difluoromethyl, -CH2CHF2, and -CH2CF3); C3-C6 cycloalkyl optionally substituted by halogen (e.g., cyclopropyl substituted by fluorine); C6-C 14 aryl optionally substituted by halogen (e.g., phenyl optionally substituted by fluorine); or 5- to 6-membered heteroaryl optionally substituted by halogen or C1-C6 alkyl (e.g., pyridyl optionally substituted by fluorine or methyl). In some embodiments, R 2 is –CH2CH2OCH3. In some embodiments, R 2 is C1-C6 alkyl substituted by both halogen and OR 3 . In some embodiments, R 2 is n-propyl substituted by both halogen and alkoxy (e.g., -CH2CH(F)CH2OCH3). In some embodiments, where R 2 is indicated as optionally substituted by R 2a , the R 2 moiety is unsubstituted. In some embodiments, where R 2 is indicated as optionally substituted by R2a is replaced by R 2 is partially replaced by an R 2a is replaced. In some embodiments, wherein R 2 is indicated as optionally being replaced by R 2a is replaced by R 2 is partially replaced by 2 to 6 or 2 to 5 or 2 to 4 or 2 to 3 identical or different R 2a moieties.

[0215] In some embodiments of the compounds of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or salts thereof, R 2 is an optionally R 2a -substituted C1-C6 alkyl. In some embodiments, R 2 is an optionally R 2a -substituted C1-C6 alkyl, wherein R 2a is: halogen (e.g., fluorine); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluorine); 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., pyrazolyl optionally substituted by methyl); -S(O)2R 3 ; -NR 4 R 5 ; -NR 3 C(O)R 4 ; oxo group; or -OR 3 . In some embodiments, R 2 is an optionally R 2a -substituted C1-C6 alkyl, wherein R 2a is: halogen (e.g., fluorine); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluorine); 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., pyrazolyl optionally substituted by methyl); 3- to 12-membered heterocyclic group optionally substituted by halogen (e.g., oxetanyl optionally substituted by fluorine); -S(O)2R 3 ; -NR 4 R 5 ; -NR 3 C(O)R 4 ; oxo group; or -OR 3 . In some embodiments, R 2 is an optionally R 2a -substituted C1-C6 alkyl, wherein R 2ais: halogen (e.g., fluorine); C3-C8 cycloalkyl optionally substituted by halogen (e.g., cyclobutyl optionally substituted by fluorine); C6-C 14 aryl (e.g., phenyl); 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl (e.g., thiazolyl or pyrazolyl optionally substituted by methyl); 3- to 12-membered heterocyclic group optionally substituted by halogen or oxo group (e.g., R 2a is: oxetanyl optionally substituted by fluorine; tetrahydrofuranyl; pyrrolidinyl optionally substituted by oxo group; morpholinyl optionally substituted by oxo group; or dioxolanyl); -S(O) 2 R3; -NR4R5; -NR 3 C(O)R 4 ; oxo group; -OR 3 ; or -CN. In some embodiments, R 2 is C1-C6 alkyl optionally substituted by -OR 3 , wherein R 3 is: hydrogen; C1-C6 alkyl optionally substituted by halogen (e.g., methyl, ethyl, difluoromethyl, -CH2CHF2, and -CH2CF3); C3-C6 cycloalkyl optionally substituted by halogen (e.g., cyclopropyl substituted by fluorine); C6-C 14 aryl (e.g., phenyl optionally substituted by fluorine); or 5- to 6-membered heteroaryl optionally substituted by halogen or C1-C6 alkyl (e.g., pyridinyl optionally substituted by fluorine or methyl). In some embodiments, R 2 is –CH2CH2OCH3. In some embodiments, R 2 is C1-C6 alkyl substituted by both halogen and OR 3 . In some embodiments, R 2 is n-propyl substituted by both halogen and alkoxy (e.g., -CH2CH(F)CH2OCH3). In some embodiments, wherein R 2 is indicated as optionally substituted by R 2a , the R 2 moiety is unsubstituted. In some embodiments, wherein R 2 is indicated as optionally substituted by R 2a , the R 2 moiety is substituted by one R 2a moiety. In some embodiments, wherein R 2 is indicated as optionally substituted by R 2a , the R 2 moiety is substituted by 2 to 6 or 2 to 5 or 2 to 4 or 2 to 3 identical or different R 2a moieties. In some embodiments, R 2is a C1-C6 alkyl group substituted by two identical or different halogen groups (e.g., two fluoro groups). In some embodiments, R 2 is a C1-C6 alkyl group substituted by two identical or different -OR 3 groups (e.g., two -OH groups, one -OH group and one –OCH3 group, or two –OCH3 groups). In some embodiments, R 2 is a C1-C6 alkyl group substituted by one halogen group (e.g., fluorine) and one -OR 3 group (e.g., -OH or -OCH3). In some embodiments, R 2 is a C1-C6 alkyl group substituted by two identical or different halogen groups (e.g., two fluoro groups) and one -OR 3 group (e.g., -OH or -OCH3). In some embodiments, R 2 is a C1-C6 alkyl group substituted by one halogen group (e.g., fluorine) and two identical or different -OR 3 groups (e.g., two -OH groups, one -OH group and one –OCH3 group, or two –OCH3 groups).

[0216] In some embodiments of the compounds of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or their salts, R 2 is an optionally R 2b substituted C3-C6 cycloalkyl group. In some embodiments, R 2 is a C3-C6 cycloalkyl group substituted by 1 or 2 identical or different R 2b moieties. In some embodiments, R 2 is an optionally halogen-substituted C3-C4 cycloalkyl group (e.g., unsubstituted cyclopropyl or cyclobutyl optionally substituted by fluorine). In some embodiments, R 2 is an optionally C3-C4 cycloalkyl group substituted by one or more deuterium or tritium atoms. For example, in some embodiments, each hydrogen bonded to a ring carbon in the foregoing groups can be replaced by the corresponding isotope (e.g., deuterium or tritium). Each hydrogen bonded to an acyclic carbon (e.g., methyl or methoxy carbon) in the foregoing groups can be replaced by the corresponding isotope (e.g., deuterium or tritium). Further, for example, the foregoing groups can be fully deuterated, where each hydrogen is replaced by deuterium; or fully tritiated, where each hydrogen is replaced by tritium. In some embodiments, one or more ring carbons in the foregoing groups can be 13C substitution. For example, in the polycycles of the foregoing groups, one or more ring carbons directly bonded to the remainder of the compound in the ring can be 13 C substitution. In the polycycles of the foregoing groups, one or more ring carbons can be 13 C substitution, and the ring substitution bonds to the ring bonded to the remainder of the compound or is fused to the ring bonded to the remainder of the compound. Further, for example, each ring carbon in the foregoing groups can be 13 C substitution.

[0217] In some embodiments of the compounds of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or their salts, R 2 is hydrogen.

[0218] In some embodiments of the compounds of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or their salts, R 2 is optionally substituted by R 2a substituted –O-C1-C6 alkyl. In some embodiments, R 2 is –OCH3.

[0219] Also provided is a compound of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or its salt, wherein R 2 is selected from the group consisting of: and any one of the foregoing groups, wherein any one or more hydrogen atoms are replaced by one or more deuterium atoms.

[0220] Also provided is a compound of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or its salt, wherein R 2Selected from the group consisting of: and any one of the foregoing groups, wherein any one or more hydrogen atoms are replaced by one or more deuterium atoms.

[0221] There is also provided a compound of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or a salt thereof, wherein R 2 is wherein R 3 and each R 2a is as defined in formula (I).

[0222] There is also provided a compound of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or a salt thereof, wherein R 2 is wherein each R 2a is as defined in formula (I).

[0223] There is also provided a compound of formula (I), (II), (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (I-D), (II-D), (I-E), (II-E), (I-F), (II-F), (I-G), (II-G), (I-H) or (II-H) or a salt thereof, wherein R 2 is wherein R 3 is as defined in formula (I).

[0224] In one embodiment of formula (I), the tetrahydronaphthyridine group is doubly deuterated at the 2-position.

[0225] In one aspect, there is provided a compound of formula (I) or a salt thereof (including its pharmaceutically acceptable salts), wherein the compound or its salt has one or more of the following structural features ("SF"):

[0226] (SFI) p is 3;

[0227] (SFII) Each R 10 , R 11 , R 12 , R 13is hydrogen;

[0228] (SFIII)R 1 is:

[0229] (A) unsubstituted 5- to 10-membered heteroaryl;

[0230] (B) 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4 or 5 identical or different R 1a groups;

[0231] wherein the 5- to 10-membered heteroaryl of (III)(A) and (III)(B) is:

[0232] (i) pyridyl;

[0233] (ii) pyrimidinyl;

[0234] (iii) quinoxalinyl;

[0235] (iv) quinazolinyl;

[0236] (v) pyrazolopyrimidinyl;

[0237] (vi) quinolinyl;

[0238] (vii) pyridopyrimidinyl;

[0239] (viii) thienopyrimidinyl;

[0240] (ix) purinyl;

[0241] (x) pyrrolopyrimidinyl;

[0242] (xi) benzoxazolyl;

[0243] (xii) benzothiazolyl;

[0244] (xiii) isoquinolinyl;

[0245] (xiv) indolyl;

[0246] (xv) benzimidazolyl;

[0247] (xvi) pyrazinyl;

[0248] (xvii) indazolyl; or

[0249] (xviii) pyrazolyl;

[0250] (C) unsubstituted naphthyl; or

[0251] (D) naphthyl substituted with 1, 2, 3, 4 or 5 identical or different R 1a groups;

[0252] (SFIV) Each R 1a is:

[0253] (A) a halogen, such as fluorine, chlorine or bromine;

[0254] (B) a C1-C6 alkyl group optionally substituted by a halogen, such as -CH3, -CHF2, -CF3 or C(CH3)3;

[0255] (C) a C3-C6 cycloalkyl group, such as cyclopropyl;

[0256] (D) a 5- to 10-membered heteroaryl group, such as pyridyl or pyrazolyl;

[0257] (E) a C6-C 14 aryl group, such as phenyl;

[0258] (F) –CN;

[0259] (G) –OR 3 , such as –OCH3; or

[0260] (H) -NR 4 R 5 , such as -N(CH3)2;

[0261] (SFV) R 2 is:

[0262] (A) an unsubstituted C1-C6 alkyl group, such as a C1-C2 alkyl group;

[0263] (B) a C1-C6 alkyl group, such as a C1-C2 alkyl group, each of which is substituted by 1, 2, 3, 4 or 5 identical or different R 2a groups;

[0264] (C) an unsubstituted -O-C1-C6 alkyl group, such as -O-C1-C2 alkyl group;

[0265] (D) -O-C1-C6 alkyl group, such as -O-C1-C2 alkyl group, each of which is substituted by 1, 2, 3, 4 or 5 identical or different R 2a groups;

[0266] (E) an unsubstituted C3-C6 cycloalkyl group, such as cyclopropyl or cyclobutyl; or

[0267] (F) a C3-C6 cycloalkyl group, such as cyclopropyl or cyclobutyl, each of which is substituted by 1, 2, 3, 4 or 5 identical or different R 2b groups; and

[0268] (SFVI) R 2a is:

[0269] (A) A halogen, such as fluorine;

[0270] (B) A C3-C8 cycloalkyl, such as cyclopropyl or cyclobutyl, each of which is optionally substituted with a halogen;

[0271] (C) A 5- to 10-membered heteroaryl optionally substituted with a C1-C6 alkyl, such as pyrazolyl substituted with a methyl group;

[0272] (D) A 3- to 12-membered heterocyclic group optionally substituted with a halogen or an oxo group, such as oxetanyl optionally substituted with a fluorine, unsubstituted tetrahydrofuranyl, pyrrolidinyl substituted with an oxo group, unsubstituted morpholinyl, morpholinyl substituted with an oxo group, or dioxolanyl;

[0273] (E) -S(O)2R 3 , such as -S(O)2CH3;

[0274] (F) –C(O)NR 4 R 5 , such as –C(O)N(CH3)2;

[0275] (G) -NR 3 C(O)R 4 , such as –NHC(O)CH3; or

[0276] (H) -OR 3 , where R 3 is:

[0277] (i) Hydrogen;

[0278] (ii) -CH3;

[0279] (iii) -CH2CH3;

[0280] (iv) -CH2CHF2;

[0281] (v) -CH2CF3;

[0282] (vi) A phenyl substituted with 0-2 fluoro groups; or

[0283] (vii) A pyridyl substituted with 0-1 methyl group.

[0284] It should be understood that the compounds or their salts having the formula (I) or any of its variants described herein may, in one embodiment, have any one or more of the structural features described above. For example, the compounds or their salts having the formula (I) or any of its variants described herein may, in one embodiment, have the following structural features: one or two or three or all of (SFI), (SFII), (SFIII), and (SFV). In one such instance, the compounds or their salts having the formula (I) or any of its variants described herein may, in one embodiment, have the following structural features: (SFI) and any one or two or all of (SFII), (SFIII), and (SFV), or any of its sub - embodiments. In one such instance, the compounds or their salts having the formula (I) or any of its variants described herein may, in one embodiment, have the following structural features: (SFII) and any one or two or all of (SFI), (SFIII), and (SFV), or any of its sub - embodiments. In one such instance, the compounds or their salts having the formula (I) or any of its variants described herein may, in one embodiment, have the following structural features: (SFIII) and any one or two or all of (SFI), (SFII), and (SFV), or any of its sub - embodiments. In one such instance, the compounds or their salts having the formula (I) or any of its variants described herein may, in one embodiment, have the following structural features: (SFV) and any one or two or all of (SFI), (SFII), and (SFIII), or any of its sub - embodiments. It should be understood that the sub - embodiments of the structural features can also be combined in any way. Although specific combinations of the structural features are specifically indicated below, it should be understood that each combination of the features is also covered. In one aspect of this variant, (SFI) and (SFII) apply. In another variant, (SFI) and (SFIII) apply. In another variant, (SFI) and (SFV) apply. In another variant, (SFII) and (SFIII) apply. In another variant, (SFII) and (SFV) apply. In another variant, (SFIII) and (SFV) apply. In another variant, (SFI), (SFII), and (SFIII) apply. In another variant, (SFI), (SFII), and (SFV) apply. In another variant, (SFI), (SFIII), and (SFV) apply. In another variant, (SFII), (SFIII), and (SFV) apply. It should be understood that each sub - embodiment of the structural features applies.For example, (SFIII) is (SFIII)(A)(i), (SFIII)(A)(ii), (SFIII)(A)(iii), (SFIII)(A)(iv), (SFIII)(A)(v), (SFIII)(A)(vi), (SFIII)(A)(vii), (SFIII)(A)(viii), (SFIII)(A)(ix), (SFIII)(A)(x), (SFIII)(A)(xi), (SFIII)(A)(xii), (SFIII)(A)(xiii), (SFIII)(A)(xiv), (SFIII)(A)(xv), (SFIII)(A)(xvi), (SFIII)(A)(xvii), (SFIII)(A)(xviii), (SFIII)(B)(i), (SFIII)(B)(ii), (SFIII)(B)(iii), (SFIII)(B)(iv), (SFIII)(B)(v), (SFIII)(B)(vi), (SFIII)(B)(vii), (SFIII)(B)(viii), (SFIII)(B)(ix), (SFIII)(B)(x), (SFIII)(B)(xi), (SFIII)(B)(xii), (SFIII)(B)(xiii), (SFIII)(B)(xiv), (SFIII)(B)(xv), (SFIII)(B)(xvi), (SFIII)(B)(xvii), (SFIII)(B)(xviii), (SFIII)(C) or (SFIII)(D). In one aspect of this variation, (SFV) is (SFV)(A), (SFV)(B), (SFV)(C), (SFV)(D), (SFV)(E) or (SFV)(F).

[0285] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(A) apply.In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(A) apply.In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(A) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(A) apply.

[0286] In another variant, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply.In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B) and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B) and (SFVI)(H)(ii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(ii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(ii) apply.In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(ii) apply.

[0287] In another variant, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) apply.In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(v) apply.In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B) and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B) and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B) and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B) and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B) and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B) and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B) and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B) and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B) and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B) and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B) and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B) and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B) and (SFVI)(H)(v) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B) and (SFVI)(H)(v) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(v) apply.

[0288] In another variant, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply.In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) apply.In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B) and (SFVI)(H)(vi) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B) and (SFVI)(H)(vi) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vi) apply.

[0289] In another variation, (SFI), (SFII), (SFIII)(A)(i), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(iv), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(v), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vi), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(vii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(viii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(ix), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(x), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xi), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(A)(xiii), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(ii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) apply.In another variant, (SFI), (SFII), (SFIII)(B)(iv), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(vii), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(A), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(C), (SFV)(B), and (SFVI)(H)(vii) apply. In another variant, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(D), (SFV)(B), and (SFVI)(H)(vii) apply.In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(E), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(F), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(G), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvi), (SFIV)(H), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(v), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(viii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(x), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xiv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xv), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xvii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply. In another variation, (SFI), (SFII), (SFIII)(B)(xviii), (SFIV)(B), (SFV)(B), and (SFVI)(H)(vii) apply.

[0290] Any variation or combination listed herein for the compound of formula (I) also applies to formula (A), with the addition of R 15 and R 16 for any possible combination.

[0291] Representative compounds are listed in Figure 1 below.

[0292] In some embodiments, there is provided a compound selected from compounds numbered 1 - 66 of Figure 1 or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof) or a salt thereof. In some embodiments, the compound is a salt of a compound selected from compounds numbered 1 - 66 of Figure 1 or a stereoisomer thereof.

[0293] In some embodiments, there is provided a compound selected from compounds numbered 1 - 147 or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof) or a salt thereof. In some embodiments, the compound is a compound selected from compounds numbered 1 - 147 or a stereoisomer thereof.

[0294] In some embodiments, there is provided a compound selected from compounds numbered 1 - 665 or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof) or a salt thereof. In some embodiments, the compound is a compound selected from compounds numbered 1 - 665 or a stereoisomer thereof.

[0295] In some embodiments, there is provided a compound selected from compounds numbered 1 - 780 or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof) or a salt thereof. In some embodiments, the compound is a compound selected from compounds numbered 1 - 780 or a stereoisomer thereof.

[0296] In one variation, the compounds detailed herein are selected from the group consisting of:

[0297] 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-(difluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0298] 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butyric acid;

[0299] 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butyric acid;

[0300] 4-((2-Hydroxy-2-methylpropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butyric acid;

[0301] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0302] 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0303] 2-((7-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0304] 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0305] 4-((3,3-Difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0306] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butyric acid;

[0307] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)butyric acid;

[0308] 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0309] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-(trifluoromethyl)quinazolin-4-yl)amino)butyric acid;

[0310] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)quinazolin-4-yl)amino)butyric acid;

[0311] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((8-(trifluoromethyl)quinazolin-4-yl)amino)butyric acid;

[0312] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butyric acid;

[0313] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,4-d]pyrimidin-4-ylamino)butyric acid;

[0314] 2-((5-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0315] 2-((6-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0316] 2-((8-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0317] 2-((6,7-Difluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0318] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0319] 2-((6-(Difluoromethyl)pyrimidin-4-yl)amino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0320] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0321] 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0322] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methyl-2-(trifluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0323] 4-((2-(Methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0324] 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0325] 4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0326] 4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0327] 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0328] 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0329] 4-(((3,3-Difluorocyclobutyl)methyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-fluoro-2-methylquinazolin-4-yl)amino)butyric acid;

[0330] 2-(Isoquinolin-1-ylamino)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0331] 4-((2-(Difluoromethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0332] 4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinolin-4-ylamino)butyric acid;

[0333] 2 - ((7 - chloroquinazolin - 4 - yl)amino)-4 - ((2 - methoxyethyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)butyric acid;

[0334] 2 - ((8 - chloroquinazolin - 4 - yl)amino)-4 - ((2 - methoxyethyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)butyric acid;

[0335] 2 - (quinazolin - 4 - ylamino)-4 - ((4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)(2-(2,2,2 - trifluoroethoxy)ethyl)amino)butyric acid;

[0336] 2 - ((7 - fluoro - 2 - methylquinazolin - 4 - yl)amino)-4 - ((2-(4 - fluorophenoxy)ethyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)butyric acid;

[0337] 4 - ((3 - fluoropropyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2 - ((7 - methoxyquinazolin - 4 - yl)amino)butyric acid;

[0338] 4 - ((2-(2,2 - difluorocyclopropoxy)ethyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2 - ((7 - fluoro - 2 - methylquinazolin - 4 - yl)amino)butyric acid;

[0339] 4 - ((3 - fluoropropyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2 - ((8 - methoxyquinazolin - 4 - yl)amino)butyric acid;

[0340] 2 - ((6-(1H - pyrazol - 1 - yl)pyrimidin - 4 - yl)amino)-4 - ((2 - methoxyethyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)butyric acid;

[0341] 4 - ((2-(3,5 - dimethyl - 1H - pyrazol - 1 - yl)ethyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2 - (quinazolin - 4 - ylamino)butyric acid;

[0342] 4 - (((S)-2 - fluoro - 3 - methoxypropyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2 - ((2 - methylquinazolin - 4 - yl)amino)butyric acid;

[0343] 4-((2-(3,5-difluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0344] 2-((8-chloroquinazolin-4-yl)amino)-4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0345] 4-((2-(pyridin-2-yloxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0346] 4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0347] 2-(pyrido[3,2-d]pyrimidin-4-ylamino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butyric acid;

[0348] 4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0349] 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0350] 4-((2-((2-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butyric acid;

[0351] 4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0352] 2-((7-fluoro-2-methylquinazolin-4-yl)amino)-4-((2-((6-methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0353] 4-((2-((6-Methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butyric acid;

[0354] 4-((2-((5-Fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0355] 4-((2-((6-Methylpyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0356] 4-((2-((5-Fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrido[3,2-d]pyrimidin-4-ylamino)butyric acid;

[0357] 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)4-((2-((5-fluoropyridin-3-yl)oxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0358] 4-(((R)-2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0359] 4-((2-Acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0360] 4-((2-(Dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0361] 2-((7-Fluoro-2-methylquinazolin-4-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid; and

[0362] 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butyric acid.

[0363] In another variation, the compounds detailed herein are selected from the group consisting of:

[0364] 2 - ((3 - cyanopyrazin - 2 - yl)amino)-4 - ((2 - methoxyethyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)butyric acid;

[0365] 2 - ((5 - cyanopyrimidin - 2 - yl)amino)-4 - ((2 - methoxypropyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)butyric acid;

[0366] 4 - ((2 - methoxypropyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2 - ((5-(trifluoromethyl)pyrimidin - 2 - yl)amino)butyric acid;

[0367] 2 - ((5 - bromopyrimidin - 2 - yl)amino)-4 - ((2 - methoxypropyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)butyric acid;

[0368] 2 - ((1H - pyrazolo[3,4 - d]pyrimidin - 4 - yl)amino)-4 - ((2 - methoxypropyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)butyric acid;

[0369] 4 - ((2 - methoxypropyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2 - ((2-(trifluoromethyl)pyrimidin - 4 - yl)amino)butyric acid;

[0370] 4 - ((2 - methoxypropyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2 - ((2 - phenylpyrimidin - 4 - yl)amino)butyric acid;

[0371] 4 - ((2 - methoxypropyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2 - ((1 - methyl - 1H - pyrazolo[3,4 - d]pyrimidin - 4 - yl)amino)butyric acid;

[0372] 4 - ((2 - hydroxyethyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)-2 - (quinazolin - 4 - ylamino)butyric acid;

[0373] 2 - ((3 - cyanopyrazin - 2 - yl)amino)-4 - ((2 - methoxypropyl)(4-(5,6,7,8 - tetrahydro - 1,8 - naphthyridin - 2 - yl)butyl)amino)butyric acid;

[0374] 2-((6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0375] 2-((5-Fluoropyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0376] 2-((1H-Pyrazolo[4,3-d]pyrimidin-7-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0377] 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butyric acid;

[0378] 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butyric acid;

[0379] 2-((1-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0380] 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0381] 2-((5-Cyanopyrimidin-2-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0382] 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butyric acid;

[0383] 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0384] 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0385] 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butyric acid;

[0386] 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butyric acid;

[0387] 2-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0388] 2-((6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0389] 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0390] 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butyric acid;

[0391] 4-((2-Phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butyric acid;

[0392] 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butyric acid;

[0393] 2-((5-Bromopyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0394] 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0395] 2-((6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0396] 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butyric acid;

[0397] 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butyric acid;

[0398] 2-((1-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0399] 4-((2-(Methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butyric acid;

[0400] 2-((5-Bromopyrimidin-2-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0401] 4-((2-(Methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0402] 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butyric acid;

[0403] 4-((2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butyric acid;

[0404] 4-((2-(Methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butyric acid;

[0405] 2-((6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0406] 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(pyridin-3-yl)quinazolin-4-yl)amino)butyric acid;

[0407] 4-((2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butyric acid;

[0408] 2-((5-cyanopyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0409] 2-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0410] 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butyric acid;

[0411] 4-(Cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0412] 2-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0413] 2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0414] 2-((5-Cyanopyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid;

[0415] 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-phenylpyrimidin-4-yl)amino)butanoic acid;

[0416] 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid;

[0417] 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-fluoropyrimidin-2-yl)amino)butanoic acid;

[0418] 4-((2,2-Difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)amino)butanoic acid;

[0419] 4-((2-(4-Fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid;

[0420] 2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid;

[0421] 2-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid;

[0422] 2-((6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)amino)-4-((2-(methylsulfonyl)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid;

[0423] 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(pyrimidin-4-ylamino)butanoic acid;

[0424] 4-((2-Fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butyric acid;

[0425] 4-((Oxetan-2-ylmethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0426] 4-((3-Hydroxy-2-(hydroxymethyl)propyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid;

[0427] 2-((5-Bromopyrimidin-2-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0428] 4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butyric acid;

[0429] 4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butyric acid;

[0430] 4-((3,3-Difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butyric acid;

[0431] 2-((5-Cyclopropylpyrimidin-2-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid;

[0432] 4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butyric acid;

[0433] 4-((3-Fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butyric acid;

[0434] 2-((5-Cyanopyrimidin-2-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid;

[0435] 4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid;

[0436] 4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)butanoic acid;

[0437] 4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid;

[0438] 4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((6-phenylpyrimidin-4-yl)amino)butanoic acid;

[0439] 2-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid;

[0440] 2-((5-bromopyrimidin-2-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid;

[0441] 4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-(trifluoromethyl)pyrimidin-4-yl)amino)butanoic acid;

[0442] 2-((5-cyclopropylpyrimidin-2-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid; and

[0443] 4-(((3-fluoroxetan-3-yl)methyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid.

[0444] In some embodiments, a composition, such as a pharmaceutical composition, is provided, wherein the composition comprises a compound selected from the group consisting of: Figure 1 one or more compounds of Compound Nos. 1-66 in Figure 1 or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof) or a salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of salts of one or more compounds of Compound Nos. 1-66. In one aspect, the composition is a pharmaceutical composition, which further comprises a pharmaceutically acceptable carrier.

[0445] 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 compounds of Compound Nos. 1-147 or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof) or a salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of salts of one or more compounds of Compound Nos. 1-147. In one aspect, the composition is a pharmaceutical composition, which further comprises a pharmaceutically acceptable carrier.

[0446] 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 compounds of Compound Nos. 1-665 or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof) or a salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of salts of one or more compounds of Compound Nos. 1-665. In one aspect, the composition is a pharmaceutical composition, which further comprises a pharmaceutically acceptable carrier.

[0447] 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 compounds of Compound Nos. 1-780 or a stereoisomer thereof (including a mixture of two or more stereoisomers thereof) or a salt thereof. In some embodiments, the composition comprises a compound selected from the group consisting of salts of one or more compounds of Compound Nos. 1-780. In one aspect, the composition is a pharmaceutical composition, which further comprises a pharmaceutically acceptable carrier.

[0448] The present invention also encompasses all salts of the compounds mentioned herein, such as pharmaceutically acceptable salts. The present invention also encompasses any or all stereochemical forms of the compounds, including any enantiomeric or diastereomeric forms, as well as any tautomeric or other forms. Unless the stereochemistry is explicitly indicated in the chemical structure or name, the structure or name is intended to cover all possible stereoisomers of the depicted compound. Additionally, in the case where a specific stereochemical form is described, it should be understood that the present invention also describes and encompasses other stereochemical forms. The present invention also covers all forms of the compounds, such as crystalline or non-crystalline forms of the compounds. It should also be understood that the present disclosure covers prodrugs, solvates, and metabolites of the compounds. It is also intended to include compositions of the compounds of the present invention, such as compositions of substantially pure compounds, including their specific stereochemical forms. The present invention also encompasses compositions that include mixtures of the compounds of the present invention in any proportion, including mixtures of two or more stereochemical forms of the compounds of the present invention in any proportion, thereby encompassing racemic, non-racemic, enantiomerically enriched, and scalemic mixtures of the compounds. When one or more tertiary amine moieties are present in the compound, N-oxides are also provided and described.

[0449] The compounds described herein are αvβ6 integrin inhibitors. In some cases, it is desirable that, in addition to αvβ6 integrin, the compounds also inhibit other integrins. In some embodiments, the compounds inhibit αvβ6 integrin and one or more of αvβ1, αvβ3, αvβ5, α2β1, α3β1, α6β1, α7β1, and α11β1 integrins. In some embodiments, the compounds inhibit αvβ6 integrin and αvβ1 integrin. In some embodiments, the compounds inhibit αvβ6 integrin, αvβ3 integrin, and αvβ5 integrin. In some embodiments, the compounds inhibit αvβ6 integrin and α2β1 integrin. In some embodiments, the compounds inhibit αvβ6 integrin, α2β1 integrin, and α3β1 integrin. In some embodiments, the compounds inhibit αvβ6 integrin and α6β1 integrin. In some embodiments, the compounds inhibit αvβ6 integrin and α7β1 integrin. In some embodiments, the compounds inhibit αvβ6 integrin and α11β1 integrin.

[0450] In some cases, it is desirable to avoid inhibiting other integrins. In some embodiments, the compound is a selective αvβ6 integrin inhibitor. In some embodiments, the compound substantially does not inhibit α4β1, αvβ8, and / or α2β3 integrin. In some embodiments, the compound inhibits αvβ6 integrin but substantially does not inhibit α4β1 integrin. In some embodiments, the compound inhibits αvβ6 integrin but substantially does not inhibit αvβ8 integrin. In some embodiments, the compound inhibits αvβ6 integrin but substantially does not inhibit α2β3 integrin. In some embodiments, the compound inhibits αvβ6 integrin but substantially does not inhibit αvβ8 integrin and α4β1 integrin.

[0451] The present invention also contemplates isotopically labeled and / or isotopically enriched forms of the compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes on one or more atoms that constitute such compounds. In some embodiments, the compound is isotopically labeled, such as an isotopically labeled compound having formula (I) or a variant thereof as described herein, wherein one or more atoms are replaced with isotopes of the same element. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 17 O, 32 P, 35 S, 18 F, 36 Cl. Incorporation of a heavier isotope (such as deuterium (i.e., 2 H or D)) can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some cases. As used herein, each instance of replacing hydrogen with deuterium also discloses replacing that hydrogen with tritium. As used herein, each instance of an atom being enriched, replaced, or substituted with a corresponding atomic isotope encompasses an isotope enrichment level of one of the following: about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%, or a range between any two of the above percentages.

[0452] The isotopically labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art, or by procedures similar to those described in the attached examples, by replacing the corresponding unlabeled reagents with appropriately isotopically labeled reagents.

[0453] In various embodiments, for each compound named or described herein, the corresponding isotopically substituted compounds are specifically disclosed according to the following description. For example, the corresponding isotopically substituted compounds are disclosed, wherein the groups corresponding to the structural variables R 1 and R 1a can be independently deuterated. For example, the structural variables R 1 and R 1a can be fully deuterated such that each hydrogen therein can be independently replaced by deuterium. Further disclosed are the corresponding isotopically substituted compounds, wherein one or more hydrogens in the group corresponding to the structural variable R 1 (rather than in the optional substituent R 1a ) can be independently replaced by deuterium. For example, the corresponding isotopically substituted compounds are disclosed, wherein each hydrogen bonded to the ring in the group corresponding to R 1 (rather than in the optional substituent R 1a ) can be replaced by deuterium. Also disclosed are the corresponding isotopically substituted compounds, wherein one or more hydrogens in R 1a can be independently replaced by deuterium. For example, each hydrogen in the group corresponding to R 1a can be replaced by deuterium.

[0454] Further disclosed are, for example, the corresponding isotopically substituted compounds, wherein the groups corresponding to the structural variables R 2 and R 2a can be independently deuterated. For example, the structural variables R 2 and R 2a can be fully deuterated such that each hydrogen therein can be independently replaced by deuterium. Also disclosed are the corresponding isotopically substituted compounds, wherein one or more hydrogens in the group corresponding to R 2 (rather than in the optional substituent R 2a ) can be independently replaced by deuterium. Additionally disclosed are the corresponding isotopically substituted compounds, wherein each hydrogen at the 1-position of R 2 (the carbon bonding R 2 to the rest of the compound) can be independently replaced by deuterium. For example, for the named compound having -CH2CH2CH2F corresponding to R 2 , the corresponding isotopically substituted compound is also disclosed, wherein R 2 is -CD2CH2CH2F; for the compound having the group corresponding to R 2The named compound of -CH2-cyclopropyl is also disclosed, and the corresponding isotopically substituted compounds are also disclosed, wherein R 2 is -CD2-cyclopropyl; and so on. The corresponding isotopically substituted compounds are disclosed, wherein each hydrogen in the group corresponding to R 2a can be independently replaced by deuterium. For example, for the compound wherein R 2a is -OCH3, the corresponding isotopically substituted compounds are also disclosed, wherein R 2a can be -OCD3; for the compound wherein R 2a is -N(CH3)2, the corresponding isotopically substituted compounds are also disclosed, wherein R 2a can be -N(CD3)2; and so on. Further disclosed are compounds wherein the 1-position of R 2 can be di-deuterated and each hydrogen in the group corresponding to R 2a can be replaced by deuterium.

[0455] The corresponding isotopically substituted compounds are also disclosed, wherein R 10 、R 11 、R 12 、R 13 and each R 14 are independently deuterated. For example, the corresponding isotopically substituted compounds are disclosed, wherein R 10 、R 11 are deuterium, or R 12 、R 13 are deuterium, or R 10 、R 11 、R 12 and R 13 are all deuterium. Compounds are also disclosed wherein R 14 is deuterium and R 14 substitutes tetrahydronaphthyridin-2-yl at the 3-position, 4-position or at the 3- and -4 positions. Compounds are also disclosed wherein R 14 is deuterium and each R 14 independently substitutes each hydrogen in tetrahydronaphthyridin-2-yl at the 5-position, 6-position, 7-position, 5- and 6-positions, 5- and 7-positions, 6- and 7-positions or 5-, 6- and 7-positions. For example, the 7-position can be substituted by two deuterium atoms.

[0456] In some embodiments, the corresponding isotopically substituted compounds are disclosed, wherein: each ring hydrogen in R 1 can be replaced by deuterium; the 1-position of R 2 can be di-deuterated; and R 2a can be fully deuterated. The corresponding isotopically substituted compounds are disclosed, wherein R 1Each ring hydrogen in can be replaced by deuterium. The corresponding isotopically substituted compounds are disclosed, wherein: R 1 Each ring hydrogen in can be replaced by deuterium; R 2 The 1-position of can be di-deuterated; R 2a can be fully deuterated; R 12 and R 13 can be deuterium; and the 7-position of tetrahydronaphthyridin-2-yl can be di-deuterated. The corresponding isotopically substituted compounds are disclosed, wherein: R 1 Each ring hydrogen in can be replaced by deuterium; and R 2a Each hydrogen in can be independently replaced by deuterium. The corresponding isotopically substituted compounds are disclosed, wherein: R 1 Each ring hydrogen in can be replaced by deuterium; R 2 The 1-position of can be di-deuterated; R 2a can be fully deuterated; and R 12 and R 13 can be deuterium. The corresponding isotopically substituted compounds are disclosed, wherein: R 1 and R 1a can be fully deuterated; R 2 The 1-position of can be di-deuterated; R 2a can be fully deuterated; R 12 and R 13 can be deuterium; and the 7-position of tetrahydronaphthyridin-2-yl can be di-deuterated. The corresponding isotopically substituted compounds are disclosed, wherein: R 1 Each ring hydrogen in can be replaced by deuterium; R 2 The 1-position of can be di-deuterated; R 2a can be fully deuterated; and R 12 and R 13 can be deuterium.

[0457] In some embodiments of the compound, each hydrogen represented by R 1 , R 1a , R 2 , R 2a , R 10 , R 11 , R 12 , R 13 and R 14 can be independently tritium. For example, the corresponding isotopically substituted compounds are disclosed, wherein one or more hydrogens in R 1 , R 1a or R 1 and R 1a can be independently replaced by tritium. The corresponding isotopically substituted compounds are disclosed, wherein R 1 , R1a or R 1 and R 1a One or more of the ring hydrogens in may be independently replaced by tritium. The corresponding isotopically substituted compounds are disclosed, wherein R 2 , R 2a or R 2 and R 2a One or more hydrogens in may be independently replaced by tritium. The corresponding isotopically substituted compounds are disclosed, wherein R 2 , R 2a or R 2 and R 2a One or more hydrogens in may be independently replaced by tritium. The corresponding isotopically substituted compounds are disclosed, wherein one of the 3-position or 4-position of the tetrahydronaphthyridin-2-yl may be tritiated, for example, the 3-position. The corresponding isotopically substituted compounds are disclosed, wherein one of the 5-position, 6-position or 7-position of the tetrahydronaphthyridin-2-yl may be mono-tritiated or di-tritiated, for example, the 7-position may be di-tritiated.

[0458] In some embodiments of naming compounds, the corresponding isotopically substituted compounds are disclosed, wherein one or more carbons may be 13 replaced by 13 C. For example, the corresponding isotopically substituted compounds are disclosed, wherein one or more carbons may be 1 replaced by 1a C, such as R 2 , R 2a , R 1 , R 1a , R 2 , R 2a and / or the carbons in the ring represented by tetrahydronaphthyridin-2-yl, etc. For example, in the ring represented by R 13 , R 1 , R 1a , R 2 , R 2a and / or tetrahydronaphthyridin-2-yl, one or more carbons may be 13 replaced by 1 , R 1a , R 2 , R 2a , R 13C substitution, wherein the ring substitution bonds to the ring bonded to the rest of the compound or fuses to the ring bonded to the rest of the compound. For example, in the tetrahydronaphthyridin-2-yl ring, the non-aromatic heterocyclic ring fuses to the ring bonded to the rest of the compound. Further, for example, each ring carbon, or each carbon in the group corresponding to R 1 , R 1a , R 2 , R 2a and / or the tetrahydronaphthyridin-2-yl ring, can be substituted by 13 C.

[0459] The present invention also encompasses any and all metabolites of any of the said compounds. Metabolites can include any chemical species produced by the biotransformation of any of the said compounds, such as intermediates and metabolites of the compounds.

[0460] Articles comprising a compound of the present invention or a salt or solvate thereof in a suitable container are provided. The container can be a vial, a jar, an ampoule, a prefilled syringe, an intravenous bag, etc.

[0461] Preferably, the compounds detailed herein are orally bioavailable. However, the compounds can also be formulated for parenteral (e.g., intravenous) administration.

[0462] One or several of the compounds described herein can be used in the preparation of a medicament by combining one or more compounds as the active ingredient with a pharmaceutically acceptable carrier, which is known in the art. Depending on the therapeutic form of the medicament, the carrier can be in various forms.

[0463] General synthetic methods

[0464] The compounds of the present invention can be prepared by many processes generally described below (and more specifically, in the examples below), such as the schemes provided in the following examples. In the process descriptions below, when symbols are used in the depicted formulas, they should be understood to represent those groups described above with respect to the formulas herein.

[0465] When it is desired to obtain a specific enantiomer of a compound, this can be accomplished from the corresponding enantiomer mixture using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives can be produced by the reaction of an enantiomer (e.g., a racemate) with a suitable chiral compound. The diastereomers can then be separated by any convenient means (e.g., by crystallization) and the desired enantiomer recovered. In another resolution process, a racemate can be separated using chiral high performance liquid chromatography. Alternatively, if desired, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the processes.

[0466] Chromatography, recrystallization, and other conventional separation procedures can also be used with intermediates or final products, where it is desirable to obtain a specific isomer of a compound or otherwise purify the reaction product.

[0467] Solvates and / or polymorphs of the compounds provided herein or their pharmaceutically acceptable salts are also contemplated. Solvates contain a stoichiometric or non-stoichiometric amount of solvent and are typically formed during the crystallization process. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is an alcohol. Polymorphs comprise different crystal packing arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and / or solubility. Various factors, such as the recrystallization solvent, crystallization rate, and storage temperature, can result in the predominance of a single crystal form.

[0468] The compounds provided herein can be prepared according to General Schemes A, B, C, and D, General Procedures A, B, C, D, E, F, G, H, and P, and the examples herein.

[0469] The compounds provided herein can be prepared according to General Schemes A, B, C, and D, General Procedures A, B, C, D, E, F, G, H, P, Q, R, S, T, and U, and the examples herein.

[0470] Compound of formula 11A can be prepared according to General Scheme A, where R 1 and R 2 are as defined in formula (I) or any applicable variation detailed herein.

[0471] General Scheme A

[0472]

[0473] In the presence of a suitable coupling agent, 1A is coupled with a compound of formula 2A to obtain a compound of formula 3A, which is reduced to obtain a compound of formula 4A. The compound of formula 4A is reductive aminated with compound 5A to obtain a compound of formula 6A. The N-Boc protecting group is removed from the compound of formula 6A by exposure to a suitable acid to obtain a compound of formula 7A, which can be coupled with a compound of formula 8A to obtain a compound of formula 10A. The compound of formula 10A is hydrolyzed in the presence of a suitable source of hydroxide to obtain a compound of formula 11A.

[0474] The reaction conditions for the transformations of General Scheme A are provided in the subsequent General Procedures, specifically, General Procedures A, D, E, F, G, H, and P.

[0475] The general protocol A can be modified to prepare variants of the compound of formula 11A, starting from variants of 1A having 5 and 6 carbon linkers between the nitrogen bearing the R 2 group and the tetrahydronaphthyridinyl group. These variants of the compound of formula 11A can be synthesized by replacing 1A with 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid or 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid using the routes described in general protocol A. The 6-oxoheptanoate and 7-oxooctanoate can be converted to 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid and 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid, respectively, by condensation with 2-aminonicotinaldehyde in the presence of a suitable catalyst and then hydrogenating the resulting naphthyridine ring to a 5,6,7,8-tetrahydronaphthyridine ring using procedures known in the chemical literature.

[0476] Alternatively, the compound of formula 11A can be prepared according to general protocol B, wherein R 1 and R 2 are as defined in formula (I) or any applicable variation detailed herein.

[0477] General protocol B

[0478]

[0479] The N-Boc group of 1B is installed in the presence of a suitable base and di-tert-butyl dicarbonate to give the compound of formula 2B, which is reduced to give the compound of formula 3B. The compound of formula 3B is oxidized with a suitable oxidizing agent to give the compound of formula 4B. The compound of formula 4B is reductive aminated with compound 2A to give the compound of formula 5B. The compound of formula 5B is reductive aminated with compound 5A to give the compound of formula 7B. The N-Boc protecting group is removed from the compound of formula 7B by exposure to a suitable acid to give the compound of formula 7A, which can be coupled with the compound of formula 8A to give the compound of formula 10A. The compound of formula 10A is hydrolyzed in the presence of a suitable source of hydroxide to give the compound of formula 11A.

[0480] The reaction conditions for the transformations of general protocol B are provided in the subsequent general procedures, specifically, general procedures B, D, F, G, H, and P.

[0481] The general protocol B can be modified to prepare variants of the compound of formula 11A, starting from those having R 2Variants of 1B having 5- and 6-carbon linkers between the nitrogen of the group and the tetrahydronaphthyridinyl group are started. These variants of the compound of formula 11A can be synthesized by substituting 1B with ethyl 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentanoate or ethyl 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexanoate using the routes described in General Scheme B. Ethyl 6-oxoheptanoate and ethyl 7-oxooctanoate can be converted to ethyl 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentanoate or ethyl 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexanoate, respectively, by condensation with 2-aminonicotinaldehyde in the presence of a suitable catalyst and then hydrogenating the resulting naphthyridine ring to a 5,6,7,8-tetrahydronaphthyridine ring using procedures known in the chemical literature.

[0482] The compound of formula 10C can be prepared according to General Scheme C, where R is C1-C5 alkyl optionally substituted by R 2a and R 1 and R 2a are as defined in formula (I) or any applicable variant detailed herein.

[0483] General Scheme C

[0484]

[0485] 1C is coupled with a compound of formula 4C in the presence of a suitable coupling agent to give a compound of formula 2C, which is reduced to give a compound of formula 3C. The compound of formula 3C is reductively aminated with compound 5A to give a compound of formula 5C. The N-Boc protecting group is removed from the compound of formula 5C in toto by exposure to a suitable acid to give a compound of formula 6C, which can be coupled with a compound of formula 8A to give a compound of formula 9C. The compound of formula 9C is hydrolyzed in the presence of a suitable source of hydroxide to give a compound of formula 10C.

[0486] The reaction conditions for the transformations of General Scheme C are provided in the subsequent General Procedures, specifically General Procedures B, D, F, G, H, and P.

[0487] The general protocol C can be modified to prepare variants of the compound of formula 10C, starting from variants of 1C having 5 and 6 carbon linkers between the nitrogen bearing the -CH2R group and the tetrahydronaphthyridinyl group. These variants of the compound of formula 10C can be synthesized by substituting 1C with 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentan-1-amine or 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexan-1-amine using the routes described in general protocol C. 6-Oxoheptanoate and 7-oxooctanoate can be converted to 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid and 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid, respectively, by condensation with 2-aminonicotinaldehyde in the presence of a suitable catalyst and then hydrogenating the resulting naphthyridine ring to a 5,6,7,8-tetrahydronaphthyridine ring using procedures known in the chemical literature. The resulting carboxylic acids can be converted to primary amines by a two-step procedure that includes coupling the carboxylic acid with a suitable ammonia source in the presence of a suitable coupling agent and then reduction.

[0488] Alternatively, the compound of formula 10C can be prepared according to general protocol D, where R is a C1-C5 alkyl optionally substituted by R 2a and R 1 and R 2a are as defined in formula (I) or any applicable variation detailed herein.

[0489] General protocol D

[0490]

[0491] Alkylate 1C with a compound of formula 2D in the presence of a suitable alkyl halide to give a compound of formula 3C. Reductive amination of the compound of formula 3C with compound 5A gives a compound of formula 5C. Removal of the N-Boc protecting group from the compound of formula 5C by exposure to a suitable acid gives a compound of formula 6C, which can be coupled with a compound of formula 9A to give a compound of formula 9C. Hydrolyze the compound of formula 8A in the presence of a suitable source of hydroxide to give a compound of formula 10C.

[0492] Reaction conditions for the transformations of general protocol D are provided in the subsequent general procedures, specifically, general procedures C, F, G, H, and P.

[0493] The general protocol D can be modified to prepare variants of the compound of formula 10C, starting from variants of 1C having 5 and 6 carbon linkers between the nitrogen bearing the -CH2R group and the tetrahydronaphthyridinyl group. These variants of the compound of formula 10C can be synthesized by substituting 1C with 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentan-1-amine or 6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexan-1-amine using the routes described in general protocol D. 6-Oxoheptanoate and 7-oxooctanoate can be converted to 5,6,7,8-tetrahydro-1,8-naphthyridine-2-pentanoic acid and 5,6,7,8-tetrahydro-1,8-naphthyridine-2-hexanoic acid, respectively, by condensation with 2-aminonicotinaldehyde in the presence of a suitable catalyst followed by hydrogenation of the resulting naphthyridine ring to a 5,6,7,8-tetrahydronaphthyridine ring using procedures known in the chemical literature. The resulting carboxylic acids can be converted to primary amines by a two-step procedure that includes coupling the carboxylic acid with a suitable ammonia source in the presence of a suitable coupling agent followed by reduction.

[0494] The compound of formula 1f can be prepared according to general protocol E. It should be understood that the ring described with Het can be any heteroaromatic ring.

[0495] General protocol E

[0496]

[0497] The compound of formula 1a is hydrolyzed to give the compound of formula 1b, which can be alkylated with a suitable electrophile to give the compound of formula 1c. The compound of formula 1c is deprotected under reducing conditions to give the compound of formula 1d. Metal-catalyzed cross-coupling of a haloarene with the compound of formula 1d gives the compound of formula 1e, which can be hydrolyzed under acidic conditions to give the compound of formula 1f.

[0498] The reaction conditions for the transformations of general protocol E are provided in the subsequent general procedures, specifically general procedures Q, R, S, T, and U.

[0499] It should be understood that the above protocols can be modified by choosing appropriate reagents and starting materials to obtain the various compounds of the present invention. 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.

[0500] The examples provide additional methods for preparing the compounds of formula (I) and their salts. As will be recognized by those skilled in the art, the preparation methods taught herein can be adapted to provide additional compounds within the scope of formula (I), for example, by selecting starting materials that will provide the desired compounds.

[0501] Pharmaceutical Compositions and Formulations

[0502] The present invention encompasses pharmaceutical compositions having any of the compounds detailed herein, including compounds of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H) or salts thereof; or Figure 1 any of the compounds or salts thereof in; or mixtures thereof. The present invention encompasses pharmaceutical compositions having any of the compounds detailed herein, including compounds of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H) or salts thereof; or Figure 1 any of the compounds or salts thereof in; or mixtures thereof. The present invention encompasses pharmaceutical compositions having a compound of formula (A) or a salt or mixture thereof. Thus, the present invention includes pharmaceutical compositions that comprise a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. The pharmaceutical compositions according to the present invention can take forms suitable for oral, buccal, parenteral, nasal, topical, or rectal administration or forms suitable for administration by inhalation. In one embodiment, the pharmaceutical composition is a composition for controlled release of any of the compounds detailed herein.

[0503] The compounds detailed herein can, in one aspect, be in a purified form, and compositions comprising the compounds in purified form are detailed herein. In one embodiment, the composition can have no more than 35% impurities, where impurities represent compounds or salts thereof other than the compound that makes up the majority of the composition, for example, selected from Figure 1 A composition of a compound can contain no more than 35% impurities, where impurities represent Figure 1 compounds other than the compound. In one embodiment, the composition can have no more than 35% impurities, where impurities represent compounds or salts thereof other than the compound that makes up the majority of the composition, for example, selected from Figure 1The composition of the compound can contain no more than 35% impurities, where the impurities represent compounds other than Figure 1 the compound or its salts. In one embodiment, the composition can contain no more than 25% impurities. In one embodiment, the composition can contain no more than 20% impurities. In additional embodiments, there are provided compositions comprising the compounds or their salts detailed herein as compositions of substantially pure compounds. A "substantially pure" composition includes no more than 10% impurities, such as compositions including less than 9%, 7%, 5%, 3%, 1%, or 0.5% impurities. In some embodiments, the compositions containing the compounds or their salts detailed herein are in substantially pure form. In yet another variation, there is provided a composition of a substantially pure compound or its salt, wherein the composition contains no more than 10% impurities. In additional variations, there are provided compositions of a substantially pure compound or its salt, wherein the composition contains no more than 9% impurities. In additional variations, there are provided compositions of a substantially pure compound or its salt, wherein the composition contains no more than 7% impurities. In additional variations, there are provided compositions of a substantially pure compound or its salt, wherein the composition contains no more than 5% impurities. In another variation, there is provided a composition of a substantially pure compound or its salt, wherein the composition contains no more than 3% impurities. In yet another variation, there is provided a composition of a substantially pure compound or its salt, wherein the composition contains no more than 1% impurities. In additional variations, there are provided compositions of a substantially pure compound or its salt, wherein the composition contains no more than 0.5% impurities. In yet another variation, a composition of a substantially pure compound means that the composition contains no more than 10% (or preferably no more than 5%, or more preferably no more than 3%, or even more preferably no more than 1% or most preferably no more than 0.5%) impurities, and the impurities can be compounds in different stereochemical forms. For example, a composition of a substantially pure (S) compound means that the composition contains no more than 10% or no more than 5% or no more than 3% or no more than 1% or no more than 0.5% of the (R) form compound.

[0504] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual (such as a human). In another variation, there are provided compositions containing the compounds in substantially pure form. In another variation, the present disclosure encompasses pharmaceutical compositions comprising the compounds detailed herein and pharmaceutically acceptable carriers or excipients. In another variation, there is provided a method of administering the compounds. The purified forms, pharmaceutical compositions, and methods of administering the compounds are applicable to any of the compounds or their forms detailed herein.

[0505] The compounds or salts thereof described herein can be formulated for any available route of delivery, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery forms. The compounds or salts thereof can be formulated with suitable carriers to provide delivery forms including but not limited to tablets, cachets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), lozenges, troches, gums, dispersions, suppositories, ointments, poultices (cataplasms), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalants), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.

[0506] One or several of the compounds or salts thereof described herein can be used in the preparation of formulations (such as pharmaceutical formulations) by combining one or more compounds or salts thereof as active ingredients with pharmaceutically acceptable carriers (such as the carriers mentioned above). Depending on the form of treatment of the system (e.g., transdermal patch vs. oral tablet), the carrier can be in various forms. Additionally, pharmaceutical formulations can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators and salts for adjusting osmotic pressure, buffers, coating agents or antioxidants. Formulations including the compounds can also contain other substances with valuable therapeutic properties. Pharmaceutical formulations can be prepared by known pharmaceutical methods. Suitable formulations can be found in, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st Edition (2005), which is incorporated herein by reference.

[0507] The compounds described herein can be administered to an individual (e.g., a human) in the form of commonly accepted oral compositions such as tablets, coated tablets and hard or soft shell gel capsules, emulsions or suspensions. Examples of carriers that can be used to prepare such compositions are lactose, corn starch or its derivatives, talc, stearates or their salts, etc. Acceptable carriers for gel capsules with soft shells are, for example, vegetable oils, waxes, fats, semi-solids and liquid polyols, etc. Additionally, pharmaceutical formulations can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators and salts for adjusting osmotic pressure, buffers, coating agents or antioxidants.

[0508] Any of the compounds described herein can be formulated in tablets in any of the described dosage forms. For example, the compounds or their pharmaceutically acceptable salts described herein can be formulated as 10 mg tablets.

[0509] Compositions comprising the compounds 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 the substantially pure compound is provided. In some embodiments, the composition is used as a human or veterinary medicine. In some embodiments, the composition is used in the methods described herein. In some embodiments, the composition is used to treat the diseases or disorders described herein.

[0510] Method of Use

[0511] The compounds and compositions of the present invention (such as pharmaceutical compositions containing a compound of any of the formulas provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient) can be used in the administration and treatment methods provided herein. The compounds and compositions can also be used in in vitro methods, such as in vitro methods of administering a compound or composition to a cell for screening and / or performing quality control assays.

[0512] In one aspect, a method of treating a fibrotic disease in an individual in need thereof is provided, the method comprising administering to the individual a therapeutically effective amount of a compound having formula (I) or any variation thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), selected from Figure 1Compounds numbered 1-66 or their stereoisomers, or pharmaceutically acceptable salts thereof. In one aspect, provided is a method for treating a fibrotic disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound having formula (I) or any variant thereof, e.g., a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compounds numbered 1-147 or their stereoisomers, or pharmaceutically acceptable salts thereof. In one aspect, provided is a method for treating a fibrotic disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound having formula (I) or any variant thereof, e.g., a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compounds numbered 1-665 or their stereoisomers, or pharmaceutically acceptable salts thereof. In one aspect, provided is a method for treating a fibrotic disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound having formula (I) or any variant thereof, e.g., a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compounds numbered 1-780 or their stereoisomers, or pharmaceutically acceptable salts thereof. In one aspect, provided is a method for treating a fibrotic disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound having formula (A) or any variant thereof, or its stereoisomers or pharmaceutically acceptable salts thereof. In one aspect, the individual is a human. The individual (such as a human) may be in need of treatment, such as a person suffering from or suspected of suffering from a fibrotic disease.

[0513] In another aspect, a method is provided for delaying the onset and / or development of a fibrotic disease in an individual (such as a human) at risk of having a fibrotic disease. It is understood that if the individual does not have a fibrotic disease, the delayed development can encompass prevention. In one aspect, an individual at risk of having a fibrotic disease has or is suspected of having one or more risk factors for having a fibrotic disease. Risk factors for fibrotic diseases can include: the age of the individual (e.g., middle-aged or elderly individuals); the presence of inflammation; having one or more genetic components associated with the development of a fibrotic disease; medical history, such as treatment with drugs or procedures (e.g., radiology) considered to be associated with an increased susceptibility to fibrosis or medical conditions considered to be associated with fibrosis; a history of smoking; the presence of occupational and / or environmental factors, such as exposure to pollutants associated with the development of a fibrotic disease. In some embodiments, the individual at risk of having a fibrotic disease is an individual having or suspected of having NAFLD, NASH, CKD, scleroderma, Crohn's disease, NSIP, PSC, PBC, or an individual who has had or is suspected of having had a myocardial infarction.

[0514] In some embodiments, the fibrotic disease is fibrosis of tissues such as the lung (pulmonary fibrosis), liver, skin, heart (cardiac fibrosis), kidney (renal fibrosis), or gastrointestinal tract (gastrointestinal fibrosis).

[0515] 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).

[0516] In some embodiments, the fibrotic disease is pulmonary fibrosis, for example, idiopathic pulmonary fibrosis (IPF). In some embodiments, pulmonary fibrosis is, for example, interstitial lung disease, radiation-induced pulmonary fibrosis, or interstitial lung disease associated with systemic sclerosis.

[0517] In some embodiments, the fibrotic disease is primary sclerosing cholangitis or biliary fibrosis. In some embodiments, the fibrotic disease is primary biliary cholangitis (also known as primary biliary cirrhosis) or biliary atresia.

[0518] In some embodiments, the fibrotic disease is fibrotic nonspecific interstitial pneumonia (NSIP).

[0519] In some embodiments, the fibrotic disease is liver fibrosis, for example, infectious liver fibrosis (from pathogens such as HCV, HBV, etc. or parasites such as schistosomes), NASH, alcohol-induced fatty liver fibrosis, and cirrhosis. In some embodiments, liver fibrosis is non-alcoholic fatty liver disease (NAFLD). In some embodiments, liver fibrosis is NASH.

[0520] In certain embodiments, the fibrotic disease is biliary fibrosis.

[0521] In some embodiments, the fibrotic disease is renal fibrosis, for example, diabetic nephrosclerosis, hypertensive nephrosclerosis, focal segmental glomerulosclerosis (“FSGS”), and acute kidney injury caused by contrast-induced nephropathy. In some embodiments, the fibrotic disease is diabetic nephropathy, diabetic kidney disease, or chronic kidney disease.

[0522] In some embodiments, the fibrotic disease is characterized by one or more of the following: glomerulonephritis, end-stage renal disease, hearing loss, ocular lens changes, hematuria, or proteinuria. In some embodiments, the fibrotic disease is Alport syndrome.

[0523] In some embodiments, the fibrotic disease is systemic and local sclerosis or scleroderma, keloids and hypertrophic scars, or postsurgical adhesions. In some embodiments, the fibrotic disease is scleroderma or systemic sclerosis.

[0524] In some embodiments, the fibrotic disease is atherosclerosis or restenosis.

[0525] In some embodiments, the fibrotic disease is gastrointestinal fibrosis, for example, Crohn's disease.

[0526] In some embodiments, the fibrotic disease is cardiac fibrosis, for example, fibrosis induced after myocardial infarction and genetic cardiomyopathy.

[0527] In some embodiments, the method can comprise modulating the activity of at least one integrin in a subject in need thereof. For example, the method can comprise modulating the activity of α V β6. The method can comprise modulating the activity of α V β1. The method can comprise modulating the activity of α V β1 and α V β6. Modulating the activity of at least one integrin can comprise, for example, inhibiting at least one integrin. The method can comprise administering to the subject an amount effective to modulate at least one integrin in the subject (e.g., α V β1 and α Vβ6) or a pharmaceutically acceptable salt thereof. The subject in need of modulation of at least one integrin activity may suffer from any fibrotic disease or condition described herein. For example, the fibrotic disease or condition may include idiopathic pulmonary fibrosis, interstitial lung disease, radiation-induced pulmonary fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease-induced fibrosis, Alport syndrome, primary sclerosing cholangitis, primary biliary cholangitis (also known as primary biliary cirrhosis), biliary atresia, interstitial lung disease associated with systemic sclerosis, scleroderma (also known as systemic sclerosis), diabetic nephropathy, diabetic kidney disease, focal segmental glomerulosclerosis, chronic kidney disease, or Crohn's disease. The method may comprise administering to the subject an amount of an integrin effective to modulate at least one integrin (e.g., α V β1 and α V β6) in the subject, the subject needs treatment for NASH. The method may comprise administering to the subject an amount effective to regulate at least one integrin (e.g., α V β1 and α V β6) or a pharmaceutically acceptable salt thereof, wherein the subject needs treatment for IPF.

[0528] Fibrotic diseases can be mainly caused by α V β6-mediated, for example, fibrotic diseases may include idiopathic pulmonary fibrosis or renal fibrosis. Thus, the method may include modulating α V The activity of β6 is mainly α V β6-mediated disorders, such as IPF. Fibrotic diseases can be primarily caused by α V β1-mediated, for example, fibrotic diseases may include NASH. Thus, the method may include modulating α V The activity of β1 is mainly α V β1-mediated disorders, such as NASH. Fibrotic diseases can be caused by α V β1 and α V β6-mediated, for example, fibrotic diseases may include PSC or biliary atresia. Thus, the method may include modulating α V β1 and α V β6 activity to treat α V β1 and α V β6-mediated diseases.

[0529] The compound can be α V β1 modulators, e.g., inhibitors. The compound may be α VModulators of β6, e.g., inhibitors. The compounds can be α V β1 and α V dual modulators of β6, such as dual inhibitors, e.g., dual selective inhibitors. For example, Table B-3 shows that some exemplary compounds are predominantly inhibitory to α V β6 over α V β1; some exemplary compounds are predominantly inhibitory to α V β1 over α V β6; while some exemplary compounds inhibit α V β1 and α V β6 equally and can be considered, e.g., “dual α V β1 / α V β6 inhibitors”.

[0530] Modulating or inhibiting the activity of either or both of α V β1 integrin and α V β6 integrin to treat a subject having a fibrotic disease, indicating that α V β1 integrin, α V β6 integrin or α V β1 integrin and α V β6 integrin are modulated or inhibited to an extent sufficient to treat the fibrotic disease in the subject.

[0531] In one aspect, there is provided a compound having formula (I) or any variant thereof, e.g., compounds of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), compounds selected from Figure 1 compounds numbered 1-66 thereof or stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0532] In one aspect, there is provided a compound having formula (I) or any variant thereof, e.g., compounds of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), compounds selected from compounds numbered 1-147 thereof or stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0533] In one aspect, there is provided a compound having formula (I) or any variant thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compounds No. 1-665 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0534] In one aspect, there is provided a compound having formula (I) or any variant thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compounds No. 1-780 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0535] There is also provided the use of a compound having formula (I) or any variant thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Figure 1 Compounds No. 1-66 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating fibrotic diseases.

[0536] There is also provided the use of a compound having formula (I) or any variant thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compounds No. 1-147 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating fibrotic diseases.

[0537] There is also provided the use of a compound having formula (I) or any variant thereof, e.g., a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compounds Nos. 1-665 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating fibrotic diseases.

[0538] There is also provided the use of a compound having formula (I) or any variant thereof, e.g., a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compounds Nos. 1-780 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating fibrotic diseases.

[0539] In another aspect, there is provided a method for inhibiting αvβ6 integrin in an individual, the method comprising administering a compound having formula (I) or any variant thereof, e.g., a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a stereoisomer thereof, or a compound selected from Figure 1 Compounds Nos. 1-66 therein or a pharmaceutically acceptable salt thereof.

[0540] In another aspect, there is provided a method for inhibiting αvβ6 integrin in an individual, the method comprising administering a compound having formula (I) or any variant thereof, e.g., a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a stereoisomer thereof, or a compound selected from Compounds Nos. 1-147 or a pharmaceutically acceptable salt thereof.

[0541] In another aspect, there is provided a method of inhibiting αvβ6 integrin in an individual, the method comprising administering a compound having formula (I) or any variant thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a stereoisomer thereof, or a compound selected from Compound Nos. 1-665 or a pharmaceutically acceptable salt thereof.

[0542] In another aspect, there is provided a method of inhibiting αvβ6 integrin in an individual, the method comprising administering a compound having formula (I) or any variant thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a stereoisomer thereof, or a compound selected from Compound Nos. 1-780 or a pharmaceutically acceptable salt thereof.

[0543] There is also provided a method of inhibiting TGFβ activation in a cell, the method comprising administering to the cell a compound having formula (I) or any variant thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1-66 Figure 1 in or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0544] There is also provided a method of inhibiting TGFβ activation in a cell, the method comprising administering to the cell a compound having formula (I) or any variant thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1-147 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0545] There is also provided a method for inhibiting TGFβ activation in a cell, the method comprising administering to the cell a compound having formula (I) or any variant thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1-665 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0546] There is also provided a method for inhibiting TGFβ activation in a cell, the method comprising administering to the cell a compound having formula (I) or any variant thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Compound Nos. 1-780 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0547] There is also provided a method for inhibiting ανβ6 integrin in an individual in need thereof, the method comprising administering to the individual a compound having formula (I) or any variant thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from Figure 1The compounds numbered 1-66 in or their stereoisomers, or pharmaceutically acceptable salts thereof. Also provided is a method of inhibiting αvβ6 integrin in an individual in need thereof, the method comprising administering to the individual a compound having formula (I) or any variant thereof, e.g., a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compounds numbered 1-147 or its stereoisomers, or pharmaceutically acceptable salts thereof. Also provided is a method of inhibiting αvβ6 integrin in an individual in need thereof, the method comprising administering to the individual a compound having formula (I) or any variant thereof, e.g., a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compounds numbered 1-665 or its stereoisomers, or pharmaceutically acceptable salts thereof. Also provided is a method of inhibiting αvβ6 integrin in an individual in need thereof, the method comprising administering to the individual a compound having formula (I) or any variant thereof, e.g., a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), a compound selected from compounds numbered 1-780 or its stereoisomers, or pharmaceutically acceptable salts thereof. In one such method, the compound is a selective αvβ6 integrin inhibitor. In another such method, the compound substantially does not inhibit α4β1, αvβ8 and / or α2β3 integrin. In yet another such method, the compound inhibits αvβ6 integrin but substantially does not inhibit α4β1 integrin. In yet another such method, the compound inhibits αvβ6 integrin but substantially does not inhibit αvβ8 integrin. In additional such methods, the compound inhibits αvβ6 integrin but substantially does not inhibit α2β3 integrin. In one embodiment, provided is a method of inhibiting αvβ6 integrin and one or more of αvβ1, αvβ3, αvβ5, α2β1, α3β1, α6β1, α7β1 and α11β1 integrins in an individual in need thereof. In another embodiment, provided is a method of inhibiting αvβ6 integrin and αvβ1 integrin.In another embodiment, a method of inhibiting αvβ6 integrin, αvβ3 integrin, and αvβ5 integrin is provided. In another embodiment, a method of inhibiting αvβ6 integrin and α2β1 integrin is provided. In another embodiment, a method of inhibiting αvβ6 integrin, α2β1 integrin, and α3β1 integrin is provided. In another embodiment, a method of inhibiting αvβ6 integrin and α6β1 integrin is provided. In another embodiment, a method of inhibiting αvβ6 integrin and α7β1 integrin is provided. In another embodiment, a method of inhibiting αvβ6 integrin and α11β1 integrin is provided. In all such embodiments, on the one hand, the inhibition method is directed to an individual in need, such as an individual suffering from or suspected of suffering from a fibrotic disease, and wherein the method comprises administering to the individual a compound having formula (I) or any variant thereof, for example, a compound of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), or (II-H), selected from. Figure 1Compounds numbered 1-66 in the compound, or its stereoisomers, or its pharmaceutically acceptable salts. In all such embodiments, on the one hand, the inhibition method is directed to an individual in need, such as an individual suffering from or suspected of suffering from a fibrotic disease, and wherein the method comprises administering to the individual a compound having formula (I) or any variant thereof, for example, compounds of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), compounds selected from compounds numbered 1-147, or its stereoisomers, or its pharmaceutically acceptable salts. In all such embodiments, on the one hand, the inhibition method is directed to an individual in need, such as an individual suffering from or suspected of suffering from a fibrotic disease, and wherein the method comprises administering to the individual a compound having formula (I) or any variant thereof, for example, compounds of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), compounds selected from compounds numbered 1-665, or its stereoisomers, or its pharmaceutically acceptable salts. In all such embodiments, on the one hand, the inhibition method is directed to an individual in need, such as an individual suffering from or suspected of suffering from a fibrotic disease, and wherein the method comprises administering to the individual a compound having formula (I) or any variant thereof, for example, compounds of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G) or (II-H), compounds selected from compounds numbered 1-780, or its stereoisomers, or its pharmaceutically acceptable salts.

[0548] The compound of formula (A) can be used in any composition, method and use described herein for formula (I) and variants of formula (I).

[0549] In any of the described methods, on the one hand, the individual is a human, such as a human in need of the method. The individual can be a human who has been diagnosed or suspected of having a fibrotic disease. The individual can be a human who has no detectable disease but has one or more risk factors for developing a fibrotic disease.

[0550] Kit

[0551] The present invention further provides a kit for performing the method of the present invention, the kit comprising one or more of the compounds or salts thereof described herein, or a pharmaceutical composition comprising the compounds described herein. The kit can employ any of the compounds disclosed herein. In one variation, the kit employs the compounds or pharmaceutically acceptable salts thereof described herein. The kit can be used for any one or more of the uses described herein and can thus contain instructions for treating fibrotic diseases.

[0552] The kit generally includes a suitable package. The kit can include one or more containers comprising any of the compounds described herein. Each component (if there is more than one component) can be packaged in a separate container, or some components can be combined in one container if cross-reactivity and shelf life permit. One or more components of the kit can be sterile and / or can be contained within a sterile package.

[0553] The kit can be in unit dosage form, bulk packaging (e.g., multi-dose packaging), or sub-unit dosage. For example, a kit can be provided that contains a sufficient dose of the compound disclosed herein (e.g., a therapeutically effective amount) and / or a second pharmaceutically active compound useful for the diseases detailed herein (e.g., fibrosis) to provide long-term effective personal treatment, such as any one of one week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or longer. The kit can also contain multiple unit doses of the compound and instructions for use and be packaged in an amount sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy and a dispensing pharmacy).

[0554] The kit can optionally contain a set of instructions, typically in written form, although an electronic storage medium (e.g., a disk or a CD) containing the instructions is also acceptable, regarding the use of one or more components of the method of the present invention. The instructions accompanying the kit typically contain information about the components and their administration to an individual.

[0555] General procedures

[0556] The compounds provided herein can be prepared according to a general protocol, as illustrated by the general procedures and examples. When following the general procedures, minor variations can be made in temperature, concentration, reaction time, and other parameters, and these variations will essentially not affect the outcome of the procedure.

[0557] When specific stereoisomers or unspecified stereoisomers or mixtures of stereoisomers are shown in the following general procedures, it should be understood that similar chemical transformations can be carried out on other specific stereoisomers or unspecified stereoisomers or their mixtures. For example, the hydrolysis of methyl (S)-4-aminobutyrate to (S)-4-aminobutyric acid can also be carried out on methyl (R)-4-aminobutyrate to prepare (R)-4-aminobutyric acid, or the hydrolysis reaction can be carried out on a mixture of methyl (S)-4-aminobutyrate and methyl (R)-4-aminobutyrate to prepare a mixture of (S)-4-aminobutyric acid and (R)-4-aminobutyric acid.

[0558] Some of the following general procedures use specific compounds to illustrate general reactions (for example, using an acid to deprotect a compound having an amine protected by Boc to a compound having a deprotected amine). The general reaction can be carried out on other specific compounds having the same functional groups (for example, other compounds having a protected amine, where the Boc protecting group can be removed in the same manner using an acid), provided that such other specific compounds do not contain other 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 other functional groups is desirable (for example, such other specific compounds have another group affected by the acid, and the effect of the acid on the other group is a desired reaction).

[0559] When specific reagents or solvents are specified for a reaction in a general procedure, those skilled in the art will recognize that other reagents or solvents can be substituted as needed. For example, in the case of using hydrochloric acid to remove the Boc group, trifluoroacetic acid can be used alternatively. As another example, in the case of using HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) as a coupling agent, BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate) or PyBOP (benzotriazol-1-yl-oxytris(pyrrolidino)phosphonium hexafluorophosphate) can be used alternatively.

[0560] General Procedure A

[0561]

[0562] N-Cyclopropyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide. At room temperature, DIPEA (13.57 mL, 77.9 mmol) was added to a mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyric acid hydrochloride (5.0 g, 19.48 mmol) and cyclopropylamine (1.51 mL, 21.42 mmol) in CH2Cl2 (80 mL). Then HATU (8.1 g, 21.42 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and purified by normal-phase silica gel chromatography to afford N-cyclopropyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide.

[0563] General procedure B

[0564]

[0565] N-(4-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide. HATU (844 mg, 2.22 mmol) was added to a mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (351 mg, 1.71 mmol) and formic acid (0.09 mL, 2.22 mmol) in 4:1 THF / DMF (5 mL), then DIPEA (0.89 mL, 5.13 mmol) was added, and the reaction was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and purified by normal-phase silica gel chromatography to afford N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide.

[0566] General procedure C

[0567]

[0568] N-(2-Methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. A mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (300 mg, 1.46 mmol), 1-bromo-2-methoxyethane (0.11 mL, 1.17 mmol) and DIPEA (0.25 mL, 1.46 mmol) in i-PrOH (3 mL) was heated to 70 °C for 18 h. The reaction mixture was cooled to room temperature, then concentrated in vacuo and purified by normal-phase silica gel chromatography to afford N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine.

[0569] General procedure D

[0570]

[0571] N-Methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. At room temperature, a solution of N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide (200 mg, 0.86 mmol) in THF (2 mL) was added dropwise to a solution of borane-tetrahydrofuran complex (1.0 M in THF, 4.0 mL, 4.0 mmol). The resulting mixture was then heated to 60 °C for 2 hours and then cooled to room temperature. The reaction mixture was diluted with MeOH and concentrated in vacuo. The crude residue was purified by normal-phase silica gel chromatography to afford N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine.

[0572] General procedure E

[0573]

[0574] N-(2-Methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (5). At room temperature, LiAlH4 (1.0 M in THF, 123 mL, 2.2 equiv) was slowly added to a solution of N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide (15.5 g, 1.0 equiv) in 1,4-dioxane (124 mL), and the resulting mixture was heated to reflux for 20 hours and then cooled to 0 °C. H2O (4.7 mL) was added to the solution, then 1 M NaOH (4.7 mL), then H2O (4.7 mL), the temperature was raised to room temperature and stirred for 30 minutes. At this time, solid MgSO4 was added and stirred for another 30 minutes. The resulting mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated in vacuo to afford N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine.

[0575] General procedure F

[0576]

[0577] (S)-Methyl 2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. At room temperature, acetic acid (0.12 mL, 2.05 mmol) was added to a mixture of N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (5) (187 mg, 0.85 mmol) in MeOH (5 mL), and then methyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (217 mg, 0.94 mmol) was added. The resulting mixture was stirred at room temperature for 15 minutes, at which point sodium cyanoborohydride (80 mg, 1.28 mmol) was added to the reaction mixture, and the mixture was stirred for 30 minutes and then concentrated in vacuo. The crude residue was purified by normal-phase silica gel chromatography to afford (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate.

[0578] General procedure G

[0579]

[0580] (S)-Methyl 2-amino-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. At room temperature, 1,4-dioxane containing 4N HCl (1 mL, 4 mmol) was added to a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (152 mg, 0.35 mmol) in CH2Cl2 (2 mL), and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo to afford (S)-methyl 2-amino-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate as the trihydrochloride.

[0581] General procedure H

[0582]

[0583] A solution of methyl (S)-2-amino-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyrate trihydrochloride (80 mg, 0.16 mmol), 4-chloro-2-methyl-6-(trifluoromethyl)pyrimidine (64 mg, 0.33 mmol) and DIPEA (0.23 mL, 1.31 mmol) in i-PrOH (1 mL) was heated at 60 °C overnight. The reaction was cooled to room temperature and then concentrated in vacuo. The resulting crude residue was purified by normal phase silica gel chromatography to afford methyl (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)amino)butyrate.

[0584] General procedure P

[0585]

[0586] (S)-2-((2-Chloro-3-fluorophenyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid At room temperature, lithium hydroxide (approx. four equivalents) was added to a solution of methyl (S)-2-((2-chloro-3-fluorophenyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyrate in 4:1:1 THF / MeOH / H2O, and the resulting mixture was stirred for 30 minutes. The reaction mixture was concentrated in vacuo and the resulting crude residue was purified by reverse phase HPLC to afford (S)-2-((2-chloro-3-fluorophenyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid in the form of the trihydrochloride.

[0587] General procedure Q

[0588]

[0589] (S)-2-(((Benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a mixture of methyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (1 g, 1.90 mmol) in H2O (3 mL), THF (3 mL), and MeOH (3 mL) was added LiOH·H2O (159.36 mg, 3.80 mmol), and the mixture was then stirred at room temperature for 1 h and the resulting mixture was concentrated in vacuo. The mixture was adjusted to pH = 6 with AcOH (2 mL), and the residue was concentrated in vacuo to give a residue, thereby obtaining the compound (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. LCMS (ESI+): m / z = 513.5 (M+H) + . 1 H NMR (400 MHz, DMSO-d): δ ppm 7.25 - 7.37 (m, 5H) 7.00 (d, J = 7.28 Hz, 1H) 6.81 (br d, J = 7.50 Hz, 1H) 6.22 (d, J = 7.28 Hz, 1H6) 4.93 - 5.05 (m, 2H) 3.68 - 3.77 (m, 1H) 3.25 - 3.34 (m, 1H) 3.15 - 3.24 (m, 5H) 2.58 (br t, J = 6.06 Hz, 2H) 2.29 - 2.49 (m, 8H) 2.16 (br dd, J = 12.90, 6.06 Hz, 1H) 1.69 - 1.78 (m, 2H) 1.58 - 1.68 (m, 1H) 1.53 (quin, J = 7.39 Hz, 2H) 1.28 - 1.40 (m, 2H) 1.00 (d, J = 5.95 Hz, 3H).

[0590] General procedure R

[0591]

[0592] (S)-tert-Butyl 2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (300 mg, 523.84 μmol, HOAc salt) in DMA (4 mL) was added N-benzyl-N,N-diethylchloroethylamine (119.32 mg, 523.84 μmol), K2CO3 (1.88 g, 13.62 mmol), and 2-bromo-2-methylpropane (3.45 g, 25.14 mmol). The mixture was stirred at 55 °C for 18 h and then cooled to room temperature. The reaction mixture was concentrated in vacuo, and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by prep-TLC to afford (S)-tert-Butyl 2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. LCMS (ESI+): m / z = 569.3 (M+H) + 。

[0593] General Procedure S

[0594]

[0595] (S)-tert-Butyl 2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. Under N2 atmosphere, Pd(OH)2 (26 mg) was added to a solution of (S)-tert-Butyl 2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (107 mg, 188.13 μmol) in i-PrOH (2 mL). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at room temperature under H2 (15 psi) for 15 h. The mixture was filtered and concentrated in vacuo to afford (S)-tert-Butyl 2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. LCMS (ESI+): m / z = 435.5 (M+H) + 。 11H NMR (400 MHz, CDCl3): δ ppm 7.06 (d, J = 7.34 Hz, 1H) 6.34 (d, J = 7.34 Hz, 1H) 4.98 (br s, 1H) 3.38 - 3.44 (m, 4H) 3.34 (s, 3H) 2.69 (t, J = 6.30 Hz, 2H) 2.51 - 2.59 (m, 5H) 2.31 (dd, J = 13.39, 5.56 Hz, 1H) 1.86 - 1.94 (m, 5H) 1.49 - 1.69 (m, 6H) 1.47 (s, 9H) 1.13 (d, J = 6.11 Hz, 3H).

[0596] General procedure T

[0597]

[0598] (S)-4-(((R)-2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid tert-butyl ester. To a solution of tert-butyl (S)-tert-butyl 2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid tert-butyl ester (100 mg, 230.09 μmol) and 2-chloro-5-methyl-pyrimidine (24.65 mg, 191.74 μmol) in 2-methyl-2-butanol (2 mL) was added t-BuONa (2 M, in THF, 191.74 μL) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (15.23 mg, 19.17 μmol), and the resulting mixture was stirred at 100 °C for 14 h. The mixture was concentrated in vacuo to afford (S)-tert-butyl 4-(((S)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate. LCMS (ESI+): m / z = 527.3 (M+H) + .

[0599] General procedure U

[0600]

[0601] (S)-4-(((R)-2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid. At 0 °C, trifluoroacetic acid (254.14 mg, 2.23 mmol) was added to a solution of tert-butyl (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate (80 mg, 151.89 μmol) in DCM (2 mL). The mixture was stirred at room temperature for 6 hours. The mixture was concentrated in vacuo and the resulting crude residue was purified by prep-HPLC to afford the compound (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid. LCMS (ESI+): m / z = 471.2 (M+H) + 。 1 H NMR (400 MHz, methanol-d4) δ ppm 8.57 (br s, 2H) 7.60 (d, J = 7.28 Hz, 1H) 6.67 (d, J = 7.28 Hz, 1H) 4.81 - 4.86 (m, 1H) 3.86 (br s, 1H) 3.41 - 3.59 (m, 4H) 3.39 (s, 3H) 3.33 - 3.38 (m, 1H) 3.12 - 3.30 (m, 3H) 2.76 - 2.86 (m, 4H) 2.54 (br s, 1H) 2.39 (br d, J = 8.82 Hz, 1H) 2.30 (s, 3H) 1.76 - 1.99 (m, 6H) 1.22 (d, J = 5.95 Hz, 3H).

[0602] The following examples

[0603] The following examples listed represent some aspects of the present invention.

[0604] Example 1. A compound of formula (I)

[0605]

[0606] or a salt thereof, wherein:

[0607] R 1 is C6-C 14 aryl or 5- to 10-membered heteroaryl, wherein the C6-C 14 aryl and 5- to 10-membered heteroaryl are optionally substituted with R 1a ;

[0608] R 2is an optionally R 2a -substituted C1-C6 alkyl; an optionally R 2b -substituted C3-C6 cycloalkyl; an optionally R 2c -substituted 3- to 12-membered heterocyclic group; or -S(O)2R 2d ;

[0609] Each R 1a is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, 3- to 12-membered heterocyclic group, 5- to 10-membered heteroaryl, C6-C 14 aryl, deuterium, halogen, -CN, -OR 3 , -SR 3 , -NR 4 R 5 , -NO2, -C=NH(OR 3 ), -C(O)R 3 , -OC(O)R 3 , -C(O)OR 3 , -C(O)NR 4 R 5 , -NR 3 C(O)R 4 , -NR 3 C(O)OR 4 , -NR 3 C(O)NR 4 R 5 , -S(O)R 3 , -S(O)2R 3 , -NR 3 S(O)R 4 , -NR 3 S(O)2R 4 , -S(O)NR 4 R 5 , -S(O)2NR 4 R 5 or -P(O)(OR 4 )(OR 5 ), where each R 1a is independently optionally, where possible, deuterium, halogen, oxo group, -OR 6 , -NR 6 R 7 , -C(O)R 6 , -CN, -S(O)R 6 , -S(O)2R 6 , -P(O)(OR 6 )(OR 7), C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, 5- to 10-membered heteroaryl, C6-C 14 aryl or C1-C6 alkyl optionally substituted with deuterium, oxo group, -OH or halogen;

[0610] Each R 2a , R 2b , R 2c , R 2e and R 2f is independently an oxo group or R 1a ;

[0611] R 2d is C1-C6 alkyl optionally substituted with R 2e or C3-C5 cycloalkyl optionally substituted with R 2f ;

[0612] R 3 is independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclic group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 3 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclic group of R 14 are independently optionally substituted with halogen, deuterium, oxo group, -CN, -OR 8 , -NR 8 R 9 , -P(O)(OR 8 )(OR 9 ) or C1-C6 alkyl optionally substituted with deuterium, halogen, -OH or oxo group;

[0613] R 4 and R 5 are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclic group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 4 and R 5 of aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclic group are independently optionally substituted with deuterium, halogen, oxo group, -CN, -OR 14 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclic group are independently optionally substituted with deuterium, halogen, -OH or oxo group; 8 , -NR 8 R 9 or C1-C6 alkyl optionally substituted with deuterium, halogen, -OH or oxo group;

[0614] or R 4 and R 5 together with the atom to which it is attached form a 3- to 6-membered heterocyclic group, which heterocyclic group is optionally substituted with deuterium, halogen, oxo, -OR 8 、-NR 8 R 9 or a C1-C6 alkyl group optionally substituted with deuterium, halogen, oxo or -OH;

[0615] R 6 and R 7 are each independently hydrogen, deuterium, a C1-C6 alkyl group optionally substituted with deuterium, halogen or oxo, a C2-C6 alkenyl group optionally substituted with deuterium, halogen or oxo or a C2-C6 alkynyl group optionally substituted with deuterium, halogen or oxo;

[0616] or R 6 and R 7 together with the atom to which it is attached form a 3- to 6-membered heterocyclic group, which heterocyclic group is optionally substituted with deuterium, halogen, oxo or a C1-C6 alkyl group optionally substituted with deuterium, halogen or oxo;

[0617] R 8 and R 9 are each independently hydrogen, deuterium, a C1-C6 alkyl group optionally substituted with deuterium, halogen or oxo, a C2-C6 alkenyl group optionally substituted with deuterium, halogen or oxo or a C2-C6 alkynyl group optionally substituted with deuterium, halogen or oxo;

[0618] or R 8 and R 9 together with the atom to which it is attached form a 3- to 6-membered heterocyclic group, which heterocyclic group is optionally substituted with deuterium, halogen, oxo or a C1-C6 alkyl group optionally substituted with deuterium, oxo or halogen;

[0619] Each R 10 、R 11 、R 12 and R 13 is independently hydrogen or deuterium;

[0620] R 14 is deuterium;

[0621] q is 0, 1, 2, 3, 4, 5, 6, 7 or 8 and

[0622] p is 3, 4, 5, 6, 7, 8 or 9.

[0623] Example 2. The compound or a salt thereof according to Example 1, wherein R 1a 、R 2a 、R 2b 、R 2c 、R2e , R 2f , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 or R 14 at least one of them is deuterium.

[0624] Example 3. The compound or its salt according to Example 1, wherein R 10 , R 11 , R 12 , R 13 and R 14 are hydrogen; p is 3; and it is represented by the compound of formula (II):

[0625]

[0626] Example 4. The compound or its salt according to Example 1, 2 or 3, wherein R 1 is a 5- to 10-membered heteroaryl optionally substituted by R 1a .

[0627] Example 5. The compound or its salt according to Example 1, 2 or 3, wherein R 1 is a pyrimidin-4-yl optionally substituted by R 1a .

[0628] Example 6. The compound or its salt according to Example 1, 2 or 3, wherein R 1 is a pyrimidin-4-yl optionally substituted by R 1a , wherein R 1a is a 5- to 10-membered heteroaryl or a C1-C6 alkyl optionally substituted by halogen.

[0629] Example 7. The compound or its salt according to Example 1, 2 or 3, wherein R 1 is a pyrimidin-4-yl optionally substituted by pyrazolyl, methyl, difluoromethyl or trifluoromethyl.

[0630] Example 8. The compound or its salt according to Example 1, 2 or 3, wherein R 1 is a pyrimidin-4-yl optionally substituted by both methyl and trifluoromethyl.

[0631] Example 9. The compound or its salt according to Example 1, 2 or 3, wherein R 1 is optionally substituted by R1a Substituted quinazolin-4-yl.

[0632] Example 10. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is quinazolin-4-yl optionally substituted by halogen, C1-C6 alkyl optionally substituted by halogen or C1-C6 alkoxy.

[0633] Example 11. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is quinazolin-4-yl optionally substituted by fluorine, chlorine, methyl, trifluoromethyl or methoxy.

[0634] Example 12. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is C1-C6 alkyl optionally substituted by R 2a substituted.

[0635] Example 13. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is C1-C6 alkyl optionally substituted by R 2a substituted, wherein R 2a is: halogen; C3-C8 cycloalkyl optionally substituted by halogen; 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl; -NR 4 R 5 ; -NR 3 C(O)R 4 ; -S(O)2R 3 ; or oxo group.

[0636] Example 14. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is C1-C6 alkyl optionally substituted by R 2a substituted, wherein R 2a is: fluorine; cyclobutyl substituted by fluorine; pyrazolyl substituted by methyl; or -S(O)2CH3.

[0637] Example 15. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is C1-C6 alkyl optionally substituted by -OR 3 substituted.

[0638] Example 16. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is C1-C6 alkyl optionally substituted by -OR 3 substituted, and R 3is: hydrogen; C1-C6 alkyl optionally substituted by halogen; C3-C6 cycloalkyl optionally substituted by halogen; C6-C 14 aryl; or 5- to 6-membered heteroaryl optionally substituted by halogen or C1-C6 alkyl.

[0639] Example 17. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is C1-C6 alkyl optionally substituted by -OR 3 , and R 3 is: hydrogen; methyl; ethyl; difluoromethyl; -CH2CHF2; -CH2CF3; cyclopropyl substituted by fluorine; phenyl optionally substituted by fluorine; or pyridyl optionally substituted by fluorine or methyl.

[0640] Example 18. The compound according to any one of Examples 1 to 11, wherein R 2 is –CH2CH2OCH3.

[0641] Example 19. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is C1-C6 alkyl substituted by both halogen and OR 3 , wherein R 3 is C1-C6 alkyl.

[0642] Example 20. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is C3-C6 cycloalkyl optionally substituted by R 2b .

[0643] Example 21. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is cyclopropyl.

[0644] Example 22. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is wherein m is 0, 1, 2 or 3, and each R 1a , where applicable, is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted by deuterium.

[0645] Example 23. The compound or a salt thereof according to Example 22, wherein R 1 is wherein each R 1a is independently deuterium, alkyl, haloalkyl or heteroaryl.

[0646] Example 24. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is wherein m is 0, 1, 2 or 3, and each R 1a is independently, where applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium.

[0647] Example 25. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is wherein m is 0, 1, 2, 3, 4 or 5, and each R 1a is independently, where applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium.

[0648] Example 26. The compound or a salt thereof according to Example 25, wherein R 1 is wherein each R 1a is independently deuterium, halogen, alkyl, haloalkyl or alkoxy.

[0649] Example 27. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is wherein m is 0, 1, 2, 3, 4 or 5, and each R 1a is independently, where applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium.

[0650] Example 28. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is wherein m is 0, 1, 2, 3 or 4, and each R 1a is independently, where applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium.

[0651] Example 29. The compound or a salt thereof according to Example 28, wherein R 1 is selected from the group consisting of:

[0652]

[0653] Example 30. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is wherein m is 0, 1, 2, 3 or 4, and each R 1a , where applicable, is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium.

[0654] Example 31. The compound or a salt thereof according to Example 30, wherein R 1 is selected from the group consisting of:

[0655]

[0656] Example 32. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is wherein m is 0, 1, 2, 3 or 4, and each R 1a , where applicable, is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium.

[0657] Example 33. The compound or a salt thereof according to Example 32, wherein R 1 is selected from the group consisting of:

[0658]

[0659] Example 34. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is wherein m is 0, 1, 2, 3, 4, 5 or 6, and each R 1a , where applicable, is independently deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium.

[0660] Example 35. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is where m is 0, 1, 2, 3, 4, 5 or 6, and each R 1a is independently, where applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, where the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium.

[0661] Example 36. The compound or a salt thereof according to Example 1, 2 or 3, where R 1 is where m is 0, 1 or 2, and each R 1a is independently, where applicable, deuterium, halogen, alkyl, haloalkyl, alkoxy, hydroxy, -CN or heteroaryl, where the alkyl, haloalkyl, alkoxy, hydroxy and heteroaryl of R 1a are independently optionally substituted with deuterium.

[0662] Example 37. The compound or a salt thereof according to Example 1, 2 or 3, where R 1 is selected from the group consisting of: and any one of the foregoing groups, where any one or more hydrogen atoms are replaced by one or more deuterium atoms.

[0663] Example 38. The compound or a salt thereof according to Example 1, 2 or 3, where R 1 is selected from the group consisting of: and any one of the foregoing groups, where any one or more hydrogen atoms are replaced by one or more deuterium atoms.

[0664] Example 39. The compound or a salt thereof according to Example 1, 2 or 3, where R 1 is selected from the group consisting of: and any one of the foregoing groups, where any one or more hydrogen atoms are replaced by one or more deuterium atoms.

[0665] Example 40. The compound or a salt thereof according to any one of Examples 1 to 11, where R 2 is where n is 1, 2, 3, 4, 5 or 6, and R 3 is C1-C2 alkyl optionally substituted with fluorine; phenyl optionally substituted with fluorine; pyridyl optionally substituted with fluorine or methyl; or cyclopropyl optionally substituted with fluorine.

[0666] Example 41. The compound or its salt according to Example 1, 2 or 3, wherein R 2 is selected from the group consisting of: and any one of the foregoing groups, wherein any one or more hydrogen atoms are replaced by one or more deuterium atoms.

[0667] Example 42. A compound or its salt selected from Compound Nos. 1-66 of Figure 1

[0668] Example 43. A compound or its salt selected from Compound Nos. 1-147.

[0669] Example 44. A compound or its salt selected from Compound Nos. 1-665.

[0670] Example 45. A pharmaceutical composition comprising the compound or its salt according to any one of Examples 1 to 44 and a pharmaceutically acceptable carrier or excipient.

[0671] Example 46. A method for treating a fibrotic disease in an individual in need thereof, the method comprising administering the compound or its pharmaceutically acceptable salt according to any one of Examples 1 to 44.

[0672] Example 47. The method according to Example 46, wherein the fibrotic disease is pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis or biliary fibrosis.

[0673] Example 48. A kit comprising the compound or its pharmaceutically acceptable salt according to any one of Examples 1 to 44.

[0674] Example 49. The kit according to Example 48, further comprising instructions for treating a fibrotic disease.

[0675] Example 50. A method for inhibiting αvβ6 integrin in an individual, the method comprising administering the compound or its pharmaceutically acceptable salt according to any one of Examples 1 to 44.

[0676] Example 51. A method for inhibiting TGFβ activation in a cell, the method comprising administering to the cell the compound or its pharmaceutically acceptable salt according to any one of Examples 1 to 44.

[0677] Example 52. Use of the compound or its pharmaceutically acceptable salt according to any one of Examples 1 to 44 in the preparation of a drug for treating a fibrotic disease. ​

[0678] Example 53. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is a C3-C5 alkyl group substituted with both fluorine and -OCH3.

[0679] Example 54. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is a C1-C6 alkyl group optionally substituted with -OR 3 , and R 3 is a phenyl group optionally substituted with fluorine.

[0680] Example 55. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is a C1-C6 alkyl group optionally substituted with -OR 3 , and R 3 is a pyridyl group optionally substituted with fluorine or methyl.

[0681] Example 56. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is a C1-C6 alkyl group substituted with R 2a , wherein R 2a is a halogen.

[0682] Example 57. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is a C1-C6 alkyl group substituted with R 2a , wherein R 2a is deuterium.

[0683] Example 58. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is a C1-C6 alkyl group substituted with R 2a , wherein R 2a is a 3- to 12-membered heterocyclic group optionally substituted with an oxo group.

[0684] Example 59. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is a C1-C6 alkyl group substituted with R 2a , wherein R 2a is a 4- to 5-membered heterocyclic group optionally substituted with an oxo group.

[0685] Example 60. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is a C1-C6 alkyl group substituted with R 2a , wherein R 2a is a C6-C 6 optionally substituted with a halogen or -OR14 Aryl.

[0686] Example 61. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is a C1-C6 alkyl group substituted by R 2a , wherein R 2a is a phenyl group optionally substituted by a halogen or -OR 6 .

[0687] Example 62. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is a C1-C6 alkyl group substituted by R 2a , wherein R 2a is a 5- to 10-membered heteroaryl group optionally substituted by a C1-C6 alkyl group.

[0688] Example 63. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is a C1-C6 alkyl group substituted by R 2a , wherein R 2a is a pyrazolyl group optionally substituted by a methyl group.

[0689] Example 64. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is a C1-C6 alkyl group substituted by R 2a , wherein R 2a is a C3-C8 cycloalkyl group optionally substituted by -CN, a halogen or -OR 6 .

[0690] Example 65. The compound or a salt thereof according to any one of Examples 1 to 11, wherein R 2 is a C1-C6 alkyl group substituted by R 2a , wherein R 2a is -S(O)2R 3 .

[0691] Example 66. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is a pyridyl group optionally substituted by R 1a .

[0692] Example 67. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is an indazolyl group optionally substituted by R 1a .

[0693] Example 68. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is an indazolyl group optionally substituted by R 1aSubstituted 1H-pyrrolopyridinyl.

[0694] Example 69. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is a quinolinyl optionally substituted by R 1a .

[0695] Example 70. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is a phenyl optionally substituted by R 1a .

[0696] Example 71. The compound or a salt thereof according to Example 1, 2 or 3, wherein R 1 is an indanyl optionally substituted by R 1a .

[0697] Synthesis Examples

[0698] The chemical reactions in the synthesis examples can be readily adapted to prepare many other compounds of the present invention, and alternative methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplary compounds according to the present invention can be successfully carried out by modifications that are obvious to those skilled in the art (e.g., by appropriately protecting interfering groups), by using other suitable reagents known in the art in addition to the described reagents, or by making routine modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered to have applicability for preparing other compounds of the present invention.

[0699] For the examples described herein, a reference to a general procedure indicates the use of reaction conditions and parameters similar to those of the general procedure described above to prepare the reaction.

[0700] Procedure

[0701] The compounds provided herein can be prepared according to the schemes, as illustrated by the procedures and examples. When following the procedures, minor variations can be made in temperature, concentration, reaction time, and other parameters, and these variations will not substantially affect the results of the procedures.

[0702] Procedure A

[0703]

[0704] N-Cyclopropyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide. At room temperature, to a mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyric acid hydrochloride (5.0 g, 19.48 mmol) and cyclopropylamine (1.51 mL, 21.42 mmol) in CH2Cl2 (80 mL) was added DIPEA (13.57 mL, 77.9 mmol). Then HATU (8.1 g, 21.42 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and purified by normal-phase silica gel chromatography to afford N-cyclopropyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide.

[0705] Procedure B

[0706]

[0707] N-(4-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide. To a mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (351 mg, 1.71 mmol) and formic acid (0.09 mL, 2.22 mmol) in 4:1 THF / DMF (5 mL) was added HATU (844 mg, 2.22 mmol), then DIPEA (0.89 mL, 5.13 mmol), and the reaction was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and purified by normal-phase silica gel chromatography to afford N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide.

[0708] Procedure C

[0709]

[0710] N-(2-Methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. A mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (300 mg, 1.46 mmol), 1-bromo-2-methoxyethane (0.11 mL, 1.17 mmol) and DIPEA (0.25 mL, 1.46 mmol) in i-PrOH (3 mL) was heated to 70 °C for 18 h. The reaction mixture was cooled to room temperature, then concentrated in vacuo and purified by normal-phase silica gel chromatography to afford N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine.

[0711] Procedure D

[0712]

[0713] N-Methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine. At room temperature, a solution of N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)formamide (200 mg, 0.86 mmol) in THF (2 mL) was added dropwise to a solution of borane-tetrahydrofuran complex (1.0 M in THF, 4.0 mL, 4.0 mmol). The resulting mixture was then heated to 60 °C for 2 hours and then cooled to room temperature. The reaction mixture was diluted with MeOH and concentrated in vacuo. The crude residue was purified by normal-phase silica gel chromatography to give N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine.

[0714] Procedure E

[0715]

[0716] N-(2-Methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (5). At room temperature, LiAlH4 (1.0 M in THF, 123 mL, 2.2 equiv) was slowly added to a solution of N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanamide (15.5 g, 1.0 equiv) in 1,4-dioxane (124 mL), and the resulting mixture was heated to reflux for 20 hours and then cooled to 0 °C. H2O (4.7 mL) was added to the solution, then 1 M NaOH (4.7 mL), then H2O (4.7 mL), the temperature was raised to room temperature and stirred for 30 minutes. At this time, solid MgSO4 was added and stirred for another 30 minutes. The resulting mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated in vacuo to give N-(2-methoxyethyl)-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine.

[0717] Procedure F

[0718]

[0719] (S)-Methyl 2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. At room temperature, acetic acid (0.12 mL, 2.05 mmol) was added to a mixture of N-methyl-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butan-1-amine (5) (187 mg, 0.85 mmol) in MeOH (5 mL), and then methyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (217 mg, 0.94 mmol) was added. The resulting mixture was stirred at room temperature for 15 minutes. At this time, sodium cyanoborohydride (80 mg, 1.28 mmol) was added to the reaction mixture, and the mixture was stirred for 30 minutes and then concentrated in vacuo. The crude residue was purified by normal-phase silica gel chromatography to give (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate.

[0720] Procedure G

[0721]

[0722] (S)-Methyl 2-amino-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. At room temperature, 1,4-dioxane containing 4N HCl (1 mL, 4 mmol) was added to a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (152 mg, 0.35 mmol) in CH2Cl2 (2 mL), and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo to give (S)-methyl 2-amino-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate as the trihydrochloride.

[0723] Procedure H

[0724]

[0725] A solution of methyl (S)-2-amino-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyrate trihydrochloride (80 mg, 0.16 mmol), 4-chloro-2-methyl-6-(trifluoromethyl)pyrimidine (64 mg, 0.33 mmol) and DIPEA (0.23 mL, 1.31 mmol) in i-PrOH (1 mL) was heated at 60 °C overnight. The reaction was cooled to room temperature and then concentrated in vacuo. The resulting crude residue was purified by normal phase silica gel chromatography to afford methyl (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)amino)butyrate.

[0726] Procedure P

[0727]

[0728] (S)-2-((2-Chloro-3-fluorophenyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid At room temperature, lithium hydroxide (approx. four equivalents) was added to a solution of methyl (S)-2-((2-chloro-3-fluorophenyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyrate in 4:1:1 THF / MeOH / H2O and the resulting mixture was stirred for 30 minutes. The reaction mixture was concentrated in vacuo and the resulting crude residue was purified by reverse phase HPLC to afford (S)-2-((2-chloro-3-fluorophenyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butyric acid.

[0729] Procedure Q

[0730]

[0731] (S)-2-(((Benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. To a mixture of methyl (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (1 g, 1.90 mmol) in H2O (3 mL), THF (3 mL), and MeOH (3 mL) was added LiOH·H2O (159.36 mg, 3.80 mmol). The mixture was then stirred at room temperature for 1 h and the resulting mixture was concentrated in vacuo. The mixture was adjusted to pH = 6 with AcOH (2 mL) and the residue was concentrated in vacuo to give a residue, thereby obtaining the compound (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid. LCMS (ESI+): m / z = 513.5 (M+H) + 。 1 H NMR (400 MHz, DMSO-d): δ ppm 7.25 - 7.37 (m, 5H) 7.00 (d, J = 7.28 Hz, 1H) 6.81 (br d, J = 7.50 Hz, 1H) 6.22 (d, J = 7.28 Hz, 1H6) 4.93 - 5.05 (m, 2H) 3.68 - 3.77 (m, 1H) 3.25 - 3.34 (m, 1H) 3.15 - 3.24 (m, 5H) 2.58 (br t, J = 6.06 Hz, 2H) 2.29 - 2.49 (m, 8H) 2.16 (br dd, J = 12.90, 6.06 Hz, 1H) 1.69 - 1.78 (m, 2H) 1.58 - 1.68 (m, 1H) 1.53 (quin, J = 7.39 Hz, 2H) 1.28 - 1.40 (m, 2H) 1.00 (d, J = 5.95 Hz, 3H).

[0732] Procedure R

[0733]

[0734] (S)-tert-Butyl 2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate: To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (300 mg, 523.84 μmol, HOAc salt) in DMA (4 mL) was added N-benzyl-N,N-diethylchloroethylamine (119.32 mg, 523.84 μmol), K2CO3 (1.88 g, 13.62 mmol), and 2-bromo-2-methylpropane (3.45 g, 25.14 mmol). The mixture was stirred at 55 °C for 18 h and then cooled to room temperature. The reaction mixture was concentrated in vacuo and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by prep-TLC to afford (S)-tert-Butyl 2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. LCMS (ESI+): m / z = 569.3 (M+H) + 。

[0735] Procedure S

[0736]

[0737] (S)-tert-Butyl 2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. Under N2 atmosphere, Pd(OH)2 (26 mg) was added to a solution of (S)-tert-Butyl 2-(((benzyloxy)carbonyl)amino)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (107 mg, 188.13 μmol) in i-PrOH (2 mL). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at room temperature under H2 (15 psi) for 15 h. The mixture was filtered and concentrated in vacuo to afford (S)-tert-Butyl 2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate. LCMS (ESI+): m / z = 435.5 (M+H) + 。 11H NMR (400 MHz, CDCl3): δ ppm 7.06 (d, J = 7.34 Hz, 1H) 6.34 (d, J = 7.34 Hz, 1H) 4.98 (br s, 1H) 3.38 - 3.44 (m, 4H) 3.34 (s, 3H) 2.69 (t, J = 6.30 Hz, 2H) 2.51 - 2.59 (m, 5H) 2.31 (dd, J = 13.39, 5.56 Hz, 1H) 1.86 - 1.94 (m, 5H) 1.49 - 1.69 (m, 6H) 1.47 (s, 9H) 1.13 (d, J = 6.11 Hz, 3H).

[0738] Procedure T

[0739]

[0740] (S)-4-(((R)-2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid tert-butyl ester. To a solution of tert-butyl (S)-tert-butyl 2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid tert-butyl ester (100 mg, 230.09 μmol) and 2-chloro-5-methyl-pyrimidine (24.65 mg, 191.74 μmol) in 2-methyl-2-butanol (2 mL) was added t-BuONa (2 M, in THF, 191.74 uL) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (15.23 mg, 19.17 μmol), and the resulting mixture was stirred at 100 °C for 14 h. The mixture was concentrated in vacuo to afford (S)-tert-butyl 4-(((S)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate. LCMS (ESI+): m / z = 527.3 (M+H) + .

[0741] Procedure U

[0742]

[0743] (S)-4-(((R)-2-Methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid. At 0 °C, trifluoroacetic acid (254.14 mg, 2.23 mmol) was added to a solution of tert-butyl (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoate (80 mg, 151.89 μmol) in DCM (2 mL). The mixture was stirred at room temperature for 6 hours. The mixture was concentrated in vacuo and the resulting crude residue was purified by prep-HPLC to afford the compound (S)-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-methylpyrimidin-2-yl)amino)butanoic acid. LCMS (ESI+): m / z = 471.2 (M+H) + . 1 H NMR (400 MHz, methanol-d4) δ ppm 8.57 (br s, 2H) 7.60 (d, J = 7.28 Hz, 1H) 6.67 (d, J = 7.28 Hz, 1H) 4.81 - 4.86 (m, 1H) 3.86 (br s, 1H) 3.41 - 3.59 (m, 4H) 3.39 (s, 3H) 3.33 - 3.38 (m, 1H) 3.12 - 3.30 (m, 3H) 2.76 - 2.86 (m, 4H) 2.54 (br s, 1H) 2.39 (br d, J = 8.82 Hz, 1H) 2.30 (s, 3H) 1.76 - 1.99 (m, 6H) 1.22 (d, J = 5.95 Hz, 3H).

[0744] Synthesis Example

[0745] The chemical reactions in the synthesis examples described herein can be readily adapted to prepare many other compounds of the present invention, and alternative methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplary compounds according to the present invention can be successfully carried out by modifications that are obvious to those skilled in the art (e.g., by appropriately protecting interfering groups), by using other suitable reagents known in the art in addition to the described reagents, or by making routine modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered to have applicability for preparing other compounds of the present invention.

[0746] For the examples described herein, reference to a procedure indicates that a reaction is prepared using reaction conditions and parameters similar to those of the procedure described above.

[0747] Example A1

[0748] (S)-2-Fluoro-3-methoxypropan-1-amine synthesis

[0749]

[0750] Dibenzyl-D-serine methyl ester. At 0 °C, benzyl bromide (241.85 g, 1.41 mol) was added to a mixture of D-serine methyl ester hydrochloride (100 g, 642.76 mmol), K2CO3 (177.67 g, 1.29 mol), and KI (53.35 g, 321.38 mmol) in DMF (1.5 L). The mixture was stirred at 25 °C for 12 hours. The mixture was quenched with H2O (3000 mL) and EtOAc (1 L x 3). The organic layer was washed with brine (1 L), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by normal-phase silica gel chromatography to give dibenzyl-D-serine methyl ester.

[0751]

[0752] (S)-Methyl 3-(dibenzylamino)-2-fluoropropionate. At 0 °C, DAST (102.65 g, 636.85 mmol, 84.14 mL) was added dropwise to a solution of dibenzyl-D-serine methyl ester (155 g, 517.77 mmol) in THF (1.2 L), and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 (1 L) at 0 °C and extracted with EtOAc (500 mL x 3). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by normal-phase silica gel chromatography to give (S)-methyl 3-(dibenzylamino)-2-fluoropropionate.

[0753]

[0754] (S)-3-(Dibenzylamino)-2-fluoropropan-1-ol. At 0 °C, LiBH4 (14.89 g, 683.58 mmol) was added to a solution of (S)-methyl 3-(dibenzylamino)-2-fluoropropionate (103 g, 341.79 mmol) in THF (1 L). The mixture was stirred at 40 °C for 12 hours. The mixture was poured into aqueous NH4Cl (500 mL) at 0 °C. The aqueous phase was extracted with ethyl acetate (300 mL x 3). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give (S)-3-(dibenzylamino)-2-fluoropropan-1-ol, which was used without further purification.

[0755]

[0756] (S)-N,N-Dibenzyl-2-fluoro-3-methoxypropan-1-amine. At 0 °C, NaH (60% dispersion in mineral oil, 11.19 g, 279.87 mmol) was added to a solution of (S)-3-(dibenzylamino)-2-fluoropropan-1-ol (51 g, 186.58 mmol) in THF (400 mL), and the resulting mixture was stirred at 0 °C for 30 minutes. Then methyl iodide (18.58 mL, 298.52 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hours. The mixture was quenched with aqueous NH4Cl (500 mL) at 0 °C. The aqueous phase was extracted with EtOAc (500 mL x 3). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude residue was purified by normal-phase silica gel chromatography to give (S)-N,N-dibenzyl-2-fluoro-3-methoxypropan-1-amine.

[0757]

[0758] (S)-2-Fluoro-3-methoxypropan-1-amine. Pd / C (3 g) was added to a solution of (S)-N,N-dibenzyl-2-fluoro-3-methoxypropan-1-amine (15 g, 52.20 mmol) in MeOH (200 mL). The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred at 50 °C under H2 (50 psi) for 12 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was treated with HCl / EtOAc (50 mL) and then concentrated in vacuo to give (S)-2-fluoro-3-methoxypropan-1-amine hydrochloride, which was used without further purification.

[0759] Example A2

[0760] Synthesis of tert-butyl 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

[0761]

[0762] tert-Butyl 7-(4-ethoxy-4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate. At 0 °C, lithium bis(trimethylsilyl)amide (25.4 mL, 25.4 mmol) was added to a solution of ethyl 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyrate (5.25 g, 21.1 mmol) and di-tert-butyl dicarbonate (5.89 mL, 25.4 mmol) in THF (70 mL). After 2 hours, the reaction was diluted with EtOAc (50 mL) and quenched with saturated NH4Cl (50 mL). After stirring for 30 minutes, the layers were separated and the organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The crude residue obtained was purified by normal-phase silica gel chromatography to afford tert-butyl 7-(4-ethoxy-4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate.

[0763]

[0764] tert-Butyl 7-(4-hydroxybutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate. At room temperature, LiBH4 (1.0 M in THF, 19.5 mL, 19.5 mmol) was added to a solution of tert-butyl 7-(4-ethoxy-4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (6.81 g, 19.5 mmol) in THF (50 mL). The mixture was stirred overnight and then quenched with saturated NH4Cl and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with H2O, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue obtained was purified by normal-phase silica gel chromatography to afford tert-butyl 7-(4-hydroxybutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate.

[0765]

[0766] tert-Butyl 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate. A solution of oxalyl chloride (2.57 mL, 29.3 mmol) in CH2Cl2 (69 mL) was cooled to -78 °C for 5 minutes. At this time, dimethyl sulfoxide (4.2 mL, 58.6 mmol) was added and the mixture was stirred for 30 minutes. A solution of tert-butyl 7-(4-hydroxybutyl)-3,4-dihydro-2H-1,8-naphthyridine-1-carboxylate (6.9 g, 22.6 mmol) in CH2Cl2 (10.5 mL) was added and the mixture was stirred at -78 °C for 1 hour. Then triethylamine (10.5 mL, 75.1 mmol) was added to the reaction mixture and stirred for 30 minutes. The reaction was quenched with water and extracted with CH2Cl2. The organic layer was collected and dried over sodium sulfate. The organic layer w...

Claims

1. A compound of formula (II-B) or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4 or 5; R 2 is a C1-C6 alkyl optionally substituted by R 2a , where R 2a is halogen, a C3-C8 cycloalkyl optionally substituted by halogen, phenyl, a 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl, a 3- to 12-membered heterocyclic group optionally substituted by halogen or oxo, -NR 3 C(O)R 4 , -OR 3 or -CN; Each R 1a independently is C1-C6 alkyl or halogen; Each R 3 is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or phenyl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl or phenyl is independently optionally substituted by halogen; and R 4 is a C1-C6 alkyl group.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2a is: halogen, C3-C8 cycloalkyl optionally substituted by halogen, 5- to 10-membered heteroaryl optionally substituted by C1-C6 alkyl, or -NR 3 C(O)R 4 .

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2a is fluorine, cyclobutyl substituted by fluorine, or pyrazolyl substituted by methyl.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is C1-C6 alkyl optionally substituted by -OR 3 .

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is C1-C6 alkyl optionally substituted by -OR 3 , and R 3 is: hydrogen; C1-C6 alkyl optionally substituted by halogen; C3-C6 cycloalkyl optionally substituted by halogen; or phenyl.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is C1-C6 alkyl optionally substituted by -OR 3 , and R 3 is: hydrogen; methyl; ethyl; difluoromethyl; -CH2CHF2; -CH2CF3; cyclopropyl substituted by fluorine; or phenyl optionally substituted by fluorine.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is –CH2CH2OCH3.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is C1-C6 alkyl substituted by both halogen and OR 3 , wherein R 3 is C1-C6 alkyl.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is wherein n is 1, 2, 3, 4, 5 or 6, and R 3 is C1-C2 alkyl optionally substituted with fluorine, phenyl optionally substituted with fluorine, or cyclopropyl optionally substituted with fluorine.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of:

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of:

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is C3-C5 alkyl substituted with both fluorine and -OCH3.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C6 alkyl optionally substituted with -OR 3 , and R 3 is phenyl optionally substituted with fluorine.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C6 alkyl substituted with R 2a , wherein R 2a is halogen.

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C6 alkyl substituted with R 2a , wherein R 2a is a 3- to 12-membered heterocyclic group optionally substituted with an oxo group.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C6 alkyl substituted with R 2a , wherein R 2a is a 4- to 5-membered heterocyclic group optionally substituted with an oxo group.

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C6 alkyl substituted with R 2a , wherein R 2a is phenyl.

18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is a C1-C6 alkyl group substituted by R 2a , wherein R 2a is a 5- to 10-membered heteroaryl group optionally substituted by a C1-C6 alkyl group.

19. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is a C1-C6 alkyl group substituted by R 2a , wherein R 2a is a pyrazolyl group optionally substituted by a methyl group.

20. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is a C1-C6 alkyl group substituted by R 2a , wherein R 2a is a C3-C8 cycloalkyl group optionally substituted by a halogen.

21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

23. Use of the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating fibrotic diseases in an individual in need thereof.

24. The use according to claim 23, wherein the fibrotic disease is pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, renal fibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis or biliary fibrosis.

25. The use according to claim 23, wherein the fibrotic disease is liver fibrosis, cardiac fibrosis, primary sclerosing cholangitis or biliary fibrosis.

26. A kit comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

27. The kit according to claim 26, further comprising instructions for treating fibrotic diseases.

28. Use of the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof in the preparation of a drug for modulating the activity of at least one integrin in a subject in need thereof, wherein the at least one integrin comprises α V β1 integrin and α VAt least one of β6 integrin, wherein the subject has a fibrotic disease or is at risk of developing the fibrotic disease, and the fibrotic disease is selected from the group consisting of: interstitial lung disease, radiation-induced pulmonary fibrosis, non-alcoholic steatohepatitis (NASH), fibrosis induced by alcoholic liver disease, Alport syndrome, primary sclerosing cholangitis (PSC), primary biliary cholangitis, biliary atresia, scleroderma, focal segmental glomerulosclerosis, and Crohn's disease.

29. The use according to claim 28, which comprises inhibiting α in the subject V β1 integrin and α V the activity of one or both of β6 integrin.

30. The use according to claim 28 or claim 29, wherein the subject is in need of treatment for non-alcoholic steatohepatitis (NASH), and the amount of the compound or its pharmaceutically acceptable salt is effective to inhibit at least α V the activity of β1 integrin, thereby treating the subject's non-alcoholic steatohepatitis (NASH).

31. The use according to claim 28 or claim 29, wherein the subject is in need of treatment for idiopathic pulmonary fibrosis (IPF), and the amount of the compound or its pharmaceutically acceptable salt is effective to inhibit at least α V the activity of β6 integrin, thereby treating the subject's idiopathic pulmonary fibrosis (IPF).

32. The use according to claim 28 or claim 29, wherein the subject is in need of treatment for primary sclerosing cholangitis (PSC), and the amount of the compound or its pharmaceutically acceptable salt is effective to inhibit α V β6 integrin and α V the activity of at least one of β1 integrin, thereby treating the subject's primary sclerosing cholangitis (PSC).

33. The compound or its pharmaceutically acceptable salt according to claim 1, wherein the compound or its pharmaceutically acceptable salt is (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

34. The compound or its pharmaceutically acceptable salt according to claim 1, wherein the compound or its pharmaceutically acceptable salt is a pharmaceutically acceptable salt of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

35. The use according to claim 23, wherein the fibrotic disease is idiopathic pulmonary fibrosis and the compound or a pharmaceutically acceptable salt thereof is (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

36. The use according to claim 23, wherein the fibrotic disease is primary sclerosing cholangitis and the compound or a pharmaceutically acceptable salt thereof is (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

37. The use according to claim 23, wherein the fibrotic disease is liver fibrosis and the compound or a pharmaceutically acceptable salt thereof is (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

38. The use according to claim 23, wherein the fibrotic disease is renal fibrosis and the compound or a pharmaceutically acceptable salt thereof is (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

39. The use according to claim 23, wherein the fibrotic disease is idiopathic pulmonary fibrosis and the compound or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

40. The use according to claim 23, wherein the fibrotic disease is primary sclerosing cholangitis and the compound or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

41. The use according to claim 23, wherein the fibrotic disease is liver fibrosis and the compound or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

42. The use according to claim 23, wherein the fibrotic disease is renal fibrosis and the compound or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butyric acid.

43. The use according to claim 28, wherein the interstitial lung disease is selected from idiopathic pulmonary fibrosis (IPF) and interstitial lung disease associated with systemic sclerosis.

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