WO2019106434A1

WO2019106434A1 - Heterobicyclic aromatic derivatives for the treatment of ferroptosis-related disorders

Info

Publication number: WO2019106434A1
Application number: PCT/IB2018/001518
Authority: WO
Inventors: John C. Warner; Carmen Baldino; Lauren MUOLLO; Craig ROSENFELD
Original assignee: Collaborative Medicinal Development Pty. Ltd.
Priority date: 2017-12-01
Filing date: 2018-11-30
Publication date: 2019-06-06

Abstract

The present application discloses heterobicyclic and non-heterobicyclic aromatic derivative compounds and compositions, and methods for treating ferroptosis-related disorders and diseases in patients using the compounds and compositions as disclosed herein.

Description

HETEROBICYCLIC AROMATIC DERIVATIVES FOR THE TREATMENT OF

FERROPTOSIS-RELATED DISORDERS

TECHNICAL FIELD

[001] Described herein are heterobicyclic and non-heterobicyclic aromatic compounds, compositions and methods of using them for treatment of ferroptosis- related disorders including lipid peroxidation-related degenerative diseases, excitotoxic diseases, neurodegenerative diseases, non-apoptotic regulated cell-death diseases, wasting- or necrosis-related diseases, intoxication-related diseases, and infectious diseases.

BACKGROUND

[002] Presently, there are no known prevention or cure for neurodegenerative diseases or disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The present application discloses compounds, compositions and methods for the treatment of such diseases or disorders.

SUMMARY

[003] Described herein are compounds, compositions and methods for treatment of lipid peroxidation-related degenerative diseases, excitotoxic diseases,

neurodegenerative diseases, non-apoptotic regulated cell-death diseases, wasting- or necrosis-related diseases, intoxication-related diseases, and infectious diseases.

[004] Accordingly, described herein is a compound of formula l-V:

wherein

n = 1 , 2 or 3;

R is H, F or CH₃;

R¹ is selected from the group consisting of H, substituted or unsubstituted C₁-C₁₀ linear or branched alkyl, C₁-C₁₀ linear or branched perfluoroalkyl, substituted or unsubstituted C₂-C₁₀ linear or branched alkenyl, substituted or unsubstituted C₂-C₁₀ linear or branched alkynyl, substituted or unsubstituted C₆-Ci₀ aryl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, C₃-C₁₀ perfluorocycloalkyl, substituted or unsubstituted C₃-C₁₀

heterocyloalklyl, substituted or unsubstituted C₅-C₁₀ heteroaryl, substituted or unsubstituted C₆-Ci₀ arylalkyl, substituted or unsubstituted C₁-C₁₀ linear or branched alkylamino and substituted or unsubstituted C₁-C₁₀ linear or branched dialkyla ino;

R² and R³ are independently selected from the group consisting of H, substituted or unsubstituted C₁-C₁₀ linear or branched alkyl, C₁-C₁₀ linear or branched perfluoroalkyl, substituted or unsubstituted C₂-C₁₀ linear or branched alkenyl, substituted or

unsubstituted C₂-C₁₀ linear or branched alkynyl, substituted or unsubstituted C₆-Ci₀ aryl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, C₃-C₁₀ perfluorocycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₅-C₁₀ heteroaryl, substituted or unsubstituted C₆-Ci₀ arylalkyl, substituted or unsubstituted C₁-C₁₀ linear or branched alkylamino, and substituted or unsubstituted C₁-C₁₀ linear or branched dialkylamino, or R² and R³ together with their mutually-attached N form a substituted or unsubstituted C₄-C₆ heterocycloalkyl group;

A is selected from the group consisting of substituted or unsubstituted C₆-C₁₀ aryl, substituted or unsubstituted C₃-C₁₀ heteroaryl, substituted or unsubstituted C₂-Ci₀ linear or branched alkenyl, substituted or unsubstituted C₂-Ci₀ linear or branched alkynyl, C=0, C=S, -CH₂-, -NH-, and S0₂;

R⁴ is selected from the group consisting of C₁-C₁₀ linear or branched alkyl, C₁-C₁₀ linear or branched alkoxy, C₁-C₁₀ linear or branched alkylamino, and C₁-C₁₀ linear or branched dialkylamino; and

R⁵, R⁶, R⁷, and R⁸ each are independently selected from the group consisting of H, methyl or halo,

provided that if A is aryl or heteroaryl, then R4 is H, alkyl or halo.

[005] Also described herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula l-V as described above, and a pharmaceutically acceptable excipient.

[006] Further described herein is a method of treating a ferroptosis-related disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the compound of formula l-V:

wherein

n = 1 , 2 or 3;

R is H, F or CH₃;

R¹ is selected from the group consisting of H, substituted or unsubstituted C1 -C10 linear or branched alkyl, C1 -C10 linear or branched perfluoroalkyl, substituted or unsubstituted C2-C10 linear or branched alkenyl, substituted or unsubstituted C2-C10 linear or branched alkynyl, substituted or unsubstituted C₆-Ci₀ aryl, substituted or unsubstituted C3-C10 cycloalkyl, C3-C10 perfluorocycloalkyl, substituted or unsubstituted C3-C10

heterocyloalklyl, substituted or unsubstituted C5-C10 heteroaryl, substituted or unsubstituted C₆-Ci₀ arylalkyl, substituted or unsubstituted C1 -C10 linear or branched alkylamino and substituted or unsubstituted C1 -C10 linear or branched dialkyla ino; R² and R³ are independently selected from the group consisting of H, substituted or unsubstituted C₁-C₁₀ linear or branched alkyl, C₁-C₁₀ linear or branched perfluoroalkyl, substituted or unsubstituted C₂-C₁₀ linear or branched alkenyl, substituted or

unsubstituted C₂-C₁₀ linear or branched alkynyl, substituted or unsubstituted C₆-Ci₀ aryl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, C₃-C₁₀ perfluorocycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₅-C₁₀ heteroaryl, substituted or unsubstituted C₆-Ci₀ arylalkyl, substituted or unsubstituted C₁-C₁₀ linear or branched alkyla ino, and substituted or unsubstituted C₁-C₁₀ linear or branched dialkyla ino, or R² and R³ together with their mutually-attached N form a substituted or unsubstituted C₄-C₆ heterocycloalkyl group;

A is selected from the group consisting of substituted or unsubstituted C₆-Ci₀ aryl, substituted or unsubstituted C₃-C₁₀ heteroaryl, substituted or unsubstituted C₂-C₁₀ linear or branched alkenyl, substituted or unsubstituted C₂-C₁₀ linear or branched alkynyl, C=0, C=S, -CH₂-, -NH-, and S0₂;

provided that if A is aryl or heteroaryl, then R4 is H, alkyl or halo.

[007] The ferroptosis-related disease may be selected from the group consisting of lipid peroxidation-related degenerative diseases, excitotoxic diseases,

[008] The ferroptosis-related disease may also be selected from the group consisting of atherosclerosis, ischemia-reperfusion, heart failure, Alzheimer’s disease, rheumatic arthritis, thalassemia, chronic obstructive pulmonary disease (COPD), age- related macular degeneration, senescence, cancer, and immunological disorders (including but not limited to autoimmune diseases (for example, diabetes mellitus, arthritis (including rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis and psoriatic arthritis), multiple sclerosis, encephalomyelitis, myasthenia gravis, systemic lupus erythematosus, autoimmune thyroiditis, dermatitis (including atopic dermatitis and eczematous dermatitis), psoriasis, Sjogren's Syndrome, Crohn's disease, aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, sepsis and septic shock, inflammatory bowel disorder, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, drug eruptions, leprosy reversal reactions, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral progressive sensorineural hearing loss, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, polychondritis, Wegener's granulomatosis, chronic active hepatitis, Stevens- Johnson syndrome, glomerulonephritis, idiopathic sprue, lichen planus, Graves' disease, sarcoidosis, primary biliary cirrhosis, uveitis posterior, interstitial lung fibrosis, graft-versus-host disease, transplantation rejection, allergies such as atopic allergy, epilepsy, kidney disease, stroke, myocardial infarction, congestive heart failure, type I diabetes, traumatic brain injury (TBI), periventricular leukomalacia (PVL), Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, Friedreich’s ataxia, ataxia-telangiectasia, Rett syndrome, X-linked adrenoleukodystrophy, Multiple sclerosis, Huntington’s Disease, transmissible spongiform encephalopathy, Charcot-Marie-Tooth disease, Lewy body dementia, Menke's disease, Wilson's disease, Creutzfeldt-Jakob disease, Fahr disease, frontotemporal dementia, amyloidosis, Tay-Sachs disease periventricular leukomalacia, corticobasal degeneration, progressive supranuclear palsy, hereditary spastic paraparesis, a reduction in cell-proliferation, an alteration in cell-differentiation or intracellular signaling, undesirable inflammation, cell death of retinal neuronal cells, cardiac muscle cells, or cells of the immune system or cell death associated with renal failure, neonatal respiratory distress, asphyxia, incarcerated hernia, placental infarct, iron-load complications, endometriosis, congenital disease, head trauma/traumatic brain injury, liver injury, injuries from environmental radiation, burns, cold injuries, mechanical injuries, decompression sickness, priapism, snake, scorpion or spider bites, UV-damage in skin, aging in skin, hair loss, muscle wasting diseases, muscular dystrophies or related diseases (e.g., Becker's muscular dystrophy, Duchenne muscular dystrophy, myotonic dystrophy, limb-girdle muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy (Steinert's disease), myotonia congenita, Thomsen's disease, and Pompe's disease, ischemia, compartment syndrome, gangrene, pressure sores, sepsis, degenerative arthritis, retinal necrosis, heart disease, liver, gastrointestinal or pancreatic necrotic diseases (such as acute necrotizing pancreatitis), avascular necrosis, diabetes, sickle cell disease, alteration of blood vessels, cancer-chemo/radiation therapy-induced cell-death, and infectious diseases caused by infection by viruses, bacteria, fungi, or other microorganisms.

DETAILED DESCRIPTION DEFINITIONS

[009] Unless specifically noted otherwise herein, the definitions of the terms used are standard definitions used in the art of organic chemistry and pharmaceutical sciences. Exemplary embodiments, aspects and variations are illustrated in the figures and drawings, and it is intended that the embodiments, aspects and variations, and the figures and drawings disclosed herein are to be considered illustrative and not limiting.

[010] While particular embodiments are shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art. It should be understood that various alternatives to the embodiments described herein may be employed in practicing the methods described herein. It is intended that the appended claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[011] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art. All patents and publications referred to herein are incorporated by reference.

[012] As used in the specification and claims, the singular form "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[013] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g. , the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g. reduction of platelet adhesion and/or cell migration. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[014] The terms "treatment," "treating," "palliating," and "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[015] A "therapeutic effect," as used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[016] The term "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[017] A "pharmaceutically acceptable salt" means a salt composition that is generally considered to have the desired pharmacological activity, is considered to be safe, non-toxic and is acceptable for veterinary and human pharmaceutical applications. Pharmaceutically acceptable salts may be derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[018] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions described herein is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[019] The terms "antagonist" and "inhibitor" are used interchangeably, and they refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the terms "antagonist" and "inhibitors" are defined in the context of the biological role of the target protein. Although antagonists herein generally interact specifically with (e.g. specifically bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within the definition of “antagonist.” An exemplary biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor, or an undesired immune response as manifested in autoimmune disease.

[020] The term "agonist" as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the term "agonist" is defined in the context of the biological role of the target polypeptide. Agonists herein generally interact specifically with (e.g. specifically bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within the definition of“agonist.”

[021] As used herein, "agent" or "biologically active agent" refers to a biological, pharmaceutical, or chemical compound or other moiety. Non-limiting examples include simple or complex organic or inorganic molecule, a peptide, a protein, an

oligonucleotide, an antibody, an antibody derivative, antibody fragment, a vitamin derivative, a carbohydrate, a toxin, or a chemotherapeutic compound. Various compounds can be synthesized, for example, small molecules and oligomers (e.g. , oligopeptides and oligonucleotides), and synthetic organic compounds based on various core structures. In addition, various natural sources can provide compounds for screening, such as plant or animal extracts, and the like. A skilled artisan can readily recognize the limits to the structural nature of the agents described herein.

[022] "Signal transduction" is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response. A modulator of a signal transduction pathway refers to a compound which modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway. A modulator may augment (agonist) or suppress (antagonist) the activity of a signaling molecule.

[023] The term "cell proliferation" refers to a phenomenon by which the cell number has changed as a result of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal.

[024] The term "selective inhibition" or "selectively inhibit" as applied to a biologically active agent refers to the agent's ability to selectively reduce the target signaling activity as compared to off-target signaling activity, via direct or interact interaction with the target.

[025] "Subject" refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the patient is a mammal, and in some

embodiments, the patient is human.

[026] "Prodrug" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi,

T., et al., "Pro-drugs as Novel Delivery Systems," A. C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American

Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.

[027] The term "in vivo" refers to an event that takes place in a subject's body.

[028] The term "in vitro" refers to an event that takes places outside of a subject's body. For example, an in vitro assay encompasses any assay run outside of a subject assay. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.

[029] As used herein, the term“lipid peroxidation-related degenerative disease” refers to a degenerative disease, disorder or condition associated with the oxidative degradation of fats, oils, waxes, sterols, triglycerides, and the like.

[030] As used herein, the term“excitotoxic disease” refers to a disease, disorder or condition associated with oxidative cell death and/or increased levels of intracellular reactive oxygen species (ROS), or diseases characterized by oxidative stress or where oxidative stress is likely to play or plays a substantial role.

[031] As used herein, the term“neurodegenerative disease” refers to a disease, disorder or condition associated with degeneration of the central or peripheral nervous system.

[032] As used herein, the term“non-apoptotic regulated cell-death disease” refers to a disease, disorder or condition associated with non-apoptotic regulated cell-death or where non-apoptotic regulated cell-death is likely to play or plays a substantial role.

[033] As used herein, the term“wasting- or necrosis-related disease” refers to a disease, disorder or condition associated with wasting or cell necrosis.

[034] As used herein, the term“intoxication-related disease” refers to a disease, disorder or condition associated with or characterized by cell, tissue, organ or organism intoxication (e.g., nephrotoxicity), including those arising from or associated with drug treatment, drug overdose, acute poisoning, or contrast-agent-induced toxicity.

[035] As used herein, the term“infectious disease” refers to a disease, disorder or condition which are the result of, arise from or are associated with forms of infection of viruses, bacteria, fungi, or other microorganisms.

[036] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds as described herein wherein one or more hydrogens are replaced by deuterium or tritium, or the replacement of one or more carbon atoms by the ¹³C- or ¹⁴C-enriched carbon isotope. Further, substitution with heavier isotopes, particularly deuterium (²H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, increased in vivo half-life, reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I). [037] The compounds described herein may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵l) or carbon-14 (¹⁴C). All isotopic variations of the compounds described herein, whether radioactive or not, are encompassed.

[038] "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a "racemic" mixture. The term

..)" is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-lngold- Prelog R--S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute

stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[039] When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[040] A "substituted" or“optionally substituted” group, means that a group (such as alkyl, aryl, heterocyclyl, cycloalkyl, hetrocyclylalkyl, arylalkyl, heteroaryl, or

heteroarylalkyl) unless specifically noted otherwise, may have 1 , 2 or 3 -H groups substituted by 1 , 2 or 3 substituents selected from halo, trifluoromethyl, trifluoromethoxy, methoxy, -COOH, -CHO, -NH₂, -N0₂, -OH, -SH, -SMe, -NHCH₃, -N(CH₃)₂, -CN and the like.

[041] "Tautomers" are structurally distinct isomers that interconvert by

tautomerization. "Tautomerization" is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry.

"Prototropic tautomerization" or "proton-shift tautomerization" involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g. in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2 ,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol- keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1 H)-one tautomers.

[042] Compounds described herein also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. "Crystalline form," "polymorph," and "novel form" may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound listed above, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.

[043] "Solvent," "organic solvent," and "inert solvent" each means a solvent inert under the conditions of the reaction being described in conjunction therewith including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone ("NMP"), pyridine and the like. Unless specified to the contrary, the solvents used in the reactions described herein are inert organic solvents. Unless specified to the contrary, for each gram of the limiting reagent, one cc (or ml.) of solvent constitutes a volume equivalent.

COMPOSITIONS

Described herein is a compound of formula l-V:

wherein n = 1, 2 or 3;

Ris H, F or CH₃; R¹ is selected from the group consisting of H, substituted or unsubstituted C₁-C₁₀ linear or branched alkyl, C₁-C₁₀ linear or branched perfluoroalkyl, substituted or unsubstituted C₂-C₁₀ linear or branched alkenyl, substituted or unsubstituted C₂-C₁₀ linear or branched alkynyl, substituted or unsubstituted C₆-Ci₀ aryl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, C₃-C₁₀ perfluorocycloalkyl, substituted or unsubstituted C₃-C₁₀

provided that if A is aryl or heteroaryl, then R4 is H, alkyl or halo.

[044] In some embodiments, the compound is of formula (I) above. In some of these embodiments, n=2.

[045] The structures of the compounds described herein, as shown in formulae I- IV, have a bicyclic structure wherein a benzene ring is fused to a five-, six- or seven- membered heterocycloalkyl ring. The benzene ring additionally has at least two substituent moieties on the non-fused positions, at least one of which is an amino or imino substitution. The various fused rings and substituent positions are shown in formulae l-V.

[046] The compounds in Table 1 below have been synthesized:

Table 1. Synthesized Compounds.

[047] Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin- layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein. However, other equivalent separation or isolation procedures can also be used. [048] When desired, the (R)- and (S)-isomers of the compounds described herein, if present, may be resolved by methods known to those skilled in the art, for example by formation of diastereomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas- liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.

Alternatively, a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

[049] The compounds described herein can be optionally contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salts.

Pharmaceutically acceptable forms of the compounds recited herein include

pharmaceutically acceptable salts, chelates, non-covalent complexes or derivatives, prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. In addition, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.

[050] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1 % and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") include those embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, that "consist of" or "consist essentially of' the described features.

[051] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of Formula l-V as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Where desired, the pharmaceutical compositions contain pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[052] The subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, a compound of Formula l-V and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time. A compound as described herein may also be used in combination with other agents, e.g. , an additional compound that is or is not of Formula l-V, for treatment of the diseases listed herein in a subject.

[053] In some embodiments, the concentration of one or more of the compounds of Formula l-V in the pharmaceutical compositions described herein is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11 %, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, 0.5%, 0.4%, 0.3%, 0.2%,

0.1 %, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01 %, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001 %, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001 % w/w, w/v or v/v.

[054] In some embodiments, the concentration of one or more of the compounds of Formula l-V is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%,

14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 1 1.75%, 1 1 .50%, 1 1.25% 11 %, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%,

2.50%, 2.25%, 2%, 1 .75%, 1.50%, 125%, 1 %, 0.5%, 0.4%, 0.3%, 0.2%, 0.1 %, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01 %, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001 %, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001 % w/w, w/v, or v/v.

[055] In some embodiments, the concentration of one or more of the compounds of Formula l-V is in the range from approximately 0.0001 % to approximately 50%, approximately 0.001 % to approximately 40%, approximately 0.01 % to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to

approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%,

approximately 0.09% to approximately 22%, approximately 0.1 % to approximately 21 %, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1 % to approximately 10% w/w, w/v or v/v.

[056] In some embodiments, the concentration of one or more of the compounds of Formula l-V is in the range from approximately 0.001 % to approximately 10%, approximately 0.01 % to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1 .5%, approximately 0.09% to approximately 1 %, approximately 0.1 % to approximately 0.9% w/w, w/v or v/v.

[057] In some embodiments, the amount of one or more of the compounds of Formula l-V is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1 .5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

[058] In some embodiments, the amount of one or more of the compounds of Formula l-V is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1 .5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

[059] In some embodiments, the amount of one or more of the compounds of Formula l-V is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1 -3 g.

[060] The compounds of Formula l-V described herein are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound of Formula l-V is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[061] A pharmaceutical composition described herein typically contains an active ingredient (e.g., a compound of Formula l-V or a pharmaceutically acceptable salt and/or coordination complex thereof), and one or more pharmaceutically acceptable excipients, carriers, including but not limited to inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[062] Described below are non-limiting exemplary pharmaceutical compositions and methods for preparing the same.

Pharmaceutical Compositions for Oral Administration

[063] Described herein is a pharmaceutical composition for oral administration containing a compound of formula l-V:

wherein n = 1, 2 or 3;

provided that if A is aryl or heteroaryl, then R4 is H, alkyl or halo,

and a pharmaceutical excipient suitable for oral administration.

[060] Also described herein is a solid pharmaceutical composition fororal administration containing: (i) an effective amount of a compound of Formula l-V; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) an effective amount of a third agent.

[061] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a

predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water- in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[062] Also described herein are anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water may be added (e.g. , 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

[063] An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

[064] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g. , ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

[065] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

[066] Disintegrants may be used in the compositions described herein to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

[067] Lubricants which can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g. , peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.

[068] When aqueous suspensions and/or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[069] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. [070] Surfactants which can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, hydrophilic surfactants, lipophilic

surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[071] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (/.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial,

pharmaceutical and cosmetic emulsions.

[072] Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[073] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof. [074] Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine,

lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.

[075] Hydrophilic non-ionic surfactants may include, but not limited to,

alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides;

polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene- polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[076] Other hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG- 40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG- 24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.

[077] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, suitable lipophilic surfactants include, but are not limited to, glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[078] In one embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound described herein and to minimize precipitation of the compound described herein. This can be especially important for compositions for non-oral use, e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[079] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, e-capro lactam, N-alkylpyrrolidone, N- hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, e-caprolactone and isomers thereof, d-va I ero lactone and isomers thereof, b-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N- methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

[080] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N- methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Suitable solubilizers include, but are not limited to, sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.

[081] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be

advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%, 2%, 1 % or even less. Typically, the solubilizer may be present in an amount of about 1 % to about 100%, more typically about 5% to about 25% by weight. [082] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[083] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of

pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

[084] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.

Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like.

Pharmaceutical Compositions for Injection.

[085] Described herein are pharmaceutical compositions for injection containing a compound of formula l-V:

wherein

n = 1 , 2 or 3;

R is H, F or CH₃;

heterocyloalklyl, substituted or unsubstituted C5-C10 heteroaryl, substituted or unsubstituted C₆-Ci₀ arylalkyl, substituted or unsubstituted C1 -C10 linear or branched alkyla ino and substituted or unsubstituted C1 -C10 linear or branched dialkylamino;

R² and R³ are independently selected from the group consisting of H, substituted or unsubstituted C1-C10 linear or branched alkyl, C1 -C10 linear or branched perfluoroalkyl, substituted or unsubstituted C2-C10 linear or branched alkenyl, substituted or

unsubstituted C2-C10 linear or branched alkynyl, substituted or unsubstituted C₆-Ci₀ aryl, substituted or unsubstituted C3-C10 cycloalkyl, C3-C10 perfluorocycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C5-C10 heteroaryl, substituted or unsubstituted C₆-Ci₀ arylalkyl, substituted or unsubstituted C1-C10 linear or branched alkylamino, and substituted or unsubstituted C1-C10 linear or branched dialkylamino, or R² and R³ together with their mutually-attached N form a substituted or unsubstituted C₄-C₆ heterocycloalkyl group;

A is selected from the group consisting of substituted or unsubstituted C₆-Ci₀ aryl, substituted or unsubstituted C3-C10 heteroaryl, substituted or unsubstituted C2-C10 linear or branched alkenyl, substituted or unsubstituted C₂-C₁₀ linear or branched alkynyl, C=0, C=S, -CH₂-, -NH-, and S0₂;

R⁴ is selected from the group consisting of C₁-C₁₀ linear or branched alkyl, C₁-C₁₀ linear or branched alkoxy, C₁-C₁₀ linear or branched alkylamino, and C₁-C₁₀ linear or branched dialkyla ino; and

provided that if A is aryl or heteroaryl, then R4 is H, alkyl or halo,

and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein.

[086] The forms in which the novel compositions described herein may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[087] Aqueous solutions in saline are also conventionally used for injection.

Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens,

chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[088] Sterile injectable solutions are prepared by incorporating a compound of Formula l-V in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.

Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Pharmaceutical Compositions for Topical ( e. Transdermal) Delivery.

[089] Also described herein is a pharmaceutical composition for transdermal delivery containing a compound of formula l-V:

wherein

n = 1 , 2 or 3;

R is H, F or CH₃;

heterocyloalklyl, substituted or unsubstituted C₅-C₁₀ heteroaryl, substituted or unsubstituted C₆-Ci₀ arylalkyl, substituted or unsubstituted C₁-C₁₀ linear or branched alkylamino and substituted or unsubstituted C₁-C₁₀ linear or branched dialkylamino;

unsubstituted C₂-C₁₀ linear or branched alkynyl, substituted or unsubstituted C₆-Ci₀ aryl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, C₃-C₁₀ perfluorocycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₅-C₁₀ heteroaryl, substituted or unsubstituted C₆-C₁₀ arylalkyl, substituted or unsubstituted C₁-C₁₀ linear or branched alkylamino, and substituted or unsubstituted C₁-C₁₀ linear or branched dialkylamino, or R² and R³ together with their mutually-attached N form a substituted or unsubstituted C₄-C₆ heterocycloalkyl group;

provided that if A is aryl or heteroaryl, then R4 is H, alkyl or halo,

and a pharmaceutical excipient suitable for transdermal delivery. [090] Compositions described herein can be formulated into preparations in solid, semi-solid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, or

dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.

[091] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those trained in the art of topical formulation. Examples of such carriers and excipients include, but are not limited to, humectants (e.g. , urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[092] Another exemplary formulation for use in the methods described herein employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of Formula l-V in controlled amounts, either with or without another agent.

[093] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g. , U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001 ,139. Such patches may be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

Pharmaceutical Compositions for Inhalation.

[094] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. The compositions may be administered by the oral or nasal respiratory route, for example, for local or systemic effect. Compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered in any manner, such as orally or nasally, from devices that deliver the formulation in an appropriate manner.

Other Pharmaceutical Compositions.

[095] Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g. , See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, N.Y., 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2004;

Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001 ; Remington’s Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.

[096] Administration of the compounds of Formula l-V or pharmaceutical compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally.

[097] The amount of a compound of Formula l-V administered will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, such as from about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, such as about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. by dividing such larger doses into several small doses for administration throughout the day.

[098] In some embodiments, a compound of Formula l-V is administered in a single dose. Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes may be used as appropriate.

[099] In some embodiments, a compound of Formula l-V is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of Formula l-V and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year.

In some cases, continuous dosing is achieved and maintained as long as necessary.

[100] Administration of the compound(s) of Formula l-V may continue as long as necessary. In some embodiments, a compound of Formula l-V is administered for more than 1 , 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of Formula I- V is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of Formula l-V is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

[101] An effective amount of a compound of Formula l-V may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[102] The compositions described herein may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.

A compound of Formula l-V may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent. In some embodiments, a compound of Formula l-V is admixed with a matrix. Such a matrix may be a polymeric matrix, and may serve to bond the compound to the stent. Polymeric matrices suitable for such use, include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters,

polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g. polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be non-degrading or may degrade with time, releasing the compound or compounds. A compound of Formula l-V may be applied to the surface of the stent by various methods such as dip/spin coating, spray coating, dip coating, and/or brush-coating. The compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent. Alternatively, a compound of Formula l-V may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall. Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of a compound of Formula l-V in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash. In yet other embodiments, a compound of Formula l-V may be covalently linked to a stent or graft. A covalent linker may be used which degrades in vivo, leading to the release of a compound of Formula I. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages. A compound of Formula l-V may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of a compound of Formula l-V via the pericardium or via adventitial application of formulations described herein may also be performed to decrease restenosis.

[103] A variety of stent devices which may be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U.S. Pat. No. 5,451 ,233; U.S. Pat. No. 5,040,548; U.S. Pat. No. 5,061 ,273; U.S. Pat. No. 5,496,346; U.S. Pat. No. 5,292,331 ; U.S. Pat. No. 5,674,278; U.S. Pat. No. 3,657,744; U.S. Pat. No. 4,739,762; U.S. Pat. No. 5,195,984; U.S. Pat. No. 5,292,331 ; U.S. Pat. No. 5,674,278; U.S. Pat. No. 5,879,382; U.S. Pat. No. 6,344,053. [104] The compounds of Formula l-V may be administered in dosages. It is known in the art that due to inter-subject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of Formula l-V may be found by routine experimentation in light of the instant disclosure.

[105] When a compound of Formula l-V is administered in a composition that comprises one or more agents, and the agent has a shorter half-life than the compound of Formula l-V unit dose forms of the agent and the compound of Formula l-V may be adjusted accordingly.

[106] The subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, or suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound of Formula l-V as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[107] Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[108] Kits are also described herein. The kits include one or more compounds of Formula l-V as described herein, in suitable packaging, and written material that can include instructions for use, discussion of clinical studies, listing of side effects, and the like. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kit may further contain another agent. In some embodiments, a compound of Formula l-V and the agent are provided as separate compositions in separate containers within the kit. In some embodiments, the compound described herein and the agent are provided as a single composition within a container in the kit. Suitable packaging and additional articles for use ( e.g ., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like) are known in the art and may be included in the kit. Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer.

Therapeutic Methods

[109] The compounds and pharmaceutical compositions described herein, in therapeutically effective amounts and as described above, are useful in methods to treat ferroptosis-related diseases such as lipid peroxidation-related degenerative diseases, excitotoxic diseases, neurodegenerative diseases, non-apoptotic regulated cell-death diseases, wasting- or necrosis-related diseases, intoxication-related diseases, and infectious diseases. The therapeutic methods described herein comprise the step of administering a therapeutically effective amount of the compound of formula l-V:

wherein

n = 1 , 2 or 3;

R is H, F or CH₃;

provided that if A is aryl or heteroaryl, then R4 is H, alkyl or halo.

[110] In one embodiment, the therapeutically effective amount of a compound described above is used in methods to treat diseases selected from the group consisting of atherosclerosis, ischemia-reperfusion, heart failure, Alzheimer’s disease, rheumatic arthritis, thalassemia, chronic obstructive pulmonary disease (COPD), age- related macular degeneration, senescence, cancer, and immunological disorders.

[111] In one aspect of the above, the disease is an immunological disorder.

Exemplary immunological disorders include autoimmune diseases (for example, diabetes mellitus, arthritis (including rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis and psoriatic arthritis), multiple sclerosis, encephalomyelitis, myasthenia gravis, systemic lupus erythematosus, autoimmune thyroiditis, dermatitis (including atopic dermatitis and eczematous dermatitis), psoriasis, Sjogren's Syndrome, Crohn's disease, aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, sepsis and septic shock, inflammatory bowel disorder, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, drug eruptions, leprosy reversal reactions, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral progressive sensorineural hearing loss, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, polychondritis, Wegener's granulomatosis, chronic active hepatitis, Stevens- Johnson syndrome, glomerulonephritis, idiopathic sprue, lichen planus,

Graves' disease, sarcoidosis, primary biliary cirrhosis, uveitis posterior, interstitial lung fibrosis, graft-versus-host disease, transplantation rejection, and allergies such as atopic allergy.

[112] In another embodiment, the therapeutically effective amount of a compound described above is used in methods to treat diseases selected from the group consisting of epilepsy, kidney disease, stroke, myocardial infarction, congestive heart failure, type I diabetes, traumatic brain injury (TBI), and periventricular leukomalacia (PVL).

[113] In still another embodiment, the therapeutically effective amount of a compound described above is used in methods to treat diseases selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, Friedreich’s ataxia, ataxia-telangiectasia, Rett syndrome, X-linked

ad renoleukodystrophy, Multiple sclerosis, Huntington’s Disease, transmissible spongiform encephalopathy, Charcot-Marie-Tooth disease, Lewy body dementia, Menke's disease, Wilson's disease, Creutzfeldt-Jakob disease, Fahr disease, frontotemporal dementia, amyloidosis, Tay-Sachs disease periventricular leukomalacia, corticobasal degeneration, progressive supranuclear palsy, and hereditary spastic paraparesis.

[114] In yet another embodiment, the therapeutically effective amount of a compound described above is used in methods to treat diseases selected from the group consisting of a reduction in cell-proliferation, an alteration in cell-differentiation or intracellular signaling, undesirable inflammation, cell death of retinal neuronal cells, cardiac muscle cells, or cells of the immune system or cell death associated with renal failure, neonatal respiratory distress, asphyxia, incarcerated hernia, placental infarct, iron-load complications, endometriosis, congenital disease, head trauma/traumatic brain injury, liver injury, injuries from environmental radiation, burns, cold injuries, mechanical injuries, decompression sickness, priapism, snake, scorpion or spider bites, UV-damage in skin, aging in skin, and hair loss.

[115] In a further embodiment, the therapeutically effective amount of a compound described above is used in methods to treat diseases selected from the group consisting of muscle wasting diseases, muscular dystrophies or related diseases (e.g., Becker's muscular dystrophy, Duchenne muscular dystrophy, myotonic dystrophy, limb-girdle muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy (Steinert's disease), myotonia congenita, Thomsen's disease, and Pompe's disease), ischemia, compartment syndrome, gangrene, pressure sores, sepsis, degenerative arthritis, retinal necrosis, heart disease, liver, gastrointestinal or pancreatic necrotic diseases (such as acute necrotizing pancreatitis), avascular necrosis, diabetes, sickle cell disease, alteration of blood vessels, and cancer-chemo/radiation therapy- induced cell-death.

[116] In another embodiment, the therapeutically effective amount of a compound described above is used in methods to treat and infectious diseases, wherein the infectious disease is caused by infection by viruses, bacteria, fungi, or other

microorganisms.

[117] In one aspect of the above, the infectious disease is caused by a virus.

Exemplary viruses include but are not limited to human immunodeficiency virus (HIV), Epstein- Barr virus (EBV), cytomegalovirus (CMV) (e.g., CMV5), human herpesviruses (HHV) (e.g., HHV6, 7 or 8), herpes simplex viruses (HSV), bovine herpes virus (BHV) (e.g., BHV4), equine herpes virus (EHV) (e.g., EHV2), human T-Cell leukemia viruses (HTLV)5, Varicella-Zoster virus (VZV), measles virus, papovaviruses (JC and BK), hepatitis viruses (E.g., HBV or HCV), myxoma virus, adenovirus, parvoviruses, polyoma virus, influenza viruses, papillomaviruses and poxviruses such as vaccinia virus, molluscum contagiosum virus (MCV), and lyssaviruses. Exemplary diseases caused by viral infection include, but are not limited to, chicken pox, Cytomegalovirus infections, genital herpes, Hepatitis B and C, influenza, shingles, and rabies.

[118] In another aspect of the above, the infectious disease is caused by bacteria. Exemplary bacteria include Campylobacter jejuni, Enterobacter species, Enterococcus faecium, Enterococcus faecalis, Escherichia coli (e.g., E. coli 0157:H7), Group A streptococci, Haemophilus influenzae, Helicobacter pylori, listeria, Mycobacterium tuberculosis, Pseudomonas aeruginosa, S. pneumoniae, Salmonella, Shigella,

Staphylococcus aureus, Staphylococcus epidermidis, Borrelia and Rickettsia. Exemplary diseases caused by bacterial infection include anthrax, cholera, diphtheria, foodborne illnesses, leprosy, meningitis, peptic ulcer disease, pneumonia, sepsis, septic shock, syphilis, tetanus, tuberculosis, typhoid fever, urinary tract infection, Lyme disease and Rocky Mountain spotted fever.

EXPERIMENTAL

[119] All reagents were purchased from commercial suppliers and used as supplied unless stated otherwise. Reactions were carried out in air unless stated otherwise. 400 MHz ¹ H NMR spectra were obtained on a JEOL AS 400 spectrometer. Low-resolution mass spectra (LRMS) were obtained on a JEOL JMS-T100LC DART / AccuTOF mass spectrometer. Measurement of reversal of protein aggregation may be carried out using such assays as Bis-ANS Fluorescence as described in, for example, W. T. Chen et al.,

J. Biol. Chem, 201 1 , 286 (1 1 ), 9646.

Example 1

Synthesis of Q-5a Esters and Amides

Scheme 1 : General Synthesis of 0-5a Esters and Amides

A. Synthesis of 6E-90 and 6E-91

Synthesis of Methyl indoline-5-carboxylate

[120] A 50 ml. RBF was charged with indoline-5-carboxylic acid (2 g, 12.3 mmol), methanol (25 ml_, 0.5 M) and H2S0₄ (1 ml_; cat.). The reaction mixture was stirred at reflux for 8 h. The methanol was concentrated under reduced pressure and the resulting residue was extracted with dichloromethane (2 x 25 ml.) and the combined organic layer was washed with sat. NaHC0₃ (1 x 20 ml_). The combined organic layer was dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to afford methyl, indoline- 5-carboxylate (2.1 g , 2.78 g theoretical, 75.5%). The product was used directly in the next step without further purification.

Synthesis of 0-1-benzyl-Q-5-methylindoline-1 ,5-dicarboxylate

[121] A 50 ml. RBF was charged with methyl, indoline-5-carboxylate, (2 g, 11 .3 mmol), DCM (20 ml_, 0.6 M), diisopropylethylamine (5.83 g, 45.1 mmol, 4.0 equiv.), and the stirred reaction mixture was then treated dropwise with benzyl chloroformate (5.78 g, 33.9 mmol, 3.0 equiv.). The reaction mixture was stirred for 24 h at RT and then concentrated under reduced pressure. The crude material was purified on silica gel (40 g Si0₂, 0-100% EtOAc-hexanes) to afford 0-1-benzyl-0-5-methylindoline-1 ,5- dicarboxylate (2.50 g, 3.52 theoretical, 71.0%). 1 H NMR (CDCI₃): d 7.79-7.75 (m, 3H), 7.40-7.20 (m, 5H), 5.20 (s, 2H), 4.00 (t, 2H), 3.81 (s, 3H), 3.14 (t, 2H); LCMS: 312 (M+1 ).

Synthesis of O-l-benzyl-O-5-methyl 7-nitroindoline-1 ,5-dicarboxylate

[122] A 50 ml. RBF was charged with 0-1 -benzyl-0-5-methyl indoline-1 ,5- dicarboxylate, (1.5 g, 4.82 mmol), TFA (10 ml_, 0.48 M) and cooled to 0 °C with stirring. The reaction mixture was treated with NaN0₂ (0.366 g, 5.30 mmol, 1.1 equiv.) and then stirred for 1 h at 0 °C and then warmed to RT and stirred for an additional 2 h period. The reaction mixture was then added to water (25 ml.) and neutralized to pH 6-8 with cone. NH4OH. The aqueous layer was extracted with DCM (3 x 20 ml.) and the combined organic layer was concentrated under reduced pressure to afford 0-1 -benzyl- O-5-methyl 7-nitroindoline-1 ,5-dicarboxylate (1.2 g, 1.9 g theoretical, 63.0%) and the compound was used directly in the next step without further purification. LCMS: 312.1 (M+1).

Synthesis of 0-1-benzyloxycarbonyl-7-nitro-indoline-5-carboxylic acid

[123] A 50 ml. RBF was charged with 0-1 -benzyl-0-5-methyl 7-nitroindoline-1 ,5- dicarboxylate, (0.9 g, 2.53 mmol), THF (5 ml_, 0.5 M) and stirred at 0 °C. The reaction mixture was then treated with LiOH (0.121 g, 5.05 mmol, 2.0 equiv.) and then water (5.0 ml_). The mixture was stirred at RT for 8 h. The organic solvent was concentrated under reduced pressure and the resulting aqueous residue was acidified with 1 N HCI and extracted with DCM (3 x 10 ml_). The combined organic layer was concentrated under reduced pressure the crude 1-benzyloxycarbonyl-7-nitro-indoline-5-carboxylic acid was used directly in the next step without further purification. 1 H NMR (DMSO-d6): d 8.10, 8.05 (2 s, 2H), 7.42-7.21 (m, 5H), 5.21 (s, 2H), 4.20 (t, 2H), 3.22 (t, 2H); LCMS: 299.0 (M+H-COOH, M+H 342 expected).

Synthesis of 0-1-benzyl-0-5-ethyl-7-nitroindoline-1 ,5-dicarboxylate

[124] A 50 mL RBF was charged with 1-benzyloxycarbonyl-7-hydroxy-indoline-5- carboxylic acid, (0.210 g, 0.670 mmol), ethanol (10 mL, 0.06 M), thionyl chloride (0.3 mL, cat.) and the reaction mixture was heated to reflux and stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was extracted with DCM (2 x 20 mL) and the combined organic layer was washed with sat. NaHC0₃ solution (50 mL). The combined organic was concentrated under reduced pressure and purified on silica gel (20 g S1O2, o-100% EtOAc-hexanes) afforded 0-1- benzyl-0-5-ethyl-7-nitroindoline-1 ,5-dicarboxylate (0.200 g, 0.227 g theoretical, 88.0%). %). 1 H NMR (CDCIs): d 8.29, 7.99 (2 s, 2H), 7.35-7.32 (m, 5H), 5.19 (s, 2H), 4.36 (q, 2H), 4.28 (t, 2H), 3.20 (t, 2H), 1.39 (t, 3H); LCMS: 327.1 (M+1 -OEt).

Synthesis of Ethyl, 7-aminoindoline-5-carboxylate (6E-90^')

[125] A 50 ml. RBF was charged with 0-1 -benzyl-0-5-ethyl-7-nitroindoline-1 ,5- dicarboxylate, 6E-89, (0.190 g, 0.513 mmol), ethanol (10 ml_, 0.05 M). 10% Pd-C (0.080 g) and the reaction mixture was stirred at RT for 2 h after being fitted with a balloon of H2. The reaction mixture was filtered and the solvent was concentrated under reduced pressure. The crude residue was purified on silica gel (20 g Si0₂, 0-100% EtOAc- hexanes) to afford Ethyl, 7-aminoindoline-5-carboxylate; (6E-90) (0.065 g, 0.1 12 g theoretical, 58.0%). 1 H NMR (CDCIs): d 7.39, 7.24 (2 s, 2H), 4.29 (q, 2H), 3.62 (t, 2H), 3.08 (t, 2H), 1 .35 (t, 3H); LCMS: 207.1 (M+H).

Synthesis of HCI salt of ethyl, 7-aminoindoline-5-carboxylate (6E-911

[126] A 25 mL RBF was charged with ethyl, 7-aminoindoline-5-carboxylate; 6E-90, (0.055 g, 0.267 mmol), dioxane (1 mL, 0.26 M), and the reaction mixture was cooled to 0 °C with stirring and treated dropwise with 0.5 M HCI in dioxane (1 mL, 0.5 mmol, 1.9 equiv.). The reaction mixture was warmed to RT over a 30-min period and then concentrated under reduced pressure to afford the hydrochloride salt of ethyl, 7- aminoindoline-5-carboxylate; (6E-91) (0.048 g, 0.065 g theoretical, 74.0%). 1 H NMR (DMSO-d6): d 7.54, 7.48 (2 s, 2H), 4.22 (q, 2H), 3.60 (t, 2H), 3.05 (t, 2H), 1.27 (t, 3H); LCMS: 207.1 (M+H). B. Synthesis of 6E-96 and 6E-97

0-1-benzyl-0-5-propyl-7-nitroindoline-1 ,5-dicarboxylate

[127] A 50 mL RBF was charged with 0-1 -benzyloxycarbonyl-7-hydroxy-indoline-5- carboxylic acid, 6E-88, (0.4 g, 1.17 mmol), n-propanol (10 mL, 0.1 M), thionyl chloride (0.8 mL, cat.) and the reaction mixture was heated to reflux and stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was extracted with DCM (2 x 20 mL) and washed with sat. NaHC0₃ solution (50 mL). The combined organic layer was concentrated under reduced pressure and the crude O- 1-benzyl-0-5-propyl-7-nitroindoline-1 ,5-dicarboxylate (0.295 g, 0.454 g theoretical, 65.0%) was used directly in the next step without further purification. LCMS: 207.1 (M+H). n-Propyl, 7-aminoindoline-5-carboxylate (6E-961

[128] A 50 mL RBF was charged with O-l -benzyl-O-5-propyl 7-nitroindoline-1 ,5- dicarboxylate, (0.285 g, 0.74 mmol), ethanol (10 mL, 0.07 M), 10% Pd-C (0.080 g) and the reaction mixture was fitted with a balloon of H2 and stirred at RT for 2 h. The reaction mixture was then filtered and concentrated under reduced pressure. The resulting crude material was purified on silica gel (20 g Si0₂, 0-100% EtOAC-hexanes) to afford n-Propyl, 7-aminoindoline-5-carboxylate; (6E-96) (0.090 g, 0.164 g theoretical, 55.0%). 1 H NMR (DMSO-d6): d 7.08, 7.06 (2 s, 2H), 4.19 (t, 2H), 3.61 (t, 2H), 2.90 (t, 2H), 1 .70 (t, 2H), 0.92 (t, 3H); LCMS: 221 .1 (M+H). HCI salt of n-propyl, 7-aminoindoline-5-carboxylate (6E-971

[129] A 25 mL RBF was charged with n-propyl, 7-aminoindoline-5-carboxylate, 6E- 96, (0.090 g, 0.409 mmol), dioxane (1 mL, 0.4 M), and the reaction mixture was cooled to 0 °C with stirring and treated dropwise with 0.5 M HCI in dioxane (1.5 mL, 0.75 mmol, 1.9 equiv.). The reaction mixture was warmed to RT over a 30-min period and then concentrated under reduced pressure to afford the hydrochloride salt of n-propyl, 7- aminoindoline-5-carboxylate; (6E-97) (0.075 g, 0.106 g theoretical, 71.0%). 1 H NMR (DMSO-d6): d 7.57, 7.50 (2 s, 2H), 4.13 (t, 2H), 3.62 (t, 2H), 3.08 (t, 2H), 1.66 (t, 2H), 0.94 (t, 3H); LCMS: 221.1 (M+H).

C. Synthesis of 6E-99 and 6S-00

Benzyl, S-fmorpholine^-carbonyl -nitro-indoline-l-carboxylate

[130] A 100 mL RBF was charged with 0-1-benzyloxycarbonyl-7-nitro-indoline-5- carboxylic acid (0.40 g, 1.17 mmol), DCM (20 mL, 0.06 M), morpholine (0.122 g, 1 .40 mmol, 1 .2 equiv.), EDC.HCI (0.448 g, 2.34 mmol, 2.0 equiv.) and triethylamine (0.355 g, 3.51 mmol, 3.0 equiv.). The reaction mixture was stirred at RT for 14 h and then concentrated under reduced pressure. The resulting crude residue was purified on silica gel (20 g Si0₂, 0-100% EtOAc-hexanes) to afford Benzyl, 5-(morpholine-4-carbonyl)-7- nitro-indoline-1-carboxylate (0.275 g, 0.483 g theoretical, 57.0%). 1 H NMR (CDCI₃): d 7.68, 7.46 (2 s, 2H), 7.36-7.35 (m, 5H), 5.19 (s, 2H), 4.27 (t, 2H), 3.80-3.50 (m, 8H), 3.18 (t, 2H), H); LCMS: 412.1 (M+H). (7-aminoindolin-5-yl)-rnorpholino-methanone (6E-991

[131] A 50 mL RBF was charged with benzyl, 5-(morpholine-4-carbonyl)-7-nitro- indoline-1 -carboxylate (0.20 g, 0.486 mmol), ethanol (10 mL, 0.05 M) 10% Pd-C (0.051 g) and the reaction mixture was fitted with a balloon of H2 and stirred at RT for 2 h. The reaction mixture was then filtered and concentrated under reduced pressure. The resulting crude (7-aminoindolin-5-yl)-morpholino-methanone, (6E-99) was used directly in the next step without further purification (0.051 g, 0.121 g theoretical, 42.0%). LCMS: 248.1 (M+H).

HCI salt of (7-aminoindolin-5-yr)-morpholino-methanone (63-001

[132] A 25 mL RBF was charged with (7-aminoindolin-5-yl)-morpholino-methanone, 6E-99, (0.025 g, 0.101 mmol), dioxane (1 mL, 0.1 M), and the reaction mixture was cooled to 0 °C with stirring and treated dropwise with 0.5M HCI in dioxane (0.5 mL, 0.25 mmol, 2.5 equiv.). The reaction mixture was warmed to RT over a 30-min period and then concentrated under reduced pressure to afford the hydrochloride salt of (7- aminoindolin-5-yl)-morpholino-methanone, (6S-00) (0.020 g, 0.029 g theoretical, 69.0%).

1 H NMR (DMSO-d6), %). 1 H NMR (CDCI₃): d 6.80 (br s, 2H), 4.18 (t, 2H), 3.81-3.50 (m, 8H), 3.12 (t, 2H); LCMS: 248.1 (M+H). Example 2

Synthesis of Q-6a Esters

Scheme 2: General Synthesis of Q-6a Esters

A. Synthesis of Ethyl, 1 ,2.3.4-tetrahvdroquinoline-6-carboxylate

[133] A 500 ml. RBF was charged with 1 ,2,3,4-tetrahydroquinoline-6-carboxylic acid (10 g, 0.064 mol) ethanol (200 ml_, 0.3 M) and the reaction mixture was treated dropwise with sulfonyl chloride (8.4 ml_, 14.0 g, 0.104 mol, 1 .6 equiv.). The reaction mixture was warmed to 85 °C and stirred for 4 h. The reaction was complete by LCMS analysis and was allowed to cool to RT. mixture was cooled to RT and poured into 800 mL of water. The solution was then made basic with the addition of solid NaHC0₃. The resulting precipitate was collected by vacuum filtration and dried under reduced pressure to afford ethyl, 1 ,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid (10.6 g, 13.1 g theoretical, 80.9%). 1 H NMR (CDCI₃): d 7.64 (m 2H), 6.37 (d 1 H), 4.27 (q 2H), 3.33 (t 2H), 2.75 (t 2H), 1.92 (m 2H), 1.33 (t 3H); LCMS: (APCI) m/e 206 (M+H).

B. Synthesis of Ethyl, 1-acetyl-3,4-dihvdro-2-(l-0-quinoline-6-carboxylate

[134] A 250 mL RBF was charged with ethyl 1 ,2,3,4-tetrahydroquinoline-6- carboxylate (8.57 g, 0.042 mol), DCM (150 mL, 0.28 M), triethylamine (11.6 mL, 0.084 mol, 2.0 equiv.) and the reaction mixture was cooled to 0 °C with stirring. The stirred reaction mixture was then treated dropwise with acetyl chloride (4.4 mL, 0.063 mol, 1.5 equiv.) over a 20-min period, maintaining the temperature between 5 and 0 °C. The mixture was stirred at 0 °C for an additional 1 h and then allowed to warm to RT and stirred for 1 h. The reaction mixture was then diluted with 50 mL of DCM and washed with 100 mL of 1 N HCI. The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to afford ethyl, 1 -acetyl-3, 4-dihydro-2-(H)- quinoline-6-carboxylate as an oil. The oil was washed with hexanes to provide 8.1 grams of a yellow solid (8.1 g, 10.4 g theoretical, 77.9%). 1 H NMR (CDCI₃): d 7.84 (m 2H), 4.34 (q 2H), 3.77 (t 2H), 2.76 (t 2H), 2.25 (s 3H), 1 .95 (m 2H), 1.37 (t 3H); LCMS: (APCI) m/e 248 (M+H).

C. Synthesis of Ethyl, 1-acetyl-8-nitro-3,4-dihvdro-2-(l-0-quinoline-6-carboxylate

[135] A 100 mL RBF was changed with ethyl 1 -acetyl-3, 4-dihydro-2-(H)-quinoline- 6-carboxylate (700 mg, 0.0034 mol), TFA (7 mL, 0.4 M) and the mixture was then cooled to 0 °C with stirring. The reaction mixture was then treated with 234 mgs of sodium nitrite (243 mg, 0.0034 mol, 1.0 equiv.) and stirred for 1 h at 0 °C. The mixture was then allowed to warm to RT and stirred. After 2 h, the reaction was complete by LCMS analysis and was then poured into 10 mL water and neutralized with cone. NFLOH. The mixture was extracted 3 x 15 mL DCM and the combined organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude residue was purified on Si0₂ (40 g, 10-100% EtOAc-hexanes) to afford of ethyl, 1-acetyl-8-nitro-3,4- dihydro-2-(H)-quinoline-6-carboxylate as a pale yellow solid (528 mg, 843 mg theoretical, 62.6%). 1 H NMR (CDCI₃): d 8.34 (s 1 H), 8.00 (s 1 H),4.38 (q 2H), 3.84 (t 2H), 2.87 (t 2H), 2.27 (s 3H), 2.09 (m 2H), 1.38 (t 3H); LCMS: (APCI) 293 (M+H). D. Synthesis of Ethyl, l-acetyl-S-amino-S^-dihvdro^-d-Q-quinoline-e-carboxylate

[136] A 50 mL RBF was charged with 520 mgs of ethyl 1 -acetyl-8-nitro-3,4-dihydro- 2-(H)-quinoline-6-carboxylate (520 mg, 0.0021 mol), 200 proof ethanol (20 mL, 0.1 M) and stirred at RT. The reaction mixture was then treated with 10% Pd-C (25 mg) and the mixture was degassed using nitrogen. The reaction flask was then fitted with a balloon of hydrogen and the reaction was stirred at 40 °C. After 2 h, the reaction was complete by LCMS analysis and the mixture was filtered and the combined organic layer was concentrated under reduced pressure to afford ethyl, 1 -acetyl-8-amino-3,4-dihydro-2- (H)-quinoline-6-carboxylate as a tan solid (460 mg, 551 mg theoretical, 83.5%). 1 H NMR (CDCIs): d 8.46 (s 1 H), 7.83 (d 1 H), 4.39 (q 2H), 4.09 (m 2H), 3.05 (m 2H), 2.71 (s 3H), 2.34 (m 2H), 1.41 (t 3H); LCMS: (APCI) 261 (M+H).

Example 3

Alternative Synthesis of Q-6a Esters

Scheme 3: Alternative Synthesis of Q-6a Esters

A. Synthesis of 5Y-64

8-amino-1 ,2.3.4-tetrahvdroquinoline-6-carboxylic acid (5Y-73^')

[137] A 50 mL Vial was charged with 8-nitroquinoline-6-carboxylic acid (80 mg, 0.367 mmol) was dissolved in 15 ml of MeOH (15 mL, 0.02 M), ammonium formate (195 mg, 2.93 mmol, 8.0 equiv.), 10% Pd-C (cat.) and the vial was flushed with N2, sealed and heated at 70 °C. after 18 h LCMS analysis confirmed a single peak with the correct mass. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to afford 8-amino-1 ,2,3,4-tetrahydroquinoline-6-carboxylic acid; (5Y- 73), (70 mg, 70.5 mg theoretical, 99%) as a tan solid that was used directly in the next step without further purification. 1 H NMR (CDCI₃): d 6.97 (d, 1 H), 6.91 (d, 1 H), 5.32 (s,

1 H), 3.27 (t, 2H), 2.65 (t, 2H), 1.77 (q, 2H); LCMS: (APCI) 193 (M+H).

Ethyl, 8-amino-1 ,2.3.4-tetrahvdroquinoline-6-carboxylate (5Y-641

[138] A 50 mL RBF was charged with 8-amino-1 ,2,3,4-tetrahydroquinoline-6- carboxylic acid, (5Y-73) (70 mg, 0.364 mmol), ethanol (10 mL, 0.036 M), cone. H2S04 (cat., 4 drops) and heated at 90 °C. After 10 h, the mixture was allowed to cool to RT, treated with DCM (40 mL) and washed with NaHC0₃ (30 mL) and water (30 mL). The DCM layer was dried over Na₂S0₄ and concentrated under reduced pressure to provide a brown residue that was washed with hexanes to afford Ethyl, 8-amino-1 ,2,3,4- tetrahydroquinoline-6-carboxylate; (5Y-64) (47 mg, 80 mg theoretical, 56.8%) as a white solid. 1 H NMR (CDCI₃): d 7.32 (d, 1 H), 7.24 (m, 1 H), 4.28 (q, 2H), 3.37 (t, 2H), 2.77 (t, 2H), 1 .91 (m, 2H), 1.34 (t, 3H); LCMS: (APCI) 221 (M+H).

B. Synthesis of 5Y-74

Propyl, 8-amino-1 ,2.3.4-tetrahvdroquinoline-6-carboxylate (5Y-741

[139] A 50 mL RBF was charged with 8-amino-1 ,2,3,4-tetrahydroquinoline-6- carboxylic acid, (5Y-73) (74 mg, 0.385 mmol), n-propanol (10 mL, 0.036 M), thionyl chloride (cat., 105 pL) and heated at 90 °C. After 10 h, the mixture was allowed to cool to RT and concentrated under reduced pressure. The resulting residue was purified on silica gel (24 g Si0₂, 0-100% EtOAc-hexanes) to provide an oil that was washed with hexanes to afford propyl, 8-amino-1 ,2,3,4-tetrahydroquinoline-6-carboxylate; (5Y-74) (43 mg, 90.2 g theoretical, 47.7%) as a white solid. 1 H NMR (DMSO): d 7.00 (d, 1 H), 6.94 (d, 1 H), 5.39 (s, 1 H), 4.55 (s, 2H), 4.07 (t, 2H), 3.27 (m, 2H), 2.66 (t, 2H), 1.77 (m, 2H), 1.64 (q, 2H) 0.93 (t, 3H); LCMS: (APCI) 235 (M+H).

Example 4

Synthesis of Substituted Q-6a Esters

Scheme 4: General Synthesis of Substituted Q-6a Esters

Propyl, 8-nitroquinoline-6-carboxylate

[140] To a solution of 1 -benzyloxycarbonyl-3,4-dihydro-2-{H}-quinoline-5-carboxylic acid (2.0 g) in n-propanol (50 ml.) was added drop-wise thionyl chloride (5 ml.) at RT, and the solution was stirred at reflux overnight. Crude LC-MS indicated the reaction was complete. The mixture was cooled to RT and poured into 50 ml. of water. The solution was made basic with the addition of saturated aq. NaHC0₃, and extracted with DCM (3 x 50 ml_). The combined organic layer was dried over Na₂S0₄, and concentrated under reduced pressure. The resulting residue was dried under vacuum at 45 °C overnight to provide propyl, 8-nitroquinoline-6-carboxylate as a pale yellow solid (1.59 g, 66% yield); LCMS: (APCI) m/e 261.1 (M+H). This propyl ester was used directly in the next step without further purification.

Propyl, 8-aminoquinoline-6-carboxylate

[141] To a suspension of propyl, 8-nitroquinoline-6-carboxylate (1.50 g, 0.577 mmol) in ethanol (5 ml.) and THF (10 ml.) was treated with Pd-C (0.080 g) and the reaction was stirred for 2 h in a hydrogen atmosphere at RT. Crude LC-MS indicated the reaction was complete. The catalyst was filtered, and washed sequentially with DCM (10 mL) and MeOH (10 mL). The combined organic layer was concentrated under reduced pressure to provide propyl, 8-aminoquinoline-6-carboxylate as a yellow oil (1 .01 g, 76% yield); LCMS: (APCI) m/e 231.1 (M+H). The amine intermediate was used directly in the next step without further purification.

Propyl, S-fbutylaminotquinoline-e-carboxylate

[142] To a solution of propyl, 8-aminoquinoline-6-carboxylate (0.250 g, 1.0 mmol) in 20 mL of DCE was treated with butyraldehyde (0.078 g, 1.0 mmol) followed by acetic acid (0.2 mL). The mixture was treated with molecular sieves, 4 A (0.200 g) and stirred at RT for 2 h, to ensure formation of imine intermediate. The mixture was then treated with sodium triacetoxyborohydride (0.460 g, 2.1 mmol) and stirred at RT overnight. The reaction mixture was then neutralized with saturated aq. NaHC0₃ and extracted with DCM (2 x 15 mL). The combined organic layer was washed with brine, dried over Na₂S0₄, and concentrated under reduced pressure to provide an oil. The LC-MS of the crude product confirmed the desired mono-alkylated compound as the major product with a small amount of di-alkylated product. The mixture was used directly in the next step without further purification. Propyl, S-fbutylaminot-l ,2.3.4-tetrahvdroquinoline-6-carboxylate (60-56)

[143] A solution of propyl, 8-(butylamino)quinoline-6-carboxylate (0.100 g, 0.35 mmol) in acetic acid (5 ml.) was treated portion-wise with sodium cyanoborohydride (0.065 g, 1.05 mmol) carefully over 5 min at RT. The reaction was stirred for 2 h providing a mixture of the desired product with a small amount of the di-alkylated product. The mixture was diluted with water (5 ml_), basified with saturated aq. NaHC0₃, extracted with DCM (5 x 5 ml_), washed with brine (5 ml.) and dried over Na2S04. The desired product was purified on silica (CombiFlash column, eluting with 5-100%

EtOAc/hexanes) to provide propyl, 8-(butylamino)-1 ,2,3,4-tetrahydroquinoline-6- carboxylate (60-56) as a pale-yellow oil (42 mg, 41.4% yield). 1 H NMR (400 MHz,

CDCI₃): d d 7.24 (s, 1 H), 7.18 (s, 1 H), 4.20 (q, 2H), 3.35 (m, 2H), 3.10 (t, 2H), 2.77 (t,

2H), 1 .75 (m, 2H), 1.73-1.62 (m, 4H), 1.45 (m, 2H), 0.96 (t, 6H); LCMS: (APCI) m/e 291 (M+H).

B. Synthesis of 60-57 (Freebasel

Propyl, 8-(2-phenylethylamino^')quinoline-6-carboxylate

[144] To a solution of propyl, 8-aminoquinoline-6-carboxylate (0.250 g, 1.0 mmol) in 20 ml. of DCE was added 2-phenylacetaldehyde (0.130 g, 1 .0 mmol) followed by acetic acid (0.2 ml.) and molecular sieves, 4 A (0.200 g). The mixture was stirred at RT for 2 h, to ensure formation of imine intermediate. The mixture was then treated with sodium triacetoxyborohydride (0.460 g, 2.1 mmol) and stirred at RT overnight. The reaction mixture was then neutralized with saturated aq. NaHC0₃ and extracted with DCM (2 x 15 ml_). The combined organic layer was washed with brine (15 ml_), dried over Na₂S0₄, and concentrated under reduced pressure to provide an oil. Crude LC-MS confirmed the desired mono-alkylated compound as the major product with a small amount of the di- alkylated product. The material was used directly in the next step without further purification.

Propyl, 8-(2-phenylethylamino^')-1 ,2.3.4-tetrahvdroquinoline-6-carboxylate (60-57^')

[145] A solution of propyl, 8-(butylamino)quinoline-6-carboxylate (0.0750 g, 0.22 mmol) in acetic acid (5 ml.) was treated portion-wise with sodium cyanoborohydride (0.042 g, 0.62 mmol) carefully over 5 min at RT and then stirred for 2 h to provide the desired product with a small amount of the di-alkylated product. The mixture was diluted with water (5 ml_), basified with saturated aq. NaHCOa, extracted with DCM (5 x 5 ml_), washed with brine (5 ml.) and dried over Na₂S0₄ and purified on silica (CombiFlash column, eluting with 10-100% EtOAc/hexanes) to provide propyl, 8-(2- phenylethylamino)-1 ,2,3,4-tetrahydroquinoline-6-carboxylate (60-57) as a pale-yellow oil, (34 mg, 43.5%). 1 H NMR (400 MHz, CDCI₃): 1 H NMR (400 MHz, CDCI₃): d d 7.26- 7.25 (m, 7H), 4.21 (t, 2H), 3.39-3.37 (m, 4H), 2.97 (t, 2H), 2.77 (t, 2H), 1.85 (m, 4H), 0.98 (t, 3H); LCMS: (APCI) m/e 339 (M+H).

C. Synthesis of 6U-05

Butyl S-fbenzylaminoM .2.3.4-tetrahvdroauinoline-6-carboxylate (611-051

[146] Butyl, 8-amino-1 ,2,3,4-tetrahydroquinoline-6-carboxylate (132 mg) was dissolved in 20 ml. of DCE and treated with benzaldehyde (68 pl_, 1.5 equiv.) and acetic acid (66 mI_). The mixture turned pale yellow and was heated at 60 °C for 1 h cooled to RT and treated with sodium triacetoxyborohydride (242 mg) and stirred at RT overnight. The reaction mixture was then diluted with DCM (20 ml.) and washed with water (30 ml_). The DCM layer was dried over Na₂S0₄ concentrated under reduced pressure and the resulting oil was purified on silica (24-gram silica column eluting with hexane/DCM) to give a pale-yellow oil, which was washed with t-butyl methyl ether to provide butyl 8- (benzylamino)-1 ,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid (48 mg, 25% yield). 1 H NMR (CDCI₃): d 7.40-7.32 (m 5H), 7.28- 7.26 (m 2H), 4.27 (s 2H), 4.23 (t 2H), 3.34 (t 2H), 2.78 (t 2H), 1.90 (m 2H), 1.70 (m 2H), 1.44 (m 2H), 0.95 (t 3H); LCMS: (APCI) m/e 339 (M+H).

D. Synthesis of 60-69 (Freebaset

Propyl 8- (pyrrolidine-1-carbonyl^')phenyllmethylaminolauinoline-6-carboxylate

[147] To a solution of propyl 8-aminoquinoline-6-carboxylate (0.200 g, 0.869 mmol) in 20 ml. of DCE was added 4-(pyrrolidine-1-carbonyl)benzaldehyde (0.177 g, 0.869 mmol) followed by acetic acid (0.2 ml_). To this mixture was added molecular sieves, 4 A (0.200 g) and stirred the contents at RT for 2 h to ensure formation of imine

intermediate. To this mixture was then added sodium triacetoxyborohydride (0.368 g, 1.74 mmol) and stirred at RT overnight. The reaction mixture was neutralized with saturated aq. NaHC0₃ and extracted with DCM (2 x 15 ml_). The combined extract was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The DCM layer was dried over Na₂S0₄ and evaporated to give an oil. The LC-MS of the crude product confirmed the desired mono-alkylated compound as the major product. This material was used directly in the next step without further purification.

Propyl 8- (pyrrolidine-1-carbonyl^')phenyllmethylaminol-1 ,2.3.4-tetrahvdroquinoline-6- carboxylate (60-691

[148] To propyl 8-[[4-(pyrrolidine-1 -carbonyl)phenyl]methylamino]quinoline-6- carboxylate (0.275 g, 2.64 mmol) in acetic acid (5 ml_), sodium cyanoborohydride (0.124 g, 1.98 mmol) was added portion-wise carefully in 5 min at RT. After 2 h, the TLC and LCMS of the reaction mixture showed conversion of starting material to the desired product together with some amount of di-alkylated product. The mixture was diluted with water, basified with saturated aq. NaHC0₃, extracted with DCM (5 x 5 mL), washed with brine and dried over sodium sulfate. The desired product was separated from the crude mixture by passing through a silica-gel CombiFlash column, eluting with hex/EtAc. The propyl 8-[[4-(pyrrolidine-1-carbonyl)phenyl]methylamino]-1 ,2,3,4-tetrahydroquinoline-6- carboxylate (60-69) was isolated as a pale-yellow viscous oil, (98 mg, 35.3%). 1 H NMR (400 MHz, CDCI₃): d 7.50-7.48 (d, 2H), 7.42-7.39 (d 2H), 7.34 (s, 1 H), 7.23 (s, 1 H), 4.31 (s, 2H), 4.20-4.17 (q, 2H), 3.65-3.61 (t, 2H), 3.42-3.33 (m, 4H), 2.80-2.77 (t, 2H), 1.93- 1.72 (m, 8H), 1.03-0.96 (t, 3H). LCMS: (APCI) m/e 422 (M+H).

E. Synthesis of 60-79 (Freebaset

Propyl 8-r(1 -methylpyrazol-4-yr)methylaminolquinoline-6-carboxylate

[149] To a solution of propyl 8-aminoquinoline-6-carboxylate (0.230 g, 1.0 mmol) in 20 ml. of DCE was added 1-methylpyrazole-4-carbaldehyde (0.100 g, 1.0 mmol) followed by acetic acid (0.2 ml_). To this mixture was added molecular sieves, 4 A (0.230 g) and stirred the contents at RT for 2 h to ensure formation of imine intermediate. To this mixture was then added sodium triacetoxyborohydride (0.422 g, 2.0 mmol) and stirred at RT overnight. The reaction mixture was neutralized with saturated aq. NaHC0₃ and extracted with DCM (2 x 15 ml_). The combined extract was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The DCM layer was dried over Na₂S0₄ and evaporated to give an oil. The LC-MS of the crude product indicated to contain the desired mono-alkylated compound as the major product. This material was used directly in the next step without further purification.

Propyl 8-r(1 -methylpyrazol-4-yr)methylaminol-1 ,2.3.4-tetrahvdroquinoline-6-carboxylate (60-791

[150] To a solution of propyl 8-[(1-methylpyrazol-4-yl)methylamino]quinoline-6- carboxylate (0.200 g, 0.61 mmol) in acetic acid (5 ml_), sodium cyanoborohydride (0.1 16 g, 1.85 mmol) was added portion-wise carefully in 5 min at RT. After 24 h, the TLC and LCMS of the reaction mixture showed conversion of starting material to the desired product. The mixture was diluted with water, basified with saturated aq. NaHC0₃, extracted with DCM (5 x 5 ml_), washed with brine and dried over sodium sulfate. The desired product was separated from the crude mixture by passing through a silica-gel CombiFlash column, eluting with hex/EtAc. The propyl 8-[(1-methylpyrazol-4- yl)methylamino]-1 ,2,3,4-tetrahydroquinoline-6-carboxylate (60-79) was isolated as a pale-yellow viscous oil, (64 mg, 31.6%). 1 H NMR (400 MHz, CDCI₃): d 1 H 7.75 (s, 1 H), 7.56 (s, 1 H), 7.53 (s, 1 H), 7.7.16 (d, 1 H), 4.23-4.16 (m, 4H), 4.02 (s, 3H), 3.36-3.35 (t, 2H), 2.78-2.76 (t, 2H), 1.74-1.71 (m, 4H), 1.00-0.96 (t, 3H). LCMS: (APCI) m/e 329 (M+H).

F. Synthesis of WBI-6Q-84 (Freebasel

Propyl S-fS-furylmethylaminotauinoline-e-carboxylate

[151] To a solution of propyl 8-aminoquinoline-6-carboxylate (0.230 g, 1.0 mmol) in 20 ml. of DCE was added furan-3-carbaldehyde (0.096 g, 1.0 mmol) followed by acetic acid (0.2 ml_). To this mixture was added molecular sieves, 4 A (0.230 g) and stirred the contents at RT for 2 h to ensure formation of imine intermediate. To this mixture was then added sodium triacetoxyborohydride (0.422 g, 2.0 mmol) and stirred at RT overnight. The reaction mixture was neutralized with saturated aq. NaHC0₃and extracted with DCM (2 x 15 ml_). The combined extract was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The DCM layer was dried over Na2S04 and evaporated to give an oil. The LC-MS of the crude product indicated to contain the desired mono-alkylated compound as the major product. This material was used directly in the next step without further purification.

Propyl S-fS-furylmethylaminol-l ,2.3.4-tetrahvdroquinoline-6-carboxylate (60-841

[152] To a solution of propyl 8-(3-furylmethylamino)quinoline-6-carboxylate (0.200 g, 0.64 mmol) in acetic acid (5 ml_), sodium cyanoborohydride (0.121 g, 1.93 mmol) was added portion-wise carefully in 5 min at RT. After 24 h, the TLC and LC-MS of the reaction mixture showed conversion of starting material to the desired product. The mixture was diluted with water, basified with saturated aq. NaHC0₃, extracted with DCM (5 x 5 ml_), washed with brine and dried over sodium sulfate. The desired product was separated from the crude mixture by passing through a silica-gel CombiFlash column, eluting with hex/EtAc. The propyl 8-(3-furylmethylamino)-1 ,2,3,4-tetrahydroquinoline-6- carboxylate (60-84) was isolated as a pale-yellow viscous oil, (63 mg, 31.1 %). 1 H NMR (400 MHz, CDCI₃): d 7.32-7.24 (m, 4H), 6.43 (s, 1 H), 4.21-4.18 (q, 2H), 4.12 (s, 2H), 3.36-3.33 (t, 2H), 2.79-2.64 (t, 2H), 1.91-1.89 (m, 2H), 1.77-1.73 (m, 2H), 1 .00-0.96 (t, 3H). LCMS: (APCI) m/e 315 (M+H).

G. Synthesis of 60-85 (Freebasel

Propyl S-fthiazol-S-ylmethylaminotquinoline-e-carboxylate

[153] To a solution of propyl 8-aminoquinoline-6-carboxylate (0.230 g, 1.0 mmol) in 20 ml. of DCE was added 3H-thiazole-5-carbaldehyde (0.1 15 g, 1 .0 mmol) followed by acetic acid (0.2 ml_). To this mixture was added molecular sieves, 4 A (0.230 g) and stirred the contents at RT for 2 h to ensure formation of imine intermediate. To this mixture was then added sodium triacetoxyborohydride (0.422 g, 2.0 mmol) and stirred at RT overnight. The reaction mixture was neutralized with saturated aq. NaHC0₃and extracted with DCM (2 x 15 ml_). The combined extract was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The DCM layer was dried over Na2S04 and evaporated to give an oil. The LC-MS of the crude product indicated to contain the desired mono-alkylated compound as the major product. This material was used directly in the next step without further purification. Propyl 8-(thiazol-5-ylmethylamino)-1 ,2,3,4-tetrahvdroquinoline-6-carboxylate (60-85)

[154] To a solution of propyl 8-(thiazol-5-ylmethylamino)quinoline-6-carboxylate (0.190 g, 0.58 mmol) in acetic acid (5 mL), sodium cyanoborohydride (0.109 g, 1.74 mmol) was added portion-wise carefully in 5 min at RT. After 24 h, the TLC and LCMS of the reaction mixture showed conversion of starting material to the desired product. The mixture was diluted with water, basified with saturated aq. NaHC0₃, extracted with DCM (5 x 5 mL), washed with brine and dried over sodium sulfate. The desired product was separated from the crude mixture by passing through a silica-gel CombiFlash column, eluting with hex/EtAc. The propyl 8-(thiazol-5-ylmethylamino)-1 , 2,3,4- tetrahydroquinoline-6-carboxylate (60-84) was isolated as a pale-yellow viscous oil, (48 mg, 25%). 1 H NMR (400 MHz, CDCI₃): d 8.72 (s, 1 H), 7.81 (s, 1 H), 7.27 (s, 2H), 4.51 (s, 2H), 4.20-4.16 (q, 2H), 3.36-3.33 (t, 2H), 2.77-2.75 (t, 2H), 1 .74 (t, 2H), 1.72-1.71 (m,

2H), 1 .00-0.96 (t, 3H). LCMS: (APCI) m/e 332 (M+H).

Example 5

Synthesis of Q-6a Amides

Scheme 5: General Synthesis of Q-6a Amides

EXP-17-FO3730

Morpholino(1 ,2,3,4-tetrahvdroquinolin-6-yl)methanone

[155] A 100 mL RBF was charged with 1 ,2,3,4-tetrahydroquinoline-6-carboxylic acid hydrochloride (1 .0 g, 4.68 mmol), EDC.HCI (1.79 g, 9.36 mmol, 2.0 equiv.), DCM (30 mL, 0.15 M), morpholine (0.408 g, 4.68 mmol, 1.0 equiv.), triethylamine (1.42 g, 1.95 ml_, 14.4 mmol, 3.1 equiv.) and the reaction mixture was stirred at RT for 18 h. The reaction mixture was then treated with 1 N HCI (10 mL), the organic layer was then washed with Dl water (10 mL), brine (10 mL) and the organic layer was dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The crude

Morpholino(1 ,2,3,4-tetrahydroquinolin-6-yl)methanone was used directly in the next step without further purification (0.910 g, 1.15 g theoretical, 78.9%). LCMS: 247 (M+H).

Benzyl e-fmorpholine^-carbonvn-S^-dihvdro^H-auinoline-l -carboxylate

[156] A 100 mL RBF was charged with morpholino(1 ,2,3,4-tetrahydroquinolin-6- yl)methanone (0.900 g, 3.65 mmol), diisopropylethylamine (1.89 g, 2.54 mL, 14.6 mmol, 4.0 equiv.), DCM (25 mL, 0.15 M), benzyl chloroformate (1.87 g, 1.56 mL, 11 .0 mmol,

3.0 equiv.) and the reaction mixture was stirred at RT for 18 h. The reaction mixture was poured into water (25 mL) and neutralized to pH 6-8 with cone. NH₄OH and extracted with DCM (3 x 20 mL). The combined organic layer was dried over anhydrous Na₂S0₄ , concentrated under reduced pressure and the crude residue was purified on silica gel (40 g Si0₂, 0-100% EtOAC- hexanes) to afford Benzyl, 6-(morpholine-4-carbonyl)-3,4- dihydro-2H-quinoline-1 -carboxylate (1.2 g, 1.39 g theoretical, 86.3%). 1 H NMR (CDCI₃) d 7.80 (s, 1 H), 7.37-7.24 (m, 7H), 5.27 (s, 2H), 4.09-3.50 (m, 10H), 2.77 (t, 2H), 1.93 (t, 2H); LCMS: 381 (M+H).

Benzyl, e-fmorpholine^-carbonvn-S-nitro-SA-dihvdro^H-quinoline-l-carboxylate

Cbz NO-

[157] A 50 mL RBF was charged with benzyl, 6-(morpholine-4-carbonyl)-3,4- dihydro-2~{H}-quinoline-1-carboxylate (0.845 g, 2.22 mmol), TFA (5 mL, 0.4 M) and the reaction mixture was stirred at 0 °C and treated with NaN0₂ (0.169 g, 2.44 mmol, 1.1 equiv.). The reaction mixture was stirred for at 0 °C for 1 h and then warmed to RT and stirred for 8 h. The reaction mixture was then poured into water (10 ml.) and neutralized to pH 6-8 with cone. NH₄OH and extracted with DCM (3 x 20 ml_). The combined organic layer was concentrated under reduced pressure and the resulting residue was purified on silica gel (40 g Si0₂, 0-100% EtOAC-hexanes) to afford Benzyl, 6-(morpholine-4- carbonyl)-8-nitro-3,4-dihydro-2H-quinoline-1-carboxylate (0.410 g, 0.945 g theoretical, 43.4%). 1 H NMR(CDCI₃) d 7.75 (s, 2H), 7.40-7.24 (m, 5H), 5.19 (s, 2H), 4.06-3.49 (m, 8H), 2.78-2.76 (m, 4H), 2.01 -1 .99 (m, 2H). LCMS: 426 (M+H)

(8-Amino-1.2.3.4-tetrahvdroquinolin-6-yr)-morpholino-methanone (60-301

[158] A 50 ml. RBF was charged with Benzyl, 6-(morpholine-4-carbonyl)-8-nitro- 3,4-dihydro-2~{H}-quinoline-1-carboxylate{0}1 -benzyl (0.250 g, 0.588 mmol), ethanol (10 ml_, 0.06 M), 10% Pd-C (0.080 g) and the reaction mixture was fitted with a balloon of H2 and stirred at RT for 4 h. The reaction mixture was then filtered and concentrated under reduced pressure. The crude material was purified silica gel (20 g Si0₂, 0-100% EtOAc-hexanes) to afford (8-Amino-1 ,2,3,4-tetrahydroquinolin-6-yl)-morpholino- methanone; (60-30), (0.090 g, 0.155 g theoretical, 58.6%). 1 H NMR(CDCI₃) d 6.62 (s,

1 H), 6.60 (s, 1 H), 3.63-3.45 (m, 6H), 3.32-3.26 (m, 4H), 2.73 (t, 2H), 1.89 (t, 2H). (LCMS: 262.1 (M+1 ).

Example 6

Synthesis of Q-6a Ketones

Scheme 6: General Synthesis of Q-6a Ketones

A. Synthesis of 6S-10 and 6S-1 1

1-Benzyloxycarbonyl-3.4-dihvdro-2H-quinoline-6-carboxylic acid

Cbz

[159] To a solution of 1 ,2,3,4-tetrahydroquinoline-6-carboxylic acid (5g, 28.2 mmol), sodium bicarbonate (21.3 g, 254 mmol) in water (25 ml) and Dioxane (25 ml) was added benzyl chloroformate (5.29 g, 31 mmol) and the reaction was stirred at RT overnight.

The solution was acidified to pH 3 with the addition of 1 N HCI and extracted with DCM (3 x 25 ml.) and the combined organic layer was dried over Na₂S0₄ and concentrated under reduced pressure to give (7.15 g, 81 %) crude product (6S-06). The material was used in the next step without further purification. LCMS: (APCI) m/e 312.0 (M+1).

Benzyl, e-rmethoxyfmethvncarbamoyll-S^-dihvdro^H-quinoline-l-carboxylate

Cbz

[160] A suspension of 1-benzyloxycarbonyl-3,4-dihydro-2~{H}-quinoline-6- carboxylic acid (3 g, 9.64 mmol) in dichloromethane (30 ml.) at 0 °C was treated with oxalyl chloride (1 ml, 11.6 mmol) followed by 2 drops of DMF. The reaction mixture was allowed to stir for 1 h at RT and then cooled to 0 °C. Triethylamine (4.03 ml_, 28.90 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.03 g, 10.6 mmol) were added, and the resulting mixture was stirred for 6 h at RT. The reaction was then quenched with sat. NaHC0₃and the resulting mixture was extracted with CH2CI2 (2 x 25 ml_), the combined organic layer washed with brine (25 ml.) and dried over anhydrous Na2S04, filtered and concentrated under vacuum. The crude product was purified by combi flash chromatography (Si0₂) to give 3.19 g (93% yield) desired product (6S-07). 1 H NMR (CDCI₃): d 7.89 (s, 1 H), 7.58-7.35 (m, 7H), 5.27 (s, 2H), 3.79-3.77 (m, 2H), 3.55 (s, 3H), 3.32 (s, 3H), 2.78-2.75 (m, 2H), 1.94-1.91 (m, 2H); LCMS: (APCI) m/e 355.1 (M+1).

Benzyl, 6-pentanoyl-3.4-dihvdro-2H-quinoline-1-carboxylate

[161] A suspension of benzyl 6-[methoxy(methyl)carbamoyl]-3,4-dihydro-2-{H}- quinoline-1-carboxylate (0.5 g, 1.41 mmol) in THF (8 ml.) was treated with

butylmagnesium chloride (1.4 ml_, 2.82 mmol, 2 M in diethylther) and the resulting mixture was stirred for 1 h at RT. The mixture was treated with 20% HCI (5 ml.) and extracted with ethyl acetate (3 x 10 ml_), the combined organic layer was then washed with brine (20 ml.) and concentrated under reduced pressure. The crude material was purified by combiflash chromatography (Si0₂) to provide 6S-08 (0.310 g, 62% yield). 1 H NMR (CDCI₃): d 7.90 (d, 1 H), 7.72-7.68 (m, 2H), 7.38-7.30 (m, 5H), 5.23 (s, 2H), 3.80 (t, 2H), 2.89 (t, 2H), 2.80 (t, 2H), 1.95-1.93 (m, 2H), 1.67-1.60 (m, 2H), 1.38-1 .36 (m, 2H), 0.94-0.90 (t, 3H); LCMS: (APCI) m/e 352.1 (M+1 ). Benzyl, 8-nitro-6-pentanoyl-3.4-dihvdro-2H-quinoline-1 -carboxylate

[162] To a solution of benzyl 6-pentanoyl-3,4-dihydro-2-{H}-quinoline-1-carboxylate (0.300 g, 0.854 mmol) in TFA (5 ml.) at 0 °C was added NaN0₂ (0.064 g, 0.939 mmol). The mixture was stirred for 1 h at 0 °C warmed to RT and stirred for an additional 8 h. The mixture was poured into water (10 ml.) and neutralized to pH 6-8 with cone. NH₄OH, extracted with DCM (3 x 10 ml.) and the combined organic layer was concentrated under reduced pressure and the residue purified by combiflash chromatography (Si0₂) to provide 6S-09 (0.185 g, 54% yield). 1 H NMR (CDCI₃): d 8.27 (s, 1 H), 7.89 (s, 1 H), 7.45- 7.31 (m, 5H), 5.27 (s, 2H), 3.90-3.88 (m, 2H), 2.93-2.89 (m, 2H), 2.89 (t, 2H), 2.01 -1 .90 (m, 2H), 1.70-1 .69 (m, 2H), 1.38-1.36 (m, 2H), 0.91 (t, 3H); LCMS: (APCI) m/e 397.1 (M+1).

1-(8-amino-1.2.3.4-tetrahvdroquinolin-6-yr)pentan-1-one (63-101

[163] Benzyl, 8-nitro-6-pentanoyl-3,4-dihydro-2-{H}-quinoline-1-carboxylate (0.175 g, 0.441 mmol) was dissolved in ethanol (5 ml.) and treated with Pd-C (0.050 g) and the reaction was stirred at RT for 2 h under a hydrogen atmosphere. The reaction mixture was filtered, and the solvent concentrated under reduced pressure. The residue was purified by combiflash chromatography (Si0₂) to provide 6S-10 (0.050 g, 48% yield). 1 H NMR (CDCIs): d 7.19 (s, 1 H), 7.16 (s, 1 H), 3.34-3.32 (m, 2H), 2.78-2.75 (m, 4H), 1 .87- 1.85 (m, 2H), 1.63-1.61 (m, 2H), 1.32-1.31 (m, 2H), 0.88-0.85 (t, 3H); LCMS: (APCI) m/e 233.2 (M+1 ). HCI salt of l-fS-amino-l tetrahvdroquinolin-e-yllpentan-l-one H l

[164] A solution of 1-(8-amino-1 ,2,3,4-tetrahydroquinolin-6-yl)pentan-1-one (0.025 g, 0.108 mmol) in dioxane (1 ml.) was treated dropwise with 0.5M HCI in dioxane (1 ml.) at 0 °C. The reaction mixture was then stirred for 30 min. and the solvent was concentrated under reduced pressure to give 6S-1 1 (0.022 g, 76% yield). 1 H NMR

(CDCIs): d 7.55 (s, 1 H), 7.50 (s, 1 H), 3.40-3.31 (m, 2H), 2.85-2.72 (m, 4H), 1.80-1.76 (m,

2H), 1 .60-1.49 (m, 2H), 1.33-1 .28 (m, 2H), 0.90-0.87 (t, 3H); LCMS: (APCI) m/e 233.1 (M+1).

B. Synthesis of 6S-14

Benzyl, 6-butanoyl-3,4-dihvdro-2H-quinoline-1-carboxylate

[165] A suspension of benzyl, 8-nitro-6-pentanoyl-3,4-dihydro-2-{H}-quinoline-1- carboxylate (0.8 g, 2.26 mmol) in THF (15 ml.) was treated with propyl magnesium chloride (2.56 ml, 5.13 mmol, 2 M in diethylther) and the resulting mixture was stirred at RT for 1 h. The reaction was then treated with 20% HCI (5 ml.) and extracted with ethyl acetate (3 x 10 ml_). The combined organic layer was washed with brine (20 ml.) and concentrated under reduced pressure. The resulting residue was purified by combiflash chromatography (Si0₂) to provide 6S-12 (0.63 g, 82% yield). 1 H NMR (CDCI3): d 7.89 (d, 1 H), 7.72-7.69 (m, 2H), 7.37-7.30 (m, 5H), 5.23 (s, 2H), 3.81 (t, 2H), 2.89 (t, 2H), 2.80 (t, 2H), 1.98-1.90 (m, 2H), 1.73-1.70 (m, 2H), 0.99-0.95 (t, 3H); LCMS: (APCI) m/e 338.2 (M+1). Benzyl, 6-butanoyl-8-nitro-3.4-dihvdro-2H-quinoline-1-carboxylate

[166] A solution of benzyl, 6-butanoyl-3,4-dihydro-2-{H}-quinoline-1-carboxylate (0.600 g, 1.78 mmol) in TFA (10 ml.) at 0 °C was treated with NaN0₂ (0.135g, 1.96 mmol). The mixture was stirred at 0 °C for 1 h and warmed to RT and stirred for an additional 8 h. The mixture was poured into water (15 ml.) and neutralized to pH 6-8 with cone. NH₄OH and extracted with DCM (3 x 10 ml_). The combined organic layer was concentrated under reduced pressure and purified by combiflash chromatography (Si0₂) to provide 6S-13 (0.355, 52% yield). 1 H NMR (CDCI₃): d 8.27 (s, 1 H), 7.90 (s, 1 H), 7.45- 7.30 (m, 5H), 5.28 (s, 2H), 3.90-3.88 (m, 2H), 2.92-2.88 (m, 4H), 2.01 -1 .90 (m, 2H), 1.75-1 .71 (m, 2H), 1.00-0.96 (t, 3H); LCMS: (APCI) m/e 383.1 (M+1 ).

1-(8-amino-1.2.3.4-tetrahvdroquinolin-6-yr)butan-1-one (63-141

[167] Benzyl, 6-butanoyl-8-nitro-3,4-dihydro-2-{H}-quinoline-1-carboxylate (0.340 g, 0.889 mmol) was dissolved in ethanol (5 ml.) and treated with Pd-C (0.060 g) stirred for 2 h in a hydrogen atmosphere at RT. The reaction mixture was filtered, and solvent was concentrated under reduced pressure. The crude material was purified by column chromatography (Si0₂) to provide 6S-14 (0.1 1 1 g, 57% yield). 1 H NMR (CDCI₃): d 7.26 (s, 1 H), 7.24 (s, 1 H), 3.45-3.35 (m, 2H), 2.84-2.75 (m, 4H), 2.00-1 .90 (m, 2H), 1.76-1.72 (m, 2H), 1.00-0.96 (t, 3H); LCMS: (APCI) m/e 219.1 (M+1).

Example 7

Synthesis of Fmoc-Protected Ketones

Scheme 7: General Synthesis of Fmoc-Protected Q-6a Ketones

1.Aldehyde/Na(OAc),BH

Reduction

2. Piperidine

l-OH-fluoren-Q-ylmethoxycarbonvn-S^-dihvdro^H-quinoline-S-carboxylic acid

[168] A mixture of 1 ,2,3,4-tetrahydroquinoline-6-carboxylic acid (5 g, 28.2 mmol) in 1 ,4-dioxane (30 ml.) and 0.5 M aqueous sodium hydroxide solution (30 ml.) was treated with 9-fluorenylmethoxycarbonyl chloride (8.3 g, 31 mmol) and stirred at RT overnight. The mixture was partitioned between 1 M HCI (50 ml.) and dichloromethane (50 ml_). The aqueous layer was extracted with dichloromethane (3 x 20 ml.) and the combined organic layer was washed with water (30 ml.) then brine (30 ml.) and dried over sodium sulfate. The solvent was removed in vacuo and the crude product purified by flash column chromatography on silica to give 1-[(9H-fluoren-9-ylmethoxy)carbonyl]-1 , 2,3,4- tetrahydroquinoline-6-carboxylic acid, 6S-23 (8.57 g, 76% yield) as a white solid. The material was used in the next step without further purification. 9H-fluoren-9-ylmethyl 6-rmethoxy(methvncarbarnoyll-3.4-dihvdro-2H-quinoline-1- carboxylate

[169] A suspension of 1-(9-{H}-fluoren-9-ylmethoxycarbonyl)-3,4-dihydro-2-{H}- quinoline-6-carboxylic acid (8.5 g, 21.3 mmol) in dichloromethane (50 ml.) was cooled to 0 °C and treated with oxalyl chloride (2.2 ml_, 25.6 mmol) and 2 drops of DMF. The reaction mixture was allowed to stir at RT for 1 h and then cooled to 0 °C and treated with triethylamine (8.9 ml_, 63.8 mmol), N,O-dimethylhydroxylamine hydrochloride (2.28 g, 23.4 mmol) and the resulting mixture was stirred at RT for 6 h. The reaction was quenched with sat. NaHC0₃ (30 Ml) and the resulting mixture was extracted with CH2CI2 (2 x 25 ml). The combined organic layer was washed with brine (50 ml_), dried over anhydrous Na₂S0₄, filtered and concentrated under vacuum. The crude material was purified by combiflash chromatography (Si0₂) to give 6S-33 (8.95 g, 84%).

Example 8

Synthesis of Q-6a Ketones by Reductive Alkylation

Scheme 8: Reductive Alkylation Reactions for Preparation of Q-6a Ketones

CHO

l-rS-fthiazol-S-ylmethylaminot-l .2,3.4-tetrahvdroquinolin-6-yllpentan-1-one

[170] To 1 -(8-amino-1 ,2,3,4-tetrahydroquinolin-6-yl)pentan-1-one(0.007 g, 0.301 mmol), thiazole-5-carbaldehyde (0.037 g, 0.331 mmol) and sodium

triacetoxyborohydride (0.076 g, 0.362 mmol) were added in 1 ,2-dichloroethane(10ml). Molecular sieve (0.1 g) was added and stirred under nitrogen for overnight at RT. The reaction was extracted with dichloromethane (2 x 10 ml), dried over Na₂S0₄ and concentrated. The crude was purified by combiflash to afford desired compound (0.015g, 15%). 1 H NMR (CDCI₃): d 8.73 (s, 1 H), 7.82 (s, 1 H), 7.29, 7.27 (2s, 2H), 5.27 (s, 2H), 4.52 (s, 2H), 3.37 (s, 2H), 2.83-2.79 (m, 4H), 1.90-1 .85 (m, 2H), 1.66-1 .61 (m, 2H),

1.37-1 .35 (m, 2H), 0.91 (t, 3H). LCMS: (APCI) m/e 330.1 (M+1).

1-r8-r(1-methylpyrazol-4-yr)methylaminol-1.2.3.4-tetrahvdroquinolin-6-vHpentan-1-one

(6R-761

[171] To a solution of 1 -(8-amino-1 ,2,3,4-tetrahydroquinolin-6-yl)pentan-1 -one (0.065 g, 0.280 mmol) in 10 mL of DCE was added 1-methylpyrazole-4-carbaldehyde (0.0678 g, 0.616 mmol) followed by acetic acid (0.032 mL). To this mixture was added molecular sieves, 4 A (0.100 g) and the contents stirred at RT for 1 h to ensure formation of imine intermediate. To this mixture was then added sodium triacetoxyborohydride (0.119 g, 0.560 mmol) and stirred at RT overnight. The reaction mixture was neutralized with saturated aq. NaHC0₃and extracted with DCM (3 x 20 mL). The combined organic extracts were washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The desired product was separated from the crude mixture by passing through a silica-gel CombiFlash column, eluting with hex/EtAc. The 1-[8-[(1-methylpyrazol-4-yl)methylamino]-1 ,2,3,4-tetrahydroquinolin-6-yl]pentan-1-one (6R-76) was isolated as a pale yellow solid (22.4 mg, 24.5%). 1 H NMR (400 MHz, DMSO-d6): d 7.62 (s, 1 H), 7.39 (s, 1 H), 7.05 (s, 1 H), 6.90 (s, 1 H), 5.68 (s, 1 H), 4.58 (s,

1 H), 4.07 (d, 2H), 3.77 (s, 3H), 3.26 (m, 2H), 2.76 (t, 2H), 2.68 (m, 2H), 1 .76 (m, 2H),

1.51 (m, 2H), 1.28 (m, 2H), 0.86 (t, 3H). LCMS: (APCI) m/e 327 (M+H). l-rS-lbutylaminol-l .2.3.4-tetrahvdroquinolin-6-yllpentan-1-one

[172] 1 10 mgs of 1-(8-a ino-1 ,2,3,4-tetrahydroquinolin-6-yl)pentan-1-one was dissolved in 10 ml of DCE. 43 mI_ of butylaldehyde was added along with some molecular sieves. The mixture was stirred for 3 hrs at RT. 200 mgs of

triacetoxyborohydride was added and the mixture was stirred overnight. LCMS shows a small amount of the starting material is still present. There is a large peak with a mass the corresponds to the oxidized product and another peak with the correct mass for the desired product. The reaction was diluted with DCM and washed with water. The DCM layer was dried over Na₂S0₄ and evaporated. The residue was run through a 12 gram silica column eluting with a gradient of 20% to 80% EtOAc in hexane.

Example 9

Synthesis of Q-6a Ketones

6-lodo-8-fluoroquinoline route to prepare Q-6a Ketones:

N l 2 0

Dess-Martin

oxidation

DiPEA 1.5 eq

80 °C

H₂ 1.0 Atm

Pt-C, 40°C

6-lodo-8-fluoroquinoline (6N-84^')

[173] A 20-mL microwave vial was treated with 6-bromo-8-fluoroquinoline (4.0 g, 17.7 mmol), dioxane (18 ml_, 0.98 M), sodium iodide (5.31 g, 35.4 mmol, 2.0 eq.), copper(l) Iodide (0.169 g, 0.885 mmol, 0.05 eq.) and N,N'-dimethyl-1 ,2-ethanediamine (0.190 ml_, 1.77 mmol, 0.1 eq.). The reaction mixture was fitted with a stir bar and purged with nitrogen for 10 minutes, and then stirred at 130 °C overnight resulting in a cloudy green/grey mixture. After 12 h, the reaction was brown/orange and was allowed to cool to RT. The reaction mixture was filtered and the solid washed with DCM (3 x 10 ml.) and was concentrated under reduced pressure to provide a brown solid. The crude material was purified on silica (ISCO Combiflash) using an isocratic 70/30 hexanes/ EtOAc mobile phase and the pure fractions were concentrated under reduced pressure to provide 6-lodo-8-fluoroquinoline (2) as a light brown solid (4.29 g, 4.83 g theoretical, 88.8%). l-lS-fluoro-e-quinolvnpentan-l-o

[174] A 50-mL round bottom flask (acetone washed, oven dried, and under nitrogen) was charged with 6-iodo-8-pyrrolidin-1-yl-quinoline (1.0 g, 3.66 mmol), THF (15 ml_, 0.24 M), fitted with a stir bar and cooled to -78° C under nitrogen. A 2-mL syringe was purged with nitrogen and used to transfer n-Butyllithium in hexanes (1.5 ml_, 4.03 mmol, 1 .1 eq.) dropwise maintaining the reaction temperature at -78° C. After 10 minutes, the reaction became colored and the reaction was then treated in a single portion with pentanal (1.15 ml_, 1 1 .0 mmol, 3.0 eq.). The reaction solution quickly turned light yellow and was allowed to stir at -78°C for 60 minutes and finally warmed to RT.

The reaction was then quenched with 10 ml. water and extracted with DCM (3 x 15 ml_). The combined organic layer was dried over magnesium sulfate and dried under reduced pressure to provide a yellow liquid. The crude material was purified on silica (ISCO Combiflash) using a gradient 10-100% EtOAc/hexanes mobile phase and the pure fractions were concentrated under reduced pressure to provide 1-(8-fluoro-6- quinolyl)pentan-1 -ol (3) as a yellow oil (569 mg, 854 mg theoretical, 66.5%). l-fS-fluoro-e-quinolvnpentan-l-one ddI

[175] A 30-mL vial was charged with 1-(8-fluoro-6-quinolyl)pentan-1 -ol (697 mg, 2.99 mmol), dichloromethane (15 ml_, 0.2 M), sodium bicarbonate (2.51 g, 29.9 mmol, 10 eq.) and the reaction mixture was stirred at RT for 5 minutes. The reaction mixture was then treated with Dess-Martin periodinane (1.9g, 4.48 mmol, 1.5 eq.) and the reaction was stirred at RT for 1 hour. Crude LCMS showed complete consumption of the starting material and the desired product. The reaction mixture was transferred to 500 ml. Erlenmeyer flack and treated with 1 M NaOH (40 ml_), 100 ml. of

dichloromethane and stirred overnight. The organic layer was collected and the aqueous layer was extracted with dichloromethane (3 x 20 ml.) and the combined organic layer was concentrated under reduced pressure to provide 1-(8-fluoro-6- quinolyl)pentan-1 -one (4) (605 mg, 691 mg theoretical, 87.7%). The compound was used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6): d 9.08 (dd, 1 H), 8.65 (m, 2H), 7.97 (m, 1 H), 7.76 (m, 1 H), 3.18 (t, 2H), 1.66 (m, 2H), 1.39 (m, 2H), 0.94 (t, 3H). LCMS: (APCI) m/e 232 (M+H).

1-(8-pynOlidin-1-yl-6-quinolyr)pentan-1-one (dN-

[176] In a 30-mL glass vial, 1-(8-fluoro-6-quinolyl)pentan-1 -one (0.306 g, 1.32 mmol) was added with N,N-diisopropylethylamine (DIEA, 0.346 mL, 01.98 mmol) and pyrrolidine (0.435 mL, 5.29 mmol). The reaction temperature was increased to 80°C with stirring. LC-MS after 2 hours reaction time suggested mass of desired product as well as possible enamine product. The reaction mixture was cooled to room temperature and diluted with dichlormethane (10 mL). This solution was then added to 4% HCI solution (~50 mL), extracted with dichloromethane (3 x ~50 mL), and the organic extracts combined and dried over magnesium sulfate. The solid was filtered off and the filtrate rotavapped down to a red liquid. The mixture was purified by column chromatography (Hexane/EtOAc as eluent). Product fractions were combined and concentrated. This was further dried in a vacuum oven overnight, yielding 1-(8-pyrrolidin-1-yl-6-quinolyl)pentan-

1-one (70.1 mg, 18.8%) as a red solid upon cooling. 1 H NMR (400 MHz, DMSO-d6): d 8.82 (dd, 1 H), 8.38 (dd, 1 H), 7.94 (d, 1 H), 7.52 (dd, 1 H), 7.15 (d, 1 H), 3.75 (m, 4H), 3.1 1 (t, 2H), 1.96 (m, 4H), 1 .64 (m, 2H), 1.39 (m, 2H), 0.93 (t, 3H). LCMS: (APCI) m/e 283 (M+H).

2-methyl-1-(8-pyrrolidin-1-yl-1 ,2.3.4-tetrahvdroquinolin-6-yl^')propan-1-one (7E-01 ^')

[177] A 20-mL glass vial was charged with 2-methyl-1-(8-pyrrolidin-1-yl-6- quinolyl)propan-1 -one (FN6897; 0.2 g, 0.745 mmol), 10 mL of 200 proof EtOH. 10% Pt- C (0.02 g) Pt-C and cat. Glacial acetic acid. The vial was then flushed with nitrogen and fitted with a balloon of hydrogen. The reaction was stirred at 40°C overnight, which provided the desired product as the major peak by crude LCMS. LCMS taken in AM which indicates primarily product mass. The reaction was then cooled to RT and filtered through a 0.45 pm PTFE syringe filter (Restek, 13mm, Lot#: 150319154) and concentrated under reduced pressure. The material was then purified on silica gel (12 g) using a hexanes/EtOAc gradient (0-100% over 45 min.) to provide 2-methyl- 1 -(8- pyrrolidin-1 -yl-1 ,2,3,4-tetrahydroquinolin-6-yl)propan-1 -one as a pale yellow oil (160 mg, 79%, 203 mg theo.). 1 H NMR (400 MHz, DMSO-d6): d 7.36 (d, 1 H), 7.34 (d, 1 H), 3.51 (m, 1 H), 3.32 (m, 2H), 2.92 (m, 4H), 2.72 (m, 2H), 1.86 (m, 4H), 1.79 (m, 2H), 1.04 (d, 6H). LCMS: (APCI) m/e 273 (M+H).

Example 10

Synthesis of Q-6a Sulfones

6-butylsulfonyl-N-cvclopentyl-1.2.3.4-tetrahvdroquinolin-8-amine (7C-42)

[178] A 100 ml. round bottom flask was charged with 6-bromo-8-fluoroquinoline (250 mg, 1.1 1 mmol), DMSO (5 ml_), Cul (320 mg, 2.21 mmol), sodium butane-1 - sulfinate (319 mg, 2.21 mmol) and the mixture was heated at 120° C for 18 h. The crude material was purified on silica gel using ethyl acetate and hexanes to provide 6- butylsulfonyl-8-fluoroquinoline (260 mg, 87% yield).

[179] 6-butylsulfonyl-8-fluoroquinoline (260 mg) was then dissolved in

cyclopentylamine (2.5 ml.) and heated at 125° C in a sealed microwave vial for 18 h. The reaction provided a clean conversion to the desired product. The excess cyclopentylamine was removed under reduced pressure to provide N-cyclopentyl-6- butylsulfonyl-quinolin-8-amine (337 g) that was used directly in the reduction step without further purification.

[180] The N-cyclopentyl-6-butylsulfonyl-quinolin-8-amine (337 mg, 1.0 mmol), ethanol (50 ml_), Pt on carbon (100 mg) was shaken in a Parr vessel under 40 psi of hydrogen for 4 h. The reaction was purified on silica gel using ethyl acetate and hexanes to provide 6-butylsulfonyl-N-cyclopentyl-1 ,2,3,4-tetrahydroquinolin-8-amine (7C-42, 136 mg, 51 %). LCMS: (APCI) m/e 337 (M+H).

N-cvclopentyl-6-methylsulfonyl-1 ,2.3.4-tetrahvdroquinolin-8-amine (70-411

[181] The compound was produced using a similar meth as described for (7C-42). LCMS: (APCI) m/e 295 (M+H).

Example 11

N27 Cell Viability Assays

[182] N27 Rat Dopaminergic Neuronal Cells (EMD Millipore # SCC048) were plated into rows B-H of three 96 well plates (Becton Dickenson) at a seeding density of 1.25x10M cells/well in 150uL/well of growth media [RPMI 1640 + Glutamax,

[Fisher/Gibco/Life Technologies 61870-036] + 10% Fetal Bovine Serum [Sigma F6178- 500mL] + 1 % Penicillin-Streptomycin-Glutamine [100X concentrate Fisher/Gibco/Life Technologies 10378-016] 150pL of Growth media was added to each well of Row A. The cells were incubated overnight at 37°C, 5% C0₂, 80-90% humidity.

Inhibitors:

[183] 10mM stocks of Liproxstatin (Cayman Chemical # 17730), Ferrostatin (Cayman Chemical # 17729) and/or test compounds were made in DMSO (Fisher Scientific D128-1 ) then sterile filtered using 0.2u nylon syringe filter. The 10mM stocks were each diluted to 20mM by adding 6 pL of stock to 2994 pL of growth media in sterile tubes. 6 pL of DMSO were added to 2994 pL of growth media as a control. Each of the compounds (and control) were serially diluted to 2 mM and 0.2 mM by adding 300 pL of the solution to 2700 pL of growth media in separate sterile tubes. Inducers:

[184] 1 mM Erastin (Cayman Chemical # 17754) in DMSO, sterile filtered, was diluted to 2mM by adding 42uL of the 1 mM stock to 21 mL of growth media in sterile tubes.

[185] 0.1 mM (1S,3R)-RSL3 (Cayman Chemical #19288) in DMSO, sterile filtered, was diluted to 0.2mM by adding 42uL of the 0.1 mM stock to 21 mL of growth media in sterile tubes.

[186] The media was aspirated from the cells, one column per plate for each condition to prevent the cells from drying out. 100uL of the inhibitors were added per well from lowest concentration to highest in replicates of six.

Columns 1-3: Media + DMSO

Columns 4-6: Liproxstatin

Columns 7-9: Ferrostatin

Columns 10-12: WBI Compound

[187] 100pL/well of growth media were added to Plate 1 (Control). 100pL/well of 2mM Erastin were added to Plate 2. 100pL/well of 0.2mM RSL3 were added to Plate 3. The cells were incubated overnight (24 hours) at 37°C, 5% C0₂, 80-90% humidity.

[188] MTT (Fisher Scientific M6494), 5mg/mL in Phosphate Buffered Saline (Sigma TMS-012), was diluted to 2.5mg/mL in growth media by mixing 7.5mL of each. 50uL were added to each well of Rows A-G of both 96 well plates. 50uL of PBS without MTT were added to Row H. The cells were incubated for 4 hours at 37°C, 5% C0₂, 80-90% humidity.

[189] The media was aspirated from the wells and the plate was gently tapped upside down on an adsorbent pad to remove any residual liquid. 150uL of DMSO were added to each well. The optical density at 595nm was measured using a Spectramax M5 plate reader (Molecular Devices) after a 5 second mix.

[190] The background absorbance from the Control plate (Row A) were averaged and subtracted from the values measured in all plates. The replicates of each test condition were averaged then the viability was expressed as a percentage of the control cells. Standard error of the mean (SEM) was calculated for each data set. Example 12

N27 Cell Viability Assay IC_sn Determinations

[191] N27 Rat Dopaminergic Neuronal Cells (EMD Millipore # SCC048) were plated into rows A-H of each 96 well plate (one plate per compound tested) at a seeding density of 1 .25x10M cells/well in 150ul_/well of growth media. The cells were incubated overnight at 37oC, 5% C02, 85-90% humidity.

Inhibitors:

[192] 10mM Ferrostatin and WBI Compounds were diluted to 10uM by adding 2.5uL into 2497.5uL of media. Each was then serially diluted two fold by transferring 1250uL of the diluted compound into 1250uL of media. Each compound was diluted to 0.0024uM. The media was aspirated from the wells individually one row at a time to prevent the cells from drying out. Columns 1 & 2 contained 100uL of media alone. 100ul_ of the lowest concentration of compound was added to each well of column 3, then the media of column 4 was aspirated and the second lowest concentration of compound was added. This process was repeated until each of 10 compound concentrations were added in columns 3 through 12.

Inducers:

[193] 100uL/well of 0.2uM RSL3 were added to each of the plates with the exception of Column 1. Column 1 received 100uL of growth media alone. Column 1 should result in 100% viability; Column 2 should be 0-5% viability. Final concentrations of compounds (after addition of RSL3) ranged from 0.0012uM-0.625uM. The cells were incubated overnight (24 hours) at 37oC, 5% C02, 85-90% humidity.

[194] MTT, 5mg/ml_, was diluted to 2.5mg/ml_ in growth media by mixing 20ml_ of each. 50uL of the MTT solution were added to each well of Rows A-G of the 96 well plates. Row H contained 50uL of PBS without MTT. The cells were incubated for 4 hours at 37oC, 5% C02, 85-90% humidity.

[195] The media was aspirated from the wells and the plate was gently tapped upside down on an adsorbent pad to remove any residual liquid. 150uL of DMSO were added to each well. The optical density at 595nm was measured using a Spectramax M5 plate reader (Molecular Devices) after a 5 seconds mix. [196] The background absorbance of the wells without MTT (Row H) were averaged and subtracted from the values measured in each plate. The viability was expressed as a percentage of the control cells (Column 1). The data was analyzed using Graphpad Prism version 7 by plotting the log of the concentration (M) vs the % viability and using a nonlinear regression 4 parameter curve fit to determine the IC₅o for each compound, as shown in Table 2 below.

Table 2. ICsnS for Synthesized Compounds.

Claims

What is claimed is:

1 . A compound of formula l-V:

wherein

n = 1 , 2 or 3;

R is H, F or CH₃;

provided that if A is aryl or heteroaryl, then R4 is H, alkyl or halo.

2. The compound of claim 1 having the formula II.

3. The compound of claim 1 having the formula III.

4. The compound of claim 1 having the formula IV.

5. The compound of claim 1 having the formula V.

6. The compound of claim 2 wherein n=2.

7. A compound of claim 1 , selected from the group consisting of Compound ID 5Y-50, 4J-36, 5Y-51 , 5Y-68, 6E-96, 5R-62, 6E-97, 5Y-90, 5Y-9, 6S-00, 6E-99,

5Y-61 , 5Y-64, 5Y-85, 5R-68, 6U-02, 60-56, 6U-06, 60-79, 60-84, 60-85, 5Y-74/6S-14, 7B-10, 6U-16, 60-69, 6U-12, 6U-13, 6U-05, 60-57, 6U-23, 6U-26, 6R-76, 6S-45, 6U-46, 6R-94, 7C-00, 6S-1 1 , 6S-10, 6S-14, 6U-39, 60-30, 6U-74, 7C-25, 6U-65, 6N-91 , 7E-01 , 7E-10, 7E-12, 7E-08, 6U-62, 7E-29, 7C-45, 7C-36, 7B-36, 7C-37, 7C-39, 7C-40, 6U-83, 6U-87, 7C-41 , and 7C-42.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.

9. A method of treating a ferroptosis-related disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of formula l-V:

wherein

n = 1 , 2 or 3;

R is H, F or CH₃;

heterocyloalklyl, substituted or unsubstituted C5-C10 heteroaryl, substituted or unsubstituted C₆-Ci₀ arylalkyl, substituted or unsubstituted C1 -C10 linear or branched alkylamino and substituted or unsubstituted C1 -C10 linear or branched dialkyla ino; R² and R³ are independently selected from the group consisting of H, substituted or unsubstituted C1-C10 linear or branched alkyl, C1-C10 linear or branched perfluoroalkyl, substituted or unsubstituted C2-C10 linear or branched alkenyl, substituted or

unsubstituted C2-C10 linear or branched alkynyl, substituted or unsubstituted C₆-Ci₀ aryl, substituted or unsubstituted C3-C10 cycloalkyl, C3-C10 perfluorocycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C5-C10 heteroaryl, substituted or unsubstituted C₆-Ci₀ arylalkyl, substituted or unsubstituted C1-C10 linear or branched alkyla ino, and substituted or unsubstituted C1-C10 linear or branched dialkyla ino, or R² and R³ together with their mutually-attached N form a substituted or unsubstituted C₄-C₆ heterocycloalkyl group;

A is selected from the group consisting of substituted or unsubstituted C₆-Ci₀ aryl, substituted or unsubstituted C₃-C1₀ heteroaryl, substituted or unsubstituted C2-C1₀ linear or branched alkenyl, substituted or unsubstituted C2-C1₀ linear or branched alkynyl, C=0, C=S, -CH2-, -NH-, and S0₂;

provided that if A is aryl or heteroaryl, then R4 is H, alkyl or halo.

10. The method of claim 9 wherein the ferroptosis-related disease is selected from the group consisting of lipid peroxidation-related degenerative diseases, excitotoxic diseases, neurodegenerative diseases, non-apoptotic regulated cell-death diseases, wasting- or necrosis-related diseases, intoxication-related diseases, and infectious diseases.

1 1 . A compound selected from the group consisting of Compound ID 6R-05, 6R-11 , 6R- 17, 6R-27, 6R-29, 6R-30, 5Y-42, 6R-34, 6R-35, 5Y-550, 5Y-48, 6N-29, 6R-44, 6N-30, 6N-49, 6R-62, 6N-34, 6N-35, 6N-39, 6R-47, 6R-46, 6R-48, 6N-38, 6N-48, 6R-58, 6K-54, 6K-55, and 6N-52.