Quinoline compound as RAGE activity regulator and application thereof

Abstract

Disclosed are quinoline compounds having a structural formula represented by the following formula: and wherein Cy, R1, R4a, R4b and n are as described herein. These compounds may be prepared as compositions, e.g., pharmaceutical compositions, or prepared as dosage forms, e.g., pharmaceutical dosage forms, and may be used in the prevention and treatment of various conditions in mammals, including humans, such as, for example, mammals. Including non-limiting examples of diabetic complications, inflammation, neurodegeneration, obesity, cancer, ischemia / reperfusion injury, cardiovascular disease, COVID-19 complications, and other diseases associated with RAGE activity.

Description

Cross - Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 410,824, filed on September 28, 2022, the entire disclosure of which is incorporated herein by reference. Government Support

[0002] This invention has been made with government support under Grant Nos. R01DK122456 and R01 DK103032 awarded by the National Institutes of Health. The government has certain rights in the invention. Technical Field

[0003] The present invention relates to quinoline compounds capable of modulating the activity of the receptor for advanced glycation end - products (RAGE). Specifically, the present invention relates to quinoline compounds capable of modulating the interaction between RAGE and its ligands, and to the use of such compounds for the treatment of diseases or disorders associated with RAGE activity. More specifically, the quinoline compounds can be used to treat diabetic complications, infections, inflammation, and neurodegeneration, obesity, cancer, ischemia / reperfusion injury, cardiovascular diseases, and other diseases associated with RAGE activity. Also included herein are compositions of quinoline compounds, pharmaceutical compositions of quinoline compounds, and methods of using them to modulate RAGE activity. Background Art

[0004] The receptor for advanced glycation end - products (RAGE) is a multi - ligand cell - surface macromolecule that plays a central role in the etiology of diabetic complications, obesity, inflammation, cancer, and neurodegeneration. The cytoplasmic domain of RAGE, namely the C - terminal RAGE or ctRAGE (RAGE tail), is crucial for RAGE - dependent signal transduction. As the most proximal membrane event, DIAPH1 (also known as mammalian Dial or mDial) binds to RAGE and is, for example, crucial for RAGE ligand - stimulated kinase phosphorylation and cellular properties such as cell proliferation / migration of smooth muscle cells; activation of cdc42 and rac1 in smooth muscle cells and transformed cells; and up - regulation of early growth response 1 in hypoxic macrophages. ctRAGE contains an unusual α - turn that mediates the DIAPH1 - RAGE interaction and is required for RAGE - dependent signal transduction (Shekhtman et al., J. Bio. Chem., 2012, 287(7):5133 - 5142).

[0005] RAGE-ligand interaction triggers central changes in cell properties, including stimulating cell migration and proliferation and leading to pathological conditions such as diabetes and its complications, Alzheimer's disease, inflammation, and cancer. RAGE also plays a key role in the process of atherosclerosis (Schmidt et al. (1999) Circ Res 84:489-497). Therefore, inhibiting RAGE activity is desirable for treating these diseases.

[0006] U.S. Application Publication US2012 / 0088778 discloses azole derivatives as modulators of RAGE-ligand interaction or RAGE activity. These azole compounds are reported to be useful for treating diseases including acute and chronic inflammation, development of advanced complications of diabetes, etc.

[0007] U.S. Application Publication US2010 / 0254983 discloses a method for treating obesity using an antagonist that binds RAGE ligand to RAGE. U.S. Application Publication US2010 / 0119512 discloses carboxamide derivatives as modulators of RAGE-ligand interaction or RAGE activity. U.S. Patent No. 7,361,678 discloses a composition of 3,5-diphenylimidazole derivatives as modulators of RAGE-ligand interaction or RAGE activity. International Application Publication WO2007 / 089616 discloses tertiary amides as modulators of RAGE-ligand interaction or RAGE activity. U.S. Application Publication US2010 / 0249038 discloses novel polypeptides as RAGE antagonists.

[0008] International Application Publication WO / 2015 / 050984 discloses amino, amide, and heterocyclic compounds as modulators of RAGE activity. International Application Publication WO2017 / 184547 discloses quinoline compounds as modulators of RAGE activity. International Application Publication WO / 2021 / 026185 discloses indole compounds as modulators of RAGE activity.

[0009] Many or most of the ligands disclosed in the above applications bind to the extracellular domain of RAGE.

[0010] In view of the above, there is a need for therapeutic agents, corresponding pharmaceutical compositions, and related treatment methods to address diseases causally related to RAGE activity, and the present invention aims to meet this need. Summary of the Invention

[0011] The following is a description of various non-limiting aspects and embodiments of the present invention.

[0012] In one aspect, the present invention provides a compound having the structure of formula (I): Wherein: Q 1 and Q 2 are independently =CH- or =N-, provided that Q 1 and Q 2 are not both =N-; L 1 and L 2 are independently -C(=O)-, -C(=NH)-, C 1 -C 6 alkyl or a combination thereof; R 1 is hydrogen, C 1 -C 6 alkyl, -C(=O)-CH 3 , or R 1 and Q 2 are fused to form an optionally substituted bicyclic heterocycle; R 2 is hydrogen, C 1 -C 6 alkyl, or R 1 and R 2 are fused to form an optionally substituted 5- or 6-membered heterocycle, or a pharmaceutically acceptable salt thereof.

[0013] In one embodiment, Q 1 is =CH-, Q 2 is =N-. In another embodiment, Q 1 is =N-, Q 2 is =CH-. In yet another embodiment, Q 1 and Q 2 are both =CH-.

[0014] In one embodiment, L 1 is -C(=O)-. In another embodiment, L 1 is -C(=NH)-. In yet another embodiment, L 1 is C 1 -C 6 alkyl. In yet another embodiment, L 1 is C 1 -C 3 alkyl.

[0015] In one embodiment, L 1 is -CH 2 -. In another embodiment, L 1 is -(CH 2 ) 2 -. In yet another embodiment, L 1 is -(C(H)CH3 )-. In yet another embodiment, L 1 is -(CH 2 )(C(H)CH 3 ).

[0016] In one embodiment, L 1 is -C(=O)- and C 1 -C 6 alkyl combination. In another embodiment, L 1 is -C(=O)- and C 1 -C 3 alkyl combination. In yet another embodiment, L1 is -(CH 2 )(C=O)-.

[0017] In one embodiment, L 2 is -C(=O)-. In another embodiment, L 2 is C 1 -C 6 alkyl. In yet another embodiment, L 2 is -CH 2 -.

[0018] In one embodiment, R 1 is hydrogen. In another embodiment, R 1 is C 1 -C 6 alkyl. In yet another embodiment, R 1 is C 1 -C 3 alkyl. In yet another embodiment, R 1 is -CH 3 . In yet another embodiment, R 1 is -C(=O)-CH 3 .

[0019] In one embodiment, R 2 is hydrogen. In another embodiment, R 2 is C 1 -C 6 alkyl. In yet another embodiment, R 2 is C 1 -C 3 alkyl. In yet another embodiment, R 2 is -CH 3 .

[0020] In one embodiment, R 1 and R 2 are fused to form an optionally substituted 5- or 6-membered heterocycle.

[0021] In one embodiment, R 1 and L 1 are fused to form an optionally substituted 5- or 6-membered heterocycle.

[0022] In one embodiment, R 1 and L 1 are

[0023] In one embodiment, R 1 and Q 2 are fused to form an optionally substituted bicyclic heterocycle.

[0024] In one embodiment, the compounds of the invention have the structure of formula (II):

[0025] In one embodiment, the compounds of the invention have a structure selected from: or a pharmaceutically acceptable salt thereof.

[0026] In one embodiment, the compounds of the invention have the following structure: or a pharmaceutically acceptable salt thereof.

[0027] In one embodiment, the compound is a racemic mixture of RAGE 406R and RAGE 406S:

[0028] In one embodiment, the compound is RAGE 406R.

[0029] In another aspect, the invention provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof in any of the above embodiments, and a pharmaceutically acceptable carrier.

[0030] In another aspect, the invention provides a pharmaceutical dosage form comprising the compound or a pharmaceutically acceptable salt thereof in any of the above embodiments, or the pharmaceutical composition in any of the above embodiments.

[0031] In yet another aspect, the invention provides a method of modulating the activity of the receptor for advanced glycation end products (RAGE) in a cell, the method comprising contacting the cell with an effective amount of the compound or a pharmaceutically acceptable salt thereof in any of the above embodiments or the pharmaceutical composition in any of the above embodiments.

[0032] In one embodiment, modulating the activity of RAGE comprises inhibiting the activity of RAGE.

[0033] In yet another aspect, the present invention provides a method for treating or ameliorating a disease or disorder associated with RAGE activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof in any of the above embodiments or a pharmaceutical composition in any of the above embodiments.

[0034] In one embodiment, the disease or disorder is selected from diabetes and its complications, insulin resistance, atherosclerosis, peripheral vascular disease and its related complications, cardiovascular disease, kidney disease, retinopathy, cardiac and cerebrovascular ischemia / reperfusion injury, heart attack, myocardial infarction, ischemic cardiomyopathy, cancer, tumor invasion and metastasis, acute and chronic inflammation, autoimmune diseases, neurodegeneration, arthritis, allergic asthma, obesity, pollution-related tissue or organ damage, infection and its complications, sepsis, pneumonia, liver injury / damage, amyloidosis, skin diseases, colitis, lupus, and wound healing disorders.

[0035] In one embodiment, the disease or disorder is diabetes and its complications. In another embodiment, the disease or disorder is coronavirus (COVID-19) infection and its complications.

[0036] In yet another aspect, the present invention provides a method for treating or ameliorating diabetes and its complications in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof in any of the above embodiments or a pharmaceutical composition in any of the above embodiments.

[0037] In one embodiment, the subject is a mammal.

[0038] In one embodiment, the compound or a pharmaceutically acceptable salt thereof in any of the above embodiments or the pharmaceutical composition in any of the above embodiments is administered orally, rectally, intravitreally, transdermally, subcutaneously, intravenously, intramuscularly, intraperitoneally, intradermally, directly into the cerebrospinal fluid, intratracheally, or intranasally.

[0039] These and other aspects of the present invention will become apparent to those skilled in the art after reading the following detailed description of the present invention, including the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 Shows the in vivo delayed-type hypersensitivity of RAGE 229, RAGE 406R, and RAGE 406S in male mice.

[0041] Figure 2 Shows the in vivo delayed-type hypersensitivity of RAGE 229, RAGE 406R, and RAGE 406S in female mice.

[0042] Figure 3 Shows the results of the fluorescence binding titration assay of RAGE 283 with ctRAGE.

[0043] Figure 4 Shows the results of the fluorescence binding titration assay of RAGE 286 with ctRAGE.

[0044] Figure 5 Shows the results of the fluorescence binding titration assay of RAGE 289 with ctRAGE.

[0045] Figure 6 Shows the results of the fluorescence binding titration assay of RAGE 290 with ctRAGE.

[0046] Figure 7 Shows the results of the fluorescence binding titration assay of RAGE 291 with ctRAGE.

[0047] Figure 8 Shows the results of the fluorescence binding titration assay of RAGE 299 with ctRAGE.

[0048] Figure 9 Shows the results of the fluorescence binding titration assay of RAGE 402 with ctRAGE.

[0049] Figure 10 Shows the results of the fluorescence binding titration assay of RAGE 406 with ctRAGE.

[0050] Figure 11 Shows the results of the fluorescence binding titration assay of RAGE 407 with ctRAGE.

[0051] Figure 12 Shows the results of the mouse SMC migration inhibition assay of RAGE 283.

[0052] Figure 13 Shows the results of the mouse SMC migration inhibition assay of RAGE 286.

[0053] Figure 14 Shows the results of the mouse SMC migration inhibition assay of RAGE 289.

[0054] Figure 15 Shows the results of the mouse SMC migration inhibition assay of RAGE 290.

[0055] Figure 16 Shows the results of the mouse SMC migration inhibition assay of RAGE 299.

[0056] Figure 17Shows the results of the RAGE 401 on the mouse SMC migration inhibition assay.

[0057] Figure 18 Shows the results of the RAGE 402 on the mouse SMC migration inhibition assay.

[0058] Figure 19 Shows the results of the RAGE 406 on the mouse SMC migration inhibition assay.

[0059] Figure 20 Shows the results of the RAGE 406R on the mouse SMC migration inhibition assay.

[0060] Figure 21 Shows the results of the RAGE 406S on the mouse SMC migration inhibition assay.

[0061] Figure 22 Shows the results of the RAGE 407 on the mouse SMC migration inhibition assay.

[0062] Figure 23A -D shows the in vivo test results of RAGE 406r in male ( Figure 23A and Figure 23C ) and female ( Figure 23B and Figure 23D ) obese (obob) mice. *p<0.05. Detailed Description

[0063] The detailed embodiments of the present invention are disclosed herein; however, it should be understood that the disclosed embodiments are only illustrative of the present invention which can be embodied in various forms. In addition, each of the examples given in connection with the various embodiments of the present invention is illustrative, not restrictive. Therefore, the specific structural and functional details disclosed herein should not be construed as limiting, but only as a representative basis for teaching those skilled in the art to use the present invention in various ways.

[0064] RAGE and its ligands have been localized at the core of chronic inflammation, which should be understood to play an important role in the pathogenesis of a variety of diseases. The compounds described herein are contemplated to be useful for treating diseases in which inflammation plays a pathological role and RAGE is involved. Such diseases and disorders include inflammatory bowel disease, delayed-type hypersensitivity, atherosclerosis, diabetic complications (including neuropathy and atherosclerosis), asthma, myocardial ischemia, atherosclerotic aneurysm formation, doxorubicin toxicity, acetaminophen toxicity, neurodegeneration, hyperlipidemia, preeclampsia, rheumatoid arthritis, pulmonary fibrosis, COVID-19 complications, and Alzheimer's disease. See, e.g., Hofmann et al. (1999, Cell 97:889-901); Akirav et al. (2014, PLoS One 9:e95678); Johnson et al. (2014, EJNMMI Res 4:26); Tekabe et al. (2014, Int J Mol Imaging 2014:695391); Song et al. (2014, Diabetes 63:1948-1965); Ullah et al. (2014, J Allergy Clin Immunol 134:440-450); Juranek et al. (2013, Brain Behav 3:701-709); Daffu et al. (2013, Int J Mol Sci 14:19891-19910); Manigrasso et al. (2014, Trends Endocrinol Metab 25:15-22); Tekabe et al. (2013, EJNMMI Res 3:37); Rai et al. (2012, J Exp Med 209:2339-2350); Ramasamy et al. (2012, Vascular Pharmacol 57:160-167); Arumugam et al. (2012, Clin Cane Res 18:4356-4364); the entire contents of each of these references are incorporated herein by reference.

[0065] In addition, identifying inhibitors of the interaction between the cytoplasmic domain of RAGE and the FH1 domain of DIAPH1 is of great significance for inhibiting RAGE signal transduction. A large amount of experimental evidence confirms that RAGE ligands mediate their pathogenic effects via RAGE by inducing intracellular signaling pathways. Therefore, inhibitors that block the RAGE-DIAPH1 interaction, which clearly can block intracellular signal transduction and changes in the expression of inflammatory / cytostimulatory genes, are envisioned as therapeutic agents capable of inhibiting the role of RAGE ligands in chronic diseases where RAGE ligands accumulate. Therefore, the small molecule inhibitors described herein are proposed as novel therapeutic agents for treating RAGE-related diseases. Definition

[0066] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0067] When describing compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms have the following meanings unless otherwise indicated. It should also be understood that any part of the definitions below can be substituted with various substituents, and the corresponding definitions are intended to include these substituted parts within their scope. It should be further understood that the terms "group" and "radical" can be considered interchangeable when used herein.

[0068] As used in this specification and the appended claims, unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" include plural references. Thus, for example, reference to "a method" includes one or more methods and / or steps of the type described herein and / or that will become apparent to one of ordinary skill in the art upon reading this disclosure.

[0069] The "treat" or "treatment" of a condition, disorder, or disease includes: (1) preventing, delaying, or reducing the incidence and / or likelihood of at least one clinical or subclinical symptom of the condition, disorder, or disease in a subject who may be predisposed to or at risk of having the condition, disorder, or disease but has not yet experienced or manifested the clinical or subclinical symptoms of the condition, disorder, or disease; or (2) inhibiting the condition, disorder, or disease, i.e., preventing, reducing, or delaying the development of the disease or its recurrence or at least one of its clinical or subclinical symptoms; or (3) alleviating the disease, i.e., causing the regression of the condition, disorder, or disease or at least one of its clinical or subclinical symptoms. The benefit to the subject being treated is either statistically significant or at least perceptible to the patient or the physician.

[0070] As used herein, "subject" or "patient" or "individual" or "animal" refers to humans, veterinary animals (e.g., cats, dogs, cows, horses, sheep, pigs, etc.), and experimental animal models of diseases (e.g., mice, rats). In a preferred embodiment, the subject is a mammal, such as a human.

[0071] As used herein, the term "effective" for a dose or amount refers to the amount of a compound or pharmaceutical composition that is sufficient to produce the desired activity when administered to a subject in need thereof. Note that when a combination of active ingredients is administered, the effective amount of the combination may or may not include the amounts of each ingredient that are effective when administered alone. The exact dose required will vary from subject to subject and will depend on the type of subject, age and general condition, the severity of the condition being treated, the particular drug used, the mode of administration, etc.

[0072] The phrase "pharmaceutically acceptable" as used in connection with the compositions of the present invention refers to the molecular entities and other ingredients of such compositions that are physiologically tolerable and typically produce no adverse reactions when administered to a mammal (such as a human). Preferably, as used herein, the term "pharmaceutically acceptable" refers to those that are approved by a federal or state regulatory agency or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeias for use in mammals, and more particularly humans.

[0073] Ranges may be expressed herein as from "about" or "approximate" one particular value and / or to "about" or "approximate" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value.

[0074] "Comprising" or "containing" or "including" means that at least the specified compound, element, particle, or method step is present in the composition or article or method, but does not exclude the presence of other compounds, materials, particles, or process steps, even if such other compounds, materials, particles, or method steps have the same function as the specified compound, material, particle, or method step.

[0075] The compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of the present invention, chemical elements are identified according to the CAS version of the Periodic Table of the Elements in the 75th edition of the Handbook of Chemistry and Physics. In addition, general principles of organic chemistry are described in Organic Chemistry (by Thomas Sorrell, published by University Science Books, Sausalito: 1999), and March's Advanced Organic Chemistry (5th edition, editors: Smith, M.B. and March, J., published by John Wiley & Sons, New York: 2001), the entire contents of which are incorporated herein by reference.

[0076] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a monocyclic, bicyclic, or tricyclic hydrocarbon (also referred to herein as a "carbocyclic", "alicyclic", or "cycloalkyl") that is completely saturated or contains one or more unsaturated units but is not aromatic, which has a single point of attachment to the remainder of the molecule. Unless otherwise indicated, aliphatic groups include 1 to 30 aliphatic carbon atoms. In some embodiments, aliphatic groups include 1 to 20 aliphatic carbon atoms. In other embodiments, aliphatic groups include 1 to 10 aliphatic carbon atoms. In still other embodiments, aliphatic groups include 1 to 6 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups include 1, 2, 3, or 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0077] As used herein, the term "alicyclic" refers to a saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic system having 3 to 14 members as described herein, wherein the alicyclic ring system is optionally substituted as described and defined herein. Alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, the cycloalkyl has 3 - 6 atoms. The term "alicyclic" may also include an alicyclic ring fused to one or more aromatic or non-aromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, wherein the radical or point of attachment is on the alicyclic ring. In some embodiments, the carbocyclic group is bicyclic. In some embodiments, the carbocyclic group is tricyclic. In some embodiments, the carbocyclic group is polycyclic. In some embodiments, "alicyclic" (or "carbocyclic" or "cycloalkyl") refers to C 3 –C 6 monocyclic hydrocarbons, or fully saturated or containing one or more unsaturated units but not aromatic C 8 –C 10 bicyclic hydrocarbons having a single point of attachment to the remainder of the molecule, or fully saturated or containing one or more unsaturated units but not aromatic C 9 –C 16 tricyclic hydrocarbons having a single point of attachment to the remainder of the molecule.

[0078] As used herein, the term "alkyl" is given its ordinary meaning in the art and may include saturated aliphatic groups, including straight-chain alkyls, branched-chain alkyls, cycloalkyls (alicyclics), alkyl-substituted cycloalkyls, and cycloalkyl-substituted alkyls. In certain embodiments, the straight-chain or branched-chain alkyl has about 1 - 20 carbon atoms in its backbone (e.g., straight-chain is C 1 -C 20 , branched-chain is C 2 -C 20 ), alternatively, about 1 - 10 carbon atoms, or about 1 to 6 carbon atoms. In some embodiments, the cycloalkyl ring has about 3 - 10 carbon atoms in its ring structure, wherein the rings are monocyclic or bicyclic, alternatively having about 5, 6, or 7 carbon atoms in the ring structure. In some embodiments, the alkyl may be a lower alkyl, wherein the lower alkyl contains 1 - 4 carbon atoms (e.g., C 1 -C 4 straight-chain lower alkyl).

[0079] As used herein, the term "alkenyl" refers to an alkyl having one or more double bonds as defined herein.

[0080] As used herein, the term "alkynyl" refers to an alkyl having one or more triple bonds as defined herein.

[0081] The term "heteroalkyl" is given its ordinary meaning in the art and refers to an alkyl group as described herein wherein one or more carbon atoms are replaced by a heteroatom (e.g., oxygen, nitrogen, sulfur, etc.). Examples of heteroalkyl include, but are not limited to, alkoxy, polyethylene glycol, alkyl-substituted amino, tetrahydrofuranyl, piperidinyl, morpholinyl, etc.

[0082] The term "aryl", used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the ring system is aromatic and wherein each ring of the ring system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aromatic ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthryl, etc., which may be substituted with one or more substituents. Within the scope of the term "aryl" as used herein, groups in which an aromatic ring is fused to one or more non-aromatic rings are also included, such as indenyl, phthalimido, naphthalimido, phenanthridinyl, or tetrahydronaphthyl, etc.

[0083] The terms "heteroaryl" and "heteroar-" when used alone or as part of a larger moiety such as "heteroarylalkyl" or "heteroaryloxy", refer to groups having 5 to 10 ring atoms (i.e., monocyclic or bicyclic), 5, 6, 9 or 10 ring atoms in some embodiments. In some embodiments, such rings have 6, 10 or 14 π electrons shared in a cyclic array; and in addition to carbon atoms, have 1 to 5 heteroatoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur, including any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Heteroaryl includes but is not limited to thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. In some embodiments, heteroaryl is heteroarylalkyl, such as bipyridyl, etc. The terms "heteroaryl" and "heteroar-" as used herein also include groups in which a heteroaryl ring is fused to one or more aryl, cycloaliphatic or heterocyclic rings, where the radical or point of attachment is on the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic, bicyclic, tricyclic, tetracyclic and / or other polycyclic. The term "heteroaryl" can be used interchangeably with "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which terms includes rings which are optionally substituted. The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl moiety and the heteroaryl moiety are independently and optionally substituted.

[0084] As used herein, the terms "heterocycle", "heterocyclic group" and "heterocyclic radical" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety which is saturated or partially unsaturated and which, in addition to carbon atoms, has one or more, preferably one to four, heteroatoms as described above. When used to refer to the ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen.

[0085] The heterocycle can be attached to a side group at any of its heteroatoms or carbon atoms so as to form a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include but are not limited to tetrahydrofuranyl, tetrahydrothienyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxolanyl, dioxolanyl, diaza yl, oxaaza Base, thiazole Base, morpholinyl and quinuclidinyl. The terms "heterocycle", "heterocyclic group", "heterocyclic moiety", "heterocyclic radical" and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocycle is fused to one or more aryl, heteroaryl or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl. Heterocyclic groups can be monocyclic, bicyclic, tricyclic, tetracyclic and / or other polycyclic. The term "heterocycloalkyl" refers to an alkyl group substituted by a heterocyclic group, wherein the alkyl moiety and the heterocyclic moiety are independently and optionally substituted.

[0086] As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double bond or triple bond. The term "partially unsaturated" is intended to include rings having multiple unsaturated sites, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0087] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; any quaternized form of any basic nitrogen; the replaceable nitrogen of a heterocycle).

[0088] As used herein, the term "unsaturated" as used herein refers to a moiety having one or more unsaturated units.

[0089] The term "halogen" refers to F, Cl, Br or I; the term "halide" refers to a halogen radical or substituent, i.e., -F, -Cl, -Br or -I.

[0090] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. Generally, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the specified moiety are replaced by a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a particular group, the substituents may be the same or different at each position. Combinations of substituents contemplated by the present invention are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" refers to a compound that does not undergo substantial change under conditions that permit its production, detection, and in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0091] Unless otherwise indicated, structures described herein also mean to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers of the compound as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures are within the scope of the present invention.

[0092] Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0093] In addition, unless otherwise indicated, structures described herein also mean to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention are within the scope of the present invention except that hydrogen is replaced by deuterium or tritium, or carbon is replaced by carbon enriched in 11 C-, 13 C or 14 C-.

[0094] It should also be understood that the mention of one or more method steps does not exclude the presence of additional method steps or intermediate method steps between those specifically identified steps. Similarly, it should also be understood that the mention of one or more components in a device or system does not exclude the presence of additional components or intermediate components between those specifically identified components.

[0095] Unless otherwise indicated, all crystalline forms of the compounds of the present invention and their salts are within the scope of the present invention. The compounds of the present invention can be isolated in various amorphous and crystalline forms, including but not limited to anhydrous, hydrated, non-solvated, or solvated forms. Exemplary hydrates include hemihydrate, monohydrate, dihydrate, etc. In some embodiments, the compounds of the present invention are anhydrous and non-solvated. "Anhydrous" means that the crystalline form of the compound contains substantially no bound water in the crystal lattice structure, i.e., the compound does not form a crystalline hydrate.

[0096] As used herein, "crystalline form" refers to a certain lattice configuration of a crystalline substance. Different crystalline forms of the same substance typically have different lattices (e.g., unit cells), and these different lattices result in each crystalline form having different physical properties. In some cases, different lattice configurations have different water or solvent contents. Different lattices can be identified by solid-state characterization methods such as X-ray powder diffraction (PXRD). Other characterization methods, such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), solid-state nuclear magnetic resonance (NMR), etc., further assist in the identification of crystalline forms and in determining stability and solvent / water content.

[0097] Crystalline forms of a substance include solvated (e.g., hydrated) and unsolvated (e.g., anhydrous) forms. A hydrated form is a crystalline form that contains water in the crystal lattice. The hydrated form can be a stoichiometric hydrate, where water is present in the crystal lattice in a certain water / molecule ratio, such as hemihydrate, monohydrate, dihydrate, etc. The hydrated form can also be non-stoichiometric, where the water content is variable and depends on external conditions such as humidity.

[0098] In some embodiments, the compounds of the present invention are substantially isolated. "Substantially isolated" means that a particular compound is at least partially separated from impurities. For example, in some embodiments, the compounds of the present invention comprise less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2.5%, less than about 1%, or less than about 0.5% impurities. Impurities generally include any substance that is not the substantially isolated compound, such as other crystalline forms and other substances. Compound

[0099] The present invention provides quinoline compounds capable of modulating the activity of the receptor for advanced glycation end products (RAGE).

[0100] Specifically, the present invention provides quinoline compounds capable of modulating the interaction between RAGE and its ligands, and the use of such compounds for the treatment of diseases or disorders associated with RAGE activity.

[0101] More specifically, the present invention provides quinoline compounds capable of modulating the interaction between RAGE and ligands that bind to the intracellular domain of RAGE, and the use of such compounds for the treatment of diseases or disorders associated with RAGE activity.

[0102] In one aspect, the present invention provides a method for preventing, treating, or ameliorating a disease or disorder causally related to in vivo RAGE activity in a mammal, which comprises administering to the mammal an effective amount for treating the disease or disorder of a compound of formula (I): Wherein: Q 1 and Q 2 are independently =CH- or =N-, provided that Q 1 and Q 2 are not both =N-; L 1 and L 2 are independently -C(=O)-, -C(=NH)-, C 1 -C 6 alkyl or combinations thereof; R 1 is hydrogen, C 1 -C6 alkyl, -C(=O)-CH 3 , or R 1 and Q 2 are fused to form an optionally substituted bicyclic heterocycle; R 2 is hydrogen, C 1 -C 6 alkyl, or R 1 and R 2 are fused to form an optionally substituted 5- or 6-membered heterocycle, or a pharmaceutically acceptable salt thereof.

[0103] In one embodiment of the compound of formula (I), Q 1 is =CH-, Q 2 is =N-. In another embodiment, Q 1 is =N-, Q 2 is =CH-. In yet another embodiment, Q 1 and Q 2 are both =CH-.

[0104] In one embodiment of the compound of formula (I), L 1 is -C(=O)-. In another embodiment, L 1 is -C(=NH)-.

[0105] In another embodiment, L 1 is C 1 -C 6 alkyl. In another embodiment, L 1 is C 1 -C 3 alkyl. In another embodiment, L 1 is -CH 2 -. In another embodiment, L 1 is -(CH 2 ) 2 -. In another embodiment, L 1 is -(C(H)CH 3 )-. In another embodiment, L 1 is -(CH 2 )-(C(H)CH 3 )-.

[0106] In one embodiment, L 1 is a combination of -C(=O)- and C 1 -C 6 alkyl. In another embodiment, L 1 is a combination of -C(=O)- and C 1 -C 3Combinations of alkyl groups. In another embodiment, L 1 is -(CH 2 )-C(=O)-.

[0107] In one embodiment of the compound of formula (I), L 2 is -C(=O)-. In another embodiment, L 2 is C 1 -C 6 alkyl. In another embodiment, L 2 is -CH 2 -.

[0108] In one embodiment of the compound of formula (I), R 1 is hydrogen.

[0109] In another embodiment, R 1 is C 1 -C 6 alkyl. In another embodiment, R 1 is C 1 -C 3 alkyl. In another embodiment, R 1 is -CH 3 .

[0110] In another embodiment, R 1 is -C(=O)-CH 3 .

[0111] In one embodiment of the compound of formula (I), R 2 is hydrogen.

[0112] In one embodiment of the compound of formula (I), R 2 is C 1 -C 6 alkyl. In another embodiment, R 2 is C 1 -C 3 alkyl. In another embodiment, R 2 is -CH 3 .

[0113] In one embodiment of the compound of formula (I), R 1 and R 2 are fused to form an optionally substituted 5- or 6-membered heterocycle.

[0114] In one embodiment of the compound of formula (I), R 1 and L 1 are fused to form an optionally substituted 5- or 6-membered heterocycle. In one embodiment, R 1 and L 1 are

[0115] In one embodiment of the compound of formula (I), R 1 and Q 2 are fused to form an optionally substituted bicyclic heterocycle.

[0116] In one embodiment of the compound of formula (I), the compound has the structure of formula (II):

[0117] In one embodiment of the compound of formula (I), the compound has a structure selected from: or a pharmaceutically acceptable salt thereof.

[0118] In one embodiment of the compound of formula (I), the structure of the compound: or a pharmaceutically acceptable salt thereof.

[0119] In one embodiment of the compound of formula (I), the compound is a racemic mixture of RAGE 406R and RAGE 406S:

[0120] In one embodiment of the compound of formula (I), the compound is RAGE 406R:

[0121] In one embodiment of the compound of formula (I), the compound is RAGE 406S:

[0122] In another aspect, the present invention provides a pharmaceutical composition comprising any one of the compounds described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0123] In yet another aspect, the present invention provides a pharmaceutical dosage form comprising any one of the compounds or pharmaceutical compositions described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Pharmaceutical composition

[0124] When used as a drug, the compounds of the present invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and include at least one active compound.

[0125] Typically, the compounds of the present invention are administered in a therapeutically effective amount. The actual amount of the compound administered is typically determined by a physician based on relevant circumstances, including the disorder to be treated, the chosen route of administration, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0126] The pharmaceutical compositions of the present invention can be administered by a variety of routes including oral, rectal, intraocular, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intradermal, direct injection into the cerebrospinal fluid, intratracheal and intranasal. Depending on the intended route of administration, the compounds of the present invention are preferably formulated as injectable or oral compositions, or are formulated as ointments, emulsions or patches, all for transdermal administration. In some embodiments, the compounds of the present invention are formulated for local injection in a suitable carrier to optimize tissue-specific delivery.

[0127] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, these compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect and combined with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or in the case of solid compositions include pills, tablets, capsules, etc. In such compositions, the active compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remainder is various vehicles or carriers and processing aids that contribute to the formation of the desired dosage form.

[0128] Liquid formulations suitable for oral administration can include suitable aqueous or non-aqueous vehicles containing buffering agents, suspending and dispensing agents, coloring agents, flavoring agents, etc. Solid forms may include, for example, any one of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate or orange flavoring.

[0129] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As previously mentioned, the active compound in such compositions is typically a minor component, usually about 0.05 to 10% by weight, and the remainder is the injectable carrier, etc.

[0130] Transdermal compositions are typically formulated as topical ointments or creams containing one or more active ingredients, usually in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by mass, more preferably about 0.1 to about 10% by mass, and most preferably about 0.5 to about 15% by mass. When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-soluble ointment base. Alternatively, the active ingredient can be formulated as a cream, for example, with an oil-in-water cream base. Such transdermal preparations are well known in the art and typically include additional ingredients to enhance the skin permeability or stability of the active ingredient or the preparation. All such known transdermal preparations and ingredients are included within the scope of the present invention.

[0300] The compounds of the present invention can also be administered by a transdermal device. Thus, transdermal administration can be achieved using a patch of the reservoir type, the porous membrane type, or the solid matrix type.

[0131] The components of the compositions for oral administration, injection, or topical administration described above are merely representative. Other materials, as well as processing techniques, etc., are set forth in Part 8 of Remington's Pharmaceutical Sciences (17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania), which is incorporated herein by reference.

[0132] The compounds of the present invention can also be topically administered to the eye for the treatment of diabetic neuropathy. Suitable compositions include those that can be administered by eye drops, injections, etc. In the case of eye drops, the composition can also optionally include, for example, ophthalmic compatibilizers such as isotonic agents, buffers, surfactants, stabilizers, and other ingredients. For injection, the compound can be provided in the form of an injectable saline solution, an injectable liposome solution, a sustained-release polymer system, etc.

[0133] The compounds of the present invention can also be administered in a sustained-release dosage form or by a sustained-release drug delivery system. A description of representative sustained-release materials can be found in Remington's Pharmaceutical Sciences.

[0134] The following formulation examples illustrate representative pharmaceutical compositions of the present invention. However, the present invention is not limited to the following pharmaceutical compositions. Formulation 1 - Tablets

[0135] The compound of the present invention is mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into tablets of 240 - 270 mg (80 - 90 mg of the active amide compound per tablet) in a tableting machine. Formulation 2 - Capsule

[0136] The compound of the present invention is mixed with a starch diluent as a dry powder in a weight ratio of about 1:1. The mixture is filled into 250 mg capsules (125 mg of the active amide compound per capsule). Formulation 3 - Liquid

[0137] The compound of the present invention (125 mg), sucrose (1.75 g) and xanthan gum (4 mg) are mixed, passed through a 10 - mesh US sieve, and then mixed with an aqueous solution of pre - prepared microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg). Sodium benzoate (10 mg), flavoring agent and coloring agent are diluted with water and added with stirring. Then enough water is added to make the total volume reach 5 mL. Formulation 4 - Tablet

[0138] The compound of the present invention is mixed with a dry gelatin binder as a dry powder in a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is made into tablets of 450 - 900 mg (150 - 300 mg of the active amide compound per tablet) in a tabletting machine. Formulation 5 - Injection

[0139] The compound of the present invention is dissolved or suspended in a buffered sterile saline - injectable aqueous medium at a concentration of about 5 mg / mL. Formulation 6 - Transdermal

[0140] Stearyl alcohol (250 g) and white petrolatum (250 g) are melted at about 75 °C, and then a mixture of the compound of the present invention (50 g), methyl paraben (0.25 g), propyl paraben (0.15 g), sodium lauryl sulfate (10 g) and propylene glycol (120 g) dissolved in water (about 370 g) is added. The resulting mixture is stirred until it solidifies. Treatment method

[0141] Type 1 and type 2 diabetes are on the rise in the United States and worldwide (International Diabetes Federation (2012), IDF Diabetes Atlas (5th ed.), International Diabetes Federation, Brussels, Belgium; Patterson et al., "Trends in childhood type 1 diabetes incidence in Europe during 1989 - 2008: evidence of non-uniformity over time in rates of increase", Diabetologia 55:2142 - 2147 (2012); Lipman et al., "Increasing Incidence of Type 1 Diabetes in Youth: Twenty years of the Philadelphia Pediatric Diabetes Registry", Diabetes Care 36:1597 - 1603 (2013)). The incidence of type 1 diabetes in adults is also increasing globally, which may lead to a significant reduction in life expectancy (Lancet diabetes Endocrinol., October 2022, 10(10):741 - 760). The long-term consequences of diabetes are caused by the direct and indirect effects of hyperglycemia. Diabetes attacks large and small blood vessels and is considered a major cause of heart attack, stroke, blindness, kidney failure, amputation, and peripheral neuropathy. The strong epidemiological link between diabetes and Alzheimer's disease increases the likelihood that diabetes often accompanies irreversible chronic diseases, resulting in a devastating loss of quality of life and life expectancy. Despite significant progress in the treatment of hyperglycemia, the exact methods for preventing diabetes complications have not emerged.In fact, strict control of hyperglycemia, especially in the elderly population, may be accompanied by serious sequelae such as severe hypoglycemia, seizures, myocardial ischemia, and death (Nathan et al., "Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes", Diabetes Care 3:193-203 (2009); (United Kingdom Prospective Diabetes Study (UKPDS)), United Kingdom Prospective Diabetes Study Group, Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), UKPDS Study Group, Lancet, pp. 837-853 (1998); Diabetes Control and Complications Trial Research Group (1993), The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin-dependent diabetes mellitus, Diabetes Control and Complications Trial Research Group, New Engl. J. Med., pp. 977-986).

[0142] Non-enzymatic glycation and oxidation products of proteins and lipids, namely advanced glycation end products (AGEs), are formed and accumulated at an accelerated rate in hyperglycemia (Frye et al., "Role of the Maillard reaction in aging of tissue proteins. Advanced glycation end product-dependent increase in imidazolium cross-links in human lens proteins", J. Biol. Chem. 273:18714-18719 (1998)). AGEs can be detected in the plasma, urine, skin, and other tissues of diabetic subjects, and their presence is associated with the development of diabetic complications. AGEs act in part through non-receptor-mediated mechanisms, such as cross-linking of body proteins, particularly long-lived proteins such as those in the basement membrane. AGEs also act through receptor-dependent mechanisms; the major receptor for AGEs is the AGE or RAGE receptor. A large body of evidence indicates that RAGE, a member of the immunoglobulin superfamily of cell surface molecules, is increased in expression in animal models and human diabetic tissues, such as in large and small blood vessel tissues. RAGE is a multi-ligand receptor, and the discovery that RAGE binds at least some members of the pro-inflammatory mediators S100 / calgranulin family and high mobility group box 1 (HMGB1) suggests that inflammatory mechanisms play an important role in the pathogenesis of complications.In fact, non-AGE RAGE ligands also accumulate in diabetic tissues of humans and animal models (Yan et al., "Tempering the wrath of RAGE: an emerging therapeutic strategy against diabetic complications, neurodegeneration, and inflammation", Ann. Med. 41:408-422 (2009); Yan et al., "The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature", Circ. Res. 106:842-853 (2010)). The role of inflammation in at least some types / stages of diabetic complications, once thought highly unlikely, is now widely recognized. Pharmacological and genetic approaches, independently pursued in multiple laboratories, have provided strong support for the role of RAGE in the pathogenesis of diabetic complications. For example, administration of antibodies against RAGE or soluble RAGE (the latter being the extracellular ligand-binding domain of RAGE) or gene deletion of RAGE significantly reduced the acceleration of diabetic atherosclerosis in mice; ischemic / reperfusion injury in the diabetic heart; pathological and functional indices of nephropathy; pathological and functional indices of neuropathy; and improved wound healing in diabetic animals (Yan et al., "Tempering the wrath of RAGE: an emerging therapeutic strategy against diabetic complications, neurodegeneration, and inflammation", Ann. Med. 41:408-422 (2009); Yan et al., "The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature", Circ. Res. 106:842-853 (2010)).

[0143] Increasing evidence suggests that the levels of soluble RAGE (cell surface-cleaved RAGE and endogenous secreted (splice variants)) may be biomarkers for diabetes and its complications in human subjects; the levels of soluble RAGE appear to be modulated by therapeutic interventions, thus enhancing the significance of measuring these forms of circulating RAGE.

[0144] In this direct context, the inventors and others demonstrated that the cytoplasmic domain of RAGE is essential for the effects of RAGE ligand-RAGE interactions in regulating gene expression and triggering vascular and inflammatory cell dysfunction. The cytoplasmic domain of RAGE does not appear to exert its downstream signaling role solely through endogenous phosphorylation; thus, the inventors sought to test the premise that intracellular binding effectors are essential for binding to the RAGE tail, thereby facilitating engagement of intracellular signaling pathways. To this end, the inventors performed a yeast two-hybrid assay using the RAGE tail as a "bait." From this experimental work, the inventors discovered and published in 2008 that the cytoplasmic domain of RAGE interacts with the formin molecule DIAPH1, and that DIAPH1 is required for the effects of RAGE signaling in a variety of cell types such as smooth muscle cells, macrophages, cardiomyocytes, and endothelial cells (Hudson et al., "Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Racl and Cdc42," J. Biol. Chem. 283:34457-34468 (2008); Rai et al., "Signal transduction in receptor for advanced glycation endproducts (RAGE): solution structure of C-terminal rage (cTRAGE) and its binding to mDial," J. Biol. Chem. 287:5133-5144 (2012); Xu et al., "Advanced glycation end product (AGE)-receptor for AGE (RAGE) signaling and up-regulation of Egr-1 in hypoxic macrophages," J. Biol. Chem.(Journal of Biological Chemistry) 285:23233 - 23240 (2010); Toure et al., "Formin mDial mediates vascular remodeling via integration of oxidative and signal transduction pathways", Circ. Res. (Circulation Research) 110:1279 - 1293 (2012); Zhu et al., Biochim Biophys Acta Biomembr. (Biochimica et Biophysica Acta - Biomembranes), January 2019, 1861(1):43 - 49; Syed et al., Eur Biophys J. (European Biophysics Journal), January 2018, 47(1):39 - 48).

[0145] Basic observations link DIAPH1 to pathological markers of RAGE signaling that are directly associated with diabetic complications. Thus, modulating the interaction between RAGE and DIAPH1 is desirable for treating diseases and disorders involving RAGE.

[0146] In addition, it is understood that the compounds described herein act as modulators of the binding of RAGE to its intracellular ligands (e.g., DIAPH1), thereby reducing or preventing the activation of NF - κB - regulated genes, such as the cytokines IL - 1 and TNF - α, and minimizing the production of oxidative stress. The ability of the compounds described herein to antagonize or inhibit the binding of physiological ligands to the intracellular tail of RAGE makes them well - suited for use as therapeutic agents for treating or controlling diseases or disorders associated with RAGE activity. More specifically, the quinoline compounds described herein can be used to treat, for example, diabetic complications, inflammation, neurodegeneration, obesity, cancer, ischemia / reperfusion injury, cardiovascular diseases, Alzheimer's disease, and other diseases understood to be associated with RAGE activity. Such compounds can be used to attenuate downstream signaling events caused by, for example, the AGE - RAGE interaction that causes diabetic complications, the S100A12 / EN - RAGE / calgranulin - RAGE interaction that causes inflammatory diseases, the β - amyloid - RAGE interaction that causes Alzheimer's disease, and the high - mobility group box 1 (HMGB1) - RAGE interaction that causes, for example, inflammation and cancer. Diabetes and Diabetic Complications

[0147] In addition, the quinoline compounds described herein can be used to manage and / or treat complications associated with diabetes. Non-enzymatic glycoxidation of macromolecules results in the formation of advanced glycation end products (AGEs). The term AGE refers to a heterogeneous group of compounds produced by the non-enzymatic glycation or glycoxidation of proteins, lipids, and nucleic acids. More specifically, AGEs are the result of a complex series of biochemical reactions that involve the formation of Amadori products, glyceraldehyde-3-phosphate, and the reactive carbonyl methylglyoxal (MG). See, for example, Manigraso et al. (Trends Endocrinol Metab 25:15-22 (2014)); the entire contents of each of these references, including the references cited therein, are incorporated herein by reference. Non-enzymatic glycoxidation of macromolecules is known to be enhanced in the presence of hyperglycemia and other conditions associated with systemic or local oxidative stress. It is also known to be enhanced in sites of renal failure, inflammation, and other sites associated with neurodegeneration, obesity, and cancer. For example, Schmidt et al. (Nature Med. 1:1002-1004 (1995)) have shown that AGEs typically accumulate in the vascular system and tissues of diabetic patients. Other studies have shown that AGEs also accumulate locally in the vascular system, as observed in joint amyloid composed of AGE-P2-microglobulin found in patients with dialysis-related amyloidosis (Abedini et al., FEBS Lett 587:1119-1127 (2013); Miyata et al., J Clin Invest 92:1243-1252 (1993); Miyata et al., J Clin Invest 98:1088-1094 (1996)). Hyperglycemia also directly accelerates the production of AGEs. The formation of AGEs is also often associated with an increase in reactive oxygen species (ROS) (Fu et al., Diabetes 43:676-683 (1994)). Although AGEs accumulate slowly in plasma and tissues during the aging process (Brownlee et al., N Engl J Med 318:1315-1321 (1988); Hallam et al., Aging Cell 9:776-784 (2010); Schleicher et al., J Clin Inv 99:457-468 (1997)), they are significantly increased in diabetic patients (Makita et al., N Engl J Med 325:836-842 (1991)).

[0148] Suitable animal models for studying diabetic complications are known in the art and are described, for example, in Manigraso et al. (2014, Trends Endocrinol Metab 25:15-22); Stirban et al. (2014, Molecular Metabolism 3:94-108); Johnson et al. (2014, EJNMMI Res 4:26); Tekabe et al. (2014, Int J Mol Imaging Article ID 695391); Kaida et al. (2013, Diabetes 62:3241-3250); Tekabe et al. (2013, EJNMMI Res 3:37); Calcutt et al. (2009, Nat Rev Drug Discov 8:417-429); Dauch et al. (2013, J Neuroinflanimation 10:64); Juranek et al. (2013, Diabetes 62:931-943); Singh et al. (2014, Korean J Physiol Pharmacol 18:1-14); Ramasamy et al. (2012, Vascular Pharmacol 57:160-167); Montagnani, (2008, Br J Pharmacol 154:725-726); Nakamura et al. (1993, Am J Pathol 143:1649-1656); Lin et al. (2003, Atherosclerosis 168:213-220); Hofmann et al. (2002, Diabetes 51:2082-2089); Lin et al. (2002, Atherosclerosis 163:303-311); Vlassara et al. (1992, Proc Natl Acad Sci 89:12043-12047); Brownlee et al. (1986, Science 232:1629-1632);Li et al. (Proc Natl Acad Sci 93:3902-3907 (1996)); Park et al. (Nature Med 4:1025-1031 (1998)); Kislinger et al. (Arteriosclerosis, Thrombosis, and Vascular Biology 21:905-910 (2001)); Bucciarelli et al. (Circulation 106:2827-2835 (2002)); Wendt et al. (Atherosclerosis 185:70-77 (2006)); the entire contents of each of these references are incorporated herein by reference.; Diabetic Complications - Heart

[0149] More specifically, animal models of human diabetes involving cardiac diabetic complications include models involving isolated perfused heart ischemia / reperfusion, left anterior descending coronary artery ligation, and cardiac autonomic neuropathy. References describing such models are known in the art and are described, for example, in Stables et al. (Autonom Neurosci 177:746-80 (2014)), Bucciarelli et al. (Circulation (Supplement) 102:#563, II-l 17 (2000)), and Aleshin et al. (Am J Physiol Heart Circ Physiol 294:H1823-H1832 (2008)); the entire contents of each of these references are incorporated herein by reference. Diabetic Complications - Kidney

[0150] More specifically, animal models of human diabetes involving diabetic complications of the kidney include OVE26 mice, streptozotocin-induced animals, Db / db mice, and nephrectomy. References describing such models are known in the art and are described, for example, in Kaur et al. (2014, Inflammopharmacology 22:279-293), Reiniger et al. (2010, Diabetes 59:2043-2054), and Wendt et al. (2003, American Journal of Pathology 162:1123-1137); the entire contents of each of these references are incorporated herein by reference. Diabetic Complications - Retinopathy

[0151] More specifically, animal models of human diabetes involving diabetic complications leading to retinopathy include streptozotocin-induced animals, Db / db mice, and Akita mice. References describing such models are known in the art and are described, for example, in Lai et al. (2013, J Diabetes Res 013:106594) and Barile et al. (2005, Invest Ophthalmol Vis Sci 46:2916-2924); the entire contents of each of these references are incorporated herein by reference. Diabetic Complications - Neuropathy

[0152] More specifically, animal models of human diabetes involving diabetic complications leading to neuropathy include Swiss Webster mice, Db / db mice, and sciatic nerve transection / crushing. References describing such models are known in the art and are described, for example, in Juranek et al. (2010, Biochem Insights 2010:47-59), Juranek et al. (2013, Diabetes 62:931-943), Islam (2013, J DiabetesRes 2013:149452); the entire contents of each of these references are incorporated herein by reference.

[0153] Animal models of diabetes generally include streptozotocin-induced animals, Akita mice, Db / db mice, and Ob / ob mice. These animal models are known in the art and are described, for example, in Park et al. (Nature Medicine 4:1025-1031, 1998), Wendt et al. (Atherosclerosis 185:70-77, 2006), Wang et al. (Curr Diabetes Rev 10:131-145, 2014), and Acharjee et al. (Can J Diabetes 37:269-276, 2013); the entire contents of each of these references are incorporated herein by reference. Immune / Inflammatory Response

[0154] The quinoline compounds described herein are contemplated to be useful for treating inflammation. Since inflammation is a common feature of all of the diseases and conditions described herein, it is reasonable to expect that these compounds will also be effective in the context of, for example, diabetic complications, obesity, cancer, ischemia / reperfusion injury, cardiovascular disease, neurodegeneration, Alzheimer's disease, cystic fibrosis, multiple sclerosis, rheumatoid arthritis, psoriasis, atopic dermatitis, and eczema.

[0155] As described above, RAGE is a receptor for many members of the S100 / calgranulin family, a closely related family of calcium-binding polypeptides that accumulate at sites of chronic immune / inflammatory responses such as those observed in cystic fibrosis and rheumatoid arthritis. In addition, RAGE is known to mediate the pro-inflammatory effects of S100 / calgranulin on a variety of cells including lymphocytes and mononuclear phagocytes. Indeed, the interaction of RAGE ligands with, for example, pro-inflammatory S100 / calgranulin, high-mobility group box 1 (HMGB1), and / or AGE is thought to play a key role in the inflammatory cascade. See, for example, Ramasamy et al. (Vascular Pharmacol 57:160-167, 2012); Andersson et al. (Annu Rev Immunol 29:139-162, 2011); the entire contents of each of these references, including the references cited therein, are incorporated herein by reference. Studies using in vitro and animal models of the delayed-type hypersensitivity (DTH) response, colitis in IL-10-deficient mice, collagen-induced arthritis, and experimental autoimmune encephalomyelitis models have further underscored the fundamental role of RAGE ligand interactions in a variety of inflammatory diseases including rheumatoid arthritis and multiple sclerosis.

[0156] RAGE is also associated with inflammatory diseases of the skin, such as but not limited to psoriasis, atopic dermatitis, and eczema. Additionally, psoriasis may be accompanied by arthropathic symptoms similar to those observed in rheumatoid arthritis. High levels of pro-inflammatory cytokines, particularly IL-1 and IL-8, have been detected in psoriatic lesions. IL-8 is a chemokine for neutrophils, and neutrophils are known to synthesize and secrete S100 proteins. As described above, S100 proteins are RAGE ligands, and their interaction leads to the propagation of immune and inflammatory responses, thereby contributing to and causing the various diseases / conditions described herein. Psoriasin (S100A7), a member of the S100 gene family, is a secreted protein isolated from psoriatic skin. Additionally, a genetic susceptibility to psoriasis has been shown to be associated with a marked overexpression of S100 proteins in the skin (Semprini et al., 2002, Hum. Genet. 111:310-3). Thus, in view of their ability to inhibit RAGE-mediated downstream signaling, the compounds described herein are contemplated as therapeutic agents for psoriasis. High Mobility Group Protein 1 (HMGB1)

[0157] HMGB1, also known as amphoterin, has dual activities. It was initially identified as a structural protein localized in the nucleus, whose function is to stabilize DNA structure and regulate transcriptional activity (Stros et al., 2010, Biochem Biophys Acta 1799:101-113). It was later also found that HMGB1 is an actively secreted cytokine produced by macrophages and other inflammatory cells in response to invading innate immune responses (Wang et al., 1999, Science 285:248-251). Like other members of the pro-inflammatory cytokine family, bioactive HMGB1 can be expressed on the plasma membrane or released by activated inflammatory cells to accumulate in vivo during infection and injury. As an effector molecule, HMGB1 is capable of altering the metabolism and immune activity of hematopoietic, epithelial, and neuronal cells. The breadth of its effector functions is reflected in its known activities, including important roles in fever, anorexia, acute-phase responses, and the vascular leak syndrome. HMGB1 acts in concert with other cytokines and pathogen-derived molecules in these diseases / conditions. The contribution of HMGB1 to these and other pathological conditions has been confirmed by numerous experiments showing that administration of drugs (antibodies, antagonist proteins, release inhibitors) that specifically inhibit HMGB1 activity to animals with ischemic and inflammatory diseases blocks the progression of tissue damage and suppresses the inflammatory response in the treated animals. See Andersson et al. (2011, Annu Rev Immunol 29:139-162).

[0158] Thus, current evidence indicates that HMGB1 is a general mediator of inflammation and is associated with multiple inflammatory and autoimmune diseases. Since HMGB1 is a ligand for RAGE, these findings confirm the role of RAGE as a general mediator of inflammation and suggest that targeting RAGE activity to inhibit its downstream signaling holds great promise. The compounds described herein for treating subjects with diseases / conditions characterized by inflammation and / or autoimmunity will alleviate the clinical signs and symptoms of inflammation in these subjects.

[0159] Animal models of autoimmunity / inflammation include those involving delayed-type hypersensitivity, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, psoriasis, Behçet's syndrome, type 1 diabetes, vasculitis, glomerulonephritis, and sarcoidosis. Such animal models are known in the art and are described, for example, in Hofmann et al. (Cell 97:889-901, 1999), Hofmann et al. (Genes and Immunity 3:123-135, 2002), Webb et al. (Biochem Pharmacol 87:121-130, 2014), Sakata et al. (Exp Diabetes Res 2012:256707, 2012), Goyal et al. (Inflammopharmacology 22:219-233, 2014), Lu et al. (Life Sci 108(1):1-6, 2014), Starr et al. (Aging Dis 5:126-136, 2014); the entire contents of each of these references are incorporated herein by reference. Obesity

[0160] Animal models of human obesity are known in the art and involve feeding mice a 45% high-fat diet or a 60% high-fat food. Such models are described, for example, in Song et al. (Diabetes 63(6):1948-1965, 2014) and Aydin et al. (Nutrition 30:1-9, 2014); the entire contents of each of these references are incorporated herein by reference. Cancer

[0161] Aberrant expression of RAGE and its ligands has been reported in many cancers, including prostate cancer, colorectal cancer, pancreatic cancer, lung cancer, and oral squamous cell carcinoma. In addition, the interaction between RAGE and its ligands is thought to contribute to cancer invasion and metastasis. The interaction between RAGE and HMGB1 triggers the activation of key cell signaling pathways, such as NF-κB, p38, p44 / 42 MAPK, and the activation of these pathways contributes to cancer progression and metastasis (Sims et al., 2010, *Annu Rev Immunol* 28:367-388; Sparvero et al., 2009, *J Transl Med* 7:17; Lodgson et al., 2007, *Curr Mol Med* 7:777-789; Kuniyasu et al., 2003, *Oncol Rep* 10:445-448; Kuniyasu et al., *Int J Cancer* 104:722-727; Sasahira et al., 2005, *Virchows Arch* 446:411-415; Kuniyasu et al., 2005, *Am J Pathol* 166:751-

[0162] 760; Kuniyasu et al., 2004, *Pathobiology* 71:129-136; Sasahira et al., 2007, *Virchows Arch* 450:287-295; Kuniyasu et al., 2002, *J Pathol* 196:163-170; the entire contents of each of these references are incorporated herein by reference). In addition to this, for example, Rai et al. (2012, *J Exp Med* 209:2339-2350) and Arumugam et al. (2012, *Clin Cane Res* 18:4356-4364) described animal model systems in which the contribution of RAGE to various cancers has been studied and validated.

[0163] In addition, RAGE and its ligand HMGB1 are thought to play important roles in prostate cancer. In fact, Zhao et al. (Am J Cancer Res 2014;4:369-377) described the significance of these effector molecules in a retrospective study designed to investigate the expression of RAGE and HMGBl and their clinical impact on prostate cancer progression and prognosis. The expression of RAGE and FIMGB1 was detected by immunohistochemistry in 85 confirmed prostate cancer lesions. Zhao et al. confirmed a strong correlation between the expression of RAGE and FnVIGB 1 (P<0.001), and the expression of RAGE, FIMGB1, and their co-expression were all associated with tumor clinical stage (P<0.05 for all). RAGE expression was also associated with prostate-specific antigen (PSA) levels (P = 0.014). Co-expression of RAGE and FnVIGB 1 was also associated with a low overall survival rate in patients with stage III and IV prostate cancer (P = 0.047). These results suggest that the expression of RAGE and HMGBl is associated with prostate cancer progression and poor prognosis. Therefore, RAGE and HMGBl are considered molecular targets for novel prostate cancer therapies. Tumor / Tumorigenesis

[0164] A variety of animal models of human cancers are known in the art, including those that mimic human lung cancer, melanoma, colon cancer, pancreatic cancer, and breast cancer, as well as cancer biological models for in silico screening. These animal models are known in the art and are described, for example, in Taguchi et al. (Nature 405:354-360 (2000)), Arumugam et al. (Journal of Biological Chemistry 279:5059-5065 (2004)), Huang et al. (Surgery 139:782-788 (2006)), Huang et al. (Surgery 139:782-788 (2006)), Fuentes et al. (Dis Colon Rectum 50:1230-1240 (2007)), Arumugan et al. (Clin Cancer Res 18:4356-4364 (2012)), Yu et al. (J Gastric Cancer 14:67-86 (2014)), Fleet (Am J Physiol Gastrointest Liver Physiol. 307(3):G249-59 (2014)), Lindner (Semin Oncol 41:146-155 (2014)), Wang et al. (Biofabrication 6(2):022001 (2014)), Budhu et al. (Curr OpinGenet Dev 24:46-51 (2014)); the entire contents of each of these references are incorporated herein by reference. Ischemia / Reperfusion Injury

[0165] For example, in an animal model of hindlimb ischemia in mice with or without diabetes, inhibition of RAGE ligands led to an improvement in the angiogenic response to limb ischemia. See, for example, Tamarat et al. (2003, Proc Natl Acad Sci 100:14); Goova et al. (2001, Am J Pathol 159:513-525); Tekabe et al. (2010, J Nuc Med 51:92-97); Tekabe et al. (2013, EJNMMi Res 3:37); Bucciarelli et al. (2008, Diabetes 57:1941-1951); Shang et al. (2010, PLoS 5:e10092); Ma et al. (2009, J Cell Mol Med 13:1751-1764); the entire contents of each of these references are incorporated herein by reference. Erectile Dysfunction

[0166] Relaxation of smooth muscle cells in the cavernous arterioles and sinusoids results in increased blood flow into the penis, elevated corporal pressure, and ultimately penile erection. Nitric oxide is thought to be the major stimulant for cavernous smooth muscle relaxation (see Wingard et al. (2001, Nature Medicine 7:119-122)). RAGE activation generates oxidants via a NADH oxidase-like enzyme (Yan et al., 1994, J. Biol. Chem. 269:9889-9887), which is thought to inhibit nitric oxide cycling. Thus, inhibition of RAGE signaling pathway activation is expected to attenuate oxidant production. Inhibition of RAGE-mediated Rho kinase activation has also been predicted to enhance and stimulate penile erection independently of nitric oxide. Thus, the compounds described herein that inhibit downstream RAGE signaling can be used to advantageously promote and improve penile erection. Respiratory Diseases

[0167] In patients with chronic obstructive pulmonary disease, increased RAGE expression is observed in the lungs, and elevated levels of soluble RAGE are found in bronchoalveolar fluid (Yan et al., 2003, Nature Med 9:287-293; Miniati et al., 2011, Respir Res 12:37). Increased levels of RAGE receptor and ligand have also been detected in asthma patients (Watanabe et al., 2010, Respir Res 105:519-525), indicating a positive role of RAGE in pulmonary inflammation. See also Wu et al. (2013, Mol Cell Biochem 380:249-257); Sukkar et al. (2012, Br J Pharmacol 167:Inline).

[0168] In addition, during severe acute exacerbations of asthma, a strong, mechanistically heterogeneous inflammatory response occurs, involving the accumulation and activation of neutrophils and eosinophils. Moreover, neutrophils are an important source of S100 proteins, which are key ligands of RAGE and are involved in the above-described immune responses and propagation of inflammation in this article. Therefore, inhibitors of RAGE downstream signaling are expected to be effective in treating asthma. Since the propagation step in the pulmonary immune response driven by the S100-RAGE interaction is thought to lead to the activation and / or recruitment of inflammatory cells such as neutrophils, which are an important source of destructive proteases in chronic obstructive pulmonary diseases such as emphysema, the compounds described herein that act as RAGE inhibitors can be used to treat chronic obstructive pulmonary diseases.

[0169] For example, Akirav et al. (2014, PLoS One 9:e95678); and Constant et al. (2002, J Clin Invest 110:1441-1448) described animal models for assessing the therapeutic potential of the compounds described herein in the context of respiratory diseases such as asthma; the entire contents of each of these references are incorporated herein by reference. Amyloidosis

[0170] The compounds described herein are also contemplated for use in the treatment of amyloidosis and Alzheimer's disease (AD). RAGE is known to bind β-sheet fibrillar material, and amyloid deposition has been shown to enhance RAGE expression. The brains of AD patients exhibit increased RAGE expression in neurons and glia (Yan et al., 1996, Nature 382:685-691). Binding of Aβ-RAGE on microglia activates these cells, as reflected by increased cytokine motility and expression, while binding of Aβ-RAGE on neurons initially activates the cells but ultimately leads to cytotoxicity. Inhibition of the RAGE-amyloid interaction reduces the expression of cellular RAGE and cellular stress markers (and NF-κB activation), and reduces amyloid deposition (Yan et al., 2000, Nat. Med. 6:643-651). These findings suggest that the RAGE-amyloid interaction plays an important role in perturbing cellular properties in the early amyloid-enriched environment of the disease and during amyloid accumulation as the disease progresses. Neurodegeneration

[0171] Animal models of human neurodegenerative diseases are known, including mouse models of Alzheimer's disease, humanized mouse models of amyotrophic lateral sclerosis, and mouse models of Huntington's disease. These animal models are described, for example, in Millington et al. (2014, Biomed Res Inst 2014:309129), Yan et al. (1996, Nature 382:685-691), Yan et al. (1997, Proc. Natl. Acad. Sci. 94:5296-5301), Bard et al. (2014, J Biomol Screen 19:191-204), Neha et al. (2014, Life Sci 109(2):73 -86)), and Turner et al. (2013, Amyotroph Lateral Scler Frontotemporal Degener. 14 Suppl 1:19-32); the entire contents of each of these references are incorporated herein by reference. Atherosclerosis

[0172] Examples of animal models of human atherosclerotic disease include apolipoprotein E-deficient mice and low density lipoprotein receptor-deficient mice. See, e.g., Kapourchali et al. (2014, World J Clin Cases 2:126-132), Harja et al. (2008, J. Clin. Invest. 1118:183-194), Nagareddy et al. (2013, Cell Metab 17:695-708); the entire contents of each of these references are incorporated herein by reference.

[0173] In view of the prominent role of RAGE, as understood in the art and described herein, in diseases / conditions characterized by acute and chronic inflammation, methods for treating such diseases / conditions are provided herein, including but not limited to diabetic complications, ischemia, skin inflammation (e.g., psoriasis and atopic dermatitis), pulmonary inflammation (e.g., asthma and chronic obstructive pulmonary disease), vascular permeability, nephropathy, atherosclerosis, retinopathy, Alzheimer's disease, erectile dysfunction, and tumor invasion and / or metastasis, the methods comprising administering to a subject in need thereof a compound described herein in a therapeutically effective amount. In a particular embodiment, at least one compound described herein is used, either alone or in combination with one or more known therapeutic agents. In another specific embodiment, the present invention provides a method for treating a RAGE-mediated human disease, wherein the treatment alleviates one or more symptoms caused by the disease, the method comprising administering to a human in need thereof a therapeutically effective amount of a compound described herein.

[0174] In vitro assays related to RAGE-mediated diseases and their animal model systems are described in US2012 / 0088778, US2010 / 0254983, US2010 / 0119512, U.S. Patent No. 7,361,678, WO2007 / 089616, and US2010 / 0249038; the entire contents of each of these references are incorporated herein by reference.

[0175] In addition thereto, the compound is a modulator of the interaction between RAGE and RAGE ligands and is used as a therapeutic agent for treating diseases in mammals that are causally related to or attributable to RAGE activity. Accordingly, the compounds and pharmaceutical compositions of the present invention can be used as therapeutic agents for preventing and / or treating various conditions related to diabetic complications in mammals, including humans.

[0176] In terms of treatment methods, the present invention provides a method for treating a mammal that is susceptible to or suffering from a condition associated with diabetic complications, Alzheimer's disease, cancer, arthritis, kidney disease, acute and chronic inflammation, retinopathy, atherosclerosis, erectile dysfunction, tumor invasion and metastasis, etc., the method comprising administering an effective amount of one or more of the pharmaceutical compositions described above.

[0177] In a further aspect of treatment methods, the present invention provides a method for treating a mammal that is susceptible to or suffering from an inflammatory condition causally related to or attributable to RAGE activity. Such conditions and disorders include, but are not limited to, diabetes and its complications, impaired wound healing, peripheral vascular disease and related complications, obesity, Alzheimer's disease, cancer, arthritis, kidney disease, acute and chronic inflammation, retinopathy, atherosclerosis, cardiovascular disease, erectile dysfunction, tumor invasion and metastasis, neuropathy, cardiac and cerebrovascular ischemia / reperfusion injury, heart attack, stroke, myocardial infarction, ischemic cardiomyopathy, renal ischemia, sepsis, pneumonia, infection, liver injury, liver damage, amyotrophic lateral sclerosis, neuropathic infection, allergy, asthma, pollutant-induced organ damage, amyloidosis, asthma, pollution-related tissue damage, skin disease, colitis, skin aging, lupus, etc. These methods include administering an effective amount for treating or preventing the disease of one or more of the pharmaceutical compositions just described.

[0178] As another aspect of the present invention, there is provided the compound for use as a medicament, particularly for treating or preventing the above-mentioned conditions and diseases. The present invention also provides the use of the compound in the preparation of a medicament for treating or preventing one of the above-mentioned conditions and diseases.

[0179] The injection dose level ranges from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, both for about 1 to about 120 hours, especially 24 to 96 hours. A preloading dose of about 0.1 mg / kg to about 10 mg / kg or higher can also be administered to achieve a sufficient steady-state level. For a human patient weighing 40 to 80 kg, the maximum total dose is not expected to exceed about 2 g / day.

[0180] For the prevention and / or treatment of long-term conditions such as arthritis, diabetes or asthma, the treatment regimen usually lasts for months or years, so oral administration is preferred for the convenience and tolerance of the patient. For oral administration, one to five times a day, especially two to four times, typically three times of oral administration is a representative regimen. Using these dosing patterns, each dose provides about 0.01 to about 20 mg / kg of the compound of the present invention, and the preferred dose is about 0.1 to about 10 mg / kg per dose, especially about 1 to about 5 mg / kg.

[0181] Transdermal doses are typically selected to provide blood levels similar to or lower than injectable doses. Also contemplated herein are modes of administration suitable for mucosal sites, including but not limited to: intrarectal swabs, enemas, intranasal sprays, and nebulized or vaporized compounds and / or compositions for delivery to pulmonary mucosa. One of ordinary skill in the art will select an appropriate delivery mode based on various parameters, including the organ or tissue site most affected by the disease or disorder in a patient suffering from the disease or disorder.

[0182] When used to prevent the onset of an inflammatory or autoimmune disease, the compounds of the invention will be administered to a patient at risk of developing the disorder or disease at the above dosage levels, typically under the advice and supervision of a physician. Patients at risk of developing a particular disorder typically include those with a family history of the disorder, or those determined by genetic testing or screening to be particularly susceptible to the disorder.

[0183] When used to treat diabetic eye disease, the compounds of the invention are capable of being administered intravitreally.

[0184] The compounds of the invention can be administered as the sole active agent or in combination with other medicaments, including other compounds that exhibit the same or similar therapeutic activity and have been determined to be safe and effective for such combination therapy. Examples

[0185] The following examples illustrate specific aspects of the present specification. These examples should not be construed as limiting, as they provide only a specific understanding and practice of the embodiments and their various aspects. General Synthesis Procedures

[0186] The quinoline compounds of the invention can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that given typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions can also be used unless otherwise stated. The optimal reaction conditions may vary depending on the specific reactants or solvents used, but one of ordinary skill in the art can determine these conditions through routine optimization procedures.

[0187] Additionally, it will be apparent to one of ordinary skill in the art that conventional protecting groups may be required to prevent unwanted reactions of certain functional groups. The selection of appropriate protecting groups for specific functional groups and the appropriate conditions for protection and deprotection are well known in the art. For example, many protecting groups and their introduction and removal are described in T.W. Greene and P.G.M. Wuts, Protecting Groups in Organic Synthesis (Second Edition, Wiley, New York, 1991) and the references cited therein.

[0188] All commercially available starting materials and solvents were of reagent grade and used without further purification. Unless otherwise stated, all reactions were carried out under a dry nitrogen atmosphere. Thin layer chromatography (TLC) plates were visualized by ultraviolet light. Flash column chromatography refers to column chromatography carried out on silica gel (100 - 200 mesh) using a glass column. Additionally, automated chromatography was performed using a Biotage Isola system with UV detection at 214, 254, or 280 nm and Biotage normal or reverse phase silica gel columns. The solvents used for samples were specified in the experimental procedures for each compound. The following system was used for liquid chromatography - mass spectrometry (LC - MS): Agilent 1260 (quaternary pump), XBridge C18 analytical column, 2.7 μm, 4.6×30 mm, 45 °C, 1 μL injection volume, 1.8 mL / min. Mobile phase: acetonitrile (0.05% FA) - water (0.05% FA), gradient from 5% acetonitrile to 95% acetonitrile in 1.0 min, held for 1.0 min, for a total of 2.5 min. The following system was used for Waters UPLC (without mass spectrometry): Waters Acquity BEH C18, 2.1×50 mm, 1.7 μm, 0.5 mL / min, 45 °C; Mobile phase: acetonitrile (0.05% TFA) - water (0.05% TFA); Gradient: 5% - 95% acetonitrile for 2 min, then held at 95% acetonitrile for 0.7 min. Nuclear magnetic resonance (NMR) spectra were measured on a Bruker spectrometer at 400 MHz ( 1 H), 376 MHz ( 19 F), or 100 MHz ( 13 C). Proton nuclear magnetic resonance data were reported as chemical shifts (δ) in parts per million (ppm) relative to the residual signal of the deuterated solvent. Example 1: Synthesis of Analogue RAGE 283 According to the Invention

[0189] Compound RAGE 283 according to the present disclosure was prepared as shown in Scheme 1 and as described below. Scheme 1 Synthesis of RAGE 283 Example 1A: Preparation of Compound RAGE 283 - 1

[0190] Methyl 4-(7 - chloro - 4-(morpholinomethyl)quinolin - 2 - yl)benzoate (500 mg, 1.26 mmol), Zn(CN) 2 (295 mg, 2.52 mmol), Xphos (120 mg, 0.252 mmol) and [Pd(allyl)Cl] 2The mixture of [[ID=]] (46 mg, 0.126 mmol) in DME (20 mL) was stirred at 120 °C for 24 h. The reaction mixture was filtered and washed with EtOAc (20 mL × 3). The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give RAGE 283-1 (400 mg, 82.0%) as a yellow solid. LC-MS [M+H] + : 387.2. Example 1B: Preparation of Compound RAGE 283-2

[0191] To a solution of methyl 4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)benzoate (400 mg, 1.03 mmol) in THF / EtOH / H 2 O (5 mL / 5 mL / 5 mL) was added LiOH-H 2 O (130 mg, 3.09 mmol). The resulting mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was acidified to pH = 3 with 1 M HCl and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 10 / 1) to give RAGE 283-2 (350 mg, yield: 90.8%) as a white solid. LC-MS [M+H] + : 374.2. Example 1C: Preparation of Compound RAGE 283

[0192] A mixture of 4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)benzoic acid (150 mg, 0.4 mmol), NH 4 Cl (106 mg, 2.0 mmol), EDCI (153 mg, 0.8 mmol), HOBT (108 mg, 0.8 mmol) and DIPEA (258 mg, 2.0 mmol) in DMF (10 mL) was stirred at 25 °C for 16 h. The reaction mixture was poured into H 2 O (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give the crude product, which was purified by Prep-HPLC to give RAGE 283 (32 mg, yield: 21.4%) as a white solid. LC-MS [M+H] +: 373.3, Rt = 1.440 min. Purity: 99.63 (214 nm), 99.67 (254 nm). NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.53 (d, J = 8.9 Hz, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.33 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 8.06 (s, 1H), 7.95 - 7.92 (m, 1H), 7.51 (s, 1H), 4.04 (s, 2H), 3.58 - 3.55 (m, 4H), 2.53–2.49 (m, 4H). Example 2: Synthesis of analog RAGE 286 according to the present invention

[0193] Compound RAGE 286 according to the present disclosure was prepared as shown in Scheme 2 and as described below. Scheme 2 RAGE 286 Synthesis Example 2A: Preparation of compound RAGE 403-2

[0194] To a solution of (4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)methanol (600 mg, 1.63 mmol) in CH 2 Cl 2 (30 mL) was added MnO 2 (3048 mg, 16.3 mmol). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was filtered and washed with CH 2 Cl 2 (30 mL × 2). The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to give RAGE 403-2 (410 mg, yield: 68.7%), as a yellow solid. LC-MS [M+H] + : 367.1. Example 2B: Preparation of compound RAGE 286-1

[0195] Methyl 4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)benzoate (410 mg, 1.12 mmol), Zn(CN) 2 (262 mg, 2.24 mmol), Xphos (107 mg, 0.224 mmol) and [Pd(allyl)Cl] 2 (41 mg, 0.112 mmol) in DMF (20 mL) was stirred at 125 °C for 24 h. After completion of the reaction, the reaction mixture was poured into H 2in O (50 mL), and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine and dried over Na 2 SO 4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to give RAGE 286-1 (300 mg, 75.1%), as a yellow solid. LC-MS [M+H] + : 358.2. Example 2C: Preparation of compound RAGE 286-2

[0196] To a reaction mixture of 2-(4-formylphenyl)-4-(morpholinomethyl)quinoline-7-carbonitrile (300 mg, 0.84 mmol) and 2-methylpropane-2-sulfinamide (203 mg, 1.68 mol) in THF (20 mL) was added Ti(i-PrO) 4 (358 mg, 1.26 mmol). The resulting solution was stirred at 70 °C for 16 h. Then MeOH (4 mL) and NaBH 4 (96 mg, 2.52 mmol) were added sequentially at 0 °C, and the solution was stirred for an additional hour at room temperature. The reaction was quenched with saturated NH 4 Cl aqueous solution (saturated aqueous solution, 30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine and dried over Na 2 SO 4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 30 / 1) to give RAGE 286-2 (200 mg, yield: 51.5%), as a yellow solid. LC-MS [M+H] + : 463.2. Example 2D: Preparation of compound RAGE 286

[0197] To a reaction mixture of N-(4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)benzyl)-2-methylpropane-2-sulfinamide (200 mg, 0.42 mmol) in 1,4-dioxane (6 mL) was added HCl (3 mL, 4 M dioxane solution, 12 mmol). The reaction was stirred at room temperature for 0.5 h. The pH of the reaction was adjusted to 8 - 9 with NaHCO 3 (saturated aqueous solution), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine and dried over Na 2 SO 4It was dried over and concentrated under reduced pressure to obtain a crude product, which was purified by Prep-HPLC to obtain RAGE 286 (35 mg, yield: 22.6%), a white solid. LC-MS [M+H] + : 359.1, Rt = 0.870 min. Purity: 100 (214 nm), 100 (254 nm). 1 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.35 (d, J = 8.9 Hz, 2H), 8.29 (s, 1H), 8.27 (s, 1H), 7.95 - 7.92 (m, 1H), 7.66 (d, J = 8.9 Hz, 2H), 4.12 (s, 2H), 4.02 (d, J = 8 Hz, 2H), 3.59–3.55 (m, 4H), 2.53–2.49 (m, 4H). Example 3: Synthesis of analog RAGE 289 according to the present invention

[0198] Compound RAGE 289 according to the present disclosure was prepared as shown in Scheme 3 and as described below. Scheme 3 Synthesis of RAGE 289 Example 3A: Preparation of compound RAGE 289-1

[0199] (2-(4-Bromophenyl)-7-chloroquinolin-4-yl)(morpholino)methanone (3.0 g, 6.95 mmol), Zn(CN) 2 (1.63 g, 13.9 mmol) and Pd(PPh 3 ) 4 (803 mg, 0.695 mmol) in DMF ((50 mL) were stirred at 100 °C for 18 h. After completion of the reaction, the reaction mixture was poured into H 2 O (100 mL) and extracted with EA (80 mL × 3). The combined organic layers were washed with brine and dried over Na 2 SO 4 to obtain a crude product by concentration under reduced pressure, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to obtain RAGE 289-1 (2.4 g, 91.4%), a yellow solid. LC-MS [M+H] + : 378.1. Example 3B: Preparation of compound RAGE 289-2

[0200] To a reaction mixture of 4-(7-chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)benzonitrile (500 mg, 1.32 mmol) and NiCl 2 ·6H 2 O (150 mg, 0.66 mmol) in MeOH (10 mL) was added Boc 2 O (576 mg, 2.64 mmol). The reaction mixture was stirred at room temperature under N 2 atmosphere for 30 min. Then the solution was cooled to 0 °C, and NaBH 4 (166 mg, 3.96 mmol) was added portionwise. The resulting reaction mixture was stirred at room temperature for another 2 h. The reaction was quenched with saturated aqueous NH 4 Cl (30 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to give RAGE 289-2 (230 mg, yield: 36.1%), as a yellow solid. LC-MS [M+H] + : 482.2. Example 3C: Preparation of compound RAGE 289-3

[0201] (tert-Butyl ((4-(7-chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)benzyl)carbamate (230 mg, 0.477 mmol), Zn(CN) 2 (112 mg, 0.954 mmol), Xphos (45 mg, 0.095 mmol) and [Pd(allyl)Cl] 2 (18 mg, 0.048 mmol) in DMF (3 mL) was heated in a microwave at 120 °C for 1 h. After completion of the reaction, the reaction mixture was poured into H 2 O (20 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to give RAGE289-3 (190 mg, 84.3%), as a yellow solid. LC-MS [M+H] + : 473.2. Example 3D: Preparation of compound RAGE 289-4

[0202] To a reaction mixture of tert-butyl ((4-(7-cyano-4-(morpholine-4-carbonyl)quinolin-2-yl)benzyl)carbamate (190 mg, 0.40 mmol) in DCM (6 mL) was added HCl (4 M dioxane solution, 3 mL, 12 mmol). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated, and the residue was adjusted to pH 8 - 9 with NaHCO 3 (saturated aqueous solution) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (30 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 15 / 1) to give RAGE 289-4 (100 mg, yield: 66.8%) as a white solid. LC-MS [M+H] + : 373.2, Rt = 0.986 min. Purity: 97.94 (214 nm), 97.50 (254 nm). 1 H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 8.42 - 8.34 (m, 3H), 8.31 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.98 - 7.93 (m, 1H), 7.64 (d, J = 8.2 Hz, 2H), 4.05 (s, 2H), 3.89 (s, 1H), 3.81–3.77 (m, 4H), 3.65 (s, 1H), 3.45 (s, 1H), 3.23 (s, 1H), 3.16 (s, 1H). Example 3E: Preparation of Compound RAGE 289

[0203] To a solution of 2-(4-(aminomethyl)phenyl)-4-(morpholine-4-carbonyl)quinoline-7-carbonitrile (100 mg, 0.27 mmol) in DCM (10 mL) at 0 °C was added Et 3 N (82 mg, 0.81 mmol), and then acetyl chloride (107 mg, 1.36 mmol) was added dropwise at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with H 2 O (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (30 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a crude product, which was purified by Prep-HPLC to give RAGE 289 (50 mg, 44.9%) as a white solid. LC-MS [M+H] + : 415.2, Rt = 1.203 min. Purity: 100 (214 nm), 100 (254 nm).1 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.47 - 8.44 (m, 1H), 8.35 (s, 1H), 8.31 (d, J = 8.9 Hz, 2H), 8.01 (d, J = 8.8 Hz, 1H), 7.95 - 7.92 (m, 1H), 7.46 (d, J = 8.9 Hz, 2H), 4.35 (d, J = 4.2 Hz, 2H), 3.92 - 3.90 (m, 1H), 3.80 - 3.70 (m, 3H), 3.37 - 3.22 (m, 2H), 3.22 - 3.15 (m, 2H), 1.91 (s, 3H). Example 4: Synthesis of analog RAGE 290 according to the present invention

[0204] Compound RAGE 290 according to the present disclosure is prepared as shown in Scheme 4 and as described below. Scheme 4 RAGE 290 Synthesis Example 4A: Preparation of compound RAGE 290-1

[0205] HCl (gas) was bubbled into a reaction mixture of 4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)benzonitrile (500 mg, 1.37 mmol) in MeOH (20 mL) under an ice bath. The reactants were stirred at room temperature for 3 h. Then the reaction solution was concentrated and dried under vacuum. The resulting mixture was diluted with MeOH (20 mL), and then NH 4 HCO 3 (216 mg, 2.74 mmol) was added thereto. The resulting mixture was stirred at room temperature for 16 h. After completion of the reaction, the reactants were concentrated under reduced pressure to obtain the crude product RAGE290-1 (500 mg, yield: 95.5%), which was a yellow solid. LC-MS [M+H] + : 381.2. Example 4B: Preparation of compound RAGE 290-2

[0206] Et 3 N (397 mg, 3.93 mmol) and Boc 2O (342 mg, 1.57 mmol). The resulting mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: EtOAc / PE = 1 / 1) to give RAGE 290-2 (350 mg, 55.4%), as a yellow solid. LC-MS [M+H] + : 481.2. Example 4C: Preparation of compound RAGE 290-3

[0207] ((4-(7-Chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)(imino)methyl)carbamic acid tert-butyl ester (350 mg, 0.728 mmol), Zn(CN) 2 (170 mg, 1.456 mmol), Xphos (70 mg, 0.146 mmol) and [Pd(allyl)Cl] 2 (27 mg, 0.073 mmol) in DMF (3 mL) was stirred in a microwave at 130 °C for 1 h. After completion of the reaction, the reaction mixture was poured into H 2 O (20 mL), and extracted with EA (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to give RAGE 290-3 (150 mg, 43.7%), as a yellow solid. LC-MS [M+H] + : 472.2. Example 4D: Preparation of compound RAGE 290

[0208] To a reaction mixture of ((4-(7-Cyano-4-(morpholinomethyl)quinolin-2-yl)phenyl)(imino)methyl)carbamic acid tert-butyl ester (150 mg, 0.318 mmol) in DCM (10 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 10 h. The pH of the reaction mixture was adjusted to 8 - 9 with NaHCO 3 (saturated aqueous solution), and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a crude product, which was purified by Prep-HPLC to give N-(4-(7-Cyano-4-(morpholine-4-carbonyl)quinolin-2-yl)benzyl)acetamide (35.8 mg, yield: 30.3%), as a white solid. LC-MS [M+H] +: 372.1, Rt = 0.867 min. Purity: 98.59 (214 nm), 98.09 (254 nm). 1 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 3H), 8.65 (d, J = 4 Hz, 1H), 8.55 - 8.50 (m, 3H), 8.37 (s, 1H), 8.02 (d, J = 8 Hz, 2H), 7.98–7.95 (m, 1H), 4.05 (s, 2H), 3.57–3.56 (m, 4H), 2.53–2.49 (m, 4H). Example 5: Synthesis of analog RAGE 291 according to the present invention

[0209] Compound RAGE 291 according to the present disclosure was prepared as shown in Scheme 5 and as described below. Scheme 5 RAGE 291 Synthesis Example 5A: Preparation of compound RAGE 291-2

[0210] At 100 °C, a solution of 1-(4-bromophenyl)ethan-1-one (49.3 g, 247.8 mmol) in EtOH (300 mL) was added to a 6 M aqueous KOH solution (200 mL) of 6-chloroindoline-2,3-dione (30.0 g, 165.2 mmol). The reaction was monitored by LC-MS until the starting material was consumed. The reaction mixture was then concentrated to remove EtOH, and the pH was adjusted to 4 - 5 with HCl (6 N). The precipitate was filtered and dried to give RAGE 291-2 (40 g, 66.8%), as a red solid. LC-MS [M+H] + : 364.0. Example 5B: Preparation of compound RAGE 291-3

[0211] A solution of 2-(4-bromophenyl)-7-chloroquinoline-4-carboxylic acid (40 g, 110.3 mmol), morpholine (14.40 g, 165.5 mmol), EDCI (42.13 g, 220.6 mmol), HOBT (29.78 g, 220.6 mmol) and DIPEA (42.69 g, 330.9 mmol) in DMF (600 mL) was stirred at room temperature for 5 h. The reaction mixture was poured into H 2 2O (800 mL), and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (600 mL), and dried over Na 2 2SO 4It was dried under reduced pressure and concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: EtOAc / PE = 1 / 1) to obtain RAGE 291-3 (39 g, 82.9%), a yellow solid. LC-MS [M+H] + : 433.1. Example 5C: Preparation of Compound RAGE 291-4

[0212] At 0 °C, BH 3 -THF (1 M THF solution, 270.9 mL, 270.9 mmol) was added to a solution of (2-(4-bromophenyl)-7-chloroquinolin-4-yl)(morpholinyl)methanone (39 g, 90.3 mmol) in THF (400 mL). The solution was stirred at room temperature for 12 h under N 2 atmosphere. The reaction was quenched by adding 200 mL of MeOH at 0 °C. The resulting mixture was heated to 50 °C for 0.5 h and then concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in water (50 mL) and extracted from water with EtOAc (50 mL × 3). The combined organic layers were washed with brine (60 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 25 / 1) to obtain RAGE 291-4 (25.0 g, yield: 66.3%), a yellow solid. LC-MS [M+H] + : 419.1. Example 5D: Preparation of Compound RAGE 291-5

[0213] To a mixture of 4-((2-(4-bromophenyl)-7-chloroquinolin-4-yl)methyl)morpholine (3.3 g, 7.9 mmol) and Et 3 N (2.39 g, 23.7 mmol) in DMF / MeOH (15 mL / 15 mL) was added Pd(dppf)Cl 2 (578 mg, 0.79 mmol). The resulting reaction mixture was stirred at 75 °C for 16 h under CO atmosphere. After cooling to room temperature, H 2 O (100 mL) was added and the mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (eluent: DCM / MeOH = 30 / 1) to obtain RAGE 291-5 (1.3 g, yield: 41.5%), a yellow solid. LC-MS [M+H] + : 397.2. Example 5E: Preparation of Compound RAGE 291-6

[0214] To a solution of methyl 4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)benzoate (1.3 g, 3.28 mmol) in THF / H 2 O (10 mL / 5 mL) was added LiOH-H 2 O (413 mg, 9.84 mmol). The resulting mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was concentrated to remove water, and the aqueous layer was acidified to pH 3 with HCl (1 N). A yellow solid precipitated out, which was filtered to obtain the yellow solid RAGE 291-6 (1.2 g, yield: 95.7%). LC-MS [M+H] + : 383.1. Example 5F: Preparation of Compound RAGE 291-7

[0215] To a cooled (0 °C) and stirred solution of 4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)benzoic acid (1.2 g, 3.13 mol) and DMF (46 mg, 0.31 mol) in DCM (30 mL) was added dropwise (COCl) 2 (478 mg, 3.76 mmol). The reaction mixture was heated to room temperature and stirred for 0.5 h. The reaction mixture was concentrated to give the crude product RAGE 291-7 (1.25 g, yield: 99.4%) as a yellow solid. LC-MS [M+H] + : 397.2. Example 5G: Preparation of Compound RAGE 291-8

[0216] To a cooled (0 °C) and stirred solution of 4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)benzoyl chloride (1.25 g, 3.11 mol) in MeCN (30 mL) was added dropwise TMSCH 2 N 2 (6.2 mL, 6.22 mol). The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated to give the crude product RAGE 291-8 (1.1 g, yield: 86.8%) as a yellow solid. LC-MS [M+H] + : 407.2. Example 5H: Preparation of Compound RAGE 291-9

[0217] To 1-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)-2-diazoethan-1-one (1.1 g, crude) in dioxane / NH 4Silver benzoate (618 mg, 2.7 mmol) was added to a solution in OH (20 mL / 5 mL). The reaction mixture was heated to 120 °C for 1 h. The mixture was cooled to room temperature and filtered through a short column of diatomaceous earth. The filtrate was diluted with ethyl acetate (30 mL × 3) and washed with brine (40 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography (eluent: PE / EtOAc = 2 / 1) to give RAGE 291-9 (400 mg, yield: 37.4%) as a yellow solid. LC-MS [M+H] + : 396.2. Example 5I: Preparation of Compound RAGE 291

[0218] A mixture of 2-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide (300 mg, 0.76 mmol), Zn(CN) 2 (178 mg, 1.52 mmol), Xphos (72 mg, 0.15 mmol) and [Pd(allyl)Cl] 2 (29 mg, 0.08 mmol) in DME (10 mL) was stirred at 125 °C for 3 h. The reaction mixture was filtered and washed with EtOAc (20 mL × 3). The filtrate was concentrated under reduced pressure to give the crude product, which was purified by Prep-HPLC to give RAGE 291 (26 mg, 8.9%) as a white solid. LC-MS [M+H] + : 387.2, Rt = 0.893 min. Purity: 98.76 (214 nm), 98.83 (254 nm). 1 H NMR (400 MHz, MeOD-d4) δ 8.56 - 8.48 (m, 2H), 8.19 - 8.15 (m, 3H), 7.76 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.9 Hz, 2H), 4.05 (s, 2H), 3.65 - 3.60 (m, 4H), 3.30 (s, 2H), 2.61 - 2.57 (m, 4H). Example 6: Synthesis of Analogue RAGE 292 According to the Invention

[0219] Compound RAGE 292 according to the present disclosure was prepared as shown in Scheme 6 and as described below. Scheme 6 RAGE 292 Synthesis Example 6A: Preparation of Compound RAGE 292-2

[0220] To a solution of methyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (1.0 g, 3.62 mmol) in THF (20 mL) was added dropwise LDA (3.6 mL, 1 M hexane solution, 3.6 mmol). After stirring at -78 °C for 1 h, a solution of MeI (1.03 g, 7.24 mmol) in THF (5 mL) was slowly added. The reaction mixture was heated to room temperature and stirred for 2 h. After completion of the reaction, the reaction was quenched with a saturated aqueous solution of NH 4 Cl (40 mL), and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (60 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluent: EA / PE = 1 / 10) to give RAGE 292-2 (850 mg, yield: 80.9%) as a colorless oil. LC-MS [M+H] + : 320.2. Example 6B: Preparation of compound RAGE 292-3

[0221] A mixture of methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propionate (450 mg, 1.55 mmol), 4-((2-bromo-7-chloroquinolin-4-yl)methyl)morpholine (530 mg, 1.55 mmol), K 3 PO 4 (986 mg, 4.65 mmol) and Pd(dppf)Cl 2 (117 mg, 0.16 mmol) in dioxane / H 2 O (20 mL / 2 mL) was stirred at 100 °C for 12 h. After completion of the reaction, the reaction mixture was filtered and washed with EtOAc (20 mL × 3). The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to give RAGE 292-3 (450 mg, 68.3%) as a yellow solid. LC-MS [M+H] + : 425.2. Example 6C: Preparation of compound RAGE 292-4

[0222] Methyl 2-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)propionate (450 mg, 1.06 mmol), Zn(CN) 2 (248 mg, 2.12 mmol), Xphos (100 mg, 0.21 mmol) and [Pd(Allyl)Cl] 2A mixture of [[ID=]] 2 (40 mg, 0.11 mmol) in DMF (5 mL) was stirred in a microwave at 120 °C for 1 h. After completion of the reaction, the reaction mixture was poured into H 2 O (20 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to give RAGE 292-4 (320 mg, 72.7%), as a yellow solid. LC-MS [M+H] + : 416.2. Example 6D: Preparation of compound RAGE 292-5

[0223] To a solution of methyl 2-(4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)phenyl)propionate (400 mg, 0.77 mmol) in THF / MeOH / H 2 O (5 mL / 5 mL / 5 mL) was added LiOH-H 2 O (97 mg, 2.31 mmol). The resulting mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was acidified to pH = 3 with 1 M HCl, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 10 / 1) to give RAGE 292-5 (280 mg, yield: 90.6%), as a white solid. LC-MS [M+H] + : 402.2. Example 6E: Preparation of compound RAGE 292

[0224] A mixture of 2-(4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)phenyl)propanoic acid (280 mg, 0.70 mmol), NH 4 Cl (186 mg, 3.5 mmol), EDCI (267 mg, 1.4 mmol), HOBT (189 mg, 1.4 mmol) and DIPEA (451 mg, 3.5 mmol) in DMF (10 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into H 2 O (30 mL), and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , concentrated under reduced pressure to obtain the crude product, which was purified by Prep-HPLC to give RAGE 292 (100 mg, yield: 35.8%), as a white solid. LC-MS [M+H] +: 401.2, Rt = 0.993 min. Purity: 100 (214 nm), 100 (254 nm). 1 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 1.2 Hz, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.24 (s, 2H), 8.22 (s, 1H), 7.92 - 7.90 (m, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.47 (s, 1H), 6.90 (s, 1H), 4.03 (s, 2H), 3.68 - 3.59 (m, 1H), 3.58 - 3.57 (m, 4H), 2.52 - 2.50 (m, 4H), 1.38 (d, J = 8.0 Hz, 3H). Example 7: Synthesis of analog RAGE 293 according to the present invention

[0225] Compound RAGE 293 according to the present disclosure was prepared as shown in Scheme 7 and as described below. Scheme 7 RAGE 293 Synthesis Example 7A: Preparation of compound RAGE 293-2

[0226] At 75 °C, a solution of 1-(6-bromopyridin-2-yl)ethan-1-one (6.6 g, 33.1 mmol) in THF (80 mL) was added to a 6M aqueous KOH solution (20 mL) of 6-chloroindoline-2,3-dione (4.0 g, 22.1 mmol). The reaction was monitored by LC-MS until the starting material was consumed. The reaction mixture was then concentrated to remove THF, and the pH of the residue was adjusted to 4 - 5. The precipitate was filtered and dried to give the desired RAGE 293 (6.4 g, yield: 80%), as a red solid. LC-MS [M+H] + : 363.2. Example 7B: Preparation of compound RAGE 293-3

[0227] A solution of 2-(6-bromopyridin-3-yl)-7-chloroquinoline-4-carboxylic acid (6.4 g, 17.7 mmol), morpholine (2.3 g, 26.6 mmol), HATU (10.1 g, 26.6 mmol) and DIPEA (6.8 g, 53.1 mmol) in DMF (50 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with H 2 2O (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL) and dried over Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: PE / EtOAc = 1 / 1) to obtain the expected RAGE 293-3 (6.5 g, yield: 85.5%), which was a yellow solid. LC-MS [M+H] + : 432.2. Example 7C: Preparation of Compound RAGE 293-4

[0228] To a solution of (2-(6-bromopyridin-3-yl)-7-chloroquinolin-4-yl)(morpholino)methanone (4.0 g, 9.3 mmol) in THF (80 mL) at 0 °C was added BH 3 -THF (1 M THF solution, 27.9 mL, 27.9 mmol). The solution was heated to 20 °C under N 2 atmosphere for 8 h. The reaction was quenched by adding 20 mL of MeOH at 0 °C. The mixture was heated to 65 °C for 1 h. The resulting solution was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in water (50 mL), and 1 M NaOH was added to adjust the pH to about 10. The product was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine and dried over Na 2 SO 4 to obtain the expected crude product RAGE 293-4 (2.6 g, crude), which was a yellow solid and was directly used for the next reaction without further purification. LC-MS [M+H] + : 418.2. Example 7D: Preparation of Compound RAGE 293-5

[0229] To a solution of 4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)aniline (1.2 g, 2.9 mmol) in MeOH / DMF (20 mL / 20 mL) was added Pd(dppf)Cl 2 (219 mg, 0.3 mmol) and TEA (879 mg, 8.7 mmol). The mixture was stirred at 80 °C under CO atmosphere for 20 h. The reaction was quenched with H 2 O (60 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine and dried over Na 2 SO 4 to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 1) to obtain the expected RAGE 293-5 (300 mg, 26%), which was a yellow solid. LC-MS [M+H] + : 398.2. Example 7E: Preparation of Compound RAGE 293-6

[0230] (2-(6-Bromo-3-pyridyl)-7-chloroquinolin-4-yl)(morpholino)methanone (300 mg, 0.8 mmol), Zn(CN) 2 (278 mg, 2.4 mmol), Xphos (38 mg, 0.08 mmol) and [Pd(allyl)Cl] 2 (29 mg, 0.08 mmol) in DMF (10 mL) was stirred at 120 °C for 2 h. The reaction mixture was filtered and washed with EtOAc (20 mL × 3). The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give the desired RAGE 293-6 (190 mg, 61%) as a yellow solid. LC-MS [M+H] + : 389.2. Example 7F: Preparation of Compound RAGE 293-7

[0231] Methyl 5-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)picolinate (190 mg, 0.5 mmol) and LiOH (63 mg, 1.5 mmol) in THF / H 2 O (5 mL / 5 mL) was stirred at room temperature for 0.5 h. The organic layer was evaporated, and the aqueous phase was acidified to pH = 3 with 1N HCl and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine and dried over Na 2 SO 4 and concentrated to give the desired RAGE 293-7 (100 mg, crude) as a yellow solid. LC-MS [M+H] + : 375.2. Example 7F: Preparation of Compound RAGE 293

[0232] To a solution of 5-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)picolinic acid (100 mg, crude), NH 4 Cl (79.5 mg, 1.5 mmol), EDCI (87 mg, 0.45 mmol) and HOBT (61 mg, 0.45 mmol) in DMF (10 mL) was added DIPEA (116 mg, 0.9 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. H 2 O (30 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine and dried over Na 2 SO 4The crude product was obtained by drying and concentrating under reduced pressure, and purified by Prep-TLC (DMC / MeOH = 10 / 1) to obtain RAGE 293 (30 mg, yield: 27%), which was a white solid. LC-MS [M+H] + : 374.1, Rt = 0.920 min. Purity: 100 (214 nm), 99.88 (254 nm). 1 1H NMR (400 MHz, CDCl3) δ 9.39 (d, J = 4.0 Hz, 1H), 8.68–8.66 (m, 1H), 8.57 (s, 1H), 8.42 - 8.38 (m, 2H), 8.08 (s, 1H), 7.91 (s, 1H), 7.75 - 7.73 (m, 1H), 5.68 (s, 1H), 4.01 (s, 2H), 3.76 - 3.74 (m, 4H), 2.58–2.54 (m, 4H). Example 8: Synthesis of analog RAGE 294 according to the present invention

[0233] Compound RAGE 294 according to the present disclosure was prepared as shown in Scheme 8 and as described below. Scheme 8 Synthesis of RAGE 294 Example 8A: Preparation of compound RAGE 294-2

[0234] To a solution of 1-(5-bromopyridin-2-yl)ethan-1-one (46.4 g, 232.1 mmol) in EtOH (450 mL) was added an aqueous solution of 6-chloroindoline-2,3-dione (35 g, 193.4 mmol) in 6M KOH (150 mL). The mixture was stirred at 100 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove EtOH, and the residue was dissolved in water (350 mL). The pH of the solution was adjusted to 3 with HCl (4N). A yellow solid was formed. The reaction mixture was filtered and washed with water (200 mL) and DCM (250). The collected filter cake was dried to obtain RAGE 294-2 (70 g crude), which was a yellow solid and was used directly in the next step without further purification. LC-MS [M+H] + : 363.1. Example 8B: Preparation of compound RAGE 294-3

[0235] To a solution of 2-(5-bromopyridin-2-yl)-7-chloroquinoline-4-carboxylic acid (70 g, crude) in DMF (350 mL) was added morpholine (42.1 g, 483.5 mmol), HOBT (39.1 g, 289.5 mmol), EDCI (55.3 g, 289.5 mmol) and DIPEA (74.7 g, 579 mmol). The resulting reaction mixture was stirred at room temperature for 24 h. After completion of the reaction, the reaction mixture was diluted with brine (400 mL) and extracted with EtOAc (400 mL × 3). The combined organic layers were washed with brine (500 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2:1) to give RAGE 294-3 (45 g, yield: 53.9%) as a yellow solid. LC-MS [M+H] + : 432.2. Example 8C: Preparation of Compound RAGE 294-4

[0236] To a solution of (2-(5-bromopyridin-2-yl)-7-chloroquinolin-4-yl)(morpholino)methanone (39 g, 90.3 mmol) in THF (225 mL) at 0 °C was slowly added BH 3 -THF (225 mL, 1 M solution in THF, 225 mmol). The resulting reaction mixture was stirred at room temperature for 20 h. After completion of the reaction, the reaction was quenched with MeOH (80 mL) and then refluxed for 30 min. The resulting solution was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM / MeOH, 15:1) to give RAGE 294-4 (25 g, yield: 66.1%) as a yellow solid. LC-MS [M+H] + : 418.2. Example 8D: Preparation of Compound RAGE 294-5

[0237] A mixture of 4-((2-(5-bromopyridin-2-yl)-7-chloroquinolin-4-yl)methyl)morpholine (20 g, 47.8 mmol), Pd(dppf)Cl 2 (3.46 g, 4.78 mmol) and TEA (14.5 g, 143.4 mmol) in DMF / MeOH (50 mL / 50 mL) was stirred at 90 °C under a CO atmosphere for 12 h. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL) and dried over Na 2 SO 4It was dried under reduced pressure and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3:1) to obtain RAGE 294-5 (6.5 g, yield: 34.2%), a white solid. LC-MS [M+H] + : 398.2. Example 8E: Preparation of Compound RAGE 294-6

[0238] A mixture of methyl 6-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)nicotinate (1 g, 2.52 mmol), Zn(CN) 2 (589.7 mg, 5.04 mmol), Xphos (238 mg, 0.5 mmol) and [Pd(allyl)Cl] 2 (183 mg, 0.5 mmol) in DMF (7 mL) was degassed for 10 min and heated in a microwave at 120 °C for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with H 2 O (40 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (80 mL) and dried over Na 2 SO 4 It was dried under reduced pressure and concentrated to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH, 20:1) to obtain RAGE 294-6 (450 mg, yield: 46%), a yellow solid. LC-MS [M+H] + : 389.2. Example 8F: Preparation of Compound RAGE 294

[0239] A solution of methyl 6-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)nicotinate (167 mg, 0.43 mmol) and NH 4 OH (10 mL) in THF (15 mL) / MeOH (7M, NH 3 in MeOH, 10 mL) was sealed in a tube and stirred at 70 °C for 18 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel Prep-HPLC to obtain RAGE 294 (30 mg, yield: 18.7%), a white solid. LC-MS [M+H] + : 374.2. LC-MS [M+H] + : 374.1, Rt = 0.959 min. Purity: 98.35 (214 nm), 96.41 (254 nm). 11H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.61 - 8.59 (m, 2H), 8.42 - 8.40 (m, 2H), 8.20 - 8.27 (m, 1H), 7.62 (s, 1H), 7.52 (s, 1H), 6.29 (s, 1H), 3.88 (s, 2H), 3.58–3.55 (m, 4H), 2.46 - 2.45 (m, 4H). Example 9: Synthesis of analog RAGE 295 according to the present invention

[0240] Compound RAGE 295 according to the present disclosure was prepared as shown in Scheme 9 and as described below. Scheme 9 Synthesis of RAGE 295 Example 9A: Preparation of compound RAGE 295-2

[0241] To a solution of 3-chloroaniline (10 g, 78.7 mmol) in xylene (200 mL) was added ethyl 3-oxobutyrate (20.5 g, 157.4 mmol) and pyridine (12.4 g, 157.4 mmol). The resulting mixture was stirred at 140 °C for 14 h. After completion of the reaction, the reaction was quenched with saturated H 2 O aqueous solution (300 mL), and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5:1) to obtain RAGE 295-2 (5 g, yield: 30.0%), as a yellow solid. LC-MS [M+H] + : 212.2. Example 9B: Preparation of compound RAGE 295-3

[0242] At 0 °C, Br 2 (5.7 g, 35.4 mmol) was added dropwise to a solution of N-(3-chlorophenyl)-3-oxobutanamide (5 g, 23.6 mmol) in AcOH (80 mL). The resulting mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was evaporated, and the pH of the residue was adjusted to 8 with NaHCO 3 (saturated aqueous solution), extracted with EtOAc (50 mL × 3), concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1) to obtain the desired RAGE 295-3 (6 g, yield: 87.7%), as a yellow solid. LC-MS [M+H] + : 290.2. Example 9C: Preparation of Compound RAGE 295-4

[0243] At 0 °C, H 2 SO 4 (20.4 g, 208 mmol) was added dropwise to a solution of 4-bromo-N-(3-chlorophenyl)-3-oxobutanamide (6 g, 20.8 mmol) in H 2 O (100 mL). The resulting mixture was stirred at 40 °C for 20 h. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NaHCO 3 (300 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1) to give the desired RAGE 295-4 (4 g, yield: 70.7%) as a yellow solid. LC-MS [M+H] + : 272.2. Example 9D: Preparation of Compound RAGE 295-5

[0244] Morpholine (1.9 g, 22.2 mmol) and Cs 2 CO 3 (9.6 g, 29.6 mmol) were added to a solution of 4-(bromomethyl)-7-chloroquinolin-2-ol (4 g, 14.8 mmol) in DMF (60 mL). The resulting mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction was quenched with H 2 O (150 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2:1) to give RAGE 295-5 (3 g, yield: 72.6%) as a yellow solid. LC-MS [M+H] + : 279.2. Example 9E: Preparation of Compound RAGE 295-6

[0245] A solution of 7-chloro-4-(morpholinomethyl)quinolin-2-ol (1 g, 3.6 mmol) and POBr 3 (5 g) was stirred at 120 °C for 2 h. The organic layer was evaporated, and the pH of the aqueous phase was adjusted to 8 with saturated aqueous NaHCO 3 , then extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), and then...​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​2 SO 4 It was dried over SO, concentrated under reduced pressure to obtain the desired RAGE 295-6 (650 mg, yield: 52.9%), which was a yellow solid. LC-MS [M+H] + : 341.2 Example 9F: Preparation of Compound RAGE 295-7

[0246] To a solution of 4-((2-bromo-7-chloroquinolin-4-yl)methyl)morpholine (400 mg, 1.2 mmol) in dioxane / H 2 O (10 mL / 1 mL) was added Pd(dppf)Cl 2 (88 mg, 0.12 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (466 mg, 1.8 mmol) and K 3 PO 4 (763 mg, 3.6 mmol). The reaction mixture was stirred at 140 °C for 14 h under a nitrogen atmosphere, quenched with H 2 O (20 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 It was dried over SO, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1) to obtain the desired RAGE 295-7 (230 mg, yield: 48.6%), which was a yellow solid. LC-MS [M+H] + : 394.2 Example 9G: Preparation of Compound RAGE 295

[0247] 5-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)isoindolin-1-one (200 mg, 0.5 mmol), Zn(CN) 2 (176 mg, 1.5 mmol), Xphos (24 mg, 0.05 mmol) and [Pd(allyl)Cl] 2 (18 mg, 0.05 mmol) in DMF (3 mL) was stirred in a microwave at 130 °C for 1 h. The reaction mixture was filtered and washed with EtOAc (10 mL × 3). The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the desired RAGE 295 (10 mg, yield: 5.2%), which was a yellow solid. LC-MS [M+H] + : 385.2. LC-MS [M+H] +: 385.2, Rt = 0.922 min. Purity: 98.17 (214 nm), 97.72 (254 nm). 1 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.61 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.46 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.32 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 4.49 (s, 2H), 4.01 (s, 2H), 3.54 - 3.45 (m, 4H), 2.55–2.51 (m, 4H). Example 10: Synthesis of analog RAGE 296 according to the present invention

[0248] Compound RAGE 296 according to the present disclosure was prepared as shown in Scheme 10 and as described below. Scheme 10 Synthesis of RAGE 296 Example 10A: Preparation of compound RAGE 296-1

[0249] To a solution of 4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)benzaldehyde (1 g, 2.7 mmol) in THF (20 mL) was added 2-methylpropane-2-sulfinamide (496 mg, 4.1 mmol) and Ti(OEt) 4 (935 mg, 4.1 mmol). The resulting mixture was stirred at 70 °C for 12 h. After completion of the reaction, the reaction mixture was quenched with saturated NH 4 Cl aqueous solution (30 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (40 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2:1) to give RAGE 296-1 (1.1 g, yield: 86.7%), as a yellow solid. LC-MS [M+H] + : 470.2. Example 10B: Preparation of compound RAGE 296-2

[0250] Under a nitrogen atmosphere at -78 °C, MeMgBr (4.6 mL, 4.6 mmol) was added to a solution of (E)-N-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)benzylidene)-2-methylpropane-2-sulfinamide (1.1 g, 2.3 mmol) in THF (20 mL). The resulting mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with saturated NH 4 Cl aqueous solution (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2:1) to give RAGE 296-2 (1 g, yield: 89.5%), as a yellow solid. LC-MS [M+H] + : 486.2. Example 10C: Preparation of Compound RAGE 296-3

[0251] (2-(6-Bromopyridin-3-yl)-7-chloroquinolin-4-yl)(morpholino)methanone (1 g, 2.1 mmol), Zn(CN) 2 (731 mg, 6.3 mmol), Xphos (95 mg, 0.2 mmol) and [Pd(allyl)Cl] 2 (73 mg, 0.2 mmol) in DMF (20 mL) was stirred at 125 °C for 2 h. The reaction mixture was filtered and washed with EtOAc (20 mL × 3). The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give RAGE 296-3 (500 mg, yield: 49.9%), as a yellow solid. LC-MS [M+H] + : 477.2. Example 10D: Preparation of Compound RAGE 296

[0252] A solution of N-(1-(4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (150 mg, 0.3 mmol) and HCl (2 mL, 4 M dioxane solution, 8 mmol) in DMF (4 mL) was stirred at room temperature for 2 h. The organic layer was evaporated, and the residue was washed with saturated NaHCO 3 aqueous solution (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (25 mL) and dried over Na 2 SO 4Drying and concentrating gave the desired RAGE 296 (14 mg, yield: 12.5%), a white solid. LC-MS [M+H] + : 373.2, Rt = 0.866 min. Purity: 99.05 (214 nm), 99.59 (254 nm). 1 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.37 (d, J = 12 Hz, 1H), 8.15 (d, J = 12 Hz, 2H), 7.99 (s, 1H), 7.68–7.65 (m, 1H), 7.57–7.55 (m, 2H), 4.29–4.24 (m, 1H), 3.96 (s, 2H), 3.74–3.72 (m, 4H), 1.48 (d, J = 4 Hz, 3H). Example 11: Synthesis of analog RAGE 297 according to the present invention

[0253] Compound RAGE 297 according to the present disclosure was prepared as shown in Scheme 11 and as described below. Scheme 11 Synthesis of RAGE 297 Example 11A: Preparation of compound RAGE 297-1

[0254] To a solution of N(1-(4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (400 mg, 0.8 mmol) in THF (10 mL) at 0 °C was added NaH (48 mg, 1.2 mmol, 60% paraffin oil suspension). The mixture was stirred at 0 °C for 0.5 h. Then CH 3 I (170 mg, 1.2 mmol) was added at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with saturated NH 4 Cl aqueous solution (15 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2:1) to give RAGE 297-1 (300 mg, yield: 76.4%), a white solid. LC-MS [M+H] + : 491.2. Example 11B: Preparation of compound RAGE 297

[0255] A solution of 2-(4-(1-(methylamino)ethyl)phenyl)-4-(morpholinomethyl)quinoline)-7-carbonitrile (300 mg, 0.6 mmol) and HCl (5 mL, 4 M dioxane solution, 20 mmol) in DCM (10 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, added to saturated NaHCO 3 aqueous solution (20 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , concentrated under reduced pressure to obtain the crude product, which was purified by Prep-HPLC to give the desired RAGE297 (150 mg, yield: 64.6%), as a white solid. LC-MS [M+H] + : 387.2, Rt = 0.874 min. Purity: 95.74 (214 nm), 95.10 (254 nm). 1 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 4 Hz, 1H), 8.50 (d, J = 8 Hz, 1H), 8.25–8.23 (m, 3H), 7.92 - 7.89 (m, 1H), 7.53 (d, J = 8 Hz, 2H), 4.03 (s, 2H), 3.69 - 3.66 (m, 1H), 3.58–3.56 (m, 4H), 2.55–2.53 (m, 4H), 2.17 (s, 3H), 1.29 (d, J = 8 Hz, 3H). Example 12: Synthesis of analog RAGE 298 according to the present invention

[0256] Compound RAGE 298 according to the present disclosure was prepared as shown in Scheme 12 and as described below. Scheme 12 Synthesis of RAGE 298 Example 12A: Preparation of compound RAGE 298-1

[0257] To a solution of 4-((2-(4-bromophenyl)-7-chloroquinolin-4-yl)methyl)morpholine 1 (2 g, 4.78 mmol) in DMF (20 mL) was added ZnCN 2 (297 mg, 2.53 mmol) and Pd(PPh 3 ) 4 (552 mg, 0.478 mmol). The resulting mixture was stirred at 100 °C for 2 h under N 2 atmosphere. After completion of the reaction, the reaction mixture was filtered, and washed with H 2Dilute with O (50 mL), and extract with EtOAc (40 mL × 3). Wash the combined organic layers with brine (40 mL), and dry over Na 2 SO 4 and concentrate under reduced pressure to obtain the crude product. Purify by silica gel column chromatography (petroleum ether / ethyl acetate, 1:1) to obtain RAGE 298-1 (1.1 g, yield: 63.2%), which is a white solid. LC-MS [M+H] + : 364.1. Example 12B: Preparation of Compound RAGE 298-2

[0258] At 0 °C, add Boc 2 O (1.32 g, 6.04 mmol) and NiCl 2 ·6H 2 O (71.8 mg, 0.30 mmol) to a solution of 4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)benzonitrile 2 (1.1 g, 3.02 mmol) in anhydrous MeOH (20 mL). Then add NaBH 4 (800 mg, 21.14 mmol) in small portions over 30 min. Heat the resulting reaction mixture to room temperature and stir for an additional 1 h. Concentrate the mixture, dissolve the residue in EtOAc (100 mL), and wash with saturated NaHCO 3 (50 mL × 2). Dry the organic layer over Na 2 SO 4 and remove the solvent under reduced pressure to obtain RAGE 298-2 (850 mg, yield: 60.2%), which is a light yellow solid. LC-MS [M+H] + : 468.1. Example 12C: Preparation of Compound RAGE 298-3

[0259] Add Zn(CN) 2 (425 mg, 3.64 mmol), allylpalladium(II) chloride dimer (66.6 mg, 0.18 mmol), and X-phos (173.5 mg, 0.36 mmol) to a solution of tert-butyl (4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)benzyl)carbamate 3 (850 mg, 1.82 mmol) in DME (10 mL). Stir the resulting mixture at 100 °C for 15 h under N 2 atmosphere. After completion of the reaction, filter the reaction mixture, dilute with H 2 O (50 mL), and extract with EtOAc (40 mL × 3). Wash the combined organic layers with brine (40 mL), and dry over Na 2 SO 4It was dried over and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1:1) to obtain RAGE 298-3 (500 mg, yield: 59.9%), a light yellow solid. LC-MS [M+H] + : 459.2. Example 12D: Preparation of Compound RAGE 286

[0260] To a solution of tert-butyl (4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)benzyl)carbamate (500 mg, 1.09 mmol) in anhydrous DCM (8 mL) was added 4 mol / L HCl-1,4-dioxane (1.36 mL, 5.45 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and neutralized with 7 mol / L NH 3 / MeOH solution until pH = 8. After concentration under reduced pressure, the mixture was purified by silica gel column chromatography (DCM / MeOH, 10:1) to obtain RAGE 286 (250 mg, yield: 64%), a light yellow solid. LC-MS [M+H] + : 359.2. Example 12E: Preparation of Compound RAGE 298

[0261] To a solution of 2-(4-(aminomethyl)phenyl)-4-(morpholinomethyl)quinoline-7-carbonitrile (100 mg, 0.28 mmol) in anhydrous CH 2 Cl 2 (10 mL) was added paraformaldehyde (25 mg, 0.84 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled to -10 °C and sodium borohydride (42 mg, 1.12 mmol) was added. Anhydrous methanol (0.5 mL) was added dropwise, and the reaction mixture was heated to room temperature and stirred for an additional 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC to obtain the desired RAGE 298 (50 mg, yield: 36.7%, TFA salt), a white solid. LC-MS [M+H] + : 373.3, Rt = 0.874 min. Purity: 99.40 (214 nm), 99.48 (254 nm). 1 1H NMR (400 MHz, MeOD-d4) δ 8.50 (s, 1H), 8.47 - 8.45 (m, 2H), 8.42 (d, J = 8 Hz, 2H), 7.94 (d, J = 12 Hz, 1H), 7.70 (d, J = 12 Hz, 2H), 4.91 (s, 2H), 4.30 (s, 2H), 3.78 (s, 4H), 3.30–3.29 (m, 4H), 2.77 (s, 3H). Example 13: Synthesis of Analogue RAGE 299 According to the Invention

[0262] Compound RAGE 299 according to the present disclosure was prepared as shown in Scheme 13 and as described below. Scheme 13 Synthesis of RAGE 299 Example 13A: Preparation of Compound RAGE 299

[0263] Paraformaldehyde (210 mg, 7.0 mmol) was added to a solution of 2-(4-(aminomethyl)phenyl)-4-(morpholinomethyl)quinoline-7-carbonitrile 5 (250 mg, 0.70 mmol) in anhydrous DCM (8 mL). The reaction mixture was refluxed for 16 h. The reaction mixture was cooled to -10 °C, and sodium borohydride (132.4 mg, 3.5 mmol) was added. Anhydrous methanol (1 mL) was added dropwise, and the reaction mixture was heated to room temperature and stirred for an additional 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the desired RAGE 299 (25 mg, yield: 8.2%, FA salt) as a white solid. LC-MS [M+H] + : 388.1, Rt = 1.001 min. Purity: 100 (214 nm), 100 (254 nm). 1 H NMR (400 MHz, MeOD-d4) δ 8.56 (d, J = 8.0 Hz, 1H), 8.52 (d, J = 1.2 Hz, 1H), 8.33 (d, J = 8.0 Hz, 2H), 8.21 (s, 1H), 7.82–7.78 (m, 1H), 7.65 (d, J = 8.2 Hz, 2H), 4.16 (s, 2H), 4.07 (s, 2H), 3.71–3.68 (m, 4H), 2.72 (s, 6H), 2.59–2.57 (m, 4H). Example 14: Synthesis of Analogue RAGE 400 According to the Invention

[0264] Compound RAGE 400 according to the present disclosure was prepared as shown in Scheme 14 and as described below. Scheme 14 Synthesis of RAGE 400 Example 14A: Preparation of Compound RAGE 400-2

[0265] At 0 °C, Boc was added to a stirred solution of 2-(4-bromophenyl)pyrrolidine 1 (950 mg, 4.20 mmol) and 2 M aqueous NaOH (4.2 mL, 8.4 mmol) in 1,4-dioxane (10 mL).2 O (1.38 mg, 6.30 mmol). The reaction mixture was stirred at room temperature for 16 h. H 2 O (30 mL) was added and the mixture was extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (30 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10:1) to give RAGE 400-2 (1.40 g, yield: quantitative) as a colorless viscous oil. LC-MS [M+H] + : 327.2. Example 14B: Preparation of Compound RAGE 400-3

[0266] A solution of tert-butyl 2-(4-bromophenyl)pyrrolidine-1-carboxylate (1.0 g, 3.07 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.3 g, 9.20 mmol), Pd(dppf)Cl 2 (449 mg, 0.61 mmol) and KOAc (602 mg, 6.13 mmol) in 1,4-dioxane (15 mL) was stirred at 85 °C under N 2 atmosphere for 16 h. The mixture was cooled to room temperature and filtered through Celite. The residue was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10:1) to give RAGE 400-3 (750 mg, yield: 65%) as a pale yellow viscous oil. LC-MS [M+H] + : 374.2. Example 14C: Preparation of Compound RAGE 400-4

[0267] To a solution of 4-((2-bromo-7-chloroquinolin-4-yl)methyl)morpholine (200 mg, 0.59 mmol) and tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-1-carboxylate 3 (438 mg, 1.17 mmol) in 1,4-dioxane (15 mL) and H 2 O (2 mL) was added Pd(dppf)Cl 2 (86 mg, 0.12 mmol) and K 3 PO 4 (249 mg, 1.17 mmol). The mixture was stirred at 80 °C under N 2Stir in the atmosphere for 16 h. Cool the mixture to room temperature and filter through diatomaceous earth. Concentrate the filtrate under reduced pressure to obtain the crude product, which is purified by silica gel column chromatography (DCM / MeOH, 10:1) to obtain RAGE 400-4 (150 mg, yield: 50%), as a white solid. LC-MS [M+H] + : 508.1. Example 14D: Preparation of Compound RAGE 400-5

[0268] To a solution of tert-butyl 2-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)pyrrolidine-1-carboxylate (100 mg, 0.20 mmol) and Zn(CN) 2 (47 mg, 0.40 mmol) in DMF (2 mL), add allyl chloride palladium(II) dimer (7 mg, 0.02 mmol) and X-phos (19 mg, 0.04 mmol). Stir the mixture in a sealed tube. After degassing with N 2 for 1 min, irradiate the reaction mixture in a microwave at 140 °C for 1 h. Cool the mixture to room temperature, dilute with H 2 O (20 mL), and extract with EtOAc (30 mL×3). Wash the combined organic matters with brine (50 mL) and dry over Na 2 SO 4 and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate, 2:1) to obtain RAGE 400-5 (80 mg, yield: 82%), as a white solid. LC-MS [M+H] + : 499.2. Example 14E: Preparation of Compound RAGE 400

[0269] Add HCl (4N 1,4-dioxane solution, 1 mL) to a solution of tert-butyl 2-(4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)phenyl)pyrrolidine-1-carboxylate 6 (80 mg, 0.16 mol) in DCM (2 mL). After stirring at room temperature for 2 h, concentrate the mixture and neutralize it to pH = 8-9 with NaHCO 3 (saturated aqueous solution). Concentrate the reactant under reduced pressure to obtain the crude product, which is purified by Prep-HPLC to obtain the desired RAGE 400 (20 mg, yield: 28%, FA salt), as a white solid. LC-MS [M+H] + : 399.2, Rt = 0.954 min. Purity: 97.99 (214 nm), 98.70 (254 nm). 11H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.55 (d, J = 8 Hz, 1H), 8.49–8.26 (m, 4H), 7.90 (d, J = 8 Hz, 1H), 7.62 (d, J = 8 Hz, 2H), 4.33–4.32 (m, 1H), 4.03 (s, 2H), 3.59–3.56 (m, 4H), 3.19–3.16 (m, 1H), 3.11–3.09 (m, 1H), 2.49–2.43 (m, 4H), 2.26–2.23 (m, 1H), 1.90–1.89 (m, 2H), 1.75–1.73 (m, 1H). Example 15: Synthesis of Analogue RAGE 401 According to the Invention

[0270] Compound RAGE 401 according to the present disclosure was prepared as shown in Scheme 15 and as described below. Scheme 15 Synthesis of RAGE 401 Example 15A: Preparation of Compound RAGE 291-6

[0271] To a solution of methyl 4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)benzoate 1 (1 g, 2.52 mmol) in THF / H 2 2O (10 mL / 3 mL) was added LiOH·H 2 2O (159 mg, 3.78 mmol). The resulting mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was acidified to pH = 4 with 1 M HCl. The reaction was diluted with water (20 mL) and extracted with EtOAc (30 mL). The combined organic layers were washed with brine (20 mL) and dried over Na 2 2SO 4 4 and concentrated under reduced pressure to give RAGE 291-6 (800 mg, yield: 83%) as a white solid. LC-MS [M+H] + : 383.1. Example 15B: Preparation of Compound RAGE 401-1

[0272] A solution of 4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)benzoic acid 2 (800 mg, 2.09 mmol), DIPEA (540 mg, 4.18 mmol), HATU (1192 mg, 3.13 mmol) and pyrrolidine (223 mg, 3.13 mmol) in DCM (10 mL) was stirred at 50 °C for 8 h. The mixture was cooled to room temperature. The resulting mixture was treated with H 2Diluted with O (20 mL) and extracted with EtOAc (25 mL × 3). The combined organic layers were washed with brine (20 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2:1) to give RAGE 401-1 (750 mg, yield: 82%), as a white solid. LC-MS [M+H] + : 436.2. Example 15C: Preparation of Compound RAGE 401-2

[0273] At 0 °C, BH 3 ·THF (5.2 mL, 1 M THF solution, 5.2 mmol) was added dropwise to a stirred solution of (4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)(pyrrolidin-1-yl)methanone 3 (750 mg, 1.72 mmol) in THF (10 mL). The mixture was stirred at 65 °C for 2 h. The reaction mixture was cooled to room temperature and quenched with MeOH (20 mL). The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2:1) to give RAGE 401-2 (300 mg, yield: 41%), as a white solid. LC-MS [M+H] + : 422.2. Example 15D: Preparation of Compound RAGE 401

[0274] 4-((7-chloro-2-(4-(pyrrolidin-1-ylmethyl)phenyl)quinolin-4-yl)methyl)morpholine 4 (300 mg, 0.71 mmol), Zn(CN) 2 (167 mg, 1.42 mmol), allylpalladium(II) chloride dimer (26 mg, 0.07 mmol) and Xphos (68 mg, 0.14 mmol) in DMF (5 mL) were stirred in a sealed tube. After degassing with N 2 for 1 min, the reaction mixture was stirred at 100 °C for 4 h. The mixture was cooled to room temperature, diluted with H 2 O (20 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product, which was purified by Prep-HPLC to give the desired RAGE 401 (33 mg, yield: 8.8%, TFA salt), as a white solid. LC-MS [M+H] +: 413.3, Rt = 0.905 min. Purity: 100 (214 nm), 99.90 (254 nm). 1 1H NMR (400 MHz, MeOD-d4) δ 8.65 (s, 1H), 8.53–8.48 (m, 2H), 8.43 (d, J = 8.2 Hz, 2H), 7.95–7.92 (m, 1H), 7.74 (d, J = 8.0 Hz, 2H), 4.50 (s, 2H), 3.88 (s, 4H), 3.53 (s, 2H), 3.32–3.32 (m, 4H), 3.31–3.27 (m, 4H), 2.15–2.11 (m, 2H), 2.04–2.02 (m, 2H). Example 16: Synthesis of analog RAGE 402 according to the present invention

[0275] Compound RAGE 402 according to the present disclosure was prepared as shown in Scheme 16 and as described below. Scheme 16 RAGE 402 Synthesis Example 16A: Preparation of compound RAGE 402-1

[0276] To a solution of (4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)methanol (1 g, 2.71 mmol) in anhydrous DCM (15 mL) was added SOCl 2 (390 mL, 5.42 mmol). The resulting mixture was stirred at room temperature for 5 h under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3:1) to give RAGE 402-1 (900 mg, yield: 85.7%), as a white solid. LC-MS [M+H] + : 387.1. Example 16B: Preparation of compound RAGE 402-2

[0277] To a solution of 4-((7-chloro-2-(4-chloromethyl)phenyl)quinolin-4-yl)methyl)morpholine (900 mg, 2.32 mmol) in anhydrous DMF (10 mL) was added DIPEA (899 mg, 6.97 mmol), NaCN (227 mg, 4.64 mmol) and NaI (34.8 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H 2 2O (50 mL), and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (50 mL), and dried over Na 2 2SO 4Dry it under reduced pressure, filter and concentrate it under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3:1) to obtain RAGE 402-2 (710 mg, yield: 81%), which is a white solid. LC-MS [M+H] + : 378.1. Example 16C: Preparation of compound RAGE 402-3

[0278] Under a nitrogen atmosphere and with stirring, 1 mol / L BH 3 ·THF (2.65 mL, 2.65 mmol) was added dropwise to a solution of 2-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetonitrile (200 mg, 0.53 mmol) in anhydrous THF (5 mL) within 15 min. After refluxing for 1 h, the mixture was cooled to 0 °C and the reaction was quenched by adding MeOH. The reaction mixture was stirred under reflux for 1 h and then concentrated to obtain RAGE 402-3 (200 mg, crude product), which is a light yellow solid. LC-MS [M+H] + : 382.1. Example 16D: Preparation of compound RAGE 402-4

[0279] TEA (157 mg, 1.56 mmol) and (Boc) 2 O (170 mg, 0.78 mmol) were added to a solution of 2-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)ethan-1-amine (200 mg, 0.52 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1:2) to obtain RAGE 402-4 (200 mg, yield: 79.8%), which is a white solid. LC-MS [M+H] + : 482.1. Example 16E: Preparation of compound RAGE 402-5

[0280] Zn(CN) 2 (53 mg, 0.46 mmol), allylpalladium(II) chloride dimer (15 mg, 0.04 mmol) and X-phos (38 mg, 0.08 mmol) were added to a solution of tert-butyl (4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenethyl)carbamate (200 mg, 0.41 mmol) in anhydrous DMF (5 mL). The resulting mixture was stirred in a microwave at 130 °C for 1 h under a N 2 atmosphere. After the reaction was completed, the reaction mixture was filtered, and with H 2Dilute with O (20 mL), and extract with DCM (30 mL × 3). Wash the combined organic layers with brine (20 mL), dry over Na 2 SO 4 and concentrate under reduced pressure to obtain the crude product. Purify by silica gel column chromatography (petroleum ether / ethyl acetate, 1:2) to obtain RAGE 402-5 (80 mg, yield: 41.3%), which is a light yellow solid. LC-MS [M+H] + : 473.2. Example 16F: Preparation of Compound RAGE 402

[0281] To a solution of tert-butyl (4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)phenethyl)carbamate (80 mg, 0.17 mmol) in anhydrous DCM (2 mL) was added 4 mol / L HCl / 1,4-dioxane (0.42 mL, 1.7 mmol). After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure, and then neutralized with 7 mol / L NH 3 / MeOH solution until pH = 8. The mixture was concentrated under reduced pressure and purified by Prep-HPLC to obtain the desired RAGE 402 (18.2 mg, yield: 28.7%), which is a white solid. LC-MS [M+H] + : 373.2, Rt = 0.824 min. Purity: 97.11 (214 nm), 97.03 (254 nm). 1 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.33 (s, 2H), 8.27–8.24 (m, 3H), 7.90 (d, J = 4.2 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 4.03 (s, 2H), 3.57 (d, J = 4.2 Hz, 4H), 2.89 (d, J = 4.2 Hz, 2H), 2.67 (s, 2H), 2.51–2.49 (m, 4H). Example 17: Synthesis of Analogue RAGE 403 According to the Present Invention

[0282] Compound RAGE 403 according to the present disclosure was prepared as shown in Scheme 17 and as described below. Scheme 17 Synthesis of RAGE 403 Example 17A: Preparation of Compound RAGE 291-5

[0283] 4-((2-(4-Bromophenyl)-7-chloroquinolin-4-yl)methyl)morpholine (2 g, 4.81 mmol), Pd(dppf)Cl 2 (352 mg, 0.48 mmol) and TEA (2.42 g, 24 mmol) in a mixture of MeOH / THF (25 mL / 25 mL) was stirred at 90 °C under a CO atmosphere for 17 h. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1:1) to give RAGE 291-5 (1.3 g, yield: 68.1%) as a yellow solid. LC-MS [M+H] + : 397.2. Example 17B: Preparation of Compound RAGE 403-1

[0284] To a solution of methyl 4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)benzoate (1.5 g, 3.78 mmol) in anhydrous THF (50 mL) at [temperature not specified] was added LiAlH 4 (5.67 mL, 1 M THF solution, 5.67 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction was quenched with Na 2 SO 4 -10H 2 O (10 g). The mixture was filtered and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM / MeOH, 15:1) to give RAGE403-1 (1.2 g, yield: 86.3%) as a yellow solid. LC-MS [M+H] + : 369.2. Example 17C: Preparation of Compound RAGE 403-2

[0285] At 0 °C, to a solution of (4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)methanol (1.2 g, 3.25 mmol) in DCM (35 mL) was added Dess-Martin periodinane reagent (2.1 g, 4.87 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched with saturated NaHCO 3 (50 mL), and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (100 mL). The organic layer was dried over Na 2 SO 4It was dried over, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (DCM / MeOH, 25:1) to obtain RAGE 403-2 (1.08 g, yield: 90.8%), as a white solid. LC-MS [M+H] + : 367.1. Example 17D: Preparation of Compound RAGE 403-3

[0286] (E)-4-(7-Chloro-2-(4-(2-nitroprop-1-en-1-yl)phenyl)quinolin-4-yl)methyl)morpholine (864 mg, 2.36 mmol) and NH 4 OAc (1.82 g, 23.6 mmol) in a mixture of nitroethane (5 mL) was stirred at 100 °C for 3 h. After completion of the reaction, the reaction mixture was diluted with H 2 O (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 It was dried over, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (DCM / MeOH, 20:1) to obtain RAGE 403-3 (750 mg, yield: 75.1%), as a yellow solid. LC-MS [M+H] + : 424.2. Example 17E: Preparation of Compound RAGE 403-4

[0287] At 0 °C, LiAlH 4 (2.6 mL, 1 M THF solution, 2.6 mmol) was slowly added to a solution of (E)-4-((7-chloro-2-(4-(2-nitroprop-1-en-1-yl)phenyl)quinolin-4-yl)methyl)morpholine (740 mg, 1.75 mmol) in THF (25 mL). The resulting reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction was quenched with Na 2 SO 4 -10 H 2 O (5 g). The reaction mixture was filtered and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to obtain RAGE 403-4 (1 g crude), as a yellow solid, which was directly used for the next step without further purification. LC-MS [M+H] + : 396.2. Example 17F: Preparation of Compound RAGE 403-5

[0288] At 0 °C, Boc 2 O (567 mg, 2.6 mmol) was added to a solution of 1-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)propan-2-amine (1 g, crude product from the previous step) and TEA (353.5 mg, 3.5 mmol) in DCM (30 mL). The resulting reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction was quenched with H 2 O (50 mL), and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (70 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH, 30:1) to give RAGE 403-5 (240 mg, total yield in two steps: 27.6%), as a white solid. LC-MS [M+H] + : 496.2. Example 17G: Preparation of Compound RAGE 403-6

[0289] (tert-Butyl (1-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)propan-2-yl)carbamate (240 mg, 0.48 mmol), Zn(CN) 2 (112.3 mg, 0.96 mmol), Xphos (90.4 mg, 0.19 mmol) and [Pd(allyl)Cl] 2 (35 mg, 0.096 mmol) in DMF (4 mL) were degassed for 10 min and heated in a microwave at 130 °C for 1 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with H 2 O (30 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (60 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a crude product, which was purified by Prep-TLC (DMC / MeOH, 20:1) to give RAGE 403-6 (170 mg, yield: 72.9%), as a white solid. LC-MS [M+H] + : 487.2. Example 17E: Preparation of Compound RAGE 403

[0290] To a solution of tert-butyl (1-(4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)phenyl)propan-2-yl)carbamate (170 mg, 0.35 mmol) in dioxane (5 mL) was added HCl (0.7 mL, 4 M 1,4-dioxane solution, 2.8 mmol). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by Prep-HPLC to give the desired RAGE 403 (40 mg, yield: 29.6%) as a white solid. LC-MS [M+H] + : 387.1, Rt = 0.892 min. Purity: 100 (214 nm), 100 (254 nm). 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.47 (d, J = 8.8 Hz, 1H), 8.37 (s, 1H), 8.25 - 8.20 (m, 3H), 7.88 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 8.9 Hz, 2H), 4.00 (s, 2H), 3.54 (s, 4H), 3.32 - 3.30 (m, 1H), 2.94 - 2.91 (m, 1H), 2.70 - 2.65 (m, 1H), 2.47 (s, 4H), 1.06 (d, J = 8.9 Hz, 3H). Example 18: Synthesis of analog RAGE 404 according to the present invention

[0291] Compound RAGE 404 according to the present disclosure was prepared as shown in Scheme 18 and as described below. Scheme 18 Synthesis of RAGE 404 Example 18A: Preparation of compound RAGE 404-1

[0292] (2-(4-Bromophenyl)-7-chloroquinolin-4-yl)(morpholino)methanone (5 g, 11.6 mmol), tributyl(1-ethoxyvinyl)stannane (8.38 g, 23.2 mmol), LiCl (0.97 g, 23.2 mmol) and Pd(PPh 3 ) 4 (1.34 g, 1.16 mmol) in 1,4-dioxane (100 mL) were mixed in N 2Stir at 120 °C for 16 h under the atmosphere. After the reaction is completed, filter the reactants through diatomaceous earth and wash with EtOAc (100 mL × 2). Concentrate the filtrate under reduced pressure to obtain the crude product, which is purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2:1) to obtain RAGE 404-1 (4.25 g, yield: 92.8%), as a yellow solid. LC-MS [M+H] + : 395.2. Example 18B: Preparation of Compound RAGE 404-2

[0293] A mixture of 1-(4-(7-chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)phenyl)ethan-1-one (2.3 g, 5.8 mmol), Zn(CN) 2 (1.36 g, 11.6 mmol), Xphos (552.2 mg, 1.16 mmol) and [Pd(Allyl)Cl] 2 (212 mg, 0.58 mmol) in DMF (15 mL) is degassed for 10 min, then sealed and heated in a microwave at 130 °C for 1 h. After the reaction is completed, cool the reactants to room temperature, dilute with H 2 O (50 mL) and extract with EtOAc (60 mL × 3). Wash the combined organic layers with brine (60 mL), dry over Na 2 SO 2 SO 4 and concentrate under reduced pressure to obtain the crude product, which is purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1) to obtain RAGE 404-2 (1.1 g, yield: 49.3%), as a yellow solid. LC-MS [M+H] + : 386.2. Example 18C: Preparation of Compound RAGE 404-3

[0294] A solution of 2-(4-acetylphenyl)-4-(morpholine-4-carbonyl)quinoline-7-carbonitrile (1.1 g, 2.85 mmol), 2-methylpropane-2-sulfinamide (517.9 mg, 4.28 mmol) and Ti(OEt) 4 (1.3 g, 5.7 mmol) in THF (30 mL) is stirred at 70 °C for 16 h under the atmosphere. After the reaction is completed, quench the reaction with water (50 mL) and extract with EtOAc (60 mL × 3). Wash the combined organic layers with brine (80 mL), dry over Na 2 SO 2 SO 4It was dried under reduced pressure and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1) to obtain RAGE 404-3 (1 g, yield: 71.9%), a yellow solid. LC-MS [M+H] + : 489.2. Example 18D: Preparation of Compound RAGE 404-4

[0295] To a solution of (E)-N-(1-(4-(7-cyano-4-(morpholine-4-carbonyl)quinolin-2-yl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (500 mg, 1.02 mmol) in MeOH (15 mL) was added NaBH 4 (76 mg, 2 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction was quenched with saturated aqueous NH 4 Cl (30 mL), and extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine (50 mL) and dried over Na 2 SO 4 It was dried under reduced pressure and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1) to obtain RAGE 404-4 (320 mg, yield: 64%), a yellow solid. LC-MS [M+H] + : 491.2. Example 18E: Preparation of Compound RAGE 404-5

[0296] To a solution of N-(1-(4-(7-cyano-4-(morpholine-4-carbonyl)quinolin-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (320 mg, 0.65 mmol) in 1,4-dioxane (5 mL) was added HCl (1.6 mL, 4 M 1,4-dioxane solution, 6.4 mmol). The resulting reaction mixture was stirred at room temperature for 30 min. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the desired HCl salt of RAGE 404-5 (350 mg, crude), which was used directly in the next step without further purification. LC-MS [M+H] + : 387.2. Example 18F: Preparation of Compound RAGE 404

[0297] To a solution of 2-(4-(1-aminoethyl)phenyl)-4-(morpholine-4-carbonyl)quinoline-7-carbonitrile (350 mg, crude) and TEA (262.2 mg, 2.6 mmol) in THF (10 mL) was added acetic anhydride (132.6 mg, 1.3 mmol). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction was quenched with water (25 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to give the crude product, which was purified by Prep-HPLC to give RAGE404 (35 mg, overall yield in two steps: 12.6%), as a white solid. LC-MS [M+H] + : 429.2, Rt = 1.147 min. Purity: 99.23 (214 nm), 98.19 (254 nm). 1 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.39 (d, J = 8.0 Hz, 1H), 8.30 (s, 1H), 8.27 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 12.0 Hz, 2H), 5.01–4.98 (m, 1H), 3.88–3.85 (s, 1H), 3.81–3.75 (m, 3H), 3.65–3.52 (m, 1H), 3.40–3.36 (m, 1H), 3.25–3.21 (m, 1H), 3.18–3.12 (m, 1H), 1.88 (s, 3H), 1.39 (d, J = 8.0 Hz, 3H). Example 19: Synthesis of analog RAGE 405 according to the present invention

[0298] Compound RAGE 405 according to the present disclosure was prepared as shown in Scheme 19 and as described below. Scheme 19 Synthesis of RAGE 405 Example 19A: Preparation of compound RAGE 405

[0299] At 0 °C, to a solution of 2-(4-(1-(methylamino)ethyl)phenyl)-4-(morpholinomethyl)quinoline-7-carbonitrile (150 mg, 0.4 mmol) and TEA (121 mg, 1.2 mmol) in THF (10 mL) was added Ac 2O (71 mg, 0.6 mmol). The mixture was stirred at room temperature for 6 h. The reaction product was washed with water (25 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH, 20:1) to give the desired RAGE 405 (35 mg, yield: 20.4%) as a white solid. ESI-MS [M+H] + : 429.2. LC-MS [M+H] + : 429.3, Rt = 0.996 min. Purity: 97.79 (214 nm), 97.61 (254 nm). 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.50 (d, J = 8 Hz, 1H), 8.31 - 8.25 (m, 3H), 7.92 (d, J = 12 Hz, 1H), 7.51 - 7.45 (m, 2H), 5.93 - 5.88 (m, 1H), 4.03 (s, 2H), 3.59 - 3.56 (m, 4H), 2.71 (s, 2H), 2.58 (s, 1H), 2.51–2.48 (m, 4H) 2.19 (s, 1H), 2.08 (s, 2H), 1.60 (d, J = 8 Hz, 1H), 1.48 (d, J = 8 Hz, 2H). Example 20: Synthesis of analog RAGE 406 according to the present invention

[0300] Compound RAGE 406 according to the present disclosure was prepared as shown in Scheme 20 and as described below. Scheme 20 RAGE 406 Synthesis Example 20A: Preparation of compound RAGE 406-1

[0301] 4-((2-(4-Bromophenyl)-7-chloroquinolin-4-yl)methyl)morpholine (2 g, 4.8 mmol), methyl 4-nitrobutyrate (1.41 g, 9.6 mmol), 2-di-tert-butylphosphino-2'-methylbiphenyl (299.5 mg, 0.96 mmol), Pd 2 (dba) 3 (351.4 mg, 0.48 mmol) and Cs 2 CO 3(3.91 g, 12 mmol) in DME (50 mL) was stirred at 120 °C for 12 h. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (60 mL), dried over Na 2 SO 4 , concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (DCM / MeOH, 15:1) to obtain RAGE406-1 (800 mg, yield: 34.5%), as a yellow solid. LC-MS [M+H] + : 484.2. Example 20B: Preparation of Compound RAGE 406-2

[0302] Methyl 4-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)nitrobutyrate (800 mg, 1.65 mmol), Fe (924 mg, 16.5 mmol) and NH 4 Cl (1.75 g, 33 mmol) in EtOH / water (5 mL / 5 mL) was stirred at 100 °C for 3 h. After completion of the reaction, the reaction mixture was filtered and washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (DCM / MeOH, 10:1) to obtain RAGE 406-2 (170 mg, yield: 24.5%), as a yellow solid. LC-MS [M+H] + : 422.2. Example 20C: Preparation of Compound RAGE 406

[0303] 5-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)pyrrolidin-2-one (170 mg, 0.4 mmol), Zn(CN) 2 (93.6 mg, 0.8 mmol), Xphos (38.1 mg, 0.08 mmol) and [Pd(allyl)Cl] 2 (14.6 mg, 0.04 mmol) in DME (5 mL) was stirred at 120 °C for 24 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with H 2 O (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na 2 SO 4 , concentrated under reduced pressure to obtain the crude product, which was purified by Prep-HPLC to obtain RAGE 406 (20 mg, yield: 12.1%), as a white solid. LC-MS [M+H] +: 413.2, Rt = 1.013 min. Purity: 96.19 (214 nm), 96.12 (254 nm). 1 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.30–8.28 (m, 3H), 8.19 (s, 1H), 7.93–7.90 (m, 1H), 7.51 (d, J = 8.0 Hz, 2H), 4.78 (t, J = 8.0 Hz, 1H), 4.03 (s, 2H), 3.56 (t, J = 4.0 Hz, 4H), 2.62–2.40 (m, 5H), 2.28 (t, J = 8.0 Hz, 2H), 1.86–1.74 (m, 1H). Example 21: Synthesis of analog RAGE 407 according to the present invention

[0304] Compound RAGE 407 according to the present disclosure is prepared as shown in Scheme 21 and as described below. Scheme 21 Synthesis of RAGE 407 Example 21A: Preparation of compound RAGE 407-2

[0305] A mixture of 6-chloroindoline-2,3-dione (10 g, 55.2 mmol) and malonic acid (22.9 g, 220.8 mmol) in AcOH (150 mL) was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was triturated with petroleum ether / ethyl acetate (5:1, 100 mL) to give RAGE 407-2 (8.5 g, yield: 69.1%), as a yellow solid. LC-MS [M+H] + : 224.1. Example 21B: Preparation of compound RAGE 407-3

[0306] A mixture of 7-chloro-2-hydroxyquinoline-4-carboxylic acid (8.5 g, 37.95 mmol), morpholine (6.6 g, 75.9 mmol), HOBT (7.69 g, 56.93 mmol), EDCI (10.87 g, 56.93 mmol) and DIPEA (14.48 g, 113.79 mmol) in DMF (150 mL) was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine and dried over Na 2 SO 4It was dried over Na₂SO₄, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2:1) to obtain RAGE 407-3 (7.3 g, yield: 65.9%), which was a yellow solid. LC-MS [M+H] + : 293.1. Example 21C: Preparation of Compound RAGE 407-4

[0307] At 0 °C, trifluoromethanesulfonic anhydride (6.93 g, 24.57 mmol) was added to a solution of (7-chloro-2-hydroxyquinolin-4-yl)(morpholinyl)methanone (4 g, 13.65 mmol) and TEA (4.14 g, 40.95 mmol) in DCM (65 mL). The reaction mixture was stirred at 0 °C for another 2 h. After completion of the reaction, the reaction was quenched with water (65 mL), and extracted with DCM (60 mL × 3). The combined organic layers were washed with brine (100 mL) and dried over Na 2 SO 4 ₂SO₄, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3:1) to obtain RAGE 407-4 (3.9 g, yield: 67.36%), which was a yellow solid. LC-MS [M+H] + : 425.1. Example 21D: Preparation of Compound RAGE 407-5

[0308] 7-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl trifluoromethanesulfonate (580 mg, 1.37 mmol), tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-1-carboxylate (765.4 mg, 2.05 mmol), Pd(dppf)Cl 2 ₂ (100 mg, 0.137 mmol) and K 3 ₃PO 4 ₄ (871.3 mg, 4.11 mmol) in 1,4-dioxane / H 2 ₂O (20 mL / 2 mL) were stirred at 80 °C for 12 h under N 2 ₂ atmosphere. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (40 mL) and dried over Na 2 ₂SO 4 ₄, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1:1) to obtain RAGE 407-5 (550 mg, yield: 76.92%), which was a yellow solid. LC-MS [M+H] +: 522.2. Example 21E: Preparation of Compound RAGE 407-6

[0309] tert-Butyl 2-(4-(7-chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)phenyl)pyrrolidine-1-carboxylate (550 mg, 1.05 mmol), Zn(CN) 2 (246.9 mg, 2.11 mmol), Xphos (100 mg, 0.21 mmol) and [Pd(Allyl)Cl] 2 (40.3 mg, 0.11 mmol) in DMF (5 mL) was degassed for 10 min, then sealed and heated in a microwave at 130 °C for 1 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with H 2 O (30 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (40 mL) and dried over Na 2 SO 2 SO 4 and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1) to obtain RAGE 407-6 (510 mg, yield: 94.8%), as a yellow solid. LC-MS [M+H] + : 513.3. Example 21F: Preparation of Compound RAGE 407

[0310] HCl (0.5 mL, 4 M 1,4-dioxane solution, 2 mmol) was added to a solution of tert-butyl 2-(4-(7-cyano-4-(morpholine-4-carbonyl)quinolin-2-yl)phenyl)pyrrolidine-1-carboxylate (100 mg, 0.19 mmol) in 1,4-dioxane (4 mL). The resulting reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by Prep-HPLC to obtain RAGE 407 (20 mg, yield: 25.5%), as a white solid. LC-MS [M+H] + : 413.2, Rt = 0.988 min. Purity: 97.60 (214 nm), 97.66 (254 nm). 11H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.67 (s, 1H), 8.28 (d, J = 8 Hz, 2H), 7.93–7.92 (m, 1H), 7.78–7.73 (m, 1H), 7.58 (d, J = 8 Hz, 2H), 4.20–4.18 (m, 1H), 4.16–4.03 (m, 4H), 3.78–3.76 (m, 1H), 3.52–3.50 (m, 1H), 3.07–2.97 (m, 3H), 2.93–2.90 (m, 1H), 2.21–2.16 (m, 1H), 1.86–1.56 (m, 2H), 1.23–1.22 (m, 1H). Example 22: Synthesis of Analogue RAGE 408 According to the Invention

[0311] Compound RAGE 408 according to the present disclosure was prepared as shown in Scheme 22 and as described below. Scheme 22 Synthesis of RAGE 408 Example 22A: Preparation of Compound RAGE 408-1

[0312] (2-(4-Bromophenyl)-7-chloroquinolin-4-yl)(morpholino)methanone (2.06 g, 4.8 mmol), methyl 4-nitrobutyrate (1.41 g, 9.6 mmol), 2-di-tert-butylphosphino-2'-methylbiphenyl (299.5 mg, 0.96 mmol), Pd 2 (dba) 3 (439 mg, 0.48 mmol) and Cs 2 CO 3 (3.91 g, 12 mmol) in DME (50 mL) was stirred at 120 °C for 12 h. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (60 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM / MeOH, 15:1) to give RAGE 408-1 (800 mg, yield: 33.5%), as a yellow solid. LC-MS [M+H] + : 498.2. Example 22B: Preparation of Compound RAGE 408-2

[0313] Methyl 4-(4-(7-chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)phenyl)-4-nitrobutyrate (800 mg, 1.61 mmol), Fe (924 mg, 16.5 mmol) and NH 4 Cl (1.75 g, 33 mmol) in a mixture of EtOH / water (5 mL / 5 mL) was stirred at 100 °C for 3 h. After completion of the reaction, the reaction mixture was filtered and washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM / MeOH, 10:1) to give RAGE 408-2 (210 mg, yield: 30%), as a yellow solid. LC-MS [M+H] + : 436.2. Example 22C: Preparation of Compound RAGE 408

[0314] A mixture of 5-(4-(7-chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)phenyl)pyrrolidin-2-one (174.4 mg, 0.4 mmol), Zn(CN) 2 (93.6 mg, 0.8 mmol), Xphos (38.1 mg, 0.08 mmol) and [Pd(Allyl)Cl] 2 (14.6 mg, 0.04 mmol) in DME (5 mL) was stirred at 125 °C for 24 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with H 2 O (20 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give a crude product, which was purified by Prep-HPLC to give RAGE 408 (35 mg, yield: 20.6%), as a white solid. LC-MS [M+H] + : 427.2, Rt = 1.138 min. Purity: 99.56 (214 nm), 99.41 (254 nm). 1HNMR(400MHz, DMSO-d6) δ 8.69(s, 1H), 8.36–8.34(m, 2H), 8.19(s, 1H), 8.02–8.01(m, 1H), 7.95–7.93(m, 1H), 7.52(d, J = 8 Hz, 2H), 4.80–4.77(m, 1H), 3.89–3.76(m, 1H), 3.72–3.68(m, 3H), 3.64–3.62(m, 1H), 3.40–3.41(m, 1H), 3.27–3.24(m, 1H), 3.23–3.20(m, 1H), 3.18–3.15(m, 1H), 2.51–2.50(m, 1H), 2.31 - 2.27(m, 2H), 1.80–1.76(m, 1H). Example 23: Synthesis of analog RAGE 409 according to the present invention

[0315] Compound RAGE 409 according to the present disclosure was prepared as shown in Scheme 23 and as described below. Scheme 23 RAGE 409 Synthesis Example 23A: Preparation of compound RAGE 409-1

[0316] (2-(4-Bromophenyl)-7-chloroquinolin-4-yl)(morpholino)methanone (5 g, 11.6 mmol), Pd(dppf)Cl 2 (841 mg, 1.16 mmol) and TEA (5.86 g, 58 mmol) in a mixture of DMF / MeOH (60 mL / 60 mL) were stirred under a CO atmosphere at 75 °C for 4 h. After completion of the reaction, the reaction mixture was diluted with water (150 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (80 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3:1) to obtain RAGE 409-1 (3.2, yield: 67.28%), as a white solid. LC-MS [M+H] + : 411.2. Example 23B: Preparation of compound RAGE 409-2

[0317] Methyl 4-(7-chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)benzoate (3.2 g, 7.8 mmol) and LiOH-H 2 O (0.49 g, 11.7 mmol) in THF / H 2The mixture in O (60 mL / 15 mL) was stirred at room temperature for 2 h. After completion of the reaction, the reactants were concentrated under reduced pressure to remove THF, and the residue was diluted with water (30 mL). The pH of the aqueous layer was adjusted to 3 with HCl (1 N) to form a white solid. The mixture was filtered and washed with water (100 mL). The filter cake was dried in vacuo to give compound RAGE 409-2 (2.3 g, yield: 74.2%), as a white solid. LC-MS [M+H] + : 397.2. Example 23C: Preparation of compound RAGE 409-3

[0318] At 0 °C, isobutyl chloroformate (668.3 mg, 4.9 mmol) was slowly added to a solution of 4-(7-chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)benzoic acid (1.5 g, 3.78 mmol) and TEA (763.6 mg, 7.56 mmol) in DCM (50 mL). The resulting reactants were stirred at 0 °C for 3 h. After completion of the reaction, the reaction was quenched with water (50 mL) and extracted with DCM (60 mL × 3). The combined organic layers were washed with brine (60 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4:1) to give RAGE 409-3 (1.45 g, yield: 77.1%), as a white solid. LC-MS [M+H] + : 497.1. Example 23D: Preparation of compound RAGE 409-4

[0319] At 0 °C, NaBH 4 (152 mg, 4 mmol) was added to a solution of 4-(7-chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)benzoic acid (isobutyl carbonate) anhydride (1.5 g, 2.01 mmol) in THF (25 mL). The resulting mixture was stirred at room temperature for 10 min. After completion of the reaction, the reaction was quenched with water (30 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (40 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1:1) to give RAGE 409-4 (650 mg, yield: 84.4%), as a white solid. LC-MS [M+H] + : 383.2. Example 23E: Preparation of compound RAGE 409-5

[0320] To a solution of (7-chloro-2-(4-hydroxymethyl)phenyl)quinolin-4-yl)(morpholinyl)methanone (650 mg, 1.7 mmol) in DCM (20 mL) was added SOCl 2 (2 mL). The resulting reaction mixture was stirred at room temperature for 5 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give RAGE 409-5 (650 mg, crude), as a yellow solid. LC-MS [M+H] + : 401.2. Example 23F: Preparation of compound RAGE 409-6

[0321] (7-Chloro-2-(4-(chloromethyl)phenyl)quinolin-4-yl)(morpholinyl)methanone (650 mg, crude), DIPEA (890.1 mg, 6.9 mmol), NaI (20.7 mg, 0.14 mmol) and NaCN (135 mg, 2.76 mmol) in DMF (20 mL) were stirred at room temperature for 2 h. After completion of the reaction, the reaction was quenched with water (30 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine (40 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3:1) to give RAGE 409-6 (485 mg, overall yield for two steps: 73%), as a yellow solid. LC-MS [M+H] + : 392.2. Example 23G: Preparation of compound RAGE 409-7

[0322] At 0 °C, acetic anhydride (316.2 mg, 3.1 mmol), NiCl 2 -6H 2 O (293.9 mg, 1.24 mmol) were added to a solution of 2-(4-(7-chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)phenyl)acetonitrile (485 mg, 1.24 mmol) in MeOH (20 mL), and then NaBH 4 (70.7 mg, 1.86 mmol) was added. The resulting reaction mixture was stirred at 0 °C for 1 h. After completion of the reaction, the reaction was quenched with water (25 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (40 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3:1) to give RAGE 409-7 (472 mg, yield: 86.5%), as a white solid. LC-MS [M+H] +: 440.1. Example 23H: Preparation of Compound RAGE 409-8

[0323] To a solution of N-(4-(7-chloro-4-(morpholine-4-carboxy)-3,4-dihydroquinolin-2-yl)phenethyl)acetamide (472 mg, 1.07 mmol) in DCM (10 mL) was added 1,2-dichloro-4,5-dicyanobenzoquinone (487 mg, 2.14 mmol). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction was quenched with water (25 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (40 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2:1) to give RAGE 409-8 (245 mg, yield: 52.3%) as a yellow solid. LC-MS [M+H] + : 438.3. Example 23I: Preparation of Compound RAGE 409

[0324] A mixture of N-(4-(7-chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)phenethyl)acetamide (175.2 mg, 0.4 mmol), Zn(CN) 2 (93.6 mg, 0.8 mmol), Xphos (38.1 mg, 0.08 mmol) and [Pd(Allyl)Cl] 2 (14.6 mg, 0.04 mmol) in DME (5 mL) was stirred at 125 °C for 24 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with H 2 O (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (40 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product, which was purified by Prep-HPLC to give RAGE 409 (35 mg, yield: 20.5%) as a white solid. LC-MS [M+H] + : 429.2, Rt = 1.042 min. Purity: 96.74 (214 nm), 96.83 (254 nm). 11H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.34 (s, 1H), 8.28 (d, J = 8.9 Hz, 2H), 8.01 - 7.91 (m, 3H), 7.43 (d, J = 8.9 Hz, 2H), 3.89 - 3.77 (m, 6H), 3.33 - 3.30 (m, 2H), 3.24 - 3.14 (m, 2H), 2.82 - 2.78 (m, 2H), 1.80 (s, 3H). Example 24: Synthesis of Analog RAGE 410 According to the Invention

[0325] Compound RAGE 410 according to the present disclosure was prepared as shown in Scheme 24 and as described below. Scheme 24 Synthesis of RAGE 410 Example 24A: Preparation of Compound RAGE 410

[0326] To a solution of 2-(4-(2-aminoethyl)phenyl)-4-(morpholinomethyl)quinoline-7-carbonitrile (40 mg, 0.11 mmol) in anhydrous DCM (2 mL) was added TEA (33 mg, 0.33 mmol), and then Ac 2 O (17 mg, 0.17 mmol). The resulting mixture was stirred at room temperature for 12 h. The reaction was diluted with H 2 O (20 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (20 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product, which was purified by Prep-TLC (DCM:MeOH = 20:1) to give the desired RAGE 410 (10.3 mg, yield: 22.6%), as a white solid. LC-MS [M+H] + : 415.2, Rt = 0.982 min. Purity: 97.55 (214 nm), 97.37 (254 nm). 1 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.47 (d, J = 4 Hz, 1H), 8.34–8.21 (m, 3H), 7.87 (s, 1H), 7.75 (t, J = 4 Hz, 1H), 7.42 (d, J = 8 Hz, 2H), 4.00 (s, 2H), 3.58 (s, 4H), 3.38–3.33 (m, 2H), 2.82–2.76 (m, 2H), 2.52–2.49 (m, 4H), 1.82 (s, 3H). Example 25: Delayed-type hypersensitivity in animals treated with RAGE 229, RAGE 406R, and RAGE 406S by oral gavage

[0327] Male and female CF-1 mice were sensitized in the left inguinal lymph nodes with methylated bovine serum albumin emulsion (mBSA, NaCl, dextran, and Freund's incomplete adjuvant). On days 19 and 20 after sensitization, the mice were given the test compounds RAGE 203, RAGE 208, and RAGE 229 (dose: 5 mg / kg body weight) or an equal volume of PBS-containing vehicle by oral gavage twice a day for a total of four times, with the last dose completed 12 hours before the last reading of the immune response. After the last compound dose, mBSA was injected into the left hind paw pad. The next morning, the injected paw was scored by a researcher blinded to the experimental conditions using a semi-quantitative scoring system. The results are as Figure 1 and Figure 2 shown. Example 26: Fluorescence binding titration experiment

[0328] Native tryptophan fluorescence experiments were performed using a Horiba Jobin Yvon Fluorolog fluorescence spectrometer. The 1 mM compound was dissolved in 10 mM phosphate buffer (pH 7.0) and 50% DMSO. A 20 nM ctRAGE solution was titrated with 100 μL of the compound in 10 mM phosphate buffer [pH 7.0] and 5% DMSO from 0.1 nM - 100 μM. The excitation and emission wavelengths were 280 nm and 352 nm, respectively. The dissociation constant K was estimated using Prism 6 software (GraphPad) based on the change in fluorescence peak intensity with free compound concentration d . The data was fitted to the equation (F - F 0 ) / F max = [compound] / (K d + [compound]), where F is the fluorescence intensity at a given compound concentration, F 0 is the fluorescence intensity of the blank sample, and F max is the maximum fluorescence intensity. The results are as Figures 3 - 11 shown, and the K D values are shown in Table 1 below. Table 1 Results of fluorescence binding titration experiment Compound Number <![CDATA[K D (nM)]]> RAGE 283 1 RAGE 286 20 RAGE 289 3 RAGE 290 1 RAGE 291 12 RAGE 299 8 RAGE 402 3 RAGE 406 3 RAGE 406R 0.6 RAGE 406S 2 RAGE 407 2 Example 27: Migration of murine primary aortic smooth muscle cells (SMCs)

[0329] As described in "Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction" by M.B. Manigrasso, J. Pan, V. Rai, J. Zhang, S. Reverdatto, N. Quadri, R.J. DeVita, R. Ramasamy, A. Shekhtman, A.M. Schmidt (Scientific reports 6, 22450 (2016)), murine SMCs were isolated and cultured from the aorta of 10-week-old male mice. Wild-type murine aortic SMCs were isolated and those with passage numbers of 8 to 12 were used. Again, as described in "Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction" by M.B. Manigrasso, J. Pan, V. Rai, J. Zhang, S. Reverdatto, N. Quadri, R.J. DeVita, R. Ramasamy, A. Shekhtman, A.M. Schmidt (Scientific reports 6, 22450 (2016)), the response of migration to the RAGE ligand CML-AGE (CML, 10 μg / ml) or the general effector PDGF-BB (10 ng / ml) (R&D Systems) of non-RAGE ligands was evaluated by scratch assay. Briefly, cells were grown to confluence in 24-well plates and starved overnight. The next morning, the serum-free medium (SFM) was removed and compounds were added in a dose-response manner. After adding the compounds, a scratch was immediately made on the monolayer cells using a p10 pipette tip. The compounds were incubated for 1.5 h. After incubation, all the compounds were removed and fresh medium containing the RAGE ligand CML-AGE (10 μg / mL) or the general effector PDGF-BB (10 ng / ml) was added for 4 h. The cells were maintained at 37 °C and 5% CO 2 2. Images were taken at 4 h. Each image was measured and the inward growth area of the effectively migrating cells was calculated. The results are as shown in Figures 12 - 20 and Table 2. Table 2 Results of murine SMC migration assay *** Example 28: Wound Healing

[0330] The potential benefit of RAGE 406R on wound healing was tested in male and female obese mice (obesity and type 2 diabetes models). As described in Manigraso et al., "Small-molecule antagonism of the interaction of the RAGE cytoplasmic domain with DIAPH1 reduces diabetic complications in mice" (Sci Transl Med. 13(621):eabf7084 (2021)), full-thickness excisional wounds were created on the backs of 8-week-old obese mice. Starting from the 3rd day after surgery until the 10th day after surgery, mice were administered RAGE 406R (5 mg / kg) locally twice a day under Tegadem. Wound photographs were taken on days 0, 7, 14, and 21, and the wound closure rate (compared to baseline) was calculated for each mouse. The mean ± standard error is shown as Figure 23A -B and representative images ( Figure 23C -D). Table 3 Number of mice tested <![CDATA Vehicle > <![CDATA RAGE 406r > Male 10 8 Female 7 10

[0331] In male and female mice, on days 14 and 21 after surgery, the wound closure rate of mice in the RAGE 406r treatment group was significantly higher than that of the vehicle treatment group. Figure 23A -D shows the wound bar graphs and representative images of male / female mice on days 0 and 21 ( Figure 23C -D, the reflective parts of the open / unhealed wounds are circled).

[0332] Since various modifications can be made to the above subject matter without departing from the scope and spirit of the present invention, all subject matter included in the above description or defined in the appended claims should be construed as illustrative of the present invention. Based on the above teachings, many modifications and variations of the present invention are possible. Therefore, this specification is intended to cover all alternatives, modifications, and variations that fall within the scope of the claims.

[0333] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety into this specification as if they physically existed in this specification.

Claims

1. A compound having the structure of formula (I): Wherein: Q 1 and Q 2 are independently =CH- or =N-, provided that Q 1 and Q 2 are not both =N-; L 1 and L 2 are independently -C(=O)-, -C(=NH)-, C 1 -C 6 alkyl or a combination thereof; R 1 is hydrogen, C 1 -C 6 alkyl, -C(=O)-CH 3 , or R 1 and Q 2 are fused to form an optionally substituted bicyclic heterocycle; R 2 is hydrogen, C 1 -C 6 alkyl, or R 1 and R 2 are fused to form an optionally substituted 5- or 6-membered heterocycle. Or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein Q 1 is =CH-, and Q 2 is =N-.

3. The compound according to claim 1, wherein Q 1 is =N-, and Q 2 is =CH-.

4. The compound according to claim 1, wherein Q 1 and Q 2 are both =CH-.

5. The compound according to any one of claims 1-4, wherein L 1 is -C(=O)-.

6. The compound according to any one of claims 1-4, wherein L 1 is -C(=NH)-.

7. The compound according to any one of claims 1-4, wherein L 1 is C 1 -C 6 alkyl.

8. The compound according to any one of claims 1-4 and 7, wherein L 1 is C 1 -C 3 alkyl.

9. A compound according to any one of claims 1-4, 7 and 8, wherein L 1 is -CH 2 -.

10. A compound according to any one of claims 1-4, 7, and 8, wherein L 1 is -(CH 2 ) 2 -.

11. A compound according to any one of claims 1-4, 7 and 8, wherein L 1 is -(C(H)CH 3 )-.

12. The compound according to any one of claims 1-4, 7 and 8, wherein L 1 is -(CH 2 )–(C(H)CH 3 )-.

13. The compound according to any one of claims 1-4, wherein L 1 is a combination of -C(=O)- and C 1 -C 6 alkyl.

14. A compound according to any one of claims 1-4 and 13, wherein L 1 is a combination of -C(=O)- and C 1 -C 3 alkyl.

15. The compound according to any one of claims 1-4, wherein L 1 is -(CH 2 )-C(=O)-.

16. The compound according to any one of claims 1-15, wherein L 2 is -C(=O)-.

17. The compound according to any one of claims 1-15, wherein L 2 is C 1 -C 6 alkyl.

18. A compound according to any one of claims 1-15 and 17, wherein L 2 is -CH 2 -.

19. The compound according to any one of claims 1-18, wherein R 1 is hydrogen.

20. The compound according to any one of claims 1-18, wherein R 1 is C 1 -C 6 alkyl.

21. The compound according to any one of claims 1-18, wherein R 1 is C 1 -C 3 alkyl.

22. The compound according to any one of claims 1-18, wherein R 1 is -CH 3 .

23. The compound according to any one of claims 1-18, wherein R 1 is -C(=O)-CH 3 .

24. The compound according to any one of claims 1-23, wherein R 2 is hydrogen.

25. The compound according to any one of claims 1-23, wherein R 2 is C 1 -C 6 alkyl.

26. The compound according to any one of claims 1-23, wherein R 2 is C 1 -C 3 alkyl.

27. A compound according to any one of claims 1-23, wherein R 2 is -CH 3 .

28. The compound according to any one of claims 1-23, Wherein, R 1 and R 2 are fused to form an optionally substituted 5- or 6-membered heterocycle.

29. The compound according to any one of claims 1-23, Wherein, R 1 and L 1 are fused to form an optionally substituted 5- or 6-membered heterocycle.

30. The compound according to claim 29, wherein R 1 and L 1 are 31. The compound according to any one of claims 1-30, Wherein, R 1 and Q 2 are fused to form an optionally substituted bicyclic heterocycle.

32. The compound according to claim 31 having the structure of formula (II):

33. The compound according to claim 1 selected from: Or a pharmaceutically acceptable salt thereof.

34. The compound according to claim 1 having the following structure: or a pharmaceutically acceptable salt thereof.

35. The compound according to claim 34, wherein the compound is a racemic mixture of RAGE 406R and RAGE 406S:

36. The compound according to claim 34, wherein the compound is RAGE 406R.

37. A pharmaceutical composition comprising the compound according to any one of claims 1-36 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

38. A pharmaceutical dosage form comprising the compound according to any one of claims 1-36 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 37.

39. A method of modulating the activity of the receptor for advanced glycation end products (RAGE) in a cell, comprising contacting the cell with an effective amount of the compound according to any one of claims 1-36 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 37.

40. The method according to claim 39, wherein modulating the activity of RAGE comprises inhibiting the activity of RAGE.

41. A method of treating or ameliorating a disease or disorder associated with RAGE activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1-36 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 37.

42. The method according to claim 41, wherein the disease or disorder is selected from diabetes and its complications, insulin resistance, atherosclerosis, peripheral vascular disease and its related complications, cardiovascular disease, kidney disease, retinopathy, cardiac and cerebrovascular ischemia / reperfusion injury, heart attack, myocardial infarction, ischemic cardiomyopathy, cancer, tumor invasion and metastasis, acute and chronic inflammation, autoimmune diseases, neurodegeneration, arthritis, allergic asthma, obesity, tissue or organ damage associated with pollution, infection and its complications, sepsis, pneumonia, liver injury / damage, amyloidosis, skin diseases, colitis, lupus, and wound healing disorders.

43. The method according to claim 41 or 42, wherein the disease or disorder is diabetes and its complications.

44. The method according to claim 41 or 42, wherein the disease or disorder is coronavirus (COVID-19) infection and its complications.

45. A method for treating or improving diabetes and its complications in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described in any one of claims 1-36 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 37.

46. The method according to any one of claims 41-45, wherein the subject is a mammal.

47. The method according to any one of claims 39-45, wherein the compound as described in any one of claims 1-36 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in claim 37 is administered orally, rectally, intravitreally, transdermally, subcutaneously, intravenously, intramuscularly, intraperitoneally, intradermally, directly into the cerebrospinal fluid, intratracheally or intranasally.

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